CN118973578A - Drug compounds - Google Patents

Abstract

A compound comprising the formula:

Description

Translated fromChinese

药物化合物Drug compounds

本发明涉及PARP1抑制剂化合物，并且特别涉及用于用在药物中的PARP1抑制剂化合物。本发明的抑制剂可以用在药物组合物中，特别是用在用于治疗癌症的药物组合物中。本发明还涉及这样的抑制剂的制备方法，以及使用这样的抑制剂的治疗方法。The present invention relates to PARP1 inhibitor compounds, and in particular to PARP1 inhibitor compounds for use in medicine. The inhibitors of the present invention can be used in pharmaceutical compositions, in particular in pharmaceutical compositions for treating cancer. The present invention also relates to methods for preparing such inhibitors, and methods of treatment using such inhibitors.

发明背景Background of the Invention

聚(ADP-核糖)聚合酶(PARP)的家族由17种PARP蛋白组成，所述PARP蛋白催化ADP-核糖向靶蛋白的转换，即被称为聚ADP核糖基化(PARylation)的翻译后过程。聚ADP核糖基化对靶蛋白的修饰会造成功能的显著变化，并且因此PARP在许多细胞过程诸如染色质重塑、转录、复制、重组、细胞周期进展和DNA损伤修复中发挥重要作用(Kamaletdinova,T.等人.Cell.2019；8:1625)。PARP1和2是被最广泛研究的PARP酶，主要因为它们在DNA损伤修复中的作用，特别是在DNA单链断裂的碱基切除修复(BER)过程中的作用(Ngoi,YL.等人.Cancer J.2021；27:521-528)。PARP1由DNA损伤断裂活化，并且随后靶蛋白的聚ADP核糖基化导致其它因子的募集，所述其它因子启动DNA损伤的修复。PARP的自身聚ADP核糖基化会触发结合的PARP从DNA释放，从而使其它DNA修复蛋白能够完成损伤修复。这凸显了PARP在帮助癌细胞修复由诸如辐射疗法和化学治疗剂等外源性因素引起的DNA损伤方面所发挥的关键作用。因此，PARP酶的抑制已经被用作一种策略以选择性地杀死在互补DNA损伤修复途径中携带遗传缺陷的癌细胞(Farmer,H.等人.Nature.2005；434:917-921)。这种合成致死方案已经在具有BRCA1和BRCA2中的表观遗传修饰或有害突变的肿瘤中得到成功证明，所述BRCA1和BRCA2是两种参与通过同源重组(HR)实现的DNA双链断裂(DSB)修复的在功能上冗余的肿瘤抑制蛋白(Lord,CJ.和Ashworth,A.Science.2017；355:1152-1158)。这样的具有HR缺陷(HRD)的肿瘤依赖于PARP功能才能生存-在这些肿瘤中发生PARP抑制后，DSB断裂将由替代性的易出错的修复途径处理，从而导致基因组不稳定性和癌细胞死亡。The family of poly (ADP-ribose) polymerases (PARPs) consists of 17 PARP proteins that catalyze the conversion of ADP-ribose to target proteins, a post-translational process known as poly ADP ribosylation (PARylation). Modification of target proteins by poly ADP ribosylation causes significant changes in function, and therefore PARP plays an important role in many cellular processes such as chromatin remodeling, transcription, replication, recombination, cell cycle progression, and DNA damage repair (Kamaletdinova, T. et al. Cell. 2019; 8: 1625). PARP1 and 2 are the most widely studied PARP enzymes, mainly because of their role in DNA damage repair, especially in the base excision repair (BER) process of DNA single-strand breaks (Ngoi, YL. et al. Cancer J. 2021; 27: 521-528). PARP1 is activated by DNA damage breaks, and subsequent poly ADP ribosylation of target proteins leads to the recruitment of other factors that initiate the repair of DNA damage. PARP's own poly ADP ribosylation triggers the release of bound PARP from DNA, allowing other DNA repair proteins to complete damage repair. This highlights the key role that PARP plays in helping cancer cells repair DNA damage caused by exogenous factors such as radiation therapy and chemotherapeutic agents. Therefore, inhibition of PARP enzymes has been used as a strategy to selectively kill cancer cells carrying genetic defects in complementary DNA damage repair pathways (Farmer, H. et al. Nature. 2005; 434: 917-921). This synthetic lethal approach has been successfully demonstrated in tumors with epigenetic modifications or deleterious mutations in BRCA1 and BRCA2, which are two functionally redundant tumor suppressor proteins involved in DNA double-strand break (DSB) repair achieved by homologous recombination (HR) (Lord, CJ. and Ashworth, A. Science. 2017; 355: 1152-1158). Such HR-deficient (HRD) tumors rely on PARP function for survival - upon PARP inhibition in these tumors, DSB breaks are processed by alternative error-prone repair pathways, leading to genomic instability and cancer cell death.

PARP的抑制可以将失活的PARP捕获在DNA损伤部位处。这会导致复制叉停滞，并且随后当复制叉到达被捕获的PARP的位置时在S期发生崩溃，从而导致遗传毒性的DNA双链断裂的产生。据信，这种PARP1-DNA捕获可以导致携带HRD的癌细胞的选择性死亡(Farmer,H.等人.Nature.2005；434:917-921。Inhibition of PARP can trap inactive PARP at sites of DNA damage. This can lead to replication fork stalling and subsequent collapse in the S phase when the replication fork reaches the site of the trapped PARP, resulting in the generation of genotoxic DNA double-strand breaks. It is believed that this PARP1-DNA trapping can lead to the selective death of cancer cells carrying HRD (Farmer, H. et al. Nature. 2005; 434: 917-921).

该策略已经导致几种用于治疗具有HRD的癌症的PARP抑制剂的成功批准，所述癌症诸如在BRCA1/2-突变的乳癌、卵巢癌和前列腺癌中，以及在携带HRD的基因组后果的卵巢癌和前列腺癌中，以及在铂敏感性作为HRD替代物的维持环境中的卵巢癌(Fong,PC.等人.N.Engl.J.Med.2009；361:123-134)。This strategy has led to the successful approval of several PARP inhibitors for the treatment of cancers with HRD, such as in BRCA1/2-mutated breast, ovarian, and prostate cancers, as well as in ovarian and prostate cancers carrying the genomic consequences of HRD, and in ovarian cancer in the maintenance setting of platinum sensitivity as a surrogate for HRD (Fong, P.C. et al. N. Engl. J. Med. 2009;361:123-134).

最近已经证实，以未修复的DNA双链断裂或微核破坏形式出现的基因组不稳定性可以通过细胞溶质DNA传感器环状GMP-AMP合酶(cGAS)触发先天性免疫系统活化，从而导致环鸟苷酸-腺苷酸(cGAMP)的产生和干扰素基因刺激因子(STING)的二聚化的诱导。STING随后从内质网转移到高尔基体，在那里它募集并活化TANK结合激酶1(TBK1)。TBK1磷酸化干扰素调节转录因子3(IRF3)，其驱动I型干扰素的产生并支持适应性免疫应答的诱导(Zhu,Y.等人.Mol.Cancer.2019,18:152)。It has recently been demonstrated that genomic instability in the form of unrepaired DNA double-strand breaks or micronuclei can trigger innate immune system activation through the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), leading to the production of cyclic guanosine monophosphate-adenylic acid (cGAMP) and the induction of dimerization of interferon gene stimulator (STING). STING then transfers from the endoplasmic reticulum to the Golgi apparatus, where it recruits and activates TANK binding kinase 1 (TBK1). TBK1 phosphorylates interferon regulatory transcription factor 3 (IRF3), which drives the production of type I interferons and supports the induction of adaptive immune responses (Zhu, Y. et al. Mol. Cancer. 2019, 18: 152).

例如，PARP抑制剂诱导的STING途径活化和抗肿瘤免疫应答已经在多种肿瘤模型中得到证实，从而为利用PARP抑制剂与免疫疗法的组合来提高治疗效果提供了理论依据(Sen,T.等人.Cancer Discov.2019；9:646-661)。例如，最近还证明PARP抑制剂奥拉帕尼与合成的环状二核苷酸STING激动剂联合在DNA损伤修复缺陷型癌细胞和BRCA-缺陷型乳癌模型中诱导合成致死效应(Pantelidou,C.等人.2021:bioRxiv)。For example, PARP inhibitor-induced STING pathway activation and anti-tumor immune responses have been confirmed in a variety of tumor models, providing a theoretical basis for the use of PARP inhibitors in combination with immunotherapy to improve the therapeutic effect (Sen, T. et al. Cancer Discov. 2019; 9: 646-661). For example, it has recently been demonstrated that the PARP inhibitor olaparib combined with the synthetic cyclic dinucleotide STING agonist induces synthetic lethality in DNA damage repair-deficient cancer cells and BRCA-deficient breast cancer models (Pantelidou, C. et al. 2021: bioRxiv).

总体而言，通过多种机制对核酸传感途径的调节已经被证明在多种细胞和动物模型中促进抗肿瘤效力，从而显示出通过使用PARP抑制剂增强免疫疗法效力和克服对免疫检验点阻断的抗性的治疗潜力。存在许多正在进行中的将PARP抑制剂与免疫疗法组合的临床试验(综述见Chabanon,RM，等人.Nat.Rev.Cancer.2021；21:701-717)。In general, modulation of nucleic acid sensing pathways through a variety of mechanisms has been shown to promote anti-tumor efficacy in a variety of cell and animal models, showing therapeutic potential for enhancing immunotherapy efficacy and overcoming resistance to immune checkpoint blockade by using PARP inhibitors. There are many ongoing clinical trials combining PARP inhibitors with immunotherapy (reviewed in Chabanon, RM, et al. Nat. Rev. Cancer. 2021; 21: 701-717).

近年来，PARP1还已经被证明与爱泼斯坦-巴尔病毒(EBV)基因组结合，并且PARP1抑制可以改变EBV染色质结构和潜在基因表达(Morgan,SM.等人.Nat.Commun.2022；13:187)。因此，PARP1抑制剂可能在其中EBV起助推作用的癌症(诸如伯基特淋巴瘤、霍奇金淋巴瘤、鼻咽癌和胃肠癌)中发挥作用。令人感兴趣的是，EBV也已经被证明是多发性硬化(MS)的诱发因素，其中EBV感染大大增加后续MS的风险(Bjornevik,K.等人.Science(2021)；375:296-301)。In recent years, PARP1 has also been shown to bind to the Epstein-Barr virus (EBV) genome, and PARP1 inhibition can alter EBV chromatin structure and potential gene expression (Morgan, SM. et al. Nat. Commun. 2022; 13: 187). Therefore, PARP1 inhibitors may play a role in cancers in which EBV plays a boosting role (such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer). Interestingly, EBV has also been shown to be a predisposing factor for multiple sclerosis (MS), in which EBV infection greatly increases the risk of subsequent MS (Bjornevik, K. et al. Science (2021); 375: 296-301).

第一代PARP抑制剂通常在PARP1和2处表现出非选择性活性。血液学毒性诸如贫血、嗜中性粒细胞减少症和血小板减少症与这些分子的临床使用有关，这会由于剂量限制性血细胞减少症而限制它们与细胞毒性的化学疗法和其它靶向药剂的联合使用(LaFargue,CJ.等人.Lancet Oncol.2019,20,e15-e28)。来自临床前小鼠研究的证据强烈表明，PARP2抑制是这些血液学毒性的主要驱动因素，其中PARP2与小鼠中的红细胞生成特别相关(Farrés,J.等人.Blood.2013；122:44-54)。此外，已经证明PARP2功能对于HRD小鼠癌症模型中的抗肿瘤活性而言是可有可无的(Ronson,G E.等人.Nat.Commun.2018,9:746)。总之，这些数据表明，在开发相对于PARP2和其它PARP而言对PARP1具有改善的选择性的抑制剂方面存在尚未满足的医疗需求，从而扩大其(1)作为单一药剂和(2)与其它抗癌剂联合使用的治疗效用。First-generation PARP inhibitors generally exhibit non-selective activity at PARP1 and 2. Hematological toxicities such as anemia, neutropenia, and thrombocytopenia are associated with the clinical use of these molecules, which limits their combined use with cytotoxic chemotherapy and other targeted agents due to dose-limiting cytopenias (LaFargue, CJ. et al. Lancet Oncol. 2019, 20, e15-e28). Evidence from preclinical mouse studies strongly suggests that PARP2 inhibition is the main driver of these hematological toxicities, with PARP2 being particularly associated with erythropoiesis in mice (Farrés, J. et al. Blood. 2013; 122: 44-54). In addition, PARP2 function has been shown to be dispensable for antitumor activity in HRD mouse cancer models (Ronson, G E. et al. Nat. Commun. 2018, 9: 746). Together, these data suggest that there is an unmet medical need to develop inhibitors with improved selectivity for PARP1 relative to PARP2 and other PARPs, thereby expanding their therapeutic utility (1) as single agents and (2) in combination with other anticancer agents.

迄今为止，两种PARP1-选择性抑制剂AZD5305和AZD9574已经进入临床开发。AZD5305被描述为一种有效的PARP1抑制剂和捕获剂，其相对于PARP2具有500倍选择性，并且针对次要药理学靶标的脱靶活性比第一代PARP抑制剂更低(Johannes,JW.等人.J.Med.Chem.2021；64:14498-14512)。重要的是，在啮齿动物模型中观察到的AZD5305的血液毒性明显低于第一代PARP抑制剂，从而证实了报道的PARP2在血液学毒性中的致病作用(Illuzzi,G.等人.Clin.Cancer Res.2022；CCR-22-0301)。To date, two PARP1-selective inhibitors, AZD5305 and AZD9574, have entered clinical development. AZD5305 is described as a potent PARP1 inhibitor and trap with 500-fold selectivity relative to PARP2 and lower off-target activity against secondary pharmacological targets than first-generation PARP inhibitors (Johannes, JW. et al. J. Med. Chem. 2021; 64: 14498-14512). Importantly, the hematologic toxicity of AZD5305 observed in rodent models was significantly lower than that of first-generation PARP inhibitors, confirming the reported pathogenic role of PARP2 in hematologic toxicity (Illuzzi, G. et al. Clin. Cancer Res. 2022; CCR-22-0301).

考虑到上述内容，本发明的目的是提供PARP1抑制剂，特别是用于药物的PARP1抑制剂。另一个目的是提供包含这样的抑制剂的药物组合物，特别是提供用于治疗癌症的化合物和药物组合物。目的还在于提供所述化合物的合成方法。In view of the above, the object of the present invention is to provide PARP1 inhibitors, in particular PARP1 inhibitors for use in medicine. Another object is to provide pharmaceutical compositions containing such inhibitors, in particular to provide compounds and pharmaceutical compositions for the treatment of cancer. The object is also to provide a method for synthesizing the compounds.

发明概述SUMMARY OF THE INVENTION

因此，本发明提供了用于药物的PARP1抑制剂化合物，所述化合物包含以下结构：Therefore, the present invention provides a PARP1 inhibitor compound for use in medicine, the compound comprising the following structure:

其中R¹选自H和被取代的或未被取代的有机基团；R²可以存在或不存在并且独立地选自H和被取代的或未被取代的有机基团；R¹和R²可以一起形成环；R³独立地选自H和被取代的或未被取代的有机基团；R⁶可以存在或不存在并且独立地选自H和被取代的或未被取代的有机基团；Z¹和Z²独立地选自C和N；且L包含具有以下结构的基团：wherein R¹ is selected from H and a substituted or unsubstituted organic group; R² may be present or absent and is independently selected from H and a substituted or unsubstituted organic group; R¹ and R² may form a ring together; R³ is independently selected from H and a substituted or unsubstituted organic group; R⁶ may be present or absent and is independently selected from H and a substituted or unsubstituted organic group; Z¹ and Z² are independently selected from C and N; and L comprises a group having the following structure:

其中，n是独立地选自0、1、2、3、4、5和6的数字；m是独立地选自0、1、2、3、4、5和6的数字；且m+n是选自2、3、4、5和6的数字；优选地其中n和m都至少是1；wherein n is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; m is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and m+n is a number selected from 2, 3, 4, 5 and 6; preferably wherein both n and m are at least 1;

其中，r是独立地选自0、1、2、3、4和5的数字；s是独立地选自0、1、2、3、4和5的数字，优选地选自1、2、3、4和5；且r+s是选自1、2、3、4和5的数字；优选地其中r和s都至少是1；wherein r is a number independently selected from 0, 1, 2, 3, 4 and 5; s is a number independently selected from 0, 1, 2, 3, 4 and 5, preferably selected from 1, 2, 3, 4 and 5; and r+s is a number selected from 1, 2, 3, 4 and 5; preferably wherein both r and s are at least 1;

并且其中，每个X¹可以相同或不同并且独立地选自C、N、O和S；每个X³可以相同或不同并且独立地选自C、N、O和S，优选地其中至少一个X³独立地是N；每个X⁶可以相同或不同并且独立地选自C和N；每个R⁴¹可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；每个R⁴³可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；且R⁴⁴可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；and wherein each X¹ may be the same or different and is independently selected from C, N, O and S; each X³ may be the same or different and is independently selected from C, N, O and S, preferably wherein at least one X³ is independently N; each X⁶ may be the same or different and is independently selected from C and N; each R⁴¹ may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group; each R⁴³ may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group; and R⁴⁴ may be present or absent and is selected from H and a substituted or unsubstituted organic group;

并且其中，虚线指示：环A可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；且独立地环C可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；and wherein the dashed lines indicate: Ring A may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic; and independently Ring C may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic;

并且其中，R⁵选自H和被取代的或未被取代的有机基团并且优选地是被取代的或未被取代的有机基团；and wherein R⁵ is selected from H and a substituted or unsubstituted organic group and is preferably a substituted or unsubstituted organic group;

并且其中每个Q¹可以相同或不同，并且可以存在或不存在，并且包含独立地选自以下结构的基团：And wherein each Q¹ may be the same or different, and may be present or absent, and comprises a group independently selected from the following structures:

其中t独立地是选自0、1、2、3、4和5的数字；u独立地是选自0、1、2、3、4和5的数字；且t+u是选自0、1、2、3、4、5和6的数字(优选选自0、1、2和3的数字)；每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团；wherein t is independently a number selected from 0, 1, 2, 3, 4 and 5; u is independently a number selected from 0, 1, 2, 3, 4 and 5; and t+u is a number selected from 0, 1, 2, 3, 4, 5 and 6 (preferably a number selected from 0, 1, 2 and 3); each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group;

并且其中Q²可以存在或不存在并且是具有以下结构的基团：And wherein^Q2 may be present or absent and is a group having the following structure:

其中，p是独立地选自0、1、2、3、4、5和6的数字；q是独立地选自0、1、2、3、4、5和6的数字；且p+q是选自2、3、4、5和6的数字；wherein p is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; q is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and p+q is a number selected from 2, 3, 4, 5 and 6;

并且其中，每个X²可以相同或不同并且独立地选自C、N、O和S；X⁵独立地选自C和N；每个R⁴²可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；and wherein each X² may be the same or different and is independently selected from C, N, O and S; X⁵ is independently selected from C and N; each R⁴² may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group;

并且其中，虚线指示：环B可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；and wherein the dashed line indicates: Ring B may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic;

并且其中Q³可以存在或不存在并且包含独立地选自以下结构的基团：And wherein Q³ may be present or absent and comprises a group independently selected from the following structures:

其中v独立地是选自0、1、2、3、4和5的数字；w独立地是选自0、1、2、3、4和5的数字；且v+w是选自0、1、2、3、4、5和6的数字(优选选自0、1和2的数字)。wherein v is independently a number selected from 0, 1, 2, 3, 4 and 5; w is independently a number selected from 0, 1, 2, 3, 4 and 5; and v+w is a number selected from 0, 1, 2, 3, 4, 5 and 6 (preferably a number selected from 0, 1 and 2).

在本发明的上下文中，Z¹、Z²、X¹、X²、X³、X⁴、X⁵和X⁶原子维持其正常价态，并且连接至这些原子的取代基的数目将取决于它们的性质和它们所具有的其它键的数目。维持化合价意味着确保原子具有其在有机化合物中的正常(通常是最常见的)化合价(即氧和二价硫为2价，氮为3价，碳为4价)。在某些情况下，氮原子可能具有4个键，但在这样的情况下，它们通常带正电荷，因此所述化合物可能具有抗衡离子。这样的化合物也被认为是本发明的一部分，并且在这些情况下，由于正电荷，显然氮原子仍然维持其正常的3价。为了避免疑惑，在R基团的数目可能根据X基团的选择而变化的情况下，它可能如下变化。In the context of the present invention, Z¹ , Z² , X¹ , X² , X³ , X⁴ , X⁵ and X⁶ atoms maintain their normal valence, and the number of substituents attached to these atoms will depend on their nature and the number of other bonds they have. Maintaining valence means ensuring that the atom has its normal (usually the most common) valence in an organic compound (i.e., 2 valences for oxygen and divalent sulfur, 3 valences for nitrogen, and 4 valences for carbon). In some cases, the nitrogen atom may have 4 bonds, but in such cases, they are usually positively charged, so the compound may have a counter ion. Such compounds are also considered to be part of the present invention, and in these cases, it is clear that the nitrogen atom still maintains its normal 3 valences due to the positive charge. To avoid doubt, in the case where the number of R groups may vary depending on the selection of the X group, it may vary as follows.

