CN117088875A - 一种高活性Wnt通路抑制剂化合物 - Google Patents
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Abstract
本发明提供了一种抑制Wnt通路活性的化合物及其制备方法，以及包含所述化合物的药物组合物。本发明还提供了所述化合物在预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病中的用途。
Description
本申请是申请号为“202180066465.5”的中国发明专利申请的分案申请。母案申请的申请日是2021年10月27日(PCT国际申请日)，中国国家申请号是“202180066465.5”(PCT国际申请号是PCT/CN2021/126539)，发明创造名称是“一种高活性Wnt通路抑制剂化合物”。
母案申请以及本分案申请要求于2020年10月28日提交到中国专利局的发明名称为“一种高活性Wnt通路抑制剂化合物”的中国专利申请202011175894.X的优先权，其内容通过引用以整体并入本文。
技术领域
本发明涉及一种杂环化合物，具体地涉及一种高活性的Wnt通路抑制剂及其用途。
背景技术
Wnt/β-catenin信号转导通路是一条在生物进化中保守的通路。在正常的体细胞中，β-catenin只是作为一种细胞骨架蛋白在胞膜处与E-cadherin形成复合体对维持同型细胞的黏附、防止细胞的移动发挥作用。当Wnt信号通路未被激活时，细胞质内的β-catenin被磷酸化与APC、Axin和GSK3β等构成β-catenin降解复合物，启动泛素系统经蛋白酶体途径降解β-catenin，使细胞质内的β-catenin维持在较低水平。当细胞受到Wnt信号刺激时，Wnt蛋白与细胞膜上特异性受体Frizzled蛋白结合，激活后的Frizzled受体招募胞内Dishevelled蛋白，抑制GSK3β等蛋白形成的β-Catenin降解复合物的降解活性，稳定细胞质中游离状态的β-Catenin蛋白。胞浆中稳定积累的β-Catenin进入细胞核后结合LEF/TCF转录因子家族，启动下游靶基因(如c-myc、c-jun，Cyclin D1等)的转录。Wnt/β-catenin信号通路的过渡激活与多种癌症(包括结肠癌、胃癌、乳腺癌等)的发生密切相关。例如结直肠癌中广泛存在Wnt经典信号通路的异常激活和β-catenin蛋白的核内积聚现象,而通过抑制Wnt信号通路活性可以抑制结肠癌增殖。85％以上的结直肠癌中均存在APC的突变，突变后的APC阻断β-catenin磷酸化降解，诱导结直肠癌的发生。此外，Axin突变、β-catenin自身突变也可引起β-catenin的胞内聚集，活化Wnt/β-catenin通路。
发明内容
在一个方面，本发明提供了具有如下结构的抑制Wnt通路活性的化合物及药学上可接受的盐、同位素衍生物、立体异构体：
在另一个方面，本发明提供一种制备如上所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体的方法，其特征在于，所述方法包括使用化合物11d作为中间体：
在又一个方面，本发明提供一种药物组合物，包括如上所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体。
在另一个方面，本发明还提供了如上述的化合物以及药学上可接受的盐、同位素衍生物、立体异构体以及药物组合物用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
特别注意的是，在本文中，当提及具有特定结构式的“化合物”时，一般地还涵盖其立体异构体、非对映异构体、对映异构体、外消旋混合物和同位素衍生物。
本领域技术人员公知，一种化合物的盐、溶剂合物、水合物是化合物的替代性存在形式，它们都可以在一定条件下转化为所述化合物，因此，特别注意的是在本文中当提到一种化合物时，一般地还包括它的可药用盐，进而还包括其溶剂合物和水合物。
相似地，在本文中当提到一种化合物时，一般地还包括其前药、代谢产物和氮氧化物。
本发明所述的可药用盐可使用例如以下的无机酸或有机酸而形成：“可药用盐”是指这样的盐，在合理的医学判断范围内，其适用于接触人和较低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比。可以在本发明化合物的最终分离和纯化期间原位制备所述盐，或单独通过将游离碱或游离酸与合适的试剂反应制备所述盐，如下概述。例如，游离碱功能可以与合适的酸反应。此外，当本发明的化合物带有酸性部分，其合适的可药用盐可包括金属盐，例如碱金属盐(如钠盐或钾盐)；和碱土金属盐(如钙盐或镁盐)。可药用的无毒酸加成盐的示例是氨基与无机酸(例如，盐酸、氢溴酸、磷酸、硫酸和高氯酸)或有机酸(例如，醋酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐，或通过使用现有技术中的其他方法如离子交换形成的盐。
本发明的可药用盐可通过常规方法制备，例如通过将本发明的化合物溶解于与水可混溶的有机溶剂(例如丙酮、甲醇、乙醇和乙腈)，向其中添加过量的有机酸或无机酸水溶液，以使得盐从所得混合物中沉淀，从中除去溶剂和剩余的游离酸，然后分离所沉淀的盐。
本发明所述的前体或代谢物可以本领域公知的前体或代谢物，只要所述的前体或代谢物通过体内代谢转化形成化合物即可。例如“前药”是指本发明化合物的那些前药，在合理的医学判断范围内，其适用于接触人和更低等动物的组织，而没有不适当的毒性、刺激性、过敏反应等，称得上合理的受益/风险比并且对其预期用途有效。术语“前药”是指在体内迅速经转化产生上述式的母体化合物的化合物，例如通过在体内代谢，或本发明化合物的N-去甲基化。