当Z¹是N时，R⁶不存在。当Z²是N时，R²不存在。每个R⁴¹可以相同或不同，前提条件是，对于每个X¹而言：当X¹是O或二价S时，R⁴¹不存在；当X¹是N且与相邻原子形成双键时，R⁴¹不存在；当X¹是N且未与相邻原子形成双键时，一个R⁴¹存在；当X¹是C且与相邻原子形成双键时，一个R⁴¹存在；并且当X¹是C且未与相邻原子形成双键时，两个R⁴¹存在。每个R⁴³可以相同或不同，前提条件是，对于每个X³而言：当X³是O或二价S时，R⁴³不存在；当X³是N且与相邻原子形成双键时，R⁴³不存在；当X³是N且未与相邻原子形成双键时，一个R⁴³存在；当X³是C且与相邻原子形成双键时，一个R⁴³存在；并且当X³是C且未与相邻原子形成双键时，两个R⁴³存在。对于每个X⁶而言：当X⁶是N或是C且与相邻原子形成双键时，R⁴³不存在；并且当X⁶是C且与相邻原子形成双键时，一个R⁴³存在。对于与其相关的X³：当X³是O或二价S时R⁴⁴不存在；当X³是N且与相邻原子形成双键时，R⁴⁴不存在；当X³是N且未与相邻原子形成双键时，一个R⁴⁴存在；当X³是C且与相邻原子形成双键时，一个R⁴⁴存在；并且当X³是C且所述C连接至R⁴³且与相邻原子形成双键时，一个R⁴⁴存在。每个R⁴²可以相同或不同，前提条件是，对于每个X²而言：当X²是O或二价S时，R⁴²不存在；当X²是N且与相邻原子形成双键时，R⁴²不存在；当X²是N且未与相邻原子形成双键时，一个R⁴²存在；当X²是C且与相邻原子形成双键时，一个R⁴²存在；并且当X²是C且未与相邻原子形成双键时，两个R⁴²存在。对于X⁵：当X⁵是N或是C且与相邻原子形成双键时，R⁴²不存在；并且当X⁵是C且未与相邻原子形成双键时，一个R⁴²存在。每个R¹¹可以相同或不同，前提条件是，对于每个X⁴而言：当X⁴是O或二价S时，R¹¹不存在；当X⁴是N且与相邻原子形成双键时，R¹¹不存在；当X⁴是N且未与相邻原子形成双键时，一个R¹¹存在；当X⁴是C且与相邻原子形成双键时，一个R¹¹存在；并且当X⁴是C且未与相邻原子形成双键时，两个R¹¹存在。与N键合的每个R¹⁴可以相同或不同，前提条件是，当所述N与相邻原子形成双键时，R¹⁴不存在。When Z¹ is N, R⁶ is absent. When Z² is N, R² is absent. Each R⁴¹ may be the same or different, provided that, for each X¹ : when X¹ is O or divalent S, R⁴¹ is absent; when X¹ is N and forms a double bond with an adjacent atom, R⁴¹ is absent; when X¹ is N and does not form a double bond with an adjacent atom, one R⁴¹ is present; when X¹ is C and forms a double bond with an adjacent atom, one R⁴¹ is present; and when X¹ is C and does not form a double bond with an adjacent atom, two R⁴¹ are present. Each R⁴³ may be the same or different, provided that, for each X³ : when X³ is O or divalent S, R⁴³ is absent; when X³ is N and forms a double bond with an adjacent atom, R⁴³ is absent; when X³ is N and does not form a double bond with an adjacent atom, one R⁴³ is present; when X³ is C and forms a double bond with an adjacent atom, one R⁴³ is present; and when X³ is C and does not form a double bond with an adjacent atom, two R⁴³ are present. For each X⁶ : when X⁶ is N or C and forms a double bond with an adjacent atom, R⁴³ is absent; and when X⁶ is C and forms a double bond with an adjacent atom, one R⁴³ is present. For X³ associated therewith: R⁴⁴ is absent when X³ is O or divalent S; R⁴⁴ is absent when X³ is N and forms a double bond with an adjacent atom; one R 44 is present when X³ is N and does not form a double bond with an adjacent atom; one R⁴⁴ is present when X³ is C and forms a double bond with an adjacent atom; and one R⁴⁴ is present when X³ is C and said C is connected to R⁴³ and forms a double bond with an^adjacent atom. Each R⁴² may be the same or different, provided that, for each X² : when X² is O or divalent S, R⁴² is absent; when X² is N and forms a double bond with an adjacent atom, R⁴² is absent; when X² is N and does not form a double bond with an adjacent atom, one R⁴² is present; when X² is C and forms a double bond with an adjacent atom, one R⁴² is present; and when X² is C and does not form a double bond with an adjacent atom, two R⁴² are present. For X⁵ : when X⁵ is N or C and forms a double bond with an adjacent atom, R⁴² is absent; and when X⁵ is C and does not form a double bond with an adjacent atom, one R⁴² is present. Each R¹¹ may be the same or different, provided that, for each X⁴ : when X⁴ is O or divalent S, R¹¹ is absent; when X⁴ is N and forms a double bond with an adjacent atom, R¹¹ is absent; when X⁴ is N and does not form a double bond with an adjacent atom, one R¹¹ is present; when X⁴ is C and forms a double bond with an adjacent atom, one R¹¹ is present; and when X⁴ is C and does not form a double bond with an adjacent atom, two R¹¹ are present. Each R¹⁴ bonded to N may be the same or different, provided that, when the N forms a double bond with an adjacent atom, R¹⁴ is absent.

在这些化合物中以及本文别处，在某些实施方案中，任何R基团可以与相邻和/或近端原子上的任何其它R基团形成环，尽管在大多数实施方案中这不是优选的，除非明确说明。因此，在某些实施方案中，下述取代基可以一起形成环：R⁵与R⁴⁴；R¹¹与另一个R¹¹；R¹³与另一个R¹³；R⁴¹与另一个R⁴¹；R⁴²与另一个R⁴²；R⁴³与另一个R⁴³；R⁴⁵与另一个R⁴⁵。在本发明的上下文中，相邻和/或近端原子可以指与原子直接键合的另一个原子(相邻)，或者可以是两个原子之间只有单个原子(近端)，或者可以指两个原子在空间上足够接近以能够形成环(近端)。优选地，连接至同一原子的R基团不一起形成环，尽管这并不被排除。In these compounds and elsewhere herein, in certain embodiments, any R group can form a ring with any other R group on adjacent and/or proximal atoms, although this is not preferred in most embodiments, unless explicitly stated. Therefore, in certain embodiments, the following substituents can form a ring together: R⁵ and R⁴⁴ ；R¹¹ and another R¹¹ ；R¹³ and another R¹³ ；R⁴¹ and another R⁴¹ ；R⁴² and another R⁴² ；R⁴³ and another R⁴³ ；R⁴⁵ and another R⁴⁵ . In the context of the present invention, adjacent and/or proximal atoms can refer to another atom (adjacent) directly bonded to atoms, or can be only a single atom (proximal) between two atoms, or can refer to two atoms spatially close enough to be able to form a ring (proximal). Preferably, the R groups connected to the same atom do not form a ring together, although this is not excluded.

在本发明的上下文中，本发明包括这样的化合物，其中在原子上的单个R基团，或在同一原子上的两个R基团，形成与该原子双键键合的基团。因此，一个R基团或两个连接至同一原子的R基团可以一起形成＝O基团或＝C(R’)₂基团(其中每个R’基团相同或不同，并且是H或有机基团，优选H或直链或支链C₁-C₆烷基基团)。这在R基团连接至C原子的情况下更为典型，在此情况下它们一起形成C＝O基团或C＝C(R’)₂基团。因此，在某些情况下，在环中的C环原子可能包含＝O基团，也可能包含X，和/或R¹¹、R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁴⁵中的一个或多个。In the context of the present invention, the present invention includes compounds in which a single R group on an atom, or two R groups on the same atom, form a group double-bonded to the atom. Thus, one R group or two R groups attached to the same atom may together form a =O group or a =C(R')₂ group (wherein each R' group is the same or different and is H or an organic group, preferably H or a straight or branched_C1 -_C6 alkyl group). This is more typical in the case where the R group is attached to a C atom, in which case they together form a C=O group or a C=C(R')₂ group. Thus, in some cases, a C ring atom in a ring may contain a =O group and may also contain X, and/or one or more of^R11 ,^R41 ,^R42 ,^R43 ,^R44 and^R45 .

在本发明的上下文中，在括号中存在的任何结构的一部分可以重复由括号(无论是普通括号还是方括号)旁边的数字给出的次数。例如，在(C(R))_0、1、2或[C(R)]_0、1、2的情况下，C-R基团可以不存在、存在一次即-C(R)-；或存在两次即-C(R)-C(R)-。In the context of the present invention, a portion of any structure present in brackets may be repeated the number of times given by the number next to the brackets (whether ordinary brackets or square brackets). For example, in the case of (C(R))_0,1,2 or [C(R)]_0,1,2 , the CR group may be absent, present once, i.e., -C(R)-; or present twice, i.e., -C(R)-C(R)-.

在本发明的上下文中，如果某种化合物的存在能够阻止或降低固定化的PARP1在与生物素化的NAD+温育后进行自身聚-ADP核糖基化(自身聚ADP核糖基化)的能力(与不存在该化合物时的相同过程相比)，则该化合物被视为PARP1抑制剂。通常，如果某种化合物在合适的测定中具有IC₅₀<10μM，则该化合物被认为是PARP1抑制剂。可以使用2nM PARP1、在20mM HEPES(pH 7.5)中的2μM生物素-NAD⁺测定溶液、100mM NaCl、2mM DTT、0.1％ BSA(w/v)、0.02％吐温(v/v)测定缓冲液进行合适的测定。聚ADP核糖基化可能在室温发生2小时，并且可以使用解离增强的镧系元素荧光免疫测定(DELFIA)读出进行检测。下面的实施例描述了一种特别合适的测定。优选地，该化合物在PARP1抑制剂测定中具有IC₅₀<1μM，更优选地<100nM且最优选地<10nM。In the context of the present invention, a compound is considered a PARP1 inhibitor if the presence of the compound is able to prevent or reduce the ability of immobilized PARP1 to undergo self-poly-ADP ribosylation (self-poly ADP ribosylation) after incubation with biotinylated NAD+ (compared to the same process in the absence of the compound). Generally, a compound is considered a PARP1 inhibitor if it has an_IC50 <10μM in a suitable assay. A suitable assay can be performed using 2nM PARP1, 2μM biotin-NAD⁺ assay solution in 20mM HEPES (pH 7.5), 100mM NaCl, 2mM DTT, 0.1% BSA (w/v), 0.02% Tween (v/v) assay buffer. Poly ADP ribosylation may occur for 2 hours at room temperature and can be detected using a dissociation enhanced lanthanide fluorescence immunoassay (DELFIA) readout. The following example describes a particularly suitable assay. Preferably, the compound has an_IC50 < 1 μM, more preferably < 100 nM and most preferably < 10 nM in a PARP1 inhibitor assay.

如果某种化合物的存在能够替代或降低高亲和力Cy5荧光染料标记的化学探针与PARP1结合的能力，同时以弱至少10倍的活性替代PARP2处的相同化学探针，则该化合物也被认为是选择性的PARP1抑制剂。通常，如果某种化合物在该测定中在PARP1处具有IC₅₀<10μM，且相对于PARP2具有至少10倍选择性偏好，则该化合物被认为是选择性的PARP1抑制剂。可以在室温使用10nM PARP1或PARP2、Tb-穴状化合物抗体和在20mM HEPES(pH 7.5)中的PARP1/2结合探针、100mM NaCl、2mM DTT、0.1％ BSA(w/v)、0.02％吐温(v/v)测定缓冲液进行合适的这样的测定1小时。可以使用均相时间分辨荧光检测探针结合替代。下面的实施例描述了一种特别合适的测定。优选地，PARP1相对于PARP2的选择性偏好是至少50倍，更优选至少100倍。A compound is also considered a selective PARP1 inhibitor if its presence displaces or reduces the ability of a high affinity Cy5 fluorescent dye labeled chemical probe to bind to PARP1 while displacing the same chemical probe at PARP2 with at least 10-fold weaker activity. Generally, a compound is considered a selective PARP1 inhibitor if it has an_IC50 < 10 μM at PARP1 and at least a 10-fold selectivity preference over PARP2 in this assay. A suitable such assay can be performed at room temperature for 1 hour using 10 nM PARP1 or PARP2, Tb-cryptate antibody and PARP1/2 binding probe in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w/v), 0.02% Tween (v/v) assay buffer. Probe binding displacement can be detected using homogeneous time-resolved fluorescence. The following example describes a particularly suitable assay. Preferably, the selectivity preference for PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold.

如果某种化合物在PARP1处具有IC₅₀<10μM，并且在NanoBRET测定中相对于PARP2具有至少10倍选择性偏好，从而表明细胞靶标参与，则该化合物也被认为是选择性的PARP1抑制剂。这些测定是基于Nano-luc-标记的蛋白(例如PARP1或PARP2)与高亲和力NAD⁺竞争性结合探针上的荧光基团之间的生物发光共振能量转移(BRET)。这样的细胞探针替代测定可以用于测量在PARP1和2处的抑制剂亲和力和选择性比率。下面的实施例描述了一种特别合适的测定。优选地，PARP1相对于PARP2的选择性偏好是至少50倍，更优选至少100倍。A compound is also considered a selective PARP1 inhibitor if it has an_IC50 <10 μM at PARP1 and at least a 10-fold selectivity preference over PARP2 in a NanoBRET assay, indicating cellular target engagement. These assays are based on bioluminescence resonance energy transfer (BRET) between a Nano-luc-tagged protein (e.g., PARP1 or PARP2) and a fluorophore on a high affinity NAD⁺ competitive binding probe. Such cellular probe replacement assays can be used to measure inhibitor affinity and selectivity ratios at PARP1 and 2. The following example describes a particularly suitable assay. Preferably, the selectivity preference for PARP1 over PARP2 is at least 50-fold, more preferably at least 100-fold.

在本发明的所有实施方案中(本文的上文和下文)，取代基(每个R基团)没有特别限制，只要它们不会阻止PARP1抑制功能发生。在上文和下文中提到的与本发明相关的所有实施方案中，取代基选自H和有机基团。因此，在上文和下文中，术语“取代基”和“有机基团”没有特别限制，并且可以是任何官能团或任何原子，尤其是在有机化学中常见的任何官能团或原子。因此，“取代基”和“有机基团”可能具有以下含义中的任一种。In all embodiments of the present invention (herein above and below), the substituents (each R group) are not particularly limited as long as they do not prevent the PARP1 inhibitory function from occurring. In all embodiments related to the present invention mentioned above and below, the substituents are selected from H and organic groups. Therefore, above and below, the terms "substituent" and "organic group" are not particularly limited and may be any functional group or any atom, especially any functional group or atom commonly used in organic chemistry. Therefore, "substituent" and "organic group" may have any of the following meanings.

所述有机基团可以包含来自元素周期表的IIIA、IVA、VA、VIA或VIIA族中的任一个中的任意一个或多个原子，诸如B、Si、N、P、O或S原子(例如OH、OR、NH₂、NHR、NR₂、SH、SR、SO₂R、SO₃H、PO₄H₂)或卤素原子(例如F、Cl、Br或I)，其中R是直链或支链低级烃(1-6个C原子)或者直链或支链高级烃(7个或更多个C原子，例如7-40个C原子)。The organic group may contain any one or more atoms from any of Groups IIIA, IVA, VA, VIA or VIIA of the Periodic Table of Elements, such as B, Si, N, P, O or S atoms (e.g., OH, OR,_NH2 , NHR,_NR2 , SH, SR,_SO2R ,_SO3H ,_PO4H2 ) or halogen atoms (e.g., F, Cl, Br or I), wherein R is_a straight or branched lower hydrocarbon (1-6 C atoms) or a straight or branched higher hydrocarbon (7 or more C atoms, e.g., 7-40 C atoms).

所述有机基团优选地包含烃基。所述烃基可以包含直链、支链或环状基团。独立地，所述烃基可以包含脂族或芳族基团。也独立地，所述烃基可以包含饱和的或不饱和的基团。The organic group preferably comprises a hydrocarbon group. The hydrocarbon group may comprise a straight chain, a branched chain or a cyclic group. Independently, the hydrocarbon group may comprise an aliphatic or an aromatic group. Also independently, the hydrocarbon group may comprise a saturated or an unsaturated group.

当所述烃包含不饱和基团时，其可以包含一个或多个烯烃官能团和/或一个或多个炔烃官能团。当所述烃包含直链或支链基团时，其可以包含一个或多个伯、仲和/或叔烷基基团。When the hydrocarbon comprises unsaturated groups, it may comprise one or more olefin functional groups and/or one or more alkyne functional groups.When the hydrocarbon comprises linear or branched groups, it may comprise one or more primary, secondary and/or tertiary alkyl groups.

当所述烃包含环状基团时，其可以包含芳族环、非芳族环、脂族环、杂环基团和/或这些基团的稠环衍生物。所述环可以是完全饱和的、部分饱和的或完全不饱和的。因此，所述环状基团可以包含苯、萘、蒽、菲、非那烯、亚联苯、并环戊二烯、茚、不对称引达省、对称引达省、苊烯、芴、荧蒽、醋菲烯、薁、庚间三烯并庚间三烯、吡咯、吡唑、咪唑、1,2,3-三唑、1,2,4-三唑、四唑、吡咯烷、呋喃、氧杂环丁烷、四氢呋喃、2-氮杂-四氢呋喃、3-氮杂-四氢呋喃、噁唑、异噁唑、呋咱、1,2,4-噁二唑、1,3,4-噁二唑、噻吩、异噻唑、噻唑、硫杂环戊烷、吡啶、哒嗪、嘧啶、吡嗪、哌啶、2-氮杂哌啶、3-氮杂哌啶、哌嗪、吡喃、四氢吡喃、2-氮杂吡喃、3-氮杂吡喃、4-氮杂吡喃、2-氮杂-四氢吡喃、3-氮杂-四氢吡喃、吗啉、噻喃、2-氮杂噻喃、3-氮杂噻喃、4-氮杂噻喃、硫杂环己烷、吲哚、吲唑、苯并咪唑、4-氮杂吲哚、5-氮杂吲哚、6-氮杂吲哚、7-氮杂吲哚、异吲哚、4-氮杂异吲哚、5-氮杂异吲哚、6-氮杂异吲哚、7-氮杂异吲哚、吲嗪、1-氮杂吲嗪、2-氮杂吲嗪、3-氮杂吲嗪、5-氮杂吲嗪、6-氮杂吲嗪、7-氮杂吲嗪、8-氮杂吲嗪、9-氮杂吲嗪、嘌呤、咔唑、咔啉、苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、喹啉、噌啉、喹唑啉、喹喔啉、5-氮杂喹啉、6-氮杂喹啉、7-氮杂喹啉、异喹啉、酞嗪、6-氮杂异喹啉、7-氮杂异喹啉、蝶啶、色烯、异色烯、吖啶、菲啶、萘嵌间二氮杂苯、菲咯啉、吩噁嗪、呫吨、吩噁噻和/或噻蒽、以及上述基团的位置异构体。这些基团通常可以连接在基团中的任意点处，并且也可以连接在杂原子处或碳原子处。在某些情况下，特定的连接点是优选的，诸如在1-基、2-基等处，并且这些在适当的情况下明确指定。这些定义包括所有互变异构环形式。例如吡咯意图包括1H-吡咯、2H-吡咯和3H-吡咯。When the hydrocarbon comprises a cyclic group, it may comprise an aromatic ring, a non-aromatic ring, an aliphatic ring, a heterocyclic group and/or a condensed ring derivative of these groups. The ring may be fully saturated, partially saturated or fully unsaturated. Therefore, the cyclic group may comprise benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, asymmetric indacene, symmetric indacene, acenaphthylene, fluorene, fluoranthene, acetophenanthene, azulene, heptaheptriene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, furan, oxetane, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4- azathiopyran, thiohexane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9-azaindolizine, Purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perylene, phenanthroline, phenoxazine, xanthene, phenoxathiol and/or thianthrene, and positional isomers of the above-mentioned groups. These groups can be connected to any point in the group usually, and can also be connected to a heteroatom or a carbon atom. In some cases, a specific point of attachment is preferred, such as at 1-base, 2-base, etc., and these are clearly specified in appropriate cases. These definitions include all tautomeric ring forms. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole.

所述烃基中的碳原子的数目没有特别限制，但优选地所述烃基包含1至40个C原子。因此，所述烃基可以是低级烃(1-6个C原子)或高级烃(7个C原子或更多，例如7-40个C原子)。所述低级烃基可以是甲基、乙基、丙基、丁基、戊基或己基基团或这些基团的位置异构体，诸如异丙基、异丁基、叔丁基等。在环状基团的环中的原子的数目没有特别限制，但优选地所述环状基团的环包含3至10个原子，诸如3、4、5、6、7、8、9或10个原子。The number of carbon atoms in the hydrocarbon group is not particularly limited, but preferably the hydrocarbon group contains 1 to 40 C atoms. Therefore, the hydrocarbon group can be a lower hydrocarbon (1-6 C atoms) or a higher hydrocarbon (7 C atoms or more, for example 7-40 C atoms). The lower hydrocarbon group can be a methyl, ethyl, propyl, butyl, pentyl or hexyl group or a positional isomer of these groups, such as isopropyl, isobutyl, tert-butyl, etc. The number of atoms in the ring of the cyclic group is not particularly limited, but preferably the ring of the cyclic group contains 3 to 10 atoms, such as 3, 4, 5, 6, 7, 8, 9 or 10 atoms.

上述包含杂原子的基团以及上面定义的任何其它基团可以包含一个或多个来自元素周期表的IIIA、IVA、VA、VIA或VIIA族中的任一个的杂原子，诸如B、Si、N、P、O或S原子或卤素原子(例如F、Cl、Br或I)。因此，所述取代基可以包含一个或多个在有机化学中的任何常见官能团，诸如羟基基团、羧酸基团、酯基团、醚基团、醛基团、酮基团、胺基团、酰胺基团、亚胺基团、硫醇基团、硫醚基团、硫酸酯基团、磺酸基团、磺酰基基团和磷酸酯基团等。所述取代基还可以包含这些基团的衍生物，诸如羧酸酸酐和羧酸酰卤。The above-mentioned heteroatom-containing groups and any other groups defined above may contain one or more heteroatoms from any of the IIIA, IVA, VA, VIA or VIIA groups of the periodic table, such as B, Si, N, P, O or S atoms or halogen atoms (e.g., F, Cl, Br or I). Thus, the substituents may contain one or more of any common functional groups in organic chemistry, such as hydroxyl groups, carboxylic acid groups, ester groups, ether groups, aldehyde groups, ketone groups, amine groups, amide groups, imine groups, thiol groups, thioether groups, sulfate groups, sulfonic acid groups, sulfonyl groups and phosphate groups, etc. The substituents may also contain derivatives of these groups, such as carboxylic acid anhydrides and carboxylic acid halides.

此外，任何取代基可以包含两个或更多个上面定义的取代基和/或官能团的组合。Furthermore, any substituent may comprise a combination of two or more of the substituents and/or functional groups defined above.

本发明的化合物的环A、B(当存在时)和C形成二环或三环结构(当在任一个环上的取代基本身形成环时，其可以包含进一步稠合的环)。环A、B、C和D中的每一个不一定受到限制，只要它们不会阻止PARP1抑制功能发生。环A、B、C和D可以独立地由芳族环、非芳族环、脂族环和/或杂环基团构成。所述环可以是完全饱和的、部分饱和的或完全不饱和的。因此，每个环可以独立地包含苯、萘、蒽、菲、非那烯、亚联苯、并环戊二烯、茚、不对称引达省、对称引达省、苊烯、芴、荧蒽、醋菲烯、薁、庚间三烯并庚间三烯、吡咯、吡唑、咪唑、1,2,3-三唑、1,2,4-三唑、四唑、吡咯烷、氧杂环丁烷、呋喃、四氢呋喃、2-氮杂-四氢呋喃、3-氮杂-四氢呋喃、噁唑、异噁唑、呋咱、1,2,4-噁二唑、1,3,4-噁二唑、噻吩、异噻唑、噻唑、硫杂环戊烷、吡啶、哒嗪、嘧啶、吡嗪、哌啶、2-氮杂哌啶、3-氮杂哌啶、哌嗪、吡喃、四氢吡喃、2-氮杂吡喃、3-氮杂吡喃、4-氮杂吡喃、2-氮杂-四氢吡喃、3-氮杂-四氢吡喃、吗啉、噻喃、2-氮杂噻喃、3-氮杂噻喃、4-氮杂噻喃、硫杂环己烷、吲哚、吲唑、苯并咪唑、4-氮杂吲哚、5-氮杂吲哚、6-氮杂吲哚、7-氮杂吲哚、异吲哚、4-氮杂异吲哚、5-氮杂异吲哚、6-氮杂异吲哚、7-氮杂异吲哚、吲嗪、1-氮杂吲嗪、2-氮杂吲嗪、3-氮杂吲嗪、5-氮杂吲嗪、6-氮杂吲嗪、7-氮杂吲嗪、8-氮杂吲嗪、9-氮杂吲嗪、嘌呤、咔唑、咔啉、苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、喹啉、噌啉、喹唑啉、喹喔啉、5-氮杂喹啉、6-氮杂喹啉、7-氮杂喹啉、异喹啉、酞嗪、6-氮杂异喹啉、7-氮杂异喹啉、蝶啶、色烯、异色烯、吖啶、菲啶、萘嵌间二氮杂苯、菲咯啉、吩噁嗪、呫吨、吩噁噻和/或噻蒽、以及上述基团的位置异构体。这些环通常可以在基团的任何点处被取代，并且也可以在杂原子处或在碳原子处被取代。这些定义包括所有互变异构环形式。例如，吡咯意图包括1H-吡咯、2H-吡咯和3H-吡咯。Rings A, B (when present) and C of the compounds of the present invention form a bicyclic or tricyclic structure (when the substituents on any one ring themselves form a ring, it may contain further fused rings). Each of rings A, B, C and D is not necessarily limited as long as they do not prevent the PARP1 inhibitory function from occurring. Rings A, B, C and D may independently be composed of an aromatic ring, a non-aromatic ring, an aliphatic ring and/or a heterocyclic group. The ring may be fully saturated, partially saturated or fully unsaturated. Thus, each ring may independently comprise benzene, naphthalene, anthracene, phenanthrene, phenalene, biphenylene, pentalene, indene, unsymmetrical indacene, symmetrical indacene, acenaphthylene, fluorene, fluoranthene, acephenanthren, azulene, heptatriene, pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, oxetane, furan, tetrahydrofuran, 2-aza-tetrahydrofuran, 3-aza-tetrahydrofuran, oxazole, isoxazole, furazan, 1,2,4-oxadiazole, 1,3,4-oxadiazole, thiophene, isothiazole, thiazole, thiolane, pyridine, pyridazine, pyrimidine, pyrazine, piperidine, 2-azapiperidine, 3-azapiperidine, piperazine, pyran, tetrahydropyran, 2-azapyran, 3-azapyran, 4-azapyran, 2-aza-tetrahydropyran, 3-aza-tetrahydropyran, morpholine, thiopyran, 2-azathiopyran, 3-azathiopyran, 4- azathiopyran, thiohexane, indole, indazole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, isoindole, 4-azaisoindole, 5-azaisoindole, 6-azaisoindole, 7-azaisoindole, indolizine, 1-azaindolizine, 2-azaindolizine, 3-azaindolizine, 5-azaindolizine, 6-azaindolizine, 7-azaindolizine, 8-azaindolizine, 9-azaindolizine, Purine, carbazole, carboline, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, quinoline, cinnoline, quinazoline, quinoxaline, 5-azaquinoline, 6-azaquinoline, 7-azaquinoline, isoquinoline, phthalazine, 6-azaisoquinoline, 7-azaisoquinoline, pteridine, chromene, isochromene, acridine, phenanthridine, perylene, phenanthroline, phenoxazine, xanthene, phenoxathiol and/or thianthrene, and positional isomers of the above-mentioned groups. These rings can be substituted at any point of the group generally, and can also be substituted at a heteroatom or at a carbon atom. These definitions include all tautomeric ring forms. For example, pyrrole is intended to include 1H-pyrrole, 2H-pyrrole and 3H-pyrrole.

在典型的实施方案中，本发明提供了如上面所定义的化合物，其中Q³不存在或者是独立地选自以下结构的基团：In typical embodiments, the present invention provides compounds as defined above, wherein Q³ is absent or is independently selected from the following groups:

其中每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团。优选的是，Q³不存在或者是wherein each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group. Preferably, Q³ is absent or is

诸如-CH₂-基团。 Such as a -CH₂ - group.

在典型的实施方案中，本发明提供了如上面所定义的化合物，其中Q²存在并且每个Q¹独立地不存在或者是独立地选自以下结构的基团：In an exemplary embodiment, the invention provides a compound as defined above, wherein Q² is present and each Q¹ is independently absent or is independently selected from a group of the following structures:

其中每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团。优选的是，Q¹不存在或者是wherein each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group. Preferably, Q¹ is absent or is

诸如-CH₂-基团，特别当Q²存在时。 Such as a -CH₂ - group, especially when Q² is present.

结合至环A的Q¹基团优选地是The^Q1 group bonded to ring A is preferably

诸如-CH₂-基团。 Such as a -CH₂ - group.

在某些实施方案中，本发明提供了如上面所定义的化合物，其中所述基团L包含具有以下结构的基团：In certain embodiments, the present invention provides a compound as defined above, wherein the group L comprises a group having the following structure:

其中Q¹不存在或者是如上面所定义的基团，Q³不存在或者是如上面所定义的基团，且n、m、p、q、r、s、X¹、X²、X³、X⁵、X⁶、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵以及环A、B和C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein^Q1 is absent or is a group as defined above,^Q3 is absent or is a group as defined above, and n, m, p, q, r, s,^X1 ,^X2 ,^X3 ,^X5 ,^X6 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 and rings A, B and C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含具有以下结构的基团：In certain embodiments, the group L comprises a group having the following structure:

其中n、m、p、q、r、s、X¹、X²、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、Q¹、Q³以及环A、B和C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein n, m, p, q, r, s,^X1 ,^X2 ,^X3 ,^X5 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 ,^Q1 ,^Q3 and rings A, B and C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含具有以下结构的基团：In certain embodiments, the group L comprises a group having the following structure:

其中n、m、p、q、r、s、X¹、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、Q¹、Q³以及环A、B和C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein n, m, p, q, r, s,^X1 ,^X3 ,^X5 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 ,^Q1 ,^Q3 and rings A, B and C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含具有以下结构的基团：In certain embodiments, the group L comprises a group having the following structure:

其中n、m、p、q、r、s、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、以及环A、B和C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein n, m, p, q, r, s,^X3 ,^X5 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 , and rings A, B and C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含具有以下结构的基团：In certain embodiments, the group L comprises a group having the following structure:

其中n、m、p、q、r、s、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵和环C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein n, m, p, q, r, s,^X3 ,^X5 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 and Ring C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含具有以下结构的基团：In certain embodiments, the group L comprises a group having the following structure:

其中n、m、p、q、r、s、X¹、X²、X³、X⁵、X⁶、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵和环C如上面所定义。优选的是，X⁵是N且无R⁴²取代基。wherein n, m, p, q, r, s,^X1 ,^X2 ,^X3 ,^X5 ,^X6 ,^R41 ,^R42 ,^R43 ,^R44 ,^R5 and Ring C are as defined above. Preferably,^X5 is N and there is no^R42 substituent.

在某些实施方案中，所述基团L包含选自以下结构的基团：In certain embodiments, the group L comprises a group selected from the following structures:

其中n、m、p、q、X³、R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁵如上面所定义。wherein n, m, p, q, X³ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁵ are as defined above.

在L基团的这些结构中，优选的是，m选自1或2，n选自2或3，p选自1、2或3(更优选2或3)，且q选自1或2。In these structures of the L group, preferably, m is selected from 1 or 2, n is selected from 2 or 3, p is selected from 1, 2 or 3 (more preferably 2 or 3), and q is selected from 1 or 2.

在某些实施方案中，基团L包含具有任何以下结构的基团：In certain embodiments, the group L comprises a group having any of the following structures:

其中，R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁵如上面所定义。wherein R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁵ are as defined above.

通常，R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁴⁵各自独立地选自H和选自下述基团的基团：Typically, R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁴⁵ are each independently selected from H and a group selected from the following groups:

-氘；-deuterium;

-卤素(诸如-F、-Cl、-Br和-I)；- halogen (such as -F, -Cl, -Br and -I);

-腈基团；- nitrile group;

-被取代的或未被取代的直链或支链C₁-C₆烷基基团(诸如Me、Et、Pr、i-Pr、n-Bu、i-Bu、t-Bu、戊基和己基)；- substituted or unsubstituted straight or branched C₁ -C₆ alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl);

-被取代的或未被取代的直链或支链C₁-C₆烷基-芳基基团(诸如-CH₂Ph、-CH₂(2、3或4)F-Ph、-CH₂(2、3或4)Cl-Ph、-CH₂(2、3或4)Br-Ph、-CH₂(2、3或4)I-Ph、-CH₂CH₂Ph、-CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂CH₂Ph和-CH₂CH₂CH₂CH₂CH₂CH₂Ph)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ alkyl-aryl groups (such as -CH₂ Ph, -CH₂ (2, 3, or 4)F-Ph, -CH₂ (2, 3, or 4)Cl-Ph, -CH₂ (2, 3, or 4)Br-Ph, -CH₂ (2, 3, or 4)I-Ph, -CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH 2 CH₂ CH₂ CH 2 Ph, -CH₂ CH₂ CH₂ CH₂ Ph, and -CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ Ph);

-被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(诸如-CH₂F、-CH₂Cl、-CH₂Br、-CH₂I、-CF₃、-CCl₃-CBr₃、-CI₃、-CH₂CF₃、-CH₂CCl₃、-CH₂CBr₃和-CH₂CI₃)；- substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl groups (such as -CH₂ F, -CH₂ Cl, -CH₂ Br, -CH₂ I, -CF₃ , -CCl₃ -CBr₃ , -CI₃ , -CH₂ CF₃ , -CH₂ CCl₃ , -CH₂ CBr₃ and -CH₂ CI₃ );

--NH₂或被取代的或未被取代的直链或支链伯、仲或叔C₁-C₆胺基团(诸如-NMeH、-NMe₂、-NEtH、-NEtMe、-NEt₂、-NPrH、-NPrMe、-NPrEt、-NPr₂、-NBuH、-NBuMe、-NBuEt、-CH₂-NH₂、-CH₂-NMeH、-CH₂-NMe₂、-CH₂-NEtH、-CH₂-NEtMe、-CH₂-NEt₂、-CH₂-NPrH、-CH₂-NPrMe和-CH₂-NPrEt)；_-NH2 or a substituted or unsubstituted linear or branched primary, secondary or tertiary_C1 -_C6 amine group (such as -NMeH,_-NMe2 , -NEtH, -NEtMe,_-NEt2 , -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt,_-CH2-NH2 , -CH2_-NMeH ,_-CH2 -NMe2, -CH2_- NEtH,_-CH2- NEtMe,_-CH2 -_NEt2 ,_-CH2- NPrH, -CH2_- NPrMe and_-CH2- NPrEt);

-被取代的或未被取代的氨基-芳基基团(诸如-NH-Ph、-NH-(2、3或4)F-Ph、-NH-(2、3或4)Cl-Ph、-NH-(2、3或4)Br-Ph、-NH-(2、3或4)I-Ph、-NH-(2、3或4)Me-Ph、-NH-(2、3或4)Et-Ph、-NH-(2、3或4)Pr-Ph、-NH-(2、3或4)Bu-Ph、NH-(2、3或4)OMe-Ph、-NH-(2、3或4)OEt-Ph、-NH-(2、3或4)OPr-Ph、-NH-(2、3或4)OBu-Ph、-NH-2,(3、4、5或6)F₂-Ph、-NH-2,(3、4、5或6)Cl₂-Ph、-NH-2,(3、4、5或6)Br₂-Ph、-NH-2,(3、4、5或6)I₂-Ph、-NH-2,(3、4、5或6)Me₂-Ph、-NH-2,(3、4、5或6)Et₂-Ph、-NH-2,(3、4、5或6)Pr₂-Ph、-NH-2,(3、4、5或6)Bu₂-Ph，-substituted or unsubstituted amino-aryl groups (such as -NH-Ph, -NH-(2, 3, or 4)F-Ph, -NH-(2, 3, or 4)Cl-Ph, -NH-(2, 3, or 4)Br-Ph, -NH-(2, 3, or 4)I-Ph, -NH-(2, 3, or 4)Me-Ph, -NH-(2, 3, or 4)Et-Ph, -NH-(2, 3, or 4)Pr-Ph, -NH-(2, 3, or 4)Bu-Ph, NH-(2, 3, or 4)OMe-Ph, -NH-(2, 3, or 4)OEt-Ph, -NH-(2, 3, or 4)OPr-Ph, -NH-(2, 3, or 4)OBu-Ph, -NH-2,(3, 4, 5, or 6)_F2 -Ph, -NH-2,(3, 4, 5, or₆ )Cl2 -Ph, -NH-2, (3, 4, 5 or 6)_Br2 -Ph, -NH-2, (3, 4, 5 or 6)_I2 -Ph, -NH-2, (3, 4, 5 or 6)_Me2- Ph, -NH-2, (3, 4, 5 or 6)_Et2 -Ph, -NH-2, (3, 4, 5 or 6)_Pr2 -Ph, -NH-2, (3, 4, 5 or 6)_Bu2 -Ph,

-被取代的或未被取代的环状的胺或酰氨基基团(诸如吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、吗啉-2-基、吗啉-3-基、吗啉-4-基、2-酮-吡咯烷基、3-酮-吡咯烷基、2-酮-哌啶基、3-酮-哌啶基和4-酮-哌啶基)；- substituted or unsubstituted cyclic amine or amido groups (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);

-被取代的或未被取代的环状C₃-C₈烷基基团(诸如环丙基、环丁基、环戊基、环己基、环庚基和环辛基)；- substituted or unsubstituted cyclic C₃ -C₈ alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl);

--OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团(诸如-CH₂OH、-CH₂CH₂OH、-CH(CH₃)CH₂OH、-C(CH₃)₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂CH₂OH、-CH(CH₃)CH₂CH₂OH、-CH(CH₃)CH(CH₃)OH、-CH(CH₂CH₃)CH₂OH、-C(CH₃)₂CH₂OH、-CH₂CH₂CH₂CH₂CH₂OH和-CH₂CH₂CH₂CH₂CH₂CH₂OH)；- an OH group or_a substituted or unsubstituted linear or branched_C1 -_C6 alcohol group (such as_-CH2OH , -CH2CH2OH,_-CH (_CH3 )_CH2OH , -C(CH3)2OH, -CH2CH2CH2OH_, -CH2CH2CH2CH2OH,_{-CH(CH3)CH2CH2OH} , -CH_{(CH3)CH(CH3)OH,-CH(CH2CH3} )_{CH2OH,-C(CH3)2CH2OH,-CH2CH2CH2CH2CH2OH,and-CH2CH2CH2CH2CH2CH2OH} )_;

-被取代的或未被取代的直链或支链C₁-C₆羧酸基团(诸如-COOH、-CH₂COOH、-CH₂CH₂COOH、-CH₂CH₂CH₂COOH、-CH₂CH₂CH₂CH₂COOH和-CH₂CH₂CH₂CH₂CH₂COOH)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ carboxylic acid groups (such as -COOH, -CH₂ COOH, -CH₂ CH₂ COOH, -CH₂ CH₂ CH₂ COOH, -CH₂ CH₂ CH₂ CH₂ COOH, and -CH₂ CH₂ CH₂ CH₂ CH₂ COOH);

-被取代的或未被取代的直链或支链羰基基团(诸如-(CO)Me、-(CO)Et、-(CO)Pr、-(CO)iPr、-(CO)nBu、-(CO)iBu、-(CO)tBu、-(CO)Ph、-(CO)CH₂Ph、-(CO)CH₂OH、-(CO)CH₂OCH₃、-(CO)CH₂NH₂、-(CO)CH₂NHMe、-(CO)CH₂NMe₂、-(CO)-环丙基、-(CO)-1,3-环氧丙烷-2-基；-(CO)NH₂、-(CO)NHMe、-(CO)NMe₂、-(CO)NHEt、-(CO)NEt₂、-(CO)-吡咯烷-N-基、-(CO)-吗啉-N-基、-(CO)-哌嗪-N-基、-(CO)-N-甲基-哌嗪-N-基、-(CO)NHCH₂CH₂OH、-(CO)NHCH₂CH₂OMe、-(CO)NHCH₂CH₂NH₂、-(CO)NHCH₂CH₂NHMe和-(CO)NHCH₂CH₂NMe₂；- substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)_nBu , -(CO)iBu, -(CO)tBu, -(CO)Ph_, -(CO)_CH2Ph , -(CO)_CH2OH , -(CO)_CH2OCH3 , -(CO)_CH2NH2 , -(CO)_CH2NHMe ,_- (CO)_CH2NMe2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)_NH2 , -(CO)_NHMe , -(CO)NMe2, -(CO)NHEt, -(CO)_NEt2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH₂ CH₂ OH, -(CO)NHCH₂ CH₂ OMe, -(CO)NHCH₂ CH₂ NH₂ , -(CO)NHCH₂ CH₂ NHMe, and -(CO)NHCH₂ CH₂ NMe₂ ;

-被取代的或未被取代的直链或支链C₁-C₆羧酸酯基团(诸如-COOMe、-COOEt、-COOPr、-COO-i-Pr、-COO-n-Bu、-COO-i-Bu、-COO-t-Bu、-CH₂COOMe、-CH₂CH₂COOMe、-CH₂CH₂CH₂COOMe和-CH₂CH₂CH₂CH₂COOMe)；- substituted or unsubstituted linear or branched C₁ -C₆ carboxylate groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH₂ COOMe, -CH₂ CH₂ COOMe_, -CH₂ CH₂ CH₂ COOMe, and -CH₂ CH 2 CH₂ CH₂ COOMe);