本发明所述的“溶剂合物”意指本发明化合物与一个或多个溶剂分子(无论有机的还是无机的)的物理缔合。该物理缔合包括氢键。在某些情形中，例如当一个或多个溶剂分子纳入结晶固体的晶格中时，溶剂化物将能够被分离。溶剂化物中的溶剂分子可按规则排列和/或无序排列存在。溶剂合物可包含化学计量或非化学计量的溶剂分子。“溶剂合物”涵盖溶液相和可分离的溶剂合物。示例性溶剂合物包括但不限于水合物、乙醇合物、甲醇合物和异丙醇合物。溶剂化方法是本领域公知的。
本发明所述的“立体异构”分为构象异构和构型异构，构型异构还可分为顺反异构和旋光异构(即光学异构)，构象异构是指具有一定构型的有机物分子由于碳、碳单键的旋转或扭曲而使得分子各原子或原子团在空间产生不同的排列方式的一种立体异构现象，常见的有烷烃和环烷烃类化合物的结构，如环己烷结构中出现的椅式构象和船式构象。“立体异构体”是指当本发明化合物含有一个或多个不对称中心，因而可作为外消旋体和外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体。本发明化合物有不对称中心，每个不对称中心会产生两个光学异构体，本发明的范围包括所有可能的光学异构体和非对映异构体混合物和纯的或部分纯的化合物。本发明所述的化合物可以以互变异构体形式存在，其通过一个或多个双键位移而具有不同的氢的连接点。例如，酮和它的烯醇形式是酮-烯醇互变异构体。各互变异构体及其混合物都包括在本发明的化合物中。所有式(I)化合物的对映异构体、非对映异构体、外消旋体、内消旋体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物等，均包括在本发明范围中。
本发明的“同位素衍生物”是指在本专利中化合物被同位素标记的分子。通常用作同位素标记的同位素是：氢同位素，2H和3H；碳同位素：11C,13C和14C；氯同位素：35Cl和37Cl；氟同位素：18F；碘同位素：123I和125I；氮同位素：13N和15N；氧同位素：15O,17O和18O和硫同位素35S。这些同位素标记化合物可以用来研究药用分子在组织中的分布情况。尤其是氘3H和碳13C，由于它们容易标记且方便检测，运用更为广泛。某些重同位素，比如重氢(2H)，的取代能增强代谢的稳定性，延长半衰期从而达到减少剂量的目而提供疗效优势的。同位素标记的化合物一般从已被标记的起始物开始，用已知的合成技术象合成非同位素标记的化合物一样来完成其合成。
本发明还提供了本发明化合物在制备用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
此外，本发明提供了用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的药物组合物，其包含本发明化合物作为活性成分。
此外，本发明提供了一种用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病、神经退行性疾病、注意力相关疾病或免疫介导性疾病的方法，其包括向有此需要的哺乳动物施用本发明化合物。
癌症或肿瘤的代表性实例可包括但不限于，皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤或浆细胞瘤。
当将本发明化合物或其可药用盐与另外的用于治疗癌症或肿瘤的抗癌剂或免疫检查点抑制剂组合施用时，本发明化合物或其可药用盐可提供增强的抗癌作用。
当将本发明化合物或其可药用盐与另外的用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂组合施用时，本发明化合物或其可药用盐可提供增强的治疗作用。
用于治疗炎症性疾病、自身免疫性疾病和免疫介导性疾病的治疗剂的代表性实例可包括但不限于，甾体药物(例如，强的松、氢化波尼松、甲基氢化波尼松、可的松、羟基可的松、倍他米松、地塞米松等)、甲氨蝶呤、来氟米特、抗TNFα剂(例如，依那西普、英夫利昔单抗、阿达利单抗等)、钙调神经磷酸酶抑制剂(例如，他克莫司、吡美莫司等)和抗组胺药(例如，苯海拉明、羟嗪、氯雷他定、依巴斯汀、酮替芬、西替利嗪、左西替利嗪、非索非那定等)，并且选自其中的至少一种治疗剂可包含于本发明药物组合物中。
本发明的化合物或其可药用盐可作为活性成分通过口服或肠胃外施用，其有效量的范围为在哺乳动物包括人(体重约70kg)的情况下0.1至2,000mg/kg体重/天、优选1至1,000mg/kg体重/天，并且每天以单次或4次分次剂量，或者遵循/不遵循预定时间施用。活性成分的剂量可根据多个相关因素(例如待治疗对象的情况、疾病类型和严重性、施用速率和医生意见)进行调整。在某些情况下，小于以上剂量的量可能是合适的。如果不引起有害的副作用则可使用大于以上剂量的量并且该量可以每天以分次剂量施用。
除此之外，本发明还提供了一种预防和/或治疗肿瘤、癌症、病毒感染、器官移植排斥、神经退行性疾病、注意力相关疾病或自身免疫性疾病的方法，其包括向有此需要的哺乳动物施用本发明的化合物或本发明的药物组合物。
可根据常规方法中的任何一种将本发明药物组合物配制成用于口服施用或肠胃外施用(包括肌内、静脉内和皮下途径、瘤内注射)的剂型，例如片剂、颗粒、粉末、胶囊、糖浆、乳剂、微乳剂、溶液或混悬液。
本发明描述示例性实施方案的过程中，本发明的其它特征将变得显而易见，给出所述实施方案用于说明本发明而不意欲成为其限制，以下实施例使用本发明所公开的方法制备、分离和表征。
可以用有机合成领域的技术人员已知的多种方式来制备本发明的化合物，可使用下述方法以及有机合成化学领域中已知的合成方法或通过本领域技术人员所了解的其变化形式来合成本发明化合物。优选方法包括但不限于下文所述的这些。在适用于所使用试剂盒材料和适用于所实现转变的溶剂或溶剂混合物中实施反应。有机合成领域的技术人员将理解，分子上存在的官能性与所提出的转变一致。这有时需要加以判断改变合成步骤的顺序或原料以获得期望的本发明化合物。
具体实施方式
术语
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本申请中，如果无另外说明，使用“或”或“和”指“和/或”。
在说明书和权利要求书中，给定化学式或名称应涵盖所有立体和光学异构体及其中存在上述异构体的外消旋物。除非另外指明，否则所有手性(对映异构体和非对映异构体)和外消旋形式均在本发明范围内。所述化合物中还可存在C＝C双键、C＝N双键、环系统等的许多几何异构体，且所有上述稳定异构体均涵盖于本发明内。本发明描述了本发明化合物的顺式-和反式-(或E-和Z-)几何异构体，且其可分离成异构体的混合物或分开的异构体形式。本发明化合物可以光学活性或外消旋形式加以分离。用于制备本发明化合物和其中制备的中间体的所有方法均视为本发明的部分。在制备对映异构体或非对映异构体产物时，其可通过常规方法(例如通过色谱或分段结晶)进行分离。取决于方法条件，以游离(中性)或盐形式获得本发明的终产物。这些终产物的游离形式和盐均在本发明的范围内。如果需要的话，则可将化合物的一种形式转化成另一种形式。可将游离碱或酸转化成盐；可将盐转化成游离化合物或另一种盐；可将本发明异构体化合物的混合物分离成单独的异构体。本发明化合物、其游离形式和盐可以多种互变异构体形式存在，其中氢原子转置到分子的其它部分上且由此分子的原子之间的化学键发生重排。应当理解的是，可存在的所有互变异构体形式均包括在本发明内。
除非另有定义，本发明的取代基的定义是各自独立而非互相关联的，例如对于取代基中Ra(或者Ra’)而言，其在不同的取代基的定义中是各自独立的。具体而言，对于Ra(或者Ra’)在一种取代基中选择一种定义时，并不意味着该Ra(或者Ra’)在其他取代基中都具有该相同的定义。更具体而言，例如(仅列举非穷举)对于NRaRa’中，当Ra(或者Ra’)的定义选自氢时，其并不意味着在-C(O)-NRaRa’中，Ra(或者Ra’)必然为氢。
当任何变量在化合物的任何组成或式中出现一次以上时，其每次出现时的定义均独立于其在其它每种情况下出现时的定义。因此，例如如果显示基团取代有0-3个R，则所述基团可任选地取代有至多三个R基团，且在每次出现时R独立地选自R的定义。此外，取代基和/或变量的组合仅在上述组合可产生稳定的化合物时才容许存在。
本文使用的术语“患者”是指通过本发明的方法进行治疗的有机体。这类有机体优选包括但不限于哺乳动物(例如鼠类、猿/猴、马、牛、猪、犬、猫等)且最优选是指人类。
本文使用的术语“有效量”意指将会引起例如研究人员或临床医师所寻求的组织、系统、动物或人的生物学或医学响应的药物或药剂(即本发明化合物)的量。此外，术语“治疗有效量”意指这样的量：与未接受上述量的相应受试者相比，所述量导致改善的治疗、治愈、预防或减轻疾病、病症或副作用，或降低在疾病或病症的进展速度。有效量可以一个或多个给药、施用或剂量给予且不意欲被特定的制剂或给药途径限制。该术语还包括在其范围内的增强正常生理机能的有效量。
本文使用的术语“治疗”包括导致改善病症、疾病、障碍等的任何效果，例如减轻、减少、调节、改善或消除，或改善其症状。
术语“药用”在本文中用于指如下那些化合物、物质、组合物和/或剂型：在合理医学判断的范围内，其适于与人类和动物的组织接触使用而无过高毒性、刺激性、过敏反应和/或其它问题或并发症，并与合理的益处/风险比相称。
本文使用的短语“药用载体”意指药用物质、组合物或媒介物，诸如液体或固体填充剂、稀释剂、赋形剂、制造助剂(例如润滑剂、滑石、硬脂酸镁、硬脂酸钙或硬脂酸锌或硬脂酸)或溶剂包囊物质，其涉及将主题化合物从一个器官或身体的部分携带或运送至另一个器官或身体的部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是“可接受的”。
术语“药物组合物”意指包含本发明化合物与至少一种其它药用载体的组合物。“药用载体”是指本领域中通常接受用于将生物活性剂递送至动物(具体为哺乳动物)的介质，包括(即)佐剂、赋形剂或媒介物，诸如稀释剂、防腐剂、填充剂、流动调控剂、崩解剂、润湿剂、乳化剂、悬浮剂、增甜剂、矫味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂，这取决于给药模式和剂型的性质。
特定药学及医学术语
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
术语“联合给药”或其类似术语，如本文所用，指将几种所选的治疗药物给一个病人用药，以相同或不同的给药方式在相同或不同的时间给药。
术语“增强”或“能增强”，如本文所用，指预期的结果能够在效价或是持续时间方面都有增加或延长。因此，在增强药物的治疗效果方面，术语“能增强”指药物在系统中有提高或延长效价或持续时间的能力。本文所用的“增效值”，指在理想的系统中，能够最大限度地的增强另外一个治疗药物的能力。
术语“免疫性疾病”指对内源性或外源性抗原产生的不良或有害反应的疾病或症状。结果通常会造成细胞的功能障碍、或因此而破坏并造成机能障碍、或破坏可能产生免疫症状的器官或组织。
术语“受试者”或“病人”包括哺乳动物和非哺乳动物。在一优选例中，所选哺乳动物是人。
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防和/或治疗由疾病或症状引起的征兆。
如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药，可以归因于或与给药有关的情况。
给药途径