-被取代的或未被取代的直链或支链C₁-C₆酰胺基团(诸如-CO-NH₂、-CO-NMeH、-CO-NMe₂、-CO-NEtH、-CO-NEtMe、-CO-NEt₂、-CO-NPrH、-CO-NPrMe和-CO-NPrEt)；- substituted or unsubstituted straight or branched C₁ -C₆ amide groups (such as -CO-NH₂ , -CO-NMeH, -CO-NMe₂ , -CO-NEtH, -CO-NEtMe, -CO-NEt₂ , -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

-被取代的或未被取代的直链或支链C₁-C₇氨基羰基基团(诸如-NH-CO-Me、-NH-CO-Et、-NH-CO-Pr、-NH-CO-Bu、-NH-CO-戊基、-NH-CO-己基、-NH-CO-Ph、-NMe-CO-Me、-NMe-CO-Et、-NMe-CO-Pr、-NMe-CO-Bu、-NMe-CO-戊基、-NMe-CO-己基、-NMe-CO-Ph；- substituted or unsubstituted straight-chain or branched C₁ -C₇ aminocarbonyl groups (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph;

-被取代的或未被取代的直链或支链C₁-C₇烷氧基或芳氧基基团(诸如-OMe、-OEt、-OPr、-O-i-Pr、-O-n-Bu、-O-i-Bu、-O-t-Bu、-O-戊基、-O-己基、-OCH₂F、-OCHF₂、-OCF₃、-OCH₂Cl、-OCHCl₂、-OCCl₃、-O-Ph、-O-CH₂-Ph、-O-CH₂-(2、3或4)-F-Ph、-O-CH₂-(2、3或4)-Cl-Ph、-CH₂OMe、-CH₂OEt、-CH₂OPr、-CH₂OBu、-CH₂CH₂OMe、-CH₂CH₂CH₂OMe、-CH₂CH₂CH₂CH₂OMe和-CH₂CH₂CH₂CH₂CH₂OMe)；- substituted or unsubstituted straight or branched C₁ -C₇ alkoxy or aryloxy groups (such as -OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH₂ F, -OCHF₂ , -OCF₃ , -OCH₂ Cl, -OCHCl₂ , -OCCl₃ , -O-Ph, -O-CH₂ -Ph, -O-CH₂ -(2, 3 or 4)-F-Ph, -O-CH₂ -(2, 3 or 4)-Cl-Ph, -CH₂ OMe, -CH₂ OEt, -CH₂ OPr, -CH₂ OBu, -CH₂ CH₂ OMe, -CH₂ CH₂ CH₂ OMe, -CH₂ CH_2CH2 OMe and -CH₂ CH₂ CH₂ CH₂ CH₂ OMe);

-被取代的或未被取代的直链或支链氨基烷氧基基团(诸如-OCH₂NH₂、-OCH₂NHMe、-OCH₂NMe₂、-OCH₂NHEt、-OCH₂NEt₂、-OCH₂CH₂NH₂、-OCH₂CH₂NHMe、-OCH₂CH₂NMe₂、-OCH₂CH₂NHEt和-OCH₂CH₂NEt₂；- substituted or unsubstituted straight-_chain or branched aminoalkoxy groups₍ such_as-OCH2NH2 ,_{-OCH2NHMe,-OCH2NMe2,-OCH2NHHEt,-OCH2NEt2,-OCH2CH2NH2,-OCH2CH2NHMe} ,_{-OCH2CH2NMe2,-OCH2CH2NHHEtand-OCH2CH2NEt2;}

-被取代的或未被取代的磺酰基基团(诸如-SO₂Me、-SO₂Et、-SO₂Pr、-SO₂iPr、-SO₂Ph、-SO₂-(2、3或4)-F-Ph、-SO₂-环丙基、-SO₂CH₂CH₂OCH₃)、-SO₂NH₂、-SO₂NHMe、-SO₂NMe₂、-SO₂NHEt、-SO₂NEt₂、-SO2-吡咯烷-N-基、-SO₂-吗啉-N-基、-SO₂NHCH₂OMe和-SO₂NHCH₂CH₂OMe；- substituted or unsubstituted sulfonyl groups (such as_-SO2Me ,_{-SO2Et, -SO2Pr} ,_-SO2iPr ,_-SO2Ph ,_-SO2- (2,₃ or₄ )-F-Ph,_-SO2- cyclopropyl,_{-SO2CH2CH2OCH3} ), -SO2NH2, -SO2NHMe,_-SO2NMe2, -SO2NHEt,_{-SO2NEt2,-SO2-} pyrrolidin-N-_yl ,_-SO2- morpholin-_N-yl ,_-SO2NHCH2OMe and_{-SO2NHCH2CH2OMe;}

-被取代的或未被取代的氨基磺酰基基团(诸如-NHSO₂Me、-NHSO₂Et、-NHSO₂Pr、-NHSO₂iPr、-NHSO₂Ph、-NHSO₂-(2、3或4)-F-Ph、-NHSO₂-环丙基、-NHSO₂CH₂CH₂OCH₃)；- substituted or unsubstituted aminosulfonyl groups (such as_-NHSO2Me , -NHSO2Et,_-NHSO2Pr ,_-NHSO2iPr ,_-NHSO2Ph ,_-NHSO2- (₂ , 3 or 4)-F-Ph,_{-NHSO2-cyclopropyl,-NHSO2CH2CH2OCH3} );

-被取代的或未被取代的芳族基团(诸如Ph-、2-F-Ph-、3-F-Ph-、4-F-Ph-、2-Cl-Ph-、3-Cl-Ph-、4-Cl-Ph-、2-Br-Ph-、3-Br-Ph-、4-Br-Ph-、2-I-Ph-、3-I-Ph、4-I-Ph-、2,(3、4、5或6)-F₂-Ph-、2,(3、4、5或6)-Cl₂-Ph-、2,(3、4、5或6)-Br₂-Ph-、2,(3、4、5或6)-I₂-Ph-、2,(3、4、5或6)-Me₂-Ph-、2,(3、4、5或6)-Et₂-Ph-、2,(3、4、5或6)-Pr₂-Ph-、2,(3、4、5或6)-Bu₂-Ph-、2,(3、4、5或6)-(CN)₂-Ph-、2,(3、4、5或6)-(NO₂)₂-Ph-、2,(3、4、5或6)-(NH₂)₂-Ph-、2,(3、4、5或6)-(MeO)₂-Ph-、2,(3、4、5或6)-(CF₃)₂-Ph-、3,(4或5)-F₂-Ph-、3,(4或5)-Cl₂-Ph-、3,(4或5)-Br₂-Ph-、3,(4或5)-I₂-Ph-、3,(4或5)-Me₂-Ph-、3,(4或5)-Et₂-Ph-、3,(4或5)-Pr₂-Ph-、3,(4或5)-Bu₂-Ph-、3,(4或5)-(CN)₂-Ph-、3,(4或5)-(NO₂)₂-Ph-、3,(4或5)-(NH₂)₂-Ph-、3,(4或5)-(MeO)₂-Ph-、3,(4或5)-(CF₃)₂-Ph-、2-Me-Ph-、3-Me-Ph-、4-Me-Ph-、2-Et-Ph-、3-Et-Ph-、4-Et-Ph-、2-Pr-Ph-、3-Pr-Ph-、4-Pr-Ph-、2-Bu-Ph-、3-Bu-Ph-、4-Bu-Ph-、2-(CN)-Ph-、3-(CN)-Ph-、4-(CN)-Ph-、2-(NO₂)-Ph-、3-(NO₂)-Ph-、4-(NO₂)-Ph-、2-(NH₂)-Ph-、3-(NH₂)-Ph-、4-(NH₂)-Ph-、2-MeO-Ph-、3-MeO-Ph-、4-MeO-Ph-、2-(NH₂-CO)-Ph-、3-(NH₂-CO)-Ph-、4-(NH₂-CO)-Ph-、2-CF₃-Ph-、3-CF₃-Ph-、4-CF₃-Ph-、2-CF₃O-Ph-、3-CF₃O-Ph-、和4-CF₃O-Ph-)；-substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3, 4, 5, or 6)-F₂ -Ph-, 2,(3, 4, 5, or 6)-Cl₂ -Ph-, 2,(3, 4, 5, or 6)-Br₂ -Ph-, 2,(3, 4, 5, or 6)-I₂ -Ph-, 2,(3, 4, 5, or 6)-Me₂ -Ph-, 2,(3, 4, 5, or 6)-Et₂ -Ph-, 2,(3,4,5 or 6)-Pr₂ -Ph-, 2,(3,4,5 or 6)-Bu₂ -Ph-, 2,(3,4,5 or 6)-(CN)₂ -Ph-, 2,(3,4,5 or 6)-(NO₂ )₂ -Ph-, 2,(3,4,5 or 6)-(NH₂ )₂ -Ph-, 2,(3,4,5 or 6)-(MeO)₂ -Ph-, 2,(3,4,5 or 6)-(CF₃ )₂ -Ph-, 3,(4 or 5)-F₂ -Ph-, 3,(4 or 5)-Cl₂ -Ph-, 3,(4 or 5)-Br₂ -Ph-, 3,(4 or 5)-I₂ -Ph-, 3,(4 or 5)-Me₂ -Ph-, 3,(4 or 5)-Et₂ -Ph-, 3,(4 or 5)-Pr₂ -Ph-, 3,(4 or 5)-Bu₂ -Ph-, 3,(4 or 5)-(CN)₂ -Ph-, 3,(4 or 5)-(NO₂ )₂ -Ph-, 3,(4 or 5)-(NH₂ )₂ -Ph-, 3,(4 or 5)-(MeO)₂ -Ph-, 3,(4 or 5)-(CF₃ )₂ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO₂ )-Ph-, 3-(NO₂ )-Ph-, 4-(NO₂ )-Ph-, 2-(NH₂ )-Ph-, 3-(NH₂ )-Ph-, 4-(NH₂ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH₂ -CO)-Ph-, 3-(NH₂ -CO)-Ph-, 4-(NH₂ -CO)-Ph-, 2-CF₃ -Ph-, 3-CF₃ -Ph-, 4-CF₃ -Ph-, 2-CF₃ O-Ph-, 3-CF₃ O-Ph-, and 4-CF₃ O-Ph-);

-饱和的或不饱和的被取代的或未被取代的杂环基团，包括芳族杂环基团和/或非芳族杂环基团(诸如吡咯-1-基、吡咯-2-基、吡咯-3-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、咪唑-1-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、1,2,3-三唑-1-基、1,2,3-三唑-4-基、1,2,3-三唑-5-基、1,2,4-三唑-1-基、1,2,4-三唑-3-基、1,2,4-三唑-5-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、嘧啶-6-基、吡嗪-2-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2-氮杂哌啶-1-基、2-氮杂哌啶-3-基、2-氮杂哌啶-4-基、3-氮杂哌啶-1-基、3-氮杂哌啶-2-基、3-氮杂哌啶-4-基、3-氮杂哌啶-5-基、哌嗪-1-基、哌嗪-2-基、呋喃-2-基、呋喃-3-基、吡喃-2-基、吡喃-3-基、吡喃-4-基、2-氮杂吡喃-2-基、2-氮杂吡喃-3-基、2-氮杂吡喃-4-基、2-氮杂吡喃-5-基、2-氮杂吡喃-6-基、3-氮杂吡喃-2-基、3-氮杂吡喃-4-基、3-氮杂吡喃-5-基、3-氮杂吡喃-6-基、4-氮杂吡喃-2-基、4-氮杂吡喃-3-基、4-氮杂吡喃-4-基、4-氮杂吡喃-5-基、4-氮杂吡喃-6-基、氧杂环丁烷-2-基、氧杂环丁烷-3-基、四氢呋喃-2-基、四氢呋喃-3-基、2-氮杂-四氢呋喃-2-基、2-氮杂-四氢呋喃-3-基、2-氮杂-四氢呋喃-4-基、2-氮杂-四氢呋喃-5-基、3-氮杂-四氢呋喃-2-基、3-氮杂-四氢呋喃-3-基、3-氮杂-四氢呋喃-4-基、3-氮杂-四氢呋喃-5-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、2-氮杂-四氢吡喃-2-基、2-氮杂-四氢吡喃-3-基、2-氮杂-四氢吡喃-4-基、2-氮杂-四氢吡喃-5-基、2-氮杂-四氢吡喃-6-基、3-氮杂-四氢吡喃-2-基、3-氮杂-四氢吡喃-3-基、3-氮杂-四氢吡喃-4-基、3-氮杂-四氢吡喃-5-基、3-氮杂-四氢吡喃-6-基、吗啉-2-基、吗啉-3-基、吗啉-4-基、噻吩-2-基、噻吩-3-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、噻喃-2-基、噻喃-3-基、噻喃-4-基、2-氮杂噻喃-2-基、2-氮杂噻喃-3-基、2-氮杂噻喃-4-基、2-氮杂噻喃-5-基、2-氮杂噻喃-6-基、3-氮杂噻喃-2-基、3-氮杂噻喃-4-基、3-氮杂噻喃-5-基、3-氮杂噻喃-6-基、4-氮杂噻喃-2-基、4-氮杂噻喃-3-基、4-氮杂噻喃-4-基、4-氮杂噻喃-5-基、4-氮杂噻喃-6-基、硫杂环戊烷-2-基、硫杂环戊烷-3-基、硫杂环己烷-2-基、硫杂环己烷-3-基、硫杂环己烷-4-基、噁唑-2-基、噁唑-4-基、噁唑-5-基、异噁唑-3-基、异噁唑-4-基、异噁唑-5-基、呋咱-3-基、(1,3,4-噁二唑)-2-基、(1,3,4-噁二唑)-5-基、(1,2,4-噁二唑)-3-基、(1,2,4-噁二唑)-5-基；和四唑-1-基、四唑-2-基、四唑-5-基)；- saturated or unsaturated substituted or unsubstituted heterocyclic groups, including aromatic heterocyclic groups and/or non-aromatic heterocyclic groups (such as pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol- 1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin- 3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-1-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran- 2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azepan-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl , 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3- aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2- Azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, yl, thiin-2-yl, thiin-3-yl, thiin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl);

-在两个R基团连接至同一个原子的情况下，它们可以一起形成与该原子双键键合的基团(诸如羰基基团(＝O)或烯烃基团(＝C(R’)₂)，其中每个R’基团相同或不同，并且是H或有机基团，优选H或直链或支链C₁-C₆烷基基团)。- In case two R groups are attached to the same atom, they may together form a group doubly bonded to that atom (such as a carbonyl group (═O) or an olefin group (═C(R′)₂ ), wherein each R′ group is identical or different and is H or an organic group, preferably H or a linear or branched C₁ -C₆ alkyl group).

在某些排列中，连接至不同原子的一对R⁴¹基团可以与环A原子一起形成环，和/或连接至不同原子的一对R⁴²基团可以与环B原子一起形成环，任选地其中一对R⁴¹基团和/或一对R⁴²基团中的每一个独立地包含(X⁷)_1或2，其中每个X⁷可以相同或不同并且独立地选自C、N、O和S；并且其中每个X⁷独立地是未被取代的或(i)当X⁷是C时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团、卤素(诸如F)或羟基的有机基团取代；且(ii)当X⁷是N时，独立地被H或选自C₁-C₆烷基基团或C₁-C₆酰胺基团的有机基团取代。In certain arrangements, a pair of R⁴¹ groups attached to different atoms may form a ring together with the ring A atom, and/or a pair of R⁴² groups attached to different atoms may form a ring together with the ring B atom, optionally wherein each of a pair of R⁴¹ groups and/or a pair of R⁴² groups independently comprises (X⁷ )_{1 or 2} , wherein each X⁷ may be the same or different and is independently selected from C, N, O and S; and wherein each X⁷ is independently unsubstituted or (i) when X⁷ is C, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group, a halogen (such as F) or a hydroxyl group; and (ii) when X⁷ is N, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group or a C₁ -C₆ amide group.

在某些排列中，基团R⁵和R⁴⁴可以与它们所连接的环C的原子X⁶和X³一起形成环，任选地其中R⁵和R⁴⁴基团一起包含(X⁸)_3、4或5，其中每个X⁸可以相同或不同并且独立地选自C、N、O和S；且其中每个X⁸独立地是未被取代的或(i)当X⁸是C时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团、卤素(诸如F)或羟基的有机基团取代；且(ii)当X⁸是N时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团或C₁-C₆酰胺基团的有机基团取代。In certain arrangements, the groups R⁵ and R⁴⁴ can form a ring together with the atoms X⁶ and X³ of the ring C to which they are attached, optionally wherein the R⁵ and R⁴⁴ groups together comprise (X⁸ )_{3, 4 or 5} , wherein each X⁸ can be the same or different and is independently selected from C, N, O and S; and wherein each X⁸ is independently unsubstituted or (i) when X⁸ is C, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group, a halogen (such as F) or a hydroxyl group; and (ii) when X⁸ is N, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group or a C₁ -C₆ amide group.

优选的是，R⁴¹、R⁴²、R⁴³和R⁴⁴各自独立地选自H、氘、卤素(诸如-F、-Cl、-Br和-I，优选F或Cl)、腈基团、被取代的或未被取代的C₁-C₆烷基基团、被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(优选CF₃或CHF₂)、环丙基基团、-OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团、被取代的或未被取代的直链或支链C₁-C₇氨基羰基基团(诸如-NH-CO-Me)、-NH₂基团或被取代的或未被取代的C₁-C₆氨基基团和被取代的或未被取代的C₁-C₆烷氧基基团；其中，当连接至不同原子的一对R⁴¹基团与环A原子一起形成环和/或连接至不同原子的一对R⁴²基团与环B原子一起形成环时，所述一对R⁴¹基团和/或一对R⁴²基团中的每一个独立地包含-CH₂-或-CH₂CH₂-；且其中，当基团R⁵和R⁴⁴与环C的原子一起形成环时，R⁵和R⁴⁴一起包含-CH＝CH-CH＝CH-或-NH-CO-NH-。Preferably, R⁴¹ , R⁴² , R⁴³ and R⁴⁴ are each independently selected from H, deuterium, halogen (such as -F, -Cl, -Br and -I, preferably F or Cl), a nitrile group, a substituted or unsubstituted C₁ -C₆ alkyl group, a substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl group (preferably CF₃ or CHF₂ ), a cyclopropyl group, an -OH group or a substituted or unsubstituted straight or branched C₁ -C₆ alcohol group, a substituted or unsubstituted straight or branched C₁ -C₇ aminocarbonyl group (such as -NH-CO-Me), a -NH₂ group or a substituted or unsubstituted C₁ -C₆ amino group and a substituted or unsubstituted C₁ -C₆ alkoxy group; wherein, when a pair of R 41 , R 42 , R 43 and R 44 are attached to different atoms, the two groups are preferably selected from: When a pair of R⁴¹ groups are taken together with the ring A atoms to form a ring and/or a pair of R⁴² groups attached to different atoms are taken together with the ring B atoms to form a ring, each of the pair of R⁴¹ groups and/or the pair of R⁴² groups independently comprises -CH₂ - or -CH₂ CH₂ -; and wherein, when groups R⁵ and R⁴⁴ are taken together with the atoms of the ring C to form a ring, R⁵ and R⁴⁴ together comprise -CH=CH-CH=CH- or -NH-CO-NH-.

优选的是，R⁴⁵选自H、卤素(诸如-F、-Cl、-Br和-I，优选-F)、被取代的或未被取代的C₁-C₆烷基基团、被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(优选CF₃)、-NH₂基团或被取代的或未被取代的C₁-C₆氨基基团、-OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团和被取代的或未被取代的C₁-C₆烷氧基基团。Preferably, R⁴⁵ is selected from H, halogen (such as -F, -Cl, -Br and -I, preferably -F), a substituted or unsubstituted C₁ -C₆ alkyl group, a substituted or unsubstituted linear or branched C₁ -C₆ haloalkyl group (preferably CF₃ ), a -NH₂ group or a substituted or unsubstituted C₁ -C₆ amino group, a -OH group or a substituted or unsubstituted linear or branched C₁ -C₆ alcohol group and a substituted or unsubstituted C₁ -C₆ alkoxy group.

通常，R⁴⁶选自H和选自下述基团的基团：Typically, R⁴⁶ is selected from H and a group selected from the following groups:

-被取代的或未被取代的直链或支链C₁-C₆烷基基团(诸如Me、Et、Pr、i-Pr、n-Bu、i-Bu、t-Bu、戊基和己基)；- substituted or unsubstituted straight or branched C₁ -C₆ alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl);

-被取代的或未被取代的直链或支链C₁-C₆烷基-芳基基团(诸如-CH₂Ph、-CH₂(2、3或4)F-Ph、-CH₂(2、3或4)Cl-Ph、-CH₂(2、3或4)Br-Ph、-CH₂(2、3或4)I-Ph、-CH₂CH₂Ph、-CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂CH₂Ph和-CH₂CH₂CH₂CH₂CH₂CH₂Ph)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ alkyl-aryl groups (such as -CH₂ Ph, -CH₂ (2, 3, or 4)F-Ph, -CH₂ (2, 3, or 4)Cl-Ph, -CH₂ (2, 3, or 4)Br-Ph, -CH₂ (2, 3, or 4)I-Ph, -CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH 2 CH₂ CH₂ CH 2 Ph, -CH₂ CH₂ CH₂ CH₂ Ph, and -CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ Ph);

-被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(诸如-CH₂F和-CH₂CF₃)；- substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl groups (such as -CH₂ F and -CH₂ CF₃ );

-被取代的或未被取代的环状的胺或酰氨基基团(诸如吡咯烷-3-基、哌啶-3-基、哌啶-4-基、2-酮-吡咯烷基、3-酮-吡咯烷基、2-酮-哌啶基、3-酮-哌啶基和4-酮-哌啶基)；- substituted or unsubstituted cyclic amine or amido groups (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);

-被取代的或未被取代的环状C₃-C₈烷基基团(诸如环丙基、环丁基、环戊基、环己基、环庚基和环辛基)；- substituted or unsubstituted cyclic C₃ -C₈ alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl);

-被取代的或未被取代的直链或支链C₂-C₆醇基团(诸如-CH₂CH₂OH、-CH(CH₃)CH₂OH、-C(CH₃)₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂CH₂OH、-CH(CH₃)CH₂CH₂OH、-CH(CH₃)CH(CH₃)OH、-CH(CH₂CH₃)CH₂OH、-C(CH₃)₂CH₂OH、-CH₂CH₂CH₂CH₂CH₂OH和-CH₂CH₂CH₂CH₂CH₂CH₂OH)；-_a substituted or unsubstituted linear or branched_C2 -_C6 alcohol group (such_as-CH2CH2OH , -CH(_CH3)CH2OH , -C(_CH3)2OH, -CH2CH2CH2OH_, -CH2CH2CH2CH2OH_, -CH(_CH3 )_CH2CH2OH , -CH(_CH3) CH_(CH3 )_{OH,-CH(CH2CH3)CH2OH,-C(CH3)2CH2OH,-CH2CH2CH2CH2CH2OH,and-CH2CH2CH2CH2CH2CH2CH2OH} );

-被取代的或未被取代的直链或支链C₂-C₆羧酸基团(诸如-CH₂COOH、-CH₂CH₂COOH、-CH₂CH₂CH₂COOH、-CH₂CH₂CH₂CH₂COOH和-CH₂CH₂CH₂CH₂CH₂COOH)；- substituted or unsubstituted linear or branched C₂ -C₆ carboxylic acid groups (such as -CH₂ COOH, -CH₂ CH₂ COOH, -CH₂ CH_2CH2 COOH, -CH₂ CH 2 CH₂ CH₂ COOH, and -CH₂ CH₂ CH₂ CH₂ CH₂ COOH);

-被取代的或未被取代的直链或支链羰基基团(诸如-(CO)Me、-(CO)Et、-(CO)Pr、-(CO)-i-Pr、-(CO)-n-Bu、-(CO)-i-Bu、-(CO)-t-Bu、-(CO)Ph、-(CO)CH₂Ph、-(CO)CH₂OH、-(CO)CH₂OCH₃、-(CO)CH₂NH₂、-(CO)CH₂NHMe、-(CO)CH₂NMe₂、-(CO)-环丙基、-(CO)-1,3-环氧丙烷-2-基；-(CO)NH₂、-(CO)NHMe、-(CO)NMe₂、-(CO)NHEt、-(CO)NEt₂、-(CO)-吡咯烷-N-基、-(CO)-吗啉-N-基、-(CO)-哌嗪-N-基、-(CO)-N-甲基-哌嗪-N-基、-(CO)NHCH₂CH₂OH、-(CO)NHCH₂CH₂OMe、-(CO)NHCH₂CH₂NH₂、-(CO)NHCH₂CH₂NHMe,和-(CO)NHCH₂CH₂NMe₂；- substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)_-t -Bu_, -(CO)_Ph , -(CO)_CH2Ph , -(CO)CH2OH, -(CO)_{CH2OCH3, -(CO)CH2NH2,} -(CO)_CH2NHMe , -(CO)_CH2NMe2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)_NH2, -(CO)NHMe, -(CO)_NMe2 , -(CO)NHEt, -(CO)_NEt2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH₂ CH₂ OH, -(CO)NHCH₂ CH₂ OMe, -(CO)NHCH₂ CH₂ NH₂ , -(CO)NHCH₂ CH₂ NHMe, and -(CO)NHCH₂ CH₂ NMe₂ ;

-被取代的或未被取代的直链或支链C₁-C₆羧酸酯基团(诸如-COOMe、-COOEt、-COOPr、-COO-i-Pr、-COO-n-Bu、-COO-i-Bu、-COO-t-Bu、-CH₂COOMe、-CH₂CH₂COOMe、-CH₂CH₂CH₂COOMe和-CH₂CH₂CH₂CH₂COOMe)；- substituted or unsubstituted linear or branched C₁ -C₆ carboxylate groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH₂ COOMe, -CH₂ CH₂ COOMe_, -CH₂ CH₂ CH₂ COOMe, and -CH₂ CH 2 CH₂ CH₂ COOMe);

-被取代的或未被取代的直链或支链C₁-C₆酰胺基团(诸如-CO-NH₂、-CO-NMeH、-CO-NMe₂、-CO-NEtH、-CO-NEtMe、-CO-NEt₂、-CO-NPrH、-CO-NPrMe和-CO-NPrEt)；- substituted or unsubstituted straight or branched C₁ -C₆ amide groups (such as -CO-NH₂ , -CO-NMeH, -CO-NMe₂ , -CO-NEtH, -CO-NEtMe, -CO-NEt₂ , -CO-NPrH, -CO-NPrMe and -CO-NPrEt);

-被取代的或未被取代的磺酰基基团(诸如-SO₂Me、-SO₂Et、-SO₂Pr、-SO₂iPr、-SO₂Ph、-SO₂-(2、3或4)-F-Ph、-SO₂-环丙基、-SO₂CH₂CH₂OCH₃)、-SO₂NH₂、-SO₂NHMe、-SO₂NMe₂、-SO₂NHEt、-SO₂NEt₂、-SO₂-吡咯烷-N-基、-SO₂-吗啉-N-基、-SO₂NHCH₂OMe和-SO₂NHCH₂CH₂OMe；- substituted or unsubstituted sulfonyl groups (such as_-SO2Me ,_{-SO2Et, -SO2Pr} ,_-SO2iPr ,_-SO2Ph ,_-SO2- (2,₃ or₄ )-F-Ph,_-SO2- cyclopropyl,_{-SO2CH2CH2OCH3} ), -SO2NH2, -SO2NHMe,_-SO2NMe2, -SO2NHEt,_{-SO2NEt2,-SO2-} pyrrolidin-N-_yl ,_-SO2- morpholin-_N-yl ,_-SO2NHCH2OMe and_{-SO2NHCH2CH2OMe);}

-被取代的或未被取代的芳族基团(诸如Ph-、2-F-Ph-、3-F-Ph-、4-F-Ph-、2-Cl-Ph-、3-Cl-Ph-、4-Cl-Ph-、2-Br-Ph-、3-Br-Ph-、4-Br-Ph-、2-I-Ph-、3-I-Ph、4-I-Ph-、2,(3、4、5或6)-F₂-Ph-、2,(3、4、5或6)-Cl₂-Ph-、2,(3、4、5或6)-Br₂-Ph-、2,(3、4、5或6)-I₂-Ph-、2,(3、4、5或6)-Me₂-Ph-、2,(3、4、5或6)-Et₂-Ph-、2,(3、4、5或6)-Pr₂-Ph-、2,(3、4、5或6)-Bu₂-Ph-、2,(3、4、5或6)-(CN)₂-Ph-、2,(3、4、5或6)-(NO₂)₂-Ph-、2,(3、4、5或6)-(NH₂)₂-Ph-、2,(3、4、5或6)-(MeO)₂-Ph-、2,(3、4、5或6)-(CF₃)₂-Ph-、3,(4或5)-F₂-Ph-、3,(4或5)-Cl₂-Ph-、3,(4或5)-Br₂-Ph-、3,(4或5)-I₂-Ph-、3,(4或5)-Me₂-Ph-、3,(4或5)-Et₂-Ph-、3,(4或5)-Pr₂-Ph-、3,(4或5)-Bu₂-Ph-、3,(4或5)-(CN)₂-Ph-、3,(4或5)-(NO₂)₂-Ph-、3,(4或5)-(NH₂)₂-Ph-、3,(4或5)-(MeO)₂-Ph-、3,(4或5)-(CF₃)₂-Ph-、2-Me-Ph-、3-Me-Ph-、4-Me-Ph-、2-Et-Ph-、3-Et-Ph-、4-Et-Ph-、2-Pr-Ph-、3-Pr-Ph-、4-Pr-Ph-、2-Bu-Ph-、3-Bu-Ph-、4-Bu-Ph-、2-(CN)-Ph-、3-(CN)-Ph-、4-(CN)-Ph-、2-(NO₂)-Ph-、3-(NO₂)-Ph-、4-(NO₂)-Ph-、2-(NH₂)-Ph-、3-(NH₂)-Ph-、4-(NH₂)-Ph-、2-MeO-Ph-、3-MeO-Ph-、4-MeO-Ph-、2-(NH₂-CO)-Ph-、3-(NH₂-CO)-Ph-、4-(NH₂-CO)-Ph-、2-CF₃-Ph-、3-CF₃-Ph-、4-CF₃-Ph-、2-CF₃O-Ph-、3-CF₃O-Ph-和4-CF₃O-Ph-)；和-substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3, 4, 5, or 6)-F₂ -Ph-, 2,(3, 4, 5, or 6)-Cl₂ -Ph-, 2,(3, 4, 5, or 6)-Br₂ -Ph-, 2,(3, 4, 5, or 6)-I₂ -Ph-, 2,(3, 4, 5, or 6)-Me₂ -Ph-, 2,(3, 4, 5, or 6)-Et₂ -Ph-, 2,(3,4,5 or 6)-Pr₂ -Ph-, 2,(3,4,5 or 6)-Bu₂ -Ph-, 2,(3,4,5 or 6)-(CN)₂ -Ph-, 2,(3,4,5 or 6)-(NO₂ )₂ -Ph-, 2,(3,4,5 or 6)-(NH₂ )₂ -Ph-, 2,(3,4,5 or 6)-(MeO)₂ -Ph-, 2,(3,4,5 or 6)-(CF₃ )₂ -Ph-, 3,(4 or 5)-F₂ -Ph-, 3,(4 or 5)-Cl₂ -Ph-, 3,(4 or 5)-Br₂ -Ph-, 3,(4 or 5)-I₂ -Ph-, 3,(4 or 5)-Me₂ -Ph-, 3,(4 or 5)-Et₂ -Ph-, 3,(4 or 5)-Pr₂ -Ph-, 3,(4 or 5)-Bu₂ -Ph-, 3,(4 or 5)-(CN)₂ -Ph-, 3,(4 or 5)-(NO₂ )₂ -Ph-, 3,(4 or 5)-(NH₂ )₂ -Ph-, 3,(4 or 5)-(MeO)₂ -Ph-, 3,(4 or 5)-(CF₃ )₂ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO₂ )-Ph-, 3-(NO₂ )-Ph-, 4-(NO₂ )-Ph-, 2-(NH₂ )-Ph-, 3-(NH₂ )-Ph-, 4-(NH₂ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH_{and​​​​​​​​}

-被取代的或未被取代的饱和的或不饱和的被取代的或未被取代的杂环基团，包括芳族杂环基团和/或非芳族杂环基团(诸如吡咯-2-基、吡咯-3-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、1,2,3-三唑-4-基、1,2,3-三唑-5-基、1,2,4-三唑-3-基、1,2,4-三唑-5-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、嘧啶-6-基、吡嗪-2-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2-氮杂哌啶-3-基、2-氮杂哌啶-4-基、3-氮杂哌啶-2-基、3-氮杂哌啶-4-基、3-氮杂哌啶-5-基、哌嗪-2-基、呋喃-2-基、呋喃-3-基、吡喃-2-基、吡喃-3-基、吡喃-4-基、2-氮杂吡喃-3-基、2-氮杂吡喃-4-基、2-氮杂吡喃-5-基、2-氮杂吡喃-6-基、3-氮杂吡喃-2-基、3-氮杂吡喃-4-基、3-氮杂吡喃-5-基、3-氮杂吡喃-6-基、4-氮杂吡喃-2-基、4-氮杂吡喃-3-基、4-氮杂吡喃-5-基、4-氮杂吡喃-6-基、氧杂环丁烷-3-基、四氢呋喃-2-基、四氢呋喃-3-基、2-氮杂-四氢呋喃-3-基、2-氮杂-四氢呋喃-4-基、2-氮杂-四氢呋喃-5-基、3-氮杂-四氢呋喃-2-基、3-氮杂-四氢呋喃-4-基、3-氮杂-四氢呋喃-5-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、2-氮杂-四氢吡喃-3-基、2-氮杂-四氢吡喃-4-基、2-氮杂-四氢吡喃-5-基、2-氮杂-四氢吡喃-6-基、3-氮杂-四氢吡喃-2-基、3-氮杂-四氢吡喃-4-基、3-氮杂-四氢吡喃-5-基、3-氮杂-四氢吡喃-6-基、吗啉-2-基、吗啉-3-基、噻吩-2-基、噻吩-3-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、噻喃-2-基、噻喃-3-基、噻喃-4-基、2-氮杂噻喃-3-基、2-氮杂噻喃-4-基、2-氮杂噻喃-5-基、2-氮杂噻喃-6-基、3-氮杂噻喃-2-基、3-氮杂噻喃-4-基、3-氮杂噻喃-5-基、3-氮杂噻喃-6-基、4-氮杂噻喃-2-基、4-氮杂噻喃-3-基、4-氮杂噻喃-5-基、4-氮杂噻喃-6-基、硫杂环戊烷-2-基、硫杂环戊烷-3-基、硫杂环己烷-2-基、硫杂环己烷-3-基、硫杂环己烷-4-基、噁唑-2-基、噁唑-4-基、噁唑-5-基、异噁唑-3-基、异噁唑-4-基、异噁唑-5-基、呋咱-3-基、(1,3,4-噁二唑)-2-基、(1,3,4-噁二唑)-5-基、(1,2,4-噁二唑)-3-基、(1,2,4-噁二唑)-5-基；和四唑-5-基)。- substituted or unsubstituted saturated or unsaturated substituted or unsubstituted heterocyclic groups, including aromatic heterocyclic groups and/or non-aromatic heterocyclic groups (such as pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4- triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-3-yl, 2-azapiperidin -4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, oxetane-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-6-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 2 ... -yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl -yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-5-yl, thiolan-6-yl, heterocyclohexan-3-yl, thioxan-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl).

优选的是，R⁴⁶选自H、被取代的或未被取代的C₁-C₆烷基基团或被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团。基团L的环A优选地包含以下结构中的任一种：Preferably, R⁴⁶ is selected from H, a substituted or unsubstituted C₁ -C₆ alkyl group or a substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl group. Ring A of group L preferably comprises any one of the following structures:

其中R⁴¹如本文中定义。wherein R⁴¹ is as defined herein.

更优选地，基团L的环A包含更优选地，基团L的环A包含以下结构中的任一种：More preferably, ring A of group L comprises More preferably, Ring A of group L comprises any one of the following structures:

特别优选地，基团L的环A包含Particularly preferably, ring A of group L comprises

在一种排列中，基团L的Q²存在并且包含以下结构中的任一种：In one arrangement,^Q2 of the group L is present and comprises any of the following structures:

其中R⁴²如本文中定义。wherein R⁴² is as defined herein.

更优选地，基团L的Q²包含以下结构中的任一种：More preferably, Q² of the group L comprises any one of the following structures:

可替换地，基团L的基团Q²不存在且仅一个Q¹基团存在。在该排列中，Q¹基团通常在线性方向上将环A与环C分隔3或4个原子，并且可以包含以下结构中的任一种：Alternatively, the group Q² of group L is absent and only one Q¹ group is present. In this arrangement, the Q¹ group typically separates ring A from ring C by 3 or 4 atoms in a linear direction and may comprise any of the following structures:

其中R⁴⁵和R⁴⁶如本文中定义。wherein R⁴⁵ and R⁴⁶ are as defined herein.

在该排列中，Q¹基团优选地包含以下结构中的任一种：In this arrangement, the^Q1 group preferably comprises any of the following structures:

优选地，基团L的环C包含以下结构中的任一种：Preferably, ring C of group L comprises any one of the following structures:

其中R⁵、R⁴³、R⁴⁴和R⁴⁶如本文中定义。wherein R⁵ , R⁴³ , R⁴⁴ and R⁴⁶ are as defined herein.

更优选地，基团L的环C包含以下结构中的任一种：More preferably, ring C of group L comprises any one of the following structures:

其中R⁵和R⁴³如本文中定义。wherein R⁵ and R⁴³ are as defined herein.

在某些排列中，R⁵是被取代的或未被取代的有机基团。In certain arrangements, R⁵ is a substituted or unsubstituted organic group.

优选地，基团R⁵不是MeO，并且更优选地选自H、-F、-Cl、-Br、-I、-CN、-CONR⁵¹R⁵¹、-NR⁵¹COR⁵²、-SO₂NR⁵¹R⁵¹、-NR⁵¹SO₂R⁵³、-O-CR⁵²R⁵²R⁵²、-CR⁵²R⁵²NR⁵¹R⁵¹和以下结构中的任一种：Preferably, the group R⁵ is not MeO, and is more preferably selected from H, -F, -Cl, -Br, -I, -CN, -CONR⁵¹ R⁵¹ , -NR⁵¹ COR⁵² , -SO₂ NR⁵¹ R⁵¹ , -NR⁵¹ SO₂ R⁵³ , -O-CR⁵² R⁵² R⁵² , -CR⁵² R⁵² NR⁵¹ R⁵¹ and any one of the following structures:

其中，R⁵¹、R⁵²和R⁵³中的每一个可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团。更优选地，基团R⁵是-CONR⁵¹R⁵¹。wherein each of R⁵¹ , R⁵² and R⁵³ may be the same or different and are independently selected from H and substituted or unsubstituted organic groups. More preferably, the group R⁵ is -CONR⁵¹ R⁵¹ .

更优选地，基团R⁵选自-F、-Cl、-CN、-CONH₂、-CONHMe、-CONHEt、-CONMe₂、-CONHCOMe、-CONHCH₂-CH₂OMe、-CONH-CH₂-CH₂F、-CONH-CH₂-CF₃、-CONH-CH₂-CHF₂、-OCHF₂、-NHCOMe、-NHSO₂Me、-SO₂NHMe、-CONHSO₂Me、More preferably, the group^R5 is selected from -F, -Cl, -CN,_-CONH2 , -CONHMe, -CONHEt,_-CONMe2 , -CONHCOMe, -CONHCH2-_CH2OMe , -CONH-_CH2 -_CH2F , -CONH-_CH2-CF3 , -CONH-_CH2 -_CHF2 ,_-OCHF2 , -NHCOMe,_-NHSO2Me ,_-SO2NHMe ,_-CONHSO2Me ,

一种特别优选的基团R⁵是-CONHMe，特别在基团L的环C包含优选的情况下。A particularly preferred group R⁵ is -CONHMe, especially when the ring C of the group L contains Best under the circumstances.

在某些实施方案中，根据本发明的化合物的基团L包含具有任何以下结构的基团：In certain embodiments, the group L of the compounds according to the present invention comprises a group having any of the following structures:

在某些实施方案中，提供了包含以下结构中的任一种的化合物：In certain embodiments, provided are compounds comprising any of the following structures:

其中，虚线指示，环D可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；每个X⁴可以相同或不同并且独立地选自C、N、O和S；每个R¹¹可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；且其中Z¹、R³、R⁶和L如本文中定义。在某些实施方案中，环D的一个X⁴是N。优选的是，至少一个X⁴是C。wherein the dashed line indicates that ring D may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic; each X⁴ may be the same or different and is independently selected from C, N, O, and S; each R¹¹ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and wherein Z¹ , R³ , R⁶ , and L are as defined herein. In certain embodiments, one X⁴ of ring D is N. Preferably, at least one X⁴ is C.

优选地，所述化合物包含以下结构中的任一种：Preferably, the compound comprises any one of the following structures:

其中环D、X⁴、R¹¹、R³、R⁶和L如本文中定义。wherein Ring D, X⁴ , R¹¹ , R³ , R⁶ and L are as defined herein.

更优选地，所述化合物包含以下结构中的任一种：More preferably, the compound comprises any one of the following structures:

其中R¹⁴选自H、C₁至C₃烷基或C₁至C₃氟代烷基；且其中R¹¹、环D、R³、R⁶和L如本文中定义。wherein R¹⁴ is selected from H, C₁ to C₃ alkyl or C₁ to C₃ fluoroalkyl; and wherein R¹¹ , Ring D, R³ , R⁶ and L are as defined herein.