适合的给药途径包括但不限于，口服、静脉注射、直肠、气雾剂、非肠道给药、眼部给药、肺部给药、经皮给药、阴道给药、耳道给药、鼻腔给药及局部给药。此外，仅作举例说明，肠道外给药，包括肌肉注射、皮下注射、静脉注射、髓内注射、心室注射、腹膜内注射、淋巴管内注射、及鼻内注射。
在一方面，此处描述的化合物给药方式是局部的而不是全身性的给药方式。在特定的具体实施例中，长效制剂通过植入给药(例如皮下或肌肉)或通过肌肉注射。此外，在另一具体化实施例中，药物通过靶向药物给药系统来给药。例如，由器官特异性抗体包裹的脂质体。在这种具体实施例中，所述脂质体被选择性的导向特定器官并吸收。
药物组合物和剂量
本发明还提供药用组合物，其包含治疗有效量的与一种或多种药用载体(添加剂)和/或稀释剂一起配制的一种或多种本发明的化合物，和任选的一种或多种上述其它治疗剂。可通过任意合适方式给予本发明化合物以用于任意上述用途。它们可单独给药，但通常使用基于所选给药途径和标准药学实践选择的药物载体给药。
根据本领域技术人员认识范围内的诸多因素来调配药用载体。这些因素包括，但不限于：所调配活性剂的类型和性质；含有活性剂的组合物所要给药的受试者；组合物的预期给药途径；及所靶向的治疗适应症。药用载体包括水性和非水性液体介质及各种固体和半固体剂型。
上述载体可包括除活性剂外的诸多不同成分和添加剂，上述其它成分出于本领域技术人员公知的各种原因包括于制剂中，例如稳定活性剂、粘合剂等。关于合适的药用载体和载体选择中所涉及的因素的描述可参见多个容易获得的来源，例如Allen L.V.Jr.etal.Remington:The Science and Practice of Pharmacy(2Volumes),22nd Edition(2012),Pharmaceutical Press。
当然，本发明化合物的剂量方案取决于已知因素而有所变化，诸如具体药剂的药效学特性及其给药模式和途径；接受者的物种、年龄、性别、健康状况、医学病状和重量；症状的性质和程度；同时治疗的种类；治疗频率；给药途径、患者的肾和肝功能及期望效应。本发明化合物可以单一日剂量给药，或可以每日两次、三次或四次的分开剂量给药总日剂量。
本发明范围包括(单独或与药物载体组合)包含治疗有效量的至少一种本发明化合物作为活性成分的药物组合物。任选地，本发明化合物可单独使用、与本发明其它化合物组合使用或与一种或多种其它治疗剂(例如抗癌剂或其它药学活性物质)组合使用。
不考虑所选择的给药路径，通过本领域技术人员已知的常规方法来将本发的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制成药用剂量形式。
可改变活性成分在本发明的药物组合物中的实际剂量水平，从而获得对于实现特定患者的期望的治疗响应、组成和给药模式有效的而对患者无毒的活性成分量。
选定的剂量水平会取决于多种因素，包括所用的本发明的特定化合物或其酯、盐或酰胺的活性；给药路径；给药时间；所用的特定化合物的排泄速率；吸收速率和程度；治疗的持续时间；与所用的特定化合物组合使用的其它药物、化合物和/或物质；所治疗的患者的年龄、性别、重量、状况、一般健康和先前的医学史等医学领域公知的因素。
具有本领域普通技术的医生或兽医可容易地确定并开出有效量的所需药物组合物。例如，为了达到所期望的治疗效果，医师或兽医可在低于所需的水平开始药物组合物中所用的本发明化合物的较量，并逐步增加剂量直至实现所期望的效果。通常，合适日剂量的本发明化合物将是有效产生治疗效果的最低剂量的化合物的量。此种有效剂量通常取决于上述因素。在本发明的某些方面中，服药为每天一次给药。
虽然本发明化合物可单独给药，但优选以药物制剂(组合物)形式给予化合物。
实施例
通用过程
未包括制备途径时，本发明所用原料与试剂均为已知产品，可以按照本领域已知的方法合成，或者可通过购买市售产品获得。使用的市售试剂均不需进一步纯化。
室温是指20-30℃。
反应实施例中无特殊说明，反应均在氮气氛下进行。氮气氛是指反应瓶连接一个约1L的氮气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。氢气氛是指反应瓶连接一个约1L的氢气气球。
微波反应使用Initiator+微波反应器。
本发明化合物的结构是通过核磁共振(NMR)和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker AscendTM 500型)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3),氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。以下简写用于NMR信号的多重性：s＝单峰，brs＝宽峰，d＝二重峰，t＝三重峰，m＝多重峰。耦合常数以J值列出，以Hz测量。
LC-MS的测定使用Thermo液质联用仪(UltiMate 3000+MSQ PLUS)。HPLC的测定使用Thermo高压液相色谱仪(UltiMate 3000)。反相制备色谱使用Thermo(UltiMate 3000)反相制备色谱仪。快速柱层析使用艾杰尔(FS-9200T)自动过柱机，硅胶预装柱使用三泰预装柱。薄层层析硅胶板用烟台黄海HSGF254或青岛GF254硅胶板，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
实施例1
(S)-4,5-二甲基-2-(((1-((6-(三氟甲基)吡啶-3-yl)甲基)-1H-吡唑-4-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物1由以下步骤制备：