更优选地，所述化合物包含以下结构中的任一种：More preferably, the compound comprises any one of the following structures:

其中R³、R¹¹、R¹⁴、R⁶和L如本文中定义。wherein R³ , R¹¹ , R¹⁴ , R⁶ and L are as defined herein.

每个R¹¹可以独立地选自H、卤素、腈基团、直链或支链C₁-C₃烷基基团、直链或支链C₁-C₃卤代烷基基团(优选氟代烷基)、-OH基团、直链或支链C₁-C₃醇基团、卤代(优选氟-)直链或支链C₁-C₃醇基团、-NH₂、直链或支链伯、仲或叔C₁-C₃胺基团、卤代(优选氟-)直链或支链伯、仲或叔C₁-C₃胺基团、直链或支链C₁-C₃烷氧基基团、直链或支链C₁-C₃卤代烷氧基基团(优选氟代烷氧基)，和/或一对R¹¹基团连接至同一原子以形成＝O；且独立地，和/或当一对连接至不同原子的R¹¹基团与环D原子一起形成环时，这一对R¹¹基团包含-CH₂CH₂CH₂-。Each R¹¹ can be independently selected from H, halogen, nitrile group, linear or branched C₁ -C₃ alkyl group, linear or branched C₁ -C₃ haloalkyl group (preferably fluoroalkyl), -OH group, linear or branched C₁ -C₃ alcohol group, halogenated (preferably fluoro-) linear or branched C₁ -C₃ alcohol group, -NH₂ , linear or branched primary, secondary or tertiary C₁ -C₃ amine group, halogenated (preferably fluoro-) linear or branched primary, secondary or tertiary C₁ -C₃ amine group, linear or branched C₁ -C₃ alkoxy group, linear or branched C₁ -C₃ haloalkoxy group (preferably fluoroalkoxy), and/or a pair of R¹¹ groups are connected to the same atom to form =0; and independently, and/or when a pair of R¹¹ groups connected to different atoms form a ring together with the ring D atom, the pair of R¹¹ groups comprises -CH₂ CH₂ CH₂ -.

优选的是，每个R¹¹独立地选自H、Cl、F、CHF₂、CF₃、CH₃、OH、CH₃O和NH₂，和/或一对R¹¹基团连接至同一原子以形成＝O；且独立地，当一对连接至不同原子的R¹¹基团与环D原子一起形成环时，这一对R¹¹基团包含-CH₂CH₂CH₂-。Preferably, each R¹¹ is independently selected from H, Cl, F, CHF₂ , CF₃ , CH₃ , OH, CH₃ O and NH₂ , and/or a pair of R¹¹ groups are attached to the same atom to form =0; and independently, when a pair of R¹¹ groups attached to different atoms form a ring together with the ring D atom, the pair of R¹¹ groups comprises -CH₂ CH₂ CH₂ -.

在某些实施方案中，提供了包含以下结构中的任一种的化合物：In certain embodiments, provided are compounds comprising any of the following structures:

其中L如本文中定义。wherein L is as defined herein.

在某些实施方案中，提供了包含以下结构中的任一种的化合物：In certain embodiments, provided are compounds comprising any of the following structures:

其中每个R¹²独立地选自H和被取代的或未被取代的有机基团，优选低级(C₁至C₆)烷基、烷氧基或卤代烷基基团、被取代的或未被取代的C₃至C₆环烷基或杂环基团和卤素基团，其中至少一个R¹²不是H；且其中每个R¹³可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；且其中R³、R⁶和L如本文中定义。wherein each R¹² is independently selected from H and a substituted or unsubstituted organic group, preferably a lower (C₁ to C₆ ) alkyl, alkoxy or haloalkyl group, a substituted or unsubstituted C₃ to C₆ cycloalkyl or heterocyclic group and a halogen group, wherein at least one R¹² is not H; and wherein each R¹³ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and wherein R³ , R⁶ and L are as defined herein.

至少一个R¹²优选地选自-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH₂Cl、-CHCl₂、-CCl₃、-CH₂F、-CHF₂、-CF₃、-Cl、-F、-Cl、-CH₂CF₃、-CH₂CH₂F、-CH₂CH₂OH、甲氧基、甲氧基甲基、甲氧基乙基、异丙基、环丙基或环丙基甲基。At least one R¹² is preferably selected from_-CH3 ,_-CH2CH3 ,_-CH2CH2CH3 ,_-CH2Cl ,_-CHCl2 ,_-CCl3 ,_-CH2F ,_-CHF2 ,_-CF3 ,_{-Cl, -F, -Cl, -CH2CF3, -CH2CH2F, -CH2CH2OH,methoxy,methoxymethyl,methoxyethyl} , isopropyl, cyclopropyl or_{cyclopropylmethyl} .

R¹³优选地选自H、F、C₁至C₃烷基或C₁至C₃氟代烷基。R¹³ is preferably selected from H, F, C₁ to C₃ alkyl or C₁ to C₃ fluoroalkyl.

R³优选地是H。^R3 is preferably H.

R⁶优选地选自H、卤素、C₁至C₃烷基、C₁至C₃卤代烷基、C₁至C₃醇或C₁至C₃氨基烷基(aminooalkyl)。^R6 is preferably selected from H, halogen,_C1 to_C3 alkyl,_C1 to_C3 haloalkyl,_C1 to_C3 alcohol or_C1 to_C3 aminoalkyl.

在某些实施方案中，提供了包含以下结构中的任一种的化合物：In certain embodiments, provided are compounds comprising any of the following structures:

其中L如本文中定义。wherein L is as defined herein.

在某些实施方案中，本发明提供了一种PARP1抑制剂化合物，其包含选自以下之一的式：In certain embodiments, the present invention provides a PARP1 inhibitor compound comprising a formula selected from one of the following:

上文已经对本发明的化合物的结构进行了详细描述。为了避免疑惑，用于本发明的任何化合物可以包含根据如下其结构的化合物或组合物：The structures of the compounds of the present invention have been described in detail above. For the avoidance of doubt, any compound used in the present invention may comprise a compound or composition according to its structure as follows:

每种结构的Each structure

-分离的对映异构体，或- separated enantiomers, or

-两种或更多种对映异构体的混合物，或- a mixture of two or more enantiomers, or

-两种或更多种非对映异构体和/或差向异构体的混合物，或- a mixture of two or more diastereomers and/or epimers, or

-外消旋混合物，或- a racemic mixture, or

-一种或多种互变异构体。- One or more tautomers.

对于上述编号的化合物，化合物1、2、5、8、12、15、17至22、25、27至30、36、40、41、45、47、48、54、59、63、75、168、173、179、192、193、227、228、238、259、260、284、295、299、300、302-305、310-312、330、361、368、369、373、375、376、379-381、383、384、387-389、394和411是非手性的。其余化合物代表一种以上的可能具有PARP1抑制活性的对映异构体结构，其作为外消旋混合物和/或作为单独的对映异构体。在下面的实施例中，带有后缀“a”的化合物(例如10a)代表，当将两种对映异构体的外消旋混合物应用于Daicel CHIRALPAK手性色谱柱时，作为第一级分洗脱的对映异构体。在下面的实施例中，带有后缀“b”的化合物(例如10b)代表，当将两种对映异构体的外消旋混合物应用于Daicel CHIRALPAK手性色谱柱时，作为第二级分洗脱的对映异构体。在下面的实施例中，没有后缀的化合物代表非手性化合物或对映异构体的外消旋混合物。在下面的实施例中，带有后缀“rac”的化合物代表对映异构体的外消旋混合物。For the above numbered compounds, compounds 1, 2, 5, 8, 12, 15, 17 to 22, 25, 27 to 30, 36, 40, 41, 45, 47, 48, 54, 59, 63, 75, 168, 173, 179, 192, 193, 227, 228, 238, 259, 260, 284, 295, 299, 300, 302-305, 310-312, 330, 361, 368, 369, 373, 375, 376, 379-381, 383, 384, 387-389, 394 and 411 are achiral. The remaining compounds represent more than one enantiomeric structure that may have PARP1 inhibitory activity, as a racemic mixture and/or as individual enantiomers. In the following examples, compounds with a suffix "a" (e.g., 10a) represent the enantiomer that eluted as the first fraction when a racemic mixture of two enantiomers was applied to a Daicel CHIRALPAK chiral chromatography column. In the following examples, compounds with a suffix "b" (e.g., 10b) represent the enantiomer that eluted as the second fraction when a racemic mixture of two enantiomers was applied to a Daicel CHIRALPAK chiral chromatography column. In the following examples, compounds without a suffix represent achiral compounds or racemic mixtures of enantiomers. In the following examples, compounds with a suffix "rac" represent racemic mixtures of enantiomers.

可以提供本文描述的化合物用于药物中。在本发明的上下文中，药用用途没有特别限制，只要是通过所述化合物的PARP1抑制作用促进的用途即可。因此，本发明的化合物可以用于可使用PARP1抑制剂预防、改善或治疗的任何疾病、病症或障碍。通常，这包括选自以下的疾病状况和/或障碍：癌症，它没有特别限制，只要所述癌症是可以通过使用PARP1抑制剂来治疗、预防或改善的癌症。因此，所述癌症可以是选自以下的癌症：实体肿瘤或液体肿瘤，包括眼癌、脑癌(诸如神经胶质瘤、胶质母细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤和星形细胞瘤)、脊髓癌、肾癌、口癌、唇癌、喉癌、口腔癌、鼻腔癌、小肠癌、结肠癌、甲状旁腺癌、胆囊癌、头颈癌、乳癌、骨癌、胆管癌、子宫颈癌、心脏癌、咽下腺癌、肺癌、支气管癌、肝癌、皮肤癌、输尿管癌、尿道癌、睾丸癌、阴道癌、肛门癌、喉腺癌、卵巢癌、甲状腺癌、食道癌、鼻咽腺癌、垂体癌、唾液腺癌、前列腺癌、胰腺癌、肾上腺癌；子宫内膜癌、口癌、黑素瘤、神经母细胞瘤、胃癌、血管瘤病、血管母细胞瘤、嗜铬细胞瘤、胰腺囊肿、肾细胞癌、威尔曼瘤、鳞状细胞癌、肉瘤、骨肉瘤、卡波西肉瘤、横纹肌肉瘤、肝细胞癌、PTEN错构瘤-肿瘤综合征(PHTS)(诸如Lhermitte-Duclos病、Cowden综合征、Proteus综合征和Proteus样综合征)、白血病和淋巴瘤(诸如急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、急性髓性白血病、慢性髓性白血病、毛细胞白血病、T-细胞幼淋巴细胞性白血病(T-PLL)、大颗粒淋巴细胞白血病、成人T-细胞白血病、幼年型粒单核细胞性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、套淋巴瘤、滤泡性淋巴瘤、原发性渗出性淋巴瘤、AIDS-有关的淋巴瘤、霍奇金淋巴瘤、弥散性B细胞淋巴瘤、伯基特淋巴瘤和皮肤T-细胞淋巴瘤)。此外，本文描述的化合物可以用于其中EBV起促成作用的癌症，诸如伯基特淋巴瘤、霍奇金淋巴瘤、鼻咽癌和胃肠癌。The compounds described herein may be provided for use in medicine. In the context of the present invention, the pharmaceutical use is not particularly limited, as long as it is a use promoted by the PARP1 inhibitory effect of the compound. Therefore, the compounds of the present invention can be used for any disease, condition or disorder that can be prevented, improved or treated using a PARP1 inhibitor. Generally, this includes disease conditions and/or disorders selected from the following: cancer, which is not particularly limited, as long as the cancer is a cancer that can be treated, prevented or improved by the use of a PARP1 inhibitor. Therefore, the cancer can be a cancer selected from the following: solid tumors or liquid tumors, including eye cancer, brain cancer (such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma and astrocytoma), spinal cord cancer, kidney cancer, mouth cancer, lip cancer, laryngeal cancer, oral cancer, nasal cancer, small intestine cancer, colon cancer, parathyroid cancer, gallbladder cancer, head and neck cancer, breast cancer, bone cancer, bile duct cancer, cervical cancer, heart cancer, hypopharyngeal gland cancer, lung Cancer, bronchial cancer, liver cancer, skin cancer, ureteral cancer, urethral cancer, testicular cancer, vaginal cancer, anal cancer, laryngeal cancer, ovarian cancer, thyroid cancer, esophageal cancer, nasopharyngeal cancer, pituitary cancer, salivary gland cancer, prostate cancer, pancreatic cancer, adrenal cancer; endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, angiomatosis, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilman tumor, squamous cell carcinoma, sarcoma, Osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma-tumor syndrome (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome and Proteus-like syndrome), leukemias and lymphomas (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, Hodgkin lymphoma, diffuse B-cell lymphoma, Burkitt lymphoma and cutaneous T-cell lymphoma). Furthermore, the compounds described herein may be used in cancers in which EBV plays a contributing role, such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma, and gastrointestinal cancer.

可以提供本文描述的化合物用于治疗缺乏DNA损伤应答修复途径、特别是同源重组依赖性DNA DSB DNA修复活性的癌症。HR依赖性DNA DSB修复途径和其它DNA损伤应答途径的组分包括、但不限于下述蛋白：ATM、ATR、ERCC1、XRCC1、XRCC2、XRCC3、RAD51、RAD51L1、RAD51C、RAD51D、RAD51L3、DMC1、RAD52、RAD54L、RAD54B、RAD50、MRE11A、NBS1、BRCA1、BRCA2、FANCP(SLX4)、FEN1、PALB2、PBRM1、SMARCA4、ARID1A、ARID1B、FANCD2、BLM。参与HR依赖性DNADSB修复的其它组分包括调节因子诸如ESMY(Hughes-Davies,L.等人.Cell.2003；115:523-535)。缺乏HR依赖性DNA DSB修复的癌症通常变得依赖于替代性DSB途径修复机制。这样的癌症包括、但不限于卵巢癌、前列腺癌、乳癌、肺癌、胃肠癌、血癌和胰腺癌。The compounds described herein can be provided for the treatment of cancers lacking DNA damage response repair pathways, particularly homologous recombination-dependent DNA DSB DNA repair activity. Components of the HR-dependent DNA DSB repair pathway and other DNA damage response pathways include, but are not limited to, the following proteins: ATM, ATR, ERCC1, XRCC1, XRCC2, XRCC3, RAD51, RAD51L1, RAD51C, RAD51D, RAD51L3, DMC1, RAD52, RAD54L, RAD54B, RAD50, MRE11A, NBS1, BRCA1, BRCA2, FANCP (SLX4), FEN1, PALB2, PBRM1, SMARCA4, ARID1A, ARID1B, FANCD2, BLM. Other components involved in HR-dependent DNA DSB repair include regulatory factors such as ESMY (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). Cancers lacking HR-dependent DNA DSB repair often become dependent on alternative DSB pathway repair mechanisms. Such cancers include, but are not limited to, ovarian cancer, prostate cancer, breast cancer, lung cancer, gastrointestinal cancer, blood cancer, and pancreatic cancer.

在某些实施方案中，所述癌细胞可能具有BRCA1和/或BRCA2缺陷表型，即，它们可能由于编码核酸中的突变、多态性或表观遗传沉默或由于编码调节因子的基因(例如，编码BRCA2调节因子的ESMY基因)中的扩增、多态性、突变而缺乏BRCA1和/或2表达和功能(Hughes-Davies,L.等人.Cell.2003；115:523-535)。ESMY基因的扩增与乳癌和卵巢癌有关。已知肿瘤抑制基因BRCA1和/或BRCA2基因中的突变的携带者具有升高的发生某些癌症(包括卵巢癌、前列腺癌和乳癌)的风险。BRCA1和/或BRCA2的野生型等位基因经常在杂合携带者的肿瘤中丢失(Jasin,M.等人.Oncogene.2002；21:8981-93)，并且它们的检测作为患者选择的手段是本领域众所周知的(Radice,PJ.等人.Exp.Clin.Cancer.Res.2002；21:9-12；Chappnis,PO和Foulkes WO.Cancer Treat Res.2002；107:29-59)。In certain embodiments, the cancer cells may have a BRCA1 and/or BRCA2 defective phenotype, i.e., they may lack BRCA1 and/or 2 expression and function due to mutations, polymorphisms or epigenetic silencing in the encoding nucleic acid or due to amplification, polymorphisms, mutations in genes encoding regulatory factors (e.g., the ESMY gene encoding the BRCA2 regulatory factor) (Hughes-Davies, L. et al. Cell. 2003; 115: 523-535). Amplification of the ESMY gene is associated with breast and ovarian cancer. Carriers of mutations in the known tumor suppressor genes BRCA1 and/or BRCA2 genes have an increased risk of developing certain cancers, including ovarian cancer, prostate cancer, and breast cancer. The wild-type alleles of BRCA1 and/or BRCA2 are frequently lost in tumors of heterozygous carriers (Jasin, M. et al. Oncogene. 2002; 21: 8981-93), and their detection as a means of patient selection is well known in the art (Radice, PJ. et al. Exp. Clin. Cancer. Res. 2002; 21: 9-12; Chappnis, PO and Foulkes WO. Cancer Treat Res. 2002; 107: 29-59).

在某些实施方案中，本文描述的化合物是如上面所定义的选择性的PARP1抑制剂。PARP1相对于PARP2的选择性抑制会减少PARP2相关的副作用，包括一种或多种血液学毒性诸如贫血、嗜中性粒细胞减少症和血小板减少症。这使得癌症患者的治疗具有减少的血液学副作用。这也使得能够给患者施用更高剂量的PARP1抑制剂并且使这样的抑制剂能够与化学治疗剂联合施用。In certain embodiments, the compounds described herein are selective PARP1 inhibitors as defined above. Selective inhibition of PARP1 relative to PARP2 reduces PARP2-related side effects, including one or more hematological toxicities such as anemia, neutropenia, and thrombocytopenia. This allows treatment of cancer patients with reduced hematological side effects. This also enables higher doses of PARP1 inhibitors to be administered to patients and enables such inhibitors to be administered in combination with chemotherapeutic agents.

本发明也提供了一种药物组合物，其包含如上面所定义的化合物。尽管所述药物组合物没有特别限制，但通常所述组合物进一步包含药学上可接受的添加剂和/或赋形剂。在所述药物组合物中，如上面所定义的化合物可以以上述形式存在，但可以可替换地呈适合于改善生物利用度、溶解度和/或活性的形式，和/或可以呈适合于改进制剂的形式。因此，所述化合物可以呈药学上可接受的盐、水合物、酸、酯的形式或其它替代性合适形式。通常，所述组合物用于治疗如上面所定义的疾病、病症或障碍。在某些情况下，所述化合物可以作为药学上可接受的盐或所述化合物的其它替代形式存在于所述组合物中，以改善药物制剂。The present invention also provides a kind of pharmaceutical composition, it comprises the compound as defined above.Although the pharmaceutical composition is not particularly limited, the composition generally further comprises a pharmaceutically acceptable additive and/or excipient.In the pharmaceutical composition, the compound as defined above can exist in the above-mentioned form, but can be replaced in a form suitable for improving bioavailability, solubility and/or activity, and/or can be in a form suitable for improving formulations.Therefore, the compound can be in the form of a pharmaceutically acceptable salt, hydrate, acid, ester or other alternative suitable form.Generally, the composition is used to treat a disease, illness or disorder as defined above.In some cases, the compound can be present in the composition as a pharmaceutically acceptable salt or other alternative forms of the compound to improve the pharmaceutical preparation.

在某些实施方案中，所述药物组合物是用于治疗癌症的组合物，其进一步包含用于治疗癌症的其它药剂。所述用于治疗癌症的其它药剂没有特别限制，只要其对癌症治疗提供某种实用性即可。但是，通常所述用于治疗癌症的其它药剂选自电离辐射、化学治疗剂诸如抗微管剂、铂配位络合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、senolytic剂、激素和激素类似物、信号转导途径抑制剂、其它DNA损伤修复途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、抗体-药物偶联物、免疫治疗剂、激素剥夺疗法、促细胞凋亡剂和细胞周期信号传递抑制剂。免疫治疗剂可以由以下组成但不限于以下(may consist of but is not limited to)：抗肿瘤疫苗、溶瘤病毒、免疫刺激性抗体诸如抗-CTLA4、抗-PD1、抗-PDL-1、抗-OX40、抗-41BB、抗-CD27、抗-CD40、抗-LAG3、抗-TIM3和抗-GITR、模式识别受体激动剂诸如STING、TLR-9或RIG-I解螺旋酶激动剂、IDO或TDO抑制剂、新颖佐剂、肽、细胞因子、嵌合抗原受体T细胞疗法(CAR-T)、小分子免疫调节剂、肿瘤微环境调节剂和抗血管生成剂。In certain embodiments, the pharmaceutical composition is a composition for treating cancer, which further comprises other agents for treating cancer. The other agents for treating cancer are not particularly limited, as long as they provide some practicality for cancer treatment. However, the other agents for treating cancer are usually selected from ionizing radiation, chemotherapeutic agents such as anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotics, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutics, hormone deprivation therapy, pro-apoptotic agents and cell cycle signaling inhibitors. Immunotherapeutic agents may consist of but is not limited to: anti-tumor vaccines, oncolytic viruses, immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR, pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists, IDO or TDO inhibitors, novel adjuvants, peptides, cytokines, chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulators, tumor microenvironment modulators and anti-angiogenic agents.

在再其它实施方案中，本发明提供了一种用于治疗癌症的药物试剂盒，所述药物试剂盒包含：In yet other embodiments, the present invention provides a pharmaceutical kit for treating cancer, the pharmaceutical kit comprising:

(a)如上面所定义的化合物；和(a) a compound as defined above; and

(b)用于治疗癌症的其它药剂；优选地其中所述用于治疗癌症的其它药剂选自电离辐射、化学治疗剂诸如抗微管剂、铂配位络合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、senolytic剂、激素和激素类似物、激素剥夺疗法、信号转导途径抑制剂、其它DNA损伤修复途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、抗体-药物偶联物、免疫治疗剂、促细胞凋亡剂和细胞周期信号传递抑制剂；(b) other agents for treating cancer; preferably wherein the other agents for treating cancer are selected from ionizing radiation, chemotherapeutic agents such as antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, hormone deprivation therapy, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutic agents, pro-apoptotic agents and cell cycle signaling inhibitors;

其中所述化合物和所述其它药剂适合于同时、依次或单独施用。The compound and the other agent are suitable for simultaneous, sequential or separate administration.

本发明进一步提供了一种治疗疾病和/或病症和/或障碍的方法，所述方法包括向患者(或受试者)施用如上面所定义的化合物或组合物或试剂盒。所述方法通常是用于治疗本文提及的任何疾病、病症或障碍的方法。在典型的实施方案中，所述方法是用于治疗癌症的方法。优选地，这样的方法包括向患者(或受试者)施用如上面所定义的化合物或组合物和如上面所定义的用于治疗癌症的其它药剂。所述化合物或组合物和所述其它药剂可以同时、依次或单独施用，取决于所涉及的药剂和患者以及所指示的癌症的类型。The present invention further provides a method for treating a disease and/or condition and/or disorder, the method comprising administering to a patient (or subject) a compound or composition or kit as defined above. The method is generally a method for treating any disease, condition or disorder mentioned herein. In a typical embodiment, the method is a method for treating cancer. Preferably, such a method comprises administering to a patient (or subject) a compound or composition as defined above and other medicaments for treating cancer as defined above. The compound or composition and the other medicaments can be administered simultaneously, sequentially or separately, depending on the medicaments involved and the patient and the type of cancer indicated.

通常，在本发明的所有实施方案中，无论在上面还是在下面，所述患者(或受试者)是动物，通常是哺乳动物，包括犬科动物、马科动物和猫科动物，更通常是人。Typically, in all embodiments of the invention, whether above or below, the patient (or subject) is an animal, typically a mammal, including canines, equines and felines, and more typically a human.

本发明进一步提供了一种合成如上面所定义的化合物的方法，所述方法包括进行(i)包含带有取代基L的一部分的环E的第一反应物与(ii)包含取代基L的剩余部分的第二反应物之间的反应，从而形成PARP1抑制剂化合物。The present invention further provides a method for synthesizing a compound as defined above, said method comprising reacting (i) a first reactant comprising ring E bearing a portion of a substituent L and (ii) a second reactant comprising the remaining portion of the substituent L, thereby forming a PARP1 inhibitor compound.

通常，在一种合成方法中，所述第一反应物包含环E和环A，并且所述第二反应物包含带有反应基团的Q1或Q2前体，所述方法包括将环A的N原子连接至Q1或Q2前体。在该方法中，Q1或Q2前体的反应基团可以包含羰基基团、烷基卤化物或烷基磺酸酯(alkylsulfonate)。通常，所述反应包含烷基化、还原胺化或酰胺形成，从而形成基团L。Typically, in a synthetic method, the first reactant comprises ring E and ring A, and the second reactant comprises a Q1 or Q2 precursor with a reactive group, and the method comprises connecting the N atom of ring A to the Q1 or Q2 precursor. In this method, the reactive group of the Q1 or Q2 precursor may comprise a carbonyl group, an alkyl halide, or an alkylsulfonate. Typically, the reaction comprises alkylation, reductive amination, or amide formation to form group L.

通常，在另一种合成方法中，所述第一反应物包含环E、环A以及Q1和Q2中的至少一个，并且所述第二反应物包含带有离去基团(诸如卤化物或磺酸酯)的环C衍生物。在此方法中，所述反应包含亲核取代反应，诸如亲核芳族取代反应，从而形成基团L。Typically, in another synthetic method, the first reactant comprises ring E, ring A, and at least one of Q1 and Q2, and the second reactant comprises a ring C derivative with a leaving group such as a halide or sulfonate. In this method, the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, to form group L.

技术人员可以根据适当的起始材料参考已知的合成技术来选择这些方法中的反应条件。在某些实施方案中，所述方法包括一个或多个另外的步骤。在本文的实施例中显示了示例性的合成方法。The technician can select the reaction conditions in these methods with reference to known synthesis techniques according to appropriate starting materials. In certain embodiments, the method includes one or more additional steps. Exemplary synthesis methods are shown in the examples herein.

通常，上式(以及本文中的所有式)以非立体异构形式显示。为了避免疑惑，在整个公开内容中，单个式意图代表特定结构的所有可能的立体异构体，包括与该式对应的所有可能的分离的对映异构体、与该式对应的对映异构体的所有可能的混合物、与该式对应的非对映异构体的所有可能的混合物、与该式对应的差向异构体的所有可能的混合物以及与该式对应的所有可能的外消旋混合物。除此之外，上式(以及本文中的所有式)意图代表与相应式等同的所有互变异构形式。Typically, the above formula (and all formulas herein) are shown in non-stereoisomeric form. For the avoidance of doubt, throughout the disclosure, a single formula is intended to represent all possible stereoisomers of a particular structure, including all possible separated enantiomers corresponding to the formula, all possible mixtures of enantiomers corresponding to the formula, all possible mixtures of diastereomers corresponding to the formula, all possible mixtures of epimers corresponding to the formula, and all possible racemic mixtures corresponding to the formula. In addition, the above formula (and all formulas herein) is intended to represent all tautomeric forms equivalent to the corresponding formula.

在本说明书和权利要求书中使用的术语“包含”在本文中是指“包括或由……组成”。该术语表示至少包括在该术语后面的特征，并且不排除包括未明确提及的其它特征。该术语还可以表示仅由在该术语后面的特征组成的实体。The term "comprising" as used in this specification and claims means herein "including or consisting of...". The term indicates that at least the features following the term are included, and does not exclude the inclusion of other features not explicitly mentioned. The term may also indicate an entity consisting of only the features following the term.

发明详述Detailed description of the invention

现在将仅作为实施例参考以下具体实施方案更详细地描述本发明。The invention will now be described in more detail, by way of example only, with reference to the following specific embodiments.

实施例Example

本发明的化合物的示例性合成Exemplary Syntheses of Compounds of the Invention

可以使用容易得到的起始材料和已知的反应来合成本发明的化合物。下面显示了三种化合物的示例性合成：The compounds of the present invention can be synthesized using readily available starting materials and known reactions. An exemplary synthesis of three compounds is shown below:

实施例1-化合物42的合成Example 1 - Synthesis of Compound 42

INT-4合成INT-4 Synthesis

2,4-二氯-5-乙基嘧啶(2)的制备Preparation of 2,4-dichloro-5-ethylpyrimidine (2)

在0℃向5-乙基-1,3-二氢嘧啶-2,4-二酮1(10.00g,0.07mol)在POCl₃(55.00g,0.36mol)中的溶液中加入DIEA(23.00g,0.18mol)。然后将混合物在120℃搅拌2h。将热反应混合物倒入冰水中并将水层用乙酸乙酯(50mL×3)萃取。将合并的有机层经Na₂SO₄干燥。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至92:8洗脱)纯化以产生作为白色固体的2,4-二氯-5-乙基嘧啶2(4.80g,38％收率)。To a solution of 5-ethyl-1,3-dihydropyrimidine-2,4-dione 1 (10.00 g, 0.07 mol) in POCl₃ (55.00 g, 0.36 mol) was added DIEA (23.00 g, 0.18 mol) at 0°C. The mixture was then stirred at 120°C for 2 h. The hot reaction mixture was poured into ice water and the aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over Na₂ SO_4. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EA=100:0 to 92:8) to give 2,4-dichloro-5-ethylpyrimidine 2 (4.80 g, 38% yield) as a white solid.

C6H6Cl2N2[M+H]⁺m/z的LCMS(ESI)计算值为176.99，实测值为177.00LCMS (ESI) calculated value of m/z for C6H6Cl2N2[M+H]⁺ is 176.99, found value is 177.00

2-氯-5-乙基-4-(2-甲氧基-5-甲基苯氧基)嘧啶(INT-4)的制备Preparation of 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine (INT-4)

在70℃向(4-甲氧基苯基)甲醇3(4.54g,32.90mmol)在THF(20mL)中的溶液中加入tBuOLi(2.30g,28.75mmol)保持15min。然后在0℃向混合物中加入2,4-二氯-5-乙基嘧啶2(4.80g,27.27mmol)。将混合物在室温搅拌3h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至93:7洗脱)纯化以产生作为白色固体的2-氯-5-乙基-4-(2-甲氧基-5-甲基苯氧基)嘧啶INT-4(4.00g,53％收率)。To a solution of (4-methoxyphenyl)methanol 3 (4.54 g, 32.90 mmol) in THF (20 mL) was added tBuOLi (2.30 g, 28.75 mmol) at 70 °C for 15 min. Then 2,4-dichloro-5-ethylpyrimidine 2 (4.80 g, 27.27 mmol) was added to the mixture at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 93:7) to produce 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine INT-4 (4.00 g, 53% yield) as a white solid.

C14H15ClN2O2[M+H]⁺m/z的LCMS(ESI)计算值为279.08，实测值为279.15。LCMS (ESI) calculated for m/z of C14H15ClN2O2[M+H]⁺ was 279.08, found was 279.15.

化合物42合成Synthesis of compound 42

3-(5-乙基-4-((4-甲氧基苄基)氧基)嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(2)的制备Preparation of tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (2)

向3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯1(500mg,1.69mmol)在1,4-二氧杂环己烷/H₂O＝4:1(15mL)中的溶液中加入2-氯-5-乙基-4-(2-甲氧基-5-甲基苯氧基)嘧啶INT-4(377.72mg,1.76mmol)和Na₂CO₃(189.11mg,3.01mmol)，然后在室温加入Pd(dppf)Cl₂(247.89mg,0.34mmol)。将反应混合物在氮气下在100℃回流并搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用石油醚/乙酸乙酯＝100:0至85:15洗脱)纯化以产生作为无色油的3-(5-乙基-4-((4-甲氧基苄基)氧基)嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯2(250mg,31％收率)。To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate 1 (500 mg, 1.69 mmol) in 1,4-dioxane/H₂ O=4:1 (15 mL) was added 2-chloro-5-ethyl-4-(2-methoxy-5-methylphenoxy)pyrimidine INT-4 (377.72 mg, 1.76 mmol) and Na₂ CO₃ (189.11 mg, 3.01 mmol), and then Pd(dppf)Cl₂ (247.89 mg, 0.34 mmol) was added at room temperature. The reaction mixture was refluxed and stirred at 100° C. under nitrogen for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with petroleum ether/ethyl acetate = 100:0 to 85:15) to give tert-butyl 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 2 (250 mg, 31% yield) as a colorless oil.

C23H29N3O4[M+H]⁺m/z的LCMS(ESI)计算值为412.22，实测值为412.28。LCMS (ESI) calcd for C23H29N3O4[M+H]⁺ m/z 412.22, found 412.28.

3-(5-乙基-4-羟基嘧啶-2-基)吡咯烷-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-(5-ethyl-4-hydroxypyrimidin-2-yl)pyrrolidine-1-carboxylate (3)

在室温向3-(5-乙基-4-((4-甲氧基苄基)氧基)嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸酯2(250mg,0.61mmol)在MeOH(15mL)中的溶液中加入Pd/C(97mg,0.91mmol)。将反应混合物在氢气下在50℃搅拌2h。冷却至室温之后，将混合物穿过硅藻土垫过滤并将滤液浓缩以产生作为无色油的3-(5-乙基-4-羟基嘧啶-2-基)吡咯烷-1-甲酸叔丁酯3(150mg,80％收率)。To a solution of 3-(5-ethyl-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 2 (250 mg, 0.61 mmol) in MeOH (15 mL) was added Pd/C (97 mg, 0.91 mmol) at room temperature. The reaction mixture was stirred at 50 °C under hydrogen for 2 h. After cooling to room temperature, the mixture was filtered through a pad of celite and the filtrate was concentrated to give tert-butyl 3-(5-ethyl-4-hydroxypyrimidin-2-yl)pyrrolidine-1-carboxylate 3 (150 mg, 80% yield) as a colorless oil.

C15H23N3O3[M+H]⁺m/z的LCMS(ESI)计算值为294.17，实测值为294.19。LCMS (ESI) calcd for C15H23N3O3[M+H]⁺ m/z was 294.17, found 294.19.

5-乙基-2-(吡咯烷-3-基)-3H-嘧啶-4-酮(4)的制备Preparation of 5-ethyl-2-(pyrrolidin-3-yl)-3H-pyrimidin-4-one (4)

在室温向3-(5-乙基-4-羟基嘧啶-2-基)吡咯烷-1-甲酸酯3(150mg,0.51mmol)溶液中加入在二氧杂环己烷中的HCl(4M,10mL)。将反应混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的5-乙基-2-(吡咯烷-3-基)-3H-嘧啶-4-酮4(100mg,94％收率)。To a solution of 3-(5-ethyl-4-hydroxypyrimidin-2-yl)pyrrolidine-1-carboxylate 3 (150 mg, 0.51 mmol) was added HCl (4M, 10 mL) in dioxane at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 5-ethyl-2-(pyrrolidin-3-yl)-3H-pyrimidin-4-one 4 (100 mg, 94% yield) as a white solid.

C10H15N3O[M+H]⁺m/z的LCMS(ESI)计算值为194.12，实测值为194.19。LCMS (ESI) calcd for C10H15N3O [M+H]⁺ m/z: 194.12, found: 194.19.

4-[3-(5-乙基-4-氧代-3H-嘧啶-2-基)吡咯烷-1-基]哌啶-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidine-1-carboxylate (6)

向5-乙基-2-(吡咯烷-3-基)-3H-嘧啶-4-酮4(100mg,0.52mmol)在MeOH(15mL)中的溶液中加入4-氧代哌啶-1-甲酸叔丁酯5(124.48mg,0.61mmol)和NaBH₃CN(145mg,3.11mmol)。将反应混合物在氮气下在50℃回流并搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的4-[3-(5-乙基-4-氧代-3H-嘧啶-2-基)吡咯烷-1-基]哌啶-1-甲酸叔丁酯6(120mg,55％收率)。To a solution of 5-ethyl-2-(pyrrolidin-3-yl)-3H-pyrimidin-4-one 4 (100 mg, 0.52 mmol) in MeOH (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate 5 (124.48 mg, 0.61 mmol) and NaBH₃ CN (145 mg, 3.11 mmol). The reaction mixture was refluxed at 50 °C under nitrogen and stirred for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 95:5) to give tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidine-1-carboxylate 6 (120 mg, 55% yield) as a white solid.

C20H32N4O3[M+H]⁺m/z的LCMS(ESI)计算值为377.25，实测值为377.30。LCMS (ESI) calcd for C20H32N4O3[M+H]⁺ m/z 377.25, found 377.30.

5-乙基-2-[1-(哌啶-4-基)吡咯烷-3-基]-3H-嘧啶-4-酮(7)的制备Preparation of 5-ethyl-2-[1-(piperidin-4-yl)pyrrolidin-3-yl]-3H-pyrimidin-4-one (7)

在室温将4-[3-(5-乙基-4-氧代-3H-嘧啶-2-基)吡咯烷-1-基]哌啶-1-甲酸叔丁酯6(120mg,0.32mmol)加入在二氧杂环己烷中的HCl(4M,10mL)中。将反应混合物在室温搅拌1h，然后在减压下浓缩以产生作为白色固体的5-乙基-2-[1-(哌啶-4-基)吡咯烷-3-基]-3H-嘧啶-4-酮7(90mg,92％收率)。Tert-butyl 4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidine-1-carboxylate 6 (120 mg, 0.32 mmol) was added to HCl (4M, 10 mL) in dioxane at room temperature. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to give 5-ethyl-2-[1-(piperidin-4-yl)pyrrolidin-3-yl]-3H-pyrimidin-4-one 7 (90 mg, 92% yield) as a white solid.

C15H24N4O[M+H]⁺m/z的LCMS(ESI)计算值为277.20，实测值为277.24。LCMS (ESI) calcd for C15H24N4O[M+H]⁺ m/z 277.20, found 277.24.

5-{4-[3-(5-乙基-4-氧代-3H-嘧啶-2-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(化合物42)的制备Preparation of 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 42)

向5-乙基-2-[1-(哌啶-4-基)吡咯烷-3-基]-3H-嘧啶-4-酮7(90mg,0.33mmol)在DMF(10mL)中的溶液中加入5-氟-N-甲基吡啶-2-甲酰胺8(104mg,0.68mmol)和Cs₂CO₃(884mg,2.71mmol)。将反应混合物在微波反应器中在150℃照射3h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的5-{4-[3-(5-乙基-4-氧代-3H-嘧啶-2-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺化合物42(20mg,95％纯度,20％收率)。To a solution of 5-ethyl-2-[1-(piperidin-4-yl)pyrrolidin-3-yl]-3H-pyrimidin-4-one 7 (90 mg, 0.33 mmol) in DMF (10 mL) was added 5-fluoro-N-methylpyridine-2-carboxamide 8 (104 mg, 0.68 mmol) and Cs₂ CO₃ (884 mg, 2.71 mmol). The reaction mixture was irradiated at 150° C. for 3 h in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 95:5) to give 5-{4-[3-(5-ethyl-4-oxo-3H-pyrimidin-2-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide compound 42 (20 mg, 95% purity, 20% yield) as a white solid.

¹H NMR(400MHz,DMSO)δ12.16(s,1H),8.42-8.38(m,1H),8.28(d,J＝2.4Hz,1H),7.83(d,J＝8.8Hz,1H),7.73(s,1H),7.42-7.39(dd,J＝8.8,2.8Hz,1H),3.87(d,J＝12.8Hz,2H),3.29-3.25(m,2H),3.17-3.13(m,1H),2.94-2.74(m,8H),2.34(q,J＝7.2Hz,2H),2.18-1.94(m,4H),1.56-1.47(m,2H),1.08(t,J＝7.6Hz,3H)。¹ H NMR (400MHz, DMSO) δ12.16 (s, 1H), 8.42-8.38 (m, 1H), 8.28 (d, J = 2.4Hz, 1H), 7.83 (d, J = 8.8Hz, 1H), 7.73(s,1H),7.42-7.39(dd,J＝8.8,2.8Hz,1H),3.87(d,J＝12.8Hz,2H),3.29-3.25(m,2H),3.17-3.13(m, 1H),2.94-2.74(m,8H),2.34(q,J＝7.2Hz,2H),2.18-1.94(m,4H),1.56-1.47(m,2H),1.08(t,J＝7.6Hz ,3H).

C22H30N6O2[M+H]⁺m/z的LCMS(ESI)计算值为411.24，实测值为411.33。LCMS (ESI) calcd for C22H30N6O2[M+H]⁺ m/z 411.24, found 411.33.

实施例2-化合物53的合成Example 2-Synthesis of Compound 53

中间体INT的合成：Synthesis of intermediate INT:

5-{1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基}-N-甲基吡啶-2-甲酰胺(3)的制备Preparation of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide (3)

向5-氟-N-甲基吡啶-2-甲酰胺1(1.00g,6.50mmol)在DMF(15mL)中的溶液中加入1,4-二氧杂-8-氮杂螺[4.5]癸烷2(1.40g,9.75mmol)，然后在室温加入Cs₂CO₃(2.12g,6.50mmol)。将反应混合物使用微波在150℃搅拌5h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至97:3洗脱)纯化以产生作为白色固体的5-{1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基}-N-甲基吡啶-2-甲酰胺3(1.50g,76％收率)。To a solution of 5-fluoro-N-methylpyridine-2-carboxamide 1 (1.00 g, 6.50 mmol) in DMF (15 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane 2 (1.40 g, 9.75 mmol), followed by Cs₂ CO₃ (2.12 g, 6.50 mmol) at room temperature. The reaction mixture was stirred at 150 °C for 5 h using microwaves. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 97:3) to yield 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide 3 (1.50 g, 76% yield) as a white solid.

C14H19N3O3[M+H]⁺m/z的LCMS(ESI)计算值为278.14，实测值为278.14。LCMS (ESI) calcd. m/z for C14H19N3O3[M+H]⁺ was 278.14, found was 278.14.