第一步：将6-三氟甲基-3-吡啶甲醇1a(4.0g，22.58mmol)溶于二氯甲烷(20mL)中，在冰浴条件下滴加氯化亚砜(26.87g，225.83mmol，16.38mL)，加完后反应升至室温，并在55℃条件下搅拌过夜。反应液浓缩得到粗品黄色的油状物1b(4.4g，收率99％)。ESI-MS(m/z):196.5[M+H]+。
第二步：将化合物1b(4.4g，22.48mmol)，化合物1c(1.8g，18.73mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入碳酸钾(6.47g，46.83mmol)，在室温条件下搅拌过夜。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相用无水硫酸钠干燥，过滤浓缩得到黄色固体1d(4.5g，收率94％)。ESI-MS(m/z):256.4[M+H]+。
第三步：将化合物1d(4.5g，17.63mmol)和盐酸羟胺(1.73g，26.45mmol)溶于乙醇(20mL)中，在室温条件下搅拌过夜。向反应液中加入锌粉(4.58g，70.53mmol)和醋酸(50mL)加热至70℃反应过夜。反应结束后，减压蒸掉大部分的溶剂，残余物用2N的氢氧化钠调节pH值为11-12，过滤。滤液用二氯甲烷萃取三次，有机相合并，无水硫酸钠干燥，过滤浓缩得到黄色油状物1e(3.5g，收率77％)。ESI-MS(m/z):257.6[M+H]+。
第四步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.7g，8.50mmol)和(S)-2-(甲基氨基)丙酸甲酯盐酸盐1g(1.70g，11.05mmol)溶解于四氢呋喃(40mL)中，加入三乙胺(2.58g，25.50mmol，3.53mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析纯化，得到黄色油状物1h(1.1g，收率46％)。ESI-MS(m/z):281[M+H]+。
第五步：将化合物1h(1.1g，3.92mmol)溶解于四氢呋喃(20mL)中，加入盐酸水溶液(6N，0.65mL)和二氧化铂(88mg，0.39mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48小时，LCMS监测反应结束。反应液用甲醇稀释，过滤，滤液浓缩后通过硅胶柱层析纯化，得到白色固体1i(900mg，收率90％)。ESI-MS(m/z):253[M+H]+。
第六步：将化合物1i(300mg，1.19mmol)，化合物1e(395mg，1.54mmol)，Pd2(dba)3(217mg，0.23mmol)，t-BuONa(342mg，3.56mmol)和X-Phos(113mg，0.23mmol)分散于甲苯(10mL)中，反应体系置换氮气后加热至100℃反应16小时，LCMS监测反应结束。反应液浓缩，残余物通过硅胶柱层析纯化，得到的粗品再通过制备HPLC纯化得到白色固体1(143mg，收率25％)。ESI-MS(m/z):473.2[M+H]+；1HNMR(500MHz,DMSO-d6)δ8.61(s,1H),8.13(s,1H),7.86(d,J＝8.0Hz,1H),7.82(dd,J＝8.0,1.5Hz,1H),7.74(s,1H),7.41(s,1H),6.67(t,J＝5.5Hz 1H),5.43(s,2H),4.28-4.16(m,2H),4.10(q,J＝7.0Hz,1H),4.04-3.96(m,1H),3.30-3.20(m,1H),2.93(s,3H),2.54-2.50(m,2H),1.95-1.85(m,1H),1.84-1.70(m,1H),1.21(d,J＝7.0Hz,3H)。
实施例11
(S)-4,5-二甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧基)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-de]蝶啶-6-酮
化合物11由以下步骤制备：
第一步：将6-(三氟甲基)吡啶-3-醇11a(1.0g，6.13mmol)溶于二甲亚砜(10mL)中，加入碳酸铯(2.0g，6.13mmol)，室温搅拌30分钟后加入2-氟吡啶-5-甲醛11b(1.53g，12.26mmol)，反应混合物继续搅拌2小时后终止反应。反应液用乙酸乙酯稀释，依次用水和饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤浓缩，残余物通过硅胶柱层析纯化得到产物11c(1.5g，收率91％)。1HNMR(500MHz,DMSO-d6)δ10.04(s,1H),8.79-8.70(m,2H),8.37(dd,J＝8.6,2.3Hz,1H),8.05(d,J＝1.0Hz,2H),7.42(d,J＝8.6Hz,1H)。
第二步：将化合物11c(1.53g，5.70mmol)溶于乙醇(5mL)，加入盐酸羟胺(792mg，11.41mmol)，室温搅拌过夜。反应液浓缩得到粗品肟，重新溶解于醋酸(5mL)中，加入锌粉(1.94g，29.66mmol)，室温搅拌2小时，LCMS检测反应完全。反应混合物过滤，滤液浓缩除去大部分醋酸，加乙酸乙酯稀释，然后用NaOH溶液(2N)碱化至pH＝11。混合物过滤，滤液浓缩得到化合物11d(1.3g)，直接用于下一步反应。ESI-MS(m/z):270.5[M+H]+。
第二步：将化合物11d(383mg)，化合物1i(300mg，1.19mmol)，Pd2(dba)3(217mg，0.23mmol)，t-BuONa(342mg，3.56mmol)和X-Phos(113mg，0.23mmol)分散于甲苯(10mL)中，体系置换氮气后加热至100℃反应16小时，LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析纯化，得到粗品再通过制备HPLC纯化得到化合物11(20mg，收率3％)。ESI-MS(m/z):486.4[M+H]+；1HNMR(500MHz,DMSO-d6)δ8.64(d,J＝2.6Hz,1H),8.17(s,1H),8.14(d,J＝2.2Hz,1H),7.98(d,J＝8.6Hz,1H),7.92-7.86(m,2H),7.18(d,J＝8.4Hz,1H),7.06(br s,1H),4.40-4.30(m,2H),4.12(q,J＝6.8Hz,1H),4.05-3.99(m,1H),3.26(d,J＝3.2Hz,1H),2.94(s,3H),1.96-1.88(m,1H),1.85-1.76(m,1H),1.24(d,J＝6.8Hz,3H)。
实施例106(W190)
(S)-5-(甲氧基甲基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物106由以下步骤制备：
第一步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(2g，10.00mmol)和O-甲基-L-丝氨酸甲酯盐酸盐106a(2.45g，15.00mmol)溶解于四氢呋喃(20mL)中，加入N,N-二异丙基乙胺(3.88g，30.00mmol，5.22mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到黄色油状物106b(2.5g，收率84％)。ESI-MS(m/z):297.2[M+H]+。
第二步：将化合物106b(2.5g，8.43mmol)溶解于四氢呋喃(30mL)中，加入盐酸水溶液(6N，1.40mL)和二氧化铂(191mg，0.84mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到灰色固体106c(2.0g，收率88％)。ESI-MS(m/z):269.3[M+H]+。
第三步：将化合物106c(500mg,1.86mmol)和碘甲烷(343mg,2.42mmol)溶解在乙腈(10mL)中，加入碳酸铯(1.21g,372mmol)，在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释，过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝20/1)纯化，得到白色固体106d(350mg,收率66％)。ESI-MS(m/z):283.3[M+H]+。
第四步：将化合物106d(50mg,176umol)，化合物11d(71mg,265umol)和一水对甲苯磺酸(3mg,17umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体106(6mg,收率7％)。ESI-MS(m/z):516.2[M+H]+；1H NMR(500MHz,DMSO-d6)δ8.63(d,J＝2.7Hz,1H),8.13(d,J＝2.4Hz,1H),7.97(d,J＝8.6Hz,1H),7.89(dd,J＝8.5,2.6Hz,2H),7.85(dd,J＝8.5,2.6Hz,2H),7.17(d,J＝8.4Hz,1H),6.99(br s,1H),4.45-4.32(m,2H),4.22(t,J＝2.8Hz,1H),4.02-3.95(m,1H),3.71-3.60(m,2H),3.40-3.30(m,1H),3.15(s,3H),2.96(s,3H),2.55-2.47(m,2H),1.88(d,J＝7.6Hz,1H),1.74(s,1H)。
实施例109(W220)
(S)-5-((R)-1-羟基乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物109由以下步骤制备：
第一步：将2,4-二氯吡啶并[3,2-d]嘧啶1f(1.0g，5.0mmol)和L-苏氨酸甲酯盐酸盐109a(1.10g，6.5mmol)溶解于四氢呋喃(10mL)中，加入N,N-二异丙基乙胺(1.94g，15.0mmol，2.61mL)，在室温条件下搅拌过夜。LCMS监测反应结束，反应液浓缩，残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到黄色油状物109b(1.3g，收率87％)。ESI-MS(m/z):297.3[M+H]+。
第二步：将化合物109b(1.3g，4.38mmol)溶解于四氢呋喃(20mL)中，加入盐酸水溶液(6M，0.73mL)和二氧化铂(99mg，0.44mmol)，反应体系用氢气球置换氢气，在室温氢气球压力下搅拌48小时，LCMS监测反应结束。反应液用甲醇稀释，硅藻土过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到灰色固体109c(0.4g，收率33％)。ESI-MS(m/z):269.3[M+H]+。
第三步：将化合物109c(150mg,0.56mmol)和碘甲烷(118mg,0.84mmol)溶解在乙腈(3mL)中，加入碳酸铯(363mg,1.12mmol)，在50℃的条件下反应2小时。LCMS监测反应结束。反应液用二氯甲烷稀释，过滤，滤液浓缩后通过硅胶柱层析(二氯甲烷/甲醇＝10/1)纯化，得到白色固体109d(100mg,收率63％)。ESI-MS(m/z):283.4[M+H]+。
第四步：将化合物109d(50mg,176umol)，化合物11d(57mg,212umol)和一水对甲苯磺酸(3.3mg,17umol)溶解在正丁醇(2mL)中，在微波160℃的条件下反应2小时。LCMS监测反应结束。反应液通过反相制备HPLC纯化，得到白色固体109(40mg,收率44％)。ESI-MS(m/z):516.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝2.6Hz,1H),8.19(s,1H),8.13(d,J＝2.4Hz,1H),7.97(d,J＝8.6Hz,1H),7.89(dd,J＝8.5,2.5Hz,1H),7.86(dd,J＝8.5,2.5Hz,2H),7.17(d,J＝8.4Hz,1H),7.02(t,J＝6.4Hz,1H),4.93(br s,1H),4.47-4.27(m,2H),4.17-4.06(m,1H),3.93-3.83(m,2H),3.17-3.10(m,1H),3.07(s,3H),2.52-247(m,2H),1.98-1.88(m,1H),1.82-1.68(m,1H),1.09(d,J＝6.2Hz,3H)。
实施例117(W237)
(S)-5-异丙基-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-缬氨酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a，用类似的方法和反应步骤，可以得到化合物117。ESI-MS(m/z):514.5[M+H]+；1HNMR(500MHz,DMSO-d6)δ8.64(d,J＝2.6Hz,1H),8.14(d,J＝2.4Hz,1H),7.98(d,J＝8.5Hz,1H),7.91(dd,J＝8.5,3.0Hz,1H),7.86(dd,J＝8.5,3.0Hz,1H),7.18(d,J＝8.3Hz,1H),7.02(brs,1H),4.45-4.33(m,2H),4.18-4.12(m,1H),3.99(d,J＝3.8Hz,1H),3.22-3.15(m,1H),3.01(s,3H),2.55-2.49(m,2H),2.18-2.13(m,1H),2.01-1.93(m,1H),1.80-1.69(m,1H),0.94(d,J＝7.0Hz,3H),0.75(d,J＝6.9Hz,3H)。
实施例119(W255)
(S)-5-乙基-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
用L-2-氨基丁酸甲酯盐酸盐替换实施例106中第一步的O-甲基-L-丝氨酸甲酯盐酸盐106a，用类似的方法和反应步骤，可以得到化合物119。ESI-MS(m/z):500.0[M+H]+；1HNMR(500MHz,DMSO-d6)δ8.62(d,J＝2.6Hz,1H),8.12(d,J＝2.3Hz,1H),7.96(d,J＝8.5Hz,1H),7.89(dd,J＝8.5,2.5Hz,2H),7.85(dd,J＝8.5,2.5Hz,2H),7.16(d,J＝8.4Hz,1H),7.00(t,J＝6.3Hz,1H),4.43-4.31(m,2H),4.15-4.10(m,1H),4.07-4.00(m,1H),3.30-3.25(m,1H),2.94(s,3H),2.55-2.49(m,2H),1.99-1.89(m,1H),1.85-1.70(m,3H),0.68(t,J＝7.4Hz,3H)。
实施例126(W308)
(R)-5-((S)-1-氟乙基)-4-甲基-2-(((6-((6-(三氟甲基)吡啶-3-基)氧代)吡啶-3-基)甲基)氨基)-4,5,9,10-四氢-6H,8H-吡啶并[3,2,1-脱]蝶啶-6-酮
化合物126由以下步骤制备：
第一步：将化合物109(30mg,58umol)溶于二氯甲烷(2mL)中，在0℃冰浴下加入二乙胺基三氟化硫(19mg,116umol)，混合物在0℃搅拌2小时。待反应完全后，加水淬灭反应，水相用乙酸乙酯萃取。合并有机相，用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩。残留物用反向制备HPLC分离得到白色固体化合物126(4.5mg，收率15％)。ESI-MS(m/z):518.3[M+H]+；1H NMR(500MHz,DMSO-d6)δ8.62(d,J＝2.6Hz,1H),8.12(d,J＝2.3Hz,1H),7.96(d,J＝8.6Hz,1H),7.88(dd,J＝8.5,2.5Hz,1H),7.85(dd,J＝8.5,2.5Hz,1H),7.16(d,J＝8.4Hz,1H),7.08(br s,1H),5.16-4.96(m,1H),4.45-4.31(m,3H),4.13-4.05(m,1H),3.31-3.20(m,1H),3.02(s,3H),2.55-2.47(m,2H),1.97-1.89(m,1H),1.80-1.68(m,1H),1.30-1.20(m,3H)。
Wnt通路抑制剂生物学筛选和结果
试验例1：Colo205-LUC-TCF/LEF-M1报告细胞系构建
Colo205细胞系(中国科学院细胞库,Cat#TCHu102)购买于中国科学院细胞库，扩增传代培养后，于细胞的指数生长期，以lipo3000脂质体转染的方法，转染带有TCF/LEF转录因子驱动的萤光素酶报告质粒(Promega)。该质粒带有抗性基因，可以进行抗性筛选。转染在10cm培养皿中进行，使用无抗性的常规完全培养基。2天后，更换带有抗性的培养基，继续培养。之后每2天更换抗性培养基，并将悬浮细胞丢弃，原始培养基离心去除细胞和碎片后保留，作为适应性培养基。当细胞长满培养皿后，将细胞消化下来，计数，传代于96孔板，使每孔中含有的细胞数量平均为1.5个/孔，传代时使用适应培养基。其余细胞进行冻存。传代后培养4小时，让细胞贴壁，然后在显微镜下观察各孔的细胞数量。每孔仅1个细胞的孔进行标记，其为单克隆孔。而后正常培养，每2天更换培养基，并进行观察。前期单克隆细胞有继续生长的孔，进行2次标记，可更换为正常的带抗性培养基。当有单克隆孔长满96孔板板孔时，将其消化传代到24孔培养板，24孔板长满后，传代到1个96孔板和1个6孔板，96孔板细胞至少6孔，其中3孔加入已知的Wnt抑制剂，另外3孔不作处理。24h后，96孔板细胞加入萤光检测试剂，检测萤光强度。选择其中不处理时有萤光表达，且抑制后萤之光降低的细胞系，进一步培养。Colo205-LUC-TCF/LEF-M1细胞系为上述筛选出的细胞系之一，其生长曲线、细胞形态、细胞生长状态与原始Colo205细胞相似，且其加抑制剂处理和不处理的萤光信号之比在所有细胞系中属于较大的，比值在4h时抑制时可达4-5倍，完全适用于后期的Wnt抑制剂的筛选。
试验例2：化合物对Colo205-LUC-TCF/LEF M1报告细胞系上抑制能力的检测
Colo205-LUC-TCF/LEF M1细胞株为稳定转pGL4.49-LUC2-TCF/LEF载体的报告工具细胞，其β-catenin Wnt通路持续激活，加入抑制剂后，Wnt通路被抑制，载体上TCF/LEF顺式元件调控的萤火虫萤光素酶表达量下降，后续加入检测底物后，检测到的光信号相应下降，从而检测出化合物的抑制效果。
向96孔的细胞培养板，每孔中加入100uL，最高浓度20uM的化合物，化合物浓度做3倍梯度稀释。然后向各孔中接种10000个稳定转染过报告基因的colo205细胞和100uL培养基，同时做相应的阳性、阴性对照孔。将细胞放入细5％CO2胞培养箱，37℃培养4h，4小时后，去除培养液，向各孔添加含相应的萤火虫荧光素酶底物的试剂(Promega)100uL，测定荧光素酶报告基因的活性。用SpectraMax在全波长模式下读取发光强度。仅由DMSO处理的细胞的光信号强度为阳性对照，无细胞孔的光信号强度为阴性对照，计算各化合物的IC50的浓度。Colo 205报告基因检测数据汇总于表1。
表1
试验例3：化合物对Wnt突变细胞株(Colo205和DU4475)和非Wnt突变细胞株(Hela和RKO)的增殖抑制试验
试验中使用的细胞株为Wnt通路持续激活的，且其增殖为Wnt通路依赖型的Colo205和DU4475细胞系；而正常情况下Wnt通路不激活，且增殖不依赖于Wnt通路的HELA和RKO细胞系作为对照细胞系，判断本发明的化合物对于Wnt依赖的增殖的抑制作用不是由于其它非特异毒性造成的。
将培养于各自的培养基中的Colo205、Du4475、HELA和RKO细胞株在对数生长期时处理，收集细胞后制备成已知浓度的均匀的细胞悬液，然后向96孔细胞培养板中加入细胞悬液，使每孔中含有1000个细胞。放入5％CO2胞培养箱，37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的，3倍梯度稀释的化合物，使细胞培养孔中的最终最高浓度为20uM，继续培养96h。本试验使用Promega的细胞活性检测试验进行检测，细胞增殖越多，则最终的信号强度越强。检测仪器为SpectraMax，全波长模式。仅加入DMSO的孔作为阳性对照孔，未接种细胞的孔为阴性对照孔，计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC50值，以及对于Wnt未激活的或增殖不依赖的细胞的增殖抑制的IC50值，评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用(表2)。
表2
试验例4：化合物对NCI-H929和HepG2细胞株的增殖抑制试验
试验中使用的细胞株为Wnt通路持续激活的，且其增殖为Wnt通路依赖型的NCI-H929和HepG2细胞系；判断本发明的化合物对于Wnt依赖的增殖的抑制作用。
将培养于各自的培养基中的NCI-H929和HepG2细胞株在对数生长期时处理，收集细胞后制备成已知浓度的均匀的细胞悬液，然后向96孔细胞培养板中加入细胞悬液，使每孔中含有4000个细胞。放入5％CO2胞培养箱，37℃培养20-24h。第二天向各细胞培养孔中加入已经完全溶解的，3倍梯度稀释的化合物，使细胞培养孔中的最终最高浓度为20uM，继续培养96h。本试验使用Promega的细胞活性检测试验进行检测，细胞增殖越多，则最终的信号强度越强。检测仪器为SpectraMax，全波长模式。仅加入DMSO的孔作为阳性对照孔，未接种细胞的孔为阴性对照孔，计算各化合物对于Wnt持续激活或增殖依赖的细胞的增殖抑制的IC50值，以及对于Wnt未激活的或增殖不依赖的细胞的增殖抑制的IC50值，评估化合物对于Wnt通路的抑制作用和对于正常细胞的毒性作用(表3)。
表3
Claims (4)
1.具有如下结构的化合物及药学上可接受的盐、同位素衍生物、立体异构体：
2.一种制备如权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体的方法，其特征在于，所述方法包括使用化合物11d作为中间体：
3.药物组合物，包括权利要求1所述的化合物及药学上可接受的盐、同位素衍生物、立体异构体。
4.权利要求1所述的化合物以及药学上可接受的盐、同位素衍生物、立体异构体以及权利要求3所述的药物组合物用于预防和/或治疗癌症、肿瘤、炎症性疾病、自身免疫性疾病或免疫介导性疾病的药物中的用途。
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