N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺(INT)的制备Preparation of N-methyl-5-(4-oxopiperidin-1-yl)pyridineamide (INT)

在室温向5-{1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基}-N-甲基吡啶-2-甲酰胺3(1.50g,5.40mmol)在H₂O(10mL)中的溶液中加入在1,4-二氧杂环己烷中的HCl(4M,20mL)。将反应混合物在50℃搅拌1h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物使用NaHCO₃溶液调至pH>7，然后用EtOAc(50mL x 3)萃取，将有机相用Na₂SO₄干燥并浓缩以产生作为黄色固体的N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(1.50g,76％收率)。To a solution of 5-{1,4-dioxa-8-azaspiro[4.5]decane-8-yl}-N-methylpyridine-2-carboxamide 3 (1.50 g, 5.40 mmol) in H₂ O (10 mL) was added HCl (4M, 20 mL) in 1,4-dioxane at room temperature. The reaction mixture was stirred at 50 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH>7 using NaHCO₃ solution, then extracted with EtOAc (50 mL x 3), and the organic phase was dried over Na₂ SO₄ and concentrated to give N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (1.50 g, 76% yield) as a yellow solid.

C12H15N3O2[M+H]⁺m/z的LCMS(ESI)计算值为234.12，实测值为234.18。LCMS (ESI) calculated value of m/z for C12H15N3O2[M+H]⁺ is 234.12, found is 234.18.

化合物53的合成Synthesis of compound 53

3-(5-氨基-6-甲氧基吡啶-2-基)-5,6-二氢-2H-吡啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate (3)

向6-溴-2-甲氧基吡啶-3-胺1(2.00g,9.90mmol)在1,4-二氧杂环己烷/H2O＝4:1(45mL)中的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢-2H-吡啶-1-甲酸叔丁酯2(3.98g,12.87mmol)，然后在室温加入Pd(dppf)Cl₂(0.72g,0.99mmol)和Na₂CO₃(3.12g,99.00mmol)。将反应混合物在氮气下在80℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-氨基-6-甲氧基吡啶-2-基)-5,6-二氢-2H-吡啶-1-甲酸叔丁酯3(3.00g,89％收率)。To a solution of 6-bromo-2-methoxypyridin-3-amine 1 (2.00 g, 9.90 mmol) in 1,4-dioxane/H2O=4:1 (45 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate 2 (3.98 g, 12.87 mmol), followed by addition of Pd(dppf)_Cl2 (0.72 g, 0.99 mmol) and_Na2CO3 (3.12 g, 99.00 mmol) at room temperature. The reaction mixture was stirred at 80°C under nitrogen for 3 h._After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EA=100:0 to 85:15) to give tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate 3 (3.00 g, 89% yield) as a white solid.

C16H23N3O3[M+H]⁺m/z的LCMS(ESI)计算值为306.17，实测值为306.19。LCMS (ESI) calcd for C16H23N3O3[M+H]⁺ m/z 306.17, found 306.19.

3-(5-氨基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)piperidine-1-carboxylate (4)

在室温向3-(5-氨基-6-甲氧基吡啶-2-基)-5,6-二氢-2H-吡啶-1-甲酸叔丁酯3(2.80g,9.20mmol)在MeOH(50mL)中的溶液中加入Pd/C(0.78g,7.36mmol)。将反应混合物在氢气下在50℃搅拌2h。冷却至室温之后，将反应混合物过滤，将溶液在减压下浓缩以产生作为白色固体的产物3-(5-氨基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯4(2.80g,89％收率)。To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-5,6-dihydro-2H-pyridine-1-carboxylate 3 (2.80 g, 9.20 mmol) in MeOH (50 mL) was added Pd/C (0.78 g, 7.36 mmol) at room temperature. The reaction mixture was stirred at 50 °C under hydrogen for 2 h. After cooling to room temperature, the reaction mixture was filtered and the solution was concentrated under reduced pressure to give the product tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)piperidine-1-carboxylate 4 (2.80 g, 89% yield) as a white solid.

C16H25N3O3[M+H]⁺m/z的LCMS(ESI)计算值为308.19，实测值为308.19。LCMS (ESI) calcd. m/z for C16H25N3O3[M+H]⁺ was 308.19, found was 308.19.

3-(5-溴-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯(5)的制备Preparation of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)piperidine-1-carboxylate (5)

向3-(5-氨基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯4(2.80g,9.10mmol)在ACN(50mL)中的溶液中加入亚硝酸叔丁酯(2.82g,27.30mmol)，搅拌15分钟，然后在室温加入CuBr(5.22g,36.40mmol)。将反应混合物在50℃搅拌2h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-溴-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯5(1.10g,30％收率)。To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)piperidine-1-carboxylate 4 (2.80 g, 9.10 mmol) in ACN (50 mL) was added tert-butyl nitrite (2.82 g, 27.30 mmol), stirred for 15 minutes, and then CuBr (5.22 g, 36.40 mmol) was added at room temperature. The reaction mixture was stirred at 50 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EA=100:0 to 85:15) to produce tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)piperidine-1-carboxylate 5 (1.10 g, 30% yield) as a white solid.

C16H23BrN2O3[M+H]⁺m/z的LCMS(ESI)计算值为371.09，实测值为371.15。LCMS (ESI) calculated value of m/z for C16H23BrN2O3[M+H]⁺ is 371.09, found is 371.15.

3-(5-乙基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)piperidine-1-carboxylate (6)

向3-(5-溴-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯5(1.10g,2.96mmol)在1,4-二氧杂环己烷(65mL)中的溶液中加入Pd(dppf)Cl₂(219mg,0.30mmol)。然后在室温加入Et₂Zn(1M,11.84mL,11.84mml)。将反应混合物在氮气下在80℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-乙基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯6(700mg,67％收率)。To a solution of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)piperidine-1-carboxylate 5 (1.10 g, 2.96 mmol) in 1,4-dioxane (65 mL) was added Pd(dppf)Cl₂ (219 mg, 0.30 mmol). Et₂ Zn (1 M, 11.84 mL, 11.84 mml) was then added at room temperature. The reaction mixture was stirred at 80 °C for 3 h under nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EA=100:0 to 85:15) to give tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)piperidine-1-carboxylate 6 (700 mg, 67% yield) as a white solid.

C18H28N2O3[M+H]⁺m/z的LCMS(ESI)计算值为321.21，实测值为321.30。LCMS (ESI) calcd for C18H28N2O3[M+H]⁺ m/z 321.21, found 321.30.

3-乙基-6-(哌啶-3-基)-1H-吡啶-2-酮(7)的制备Preparation of 3-ethyl-6-(piperidin-3-yl)-1H-pyridin-2-one (7)

向3-(5-乙基-6-甲氧基吡啶-2-基)哌啶-1-甲酸叔丁酯6(200mg,0.62mmol)在HBr水溶液(48％,6mL)中的溶液中。将反应混合物在100℃搅拌6h。冷却至室温之后，将反应混合物在减压下浓缩以产生作为黄色固体的3-乙基-6-(哌啶-3-基)-1H-吡啶-2-酮7(80mg,56％收率)。To a solution of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)piperidine-1-carboxylate 6 (200 mg, 0.62 mmol) in aqueous HBr (48%, 6 mL) was added. The reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-ethyl-6-(piperidin-3-yl)-1H-pyridin-2-one 7 (80 mg, 56% yield) as a yellow solid.

C12H18N2O[M+H]⁺m/z的LCMS(ESI)计算值为207.14，实测值为206.95。LCMS (ESI) calcd for C12H18N2O [M+H]⁺ m/z 207.14, found 206.95.

5-{4-[3-(5-乙基-6-氧代-1H-吡啶-2-基)哌啶-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(8)的制备Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (8)

向3-乙基-6-(哌啶-3-基)-1H-吡啶-2-酮7(80mg,0.38mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT(89mg,0.38mmol)。然后在室温加入两滴乙酸和NaBH₃CN(24mg,0.38mml)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的5-{4-[3-(5-乙基-6-氧代-1H-吡啶-2-基)哌啶-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺8(48mg,31％收率)。To a solution of 3-ethyl-6-(piperidin-3-yl)-1H-pyridin-2-one 7 (80 mg, 0.38 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT (89 mg, 0.38 mmol). Two drops of acetic acid and NaBH₃ CN (24 mg, 0.38 mml) were then added at room temperature. The reaction mixture was stirred at 50 ° C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 95:5) to produce 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide 8 (48 mg, 31% yield) as a white solid.

C24H33N5O2[M+H]⁺m/z的LCMS(ESI)计算值为424.26，实测值为424.37。LCMS (ESI) calcd for C24H33N5O2[M+H]⁺ m/z 424.26, found 424.37.

5-{4-[3-(5-乙基-6-氧代-1H-吡啶-2-基)哌啶-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(化合物53a和化合物53b)的制备Preparation of 5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 53a and Compound 53b)

将5-{4-[3-(5-乙基-6-氧代-1H-吡啶-2-基)哌啶-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺8通过SFC(柱：Daicel CHIRALPAK AD-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝75/25)分离并在减压下浓缩以提供作为化合物53a的第一级分(7.16mg,95％纯度,ee％:100，白色固体)和作为化合物53b的第二级分(6.57mg,99％纯度,ee％:100，白色固体)5-{4-[3-(5-ethyl-6-oxo-1H-pyridin-2-yl)piperidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide 8 was separated by SFC (column: Daicel CHIRALPAK AD-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=75/25) and concentrated under reduced pressure to give a first fraction as compound 53a (7.16 mg, 95% purity, ee%: 100, white solid) and a second fraction as compound 53b (6.57 mg, 99% purity, ee%: 100, white solid)

化合物53aCompound 53a

¹H NMR(400MHz,DMSO)δ11.48(s,1H),8.39(q,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),7.17(d,J＝6.8Hz,1H),5.98(d,J＝7.2Hz,1H),3.97(d,J＝12.4Hz,2H),2.91-2.77(m,7H),2.67-2.54(m,2H),2.36-2.28(m,4H),1.83-1.81(m,3H),1.68-1.65(m,1H),1.59-1.40(m,4H),1.05(t,J＝7.6Hz,3H)。¹ H NMR (400MHz, DMSO) δ11.48 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.26 (d, J = 2.8Hz, 1H), 7.81 (d, J = 8.8Hz, 1H),7.40(dd,J＝8.8,2.8Hz,1H),7.17(d,J＝6.8Hz,1H),5.98(d,J＝7.2 Hz,1H),3.97(d,J＝12.4Hz,2H),2.91-2.77(m,7H),2.67-2.54(m,2H),2.36-2.28(m,4H),1.83-1.81(m, 3H), 1.68-1.65 (m, 1H), 1.59-1.40 (m, 4H), 1.05 (t, J = 7.6Hz, 3H).

化合物53bCompound 53b

¹H NMR(400MHz,DMSO)δ11.48(s,1H),8.39(q,J＝4.4Hz,1H),8.26(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.40(dd,J＝9.2,3.2Hz,1H),7.17(d,J＝7.2Hz,1H),5.98(d,J＝6.8Hz,1H),3.97(d,J＝12.4Hz,2H),2.91-2.77(m,7H),2.66-2.54(m,2H),2.36-2.25(m,4H),1.83-1.80(m,3H),1.67-1.64(m,1H),1.59-1.36(m,4H),1.05(t,J＝7.6Hz,3H)。¹ H NMR (400MHz, DMSO) δ11.48 (s, 1H), 8.39 (q, J = 4.4Hz, 1H), 8.26 (d, J = 2.8Hz, 1H), 7.81 (d, J = 8.8Hz, 1H),7.40(dd,J＝9.2,3.2Hz,1H),7.17(d,J＝7.2Hz,1H),5.98(d,J＝6.8 Hz,1H),3.97(d,J＝12.4Hz,2H),2.91-2.77(m,7H),2.66-2.54(m,2H),2.36-2.25(m,4H),1.83-1.80(m, 3H), 1.67-1.64 (m, 1H), 1.59-1.36 (m, 4H), 1.05 (t, J = 7.6Hz, 3H).

实施例3-化合物2的合成Example 3 - Synthesis of Compound 2

5-羟基-N-甲基吡啶酰胺(2)的制备Preparation of 5-hydroxy-N-methylpicolinamide (2)

向5-羟基吡啶甲酸1(4.00g,28.72mmol)在DMF(15mL)中的溶液中加入HATU(12.55g,33.01mmol)和DIEA(9.28g,71.80mmol)。然后在室温加入甲胺(2M,15mL,30.00mmol)。然后将混合物在室温搅拌1h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至93:7洗脱)纯化以产生作为白色固体的5-羟基-N-甲基吡啶酰胺2(2.00g,46％收率)。To a solution of 5-hydroxypicolinic acid 1 (4.00 g, 28.72 mmol) in DMF (15 mL) was added HATU (12.55 g, 33.01 mmol) and DIEA (9.28 g, 71.80 mmol). Methylamine (2 M, 15 mL, 30.00 mmol) was then added at room temperature. The mixture was then stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 93:7) to produce 5-hydroxy-N-methylpicolinamide 2 (2.00 g, 46% yield) as a white solid.

C7H8N2O2[M+H]⁺m/z的LCMS(ESI)计算值为153.06，实测值为153.10。LCMS (ESI) calcd for C7H8N2O2[M+H]⁺ m/z: 153.06, found: 153.10.

5-(3-羟基丙氧基)-N-甲基吡啶酰胺(3)的制备Preparation of 5-(3-hydroxypropoxy)-N-methylpicolinamide (3)

在室温向5-羟基-N-甲基吡啶酰胺2(1.00g,6.61mmol)在DMF(10mL)中的溶液中加入3-溴丙烷-1-醇(2.75g,19.58mmol)和Cs₂CO₃(3.23g,9.93mmol)。然后将混合物在室温搅拌18h。将反应混合物过滤以产生作为油的5-(3-羟基丙氧基)-N-甲基吡啶酰胺3(1.00g,65％收率)。To a solution of 5-hydroxy-N-methylpicolinamide 2 (1.00 g, 6.61 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (2.75 g, 19.58 mmol) and Cs₂ CO₃ (3.23 g, 9.93 mmol) at room temperature. The mixture was then stirred at room temperature for 18 h. The reaction mixture was filtered to yield 5-(3-hydroxypropoxy)-N-methylpicolinamide 3 (1.00 g, 65% yield) as an oil.

C10H14N2O3[M+H]⁺m/z的LCMS(ESI)计算值为211.10，实测值为211.05。LCMS (ESI) calcd for C10H14N2O3[M+H]⁺ m/z 211.10, found 211.05.

5-(3-溴丙氧基)-N-甲基吡啶酰胺(INT-4-1)的制备Preparation of 5-(3-bromopropoxy)-N-methylpicolinamide (INT-4-1)

向5-(3-羟基丙氧基)-N-甲基吡啶酰胺3(250.00mg,1.19mmol)在DCM(15mL)中的溶液中加入CBr₄(788.74mg,2.38mmol)。然后在室温加入PPh₃(623.83mg,2.38mmol)。然后将混合物在室温搅拌2h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的5-(3-溴丙氧基)-N-甲基吡啶酰胺INT-4-1(300mg,69％收率)。To a solution of 5-(3-hydroxypropoxy)-N-methylpicolinamide 3 (250.00 mg, 1.19 mmol) in DCM (15 mL) was added CBr₄ (788.74 mg, 2.38 mmol). PPh₃ (623.83 mg, 2.38 mmol) was then added at room temperature. The mixture was then stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 95:5) to produce 5-(3-bromopropoxy)-N-methylpicolinamide INT-4-1 (300 mg, 69% yield) as a white solid.

C10H13BrN2O2[M+H]⁺m/z的LCMS(ESI)计算值为273.02，实测值为274.85。LCMS (ESI) calculated value of m/z for C10H13BrN2O2[M+H]⁺ is 273.02, found is 274.85.

N-甲基-5-(3-(4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)丙氧基)吡啶酰胺(化合物2)的制备Preparation of N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)propoxy)picolinamide (Compound 2)

向5-(3-溴丙氧基)-N-甲基吡啶酰胺INT-4-1(150.00mg,0.55mmol)在ACN(10mL)中的溶液中加入2-(哌啶-4-基)-3H-喹唑啉-4-酮INT-5(151.10mg,0.66mmol)。然后在室温加入DIEA(212.94mg,1.65mmol)。然后将混合物在67℃搅拌18h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为白色固体的N-甲基-5-(3-(4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)丙氧基)吡啶酰胺化合物2(100mg,78％收率)。2-(piperidin-4-yl)-3H-quinazolin-4-one INT-5 (151.10 mg, 0.66 mmol) was added to a solution of 5-(3-bromopropoxy)-N-methylpicolinamide INT-4-1 (150.00 mg, 0.55 mmol) in ACN (10 mL). DIEA (212.94 mg, 1.65 mmol) was then added at room temperature. The mixture was then stirred at 67 ° C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to produce N-methyl-5-(3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)propoxy)picolinamide compound 2 (100 mg, 78% yield) as a white solid.

1H NMR(400MHz,DMSO)δ12.15(s,1H),8.57-8.54(m,1H),8.29(d,J＝2.8Hz,1H),8.08(d,J＝8.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.78(t,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,1H),7.54(dd,J＝8.8,2.8Hz,1H),7.47(t,J＝7.6Hz,1H),4.18(t,J＝5.6Hz,2H),3.10-2.86(m,2H),2.79(d,J＝4.8Hz,3H),2.65-2.53(m,1H),2.49-2.41(m,2H),1.94(s,8H)。1H NMR (400MHz, DMSO) δ12.15 (s, 1H), 8.57-8.54 (m, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.08 (d ,J＝8.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.78(t,J＝7.6Hz,1H),7.60(d,J＝8.0Hz,1H), 7.54(dd,J＝8.8,2.8Hz,1H),7.47(t,J＝7.6Hz,1H),4.18(t,J＝5.6Hz,2H),3.10-2.8 6(m,2H),2.79(d,J＝4.8Hz,3H),2.65-2.53(m,1H),2.49-2.41(m,2H),1.94(s,8H).

C23H27N5O3[M+H]⁺m/z的LCMS(ESI)计算值为422.21，实测值为422.30。LCMS (ESI) calcd for C23H27N5O3[M+H]⁺ m/z 422.21, found 422.30.

实施例4-化合物6的合成Example 4-Synthesis of Compound 6

3-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3)

向2-氨基苯甲酰胺1(6.00g,44.10mmol)和1-(叔丁氧基羰基)哌啶-3-甲酸2(10.11g,44.10mmol)在吡啶(50mL)中的溶液中加入EDCI(8.45g,44.10mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物3-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯3(12.00g,79％收率)。To a solution of 2-aminobenzamide 1 (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid 2 (10.11 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 3 (12.00 g, 79% yield) as a white solid.

C18H25N3O4[M-H]^-m/z的LCMS(ESI)计算值为346.18，实测值为346.20。LCMS (ESI) calcd. m/z for C18H25N3O4[MH]^- 346.18, found 346.20.

3-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4)

向3-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯3(12.00g,34.50mmol)在二甘醇二甲醚(80mL)中的溶液中加入KOH(2.13g,37.95mmol)，加热至140℃搅拌2h，冷却至0℃，加入冰水(100mL)，然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物3-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯4(11.00g,97％收率)。To a solution of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 3 (12.00 g, 34.50 mmol) in diethylene glycol dimethyl ether (80 mL) was added KOH (2.13 g, 37.95 mmol), heated to 140 ° C and stirred for 2 h, cooled to 0 ° C, added ice water (100 mL), and then adjusted to pH <7 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 4 (11.00 g, 97% yield) as a white solid.

C18H23N3O3[M+H]⁺m/z的LCMS(ESI)计算值为330.17，实测值为330.20。LCMS (ESI) calcd for C18H23N3O3[M+H]⁺ m/z 330.17, found 330.20.

2-(哌啶-3-基)喹唑啉-4(3H)-酮(INT-5-1)的制备Preparation of 2-(piperidin-3-yl)quinazolin-4(3H)-one (INT-5-1)

向3-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯4(3.30g,10.00mmol)在DCM(10mL)中的溶液中加入TFA(10mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(20mL)，然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物2-(哌啶-3-基)喹唑啉-4(3H)-酮INT-5-1(1.50g,66％收率)。To a solution of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 4 (3.30 g, 10.00 mmol) in DCM (10 mL) was added TFA (10 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (20 mL) was added, and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product 2-(piperidin-3-yl)quinazolin-4(3H)-one INT-5-1 (1.50 g, 66% yield) as a white solid.

C13H15N3O[M+H]⁺m/z的LCMS(ESI)计算值为230.12，实测值为230.00。LCMS (ESI) calcd for C13H15N3O [M+H]⁺ m/z 230.12, found 230.00.

3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-甲酸叔丁酯(7)的制备Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidinyl]-1'-carboxylate (7)

向2-(哌啶-3-基)喹唑啉-4(3H)-酮INT-5-1(460mg,2.01mmol)在MeOH(15mL)中的溶液中加入4-氧代哌啶-1-甲酸叔丁酯6(8.45g,44.10mmol)，然后在室温加入两滴乙酸和NaBH₃CN(189.11mg,3.01mmol)。将反应混合物在50℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至93:7洗脱)纯化以产生作为白色固体的3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-甲酸叔丁酯7(300mg,36％收率)。To a solution of 2-(piperidin-3-yl)quinazolin-4(3H)-one INT-5-1 (460 mg, 2.01 mmol) in MeOH (15 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate 6 (8.45 g, 44.10 mmol), followed by two drops of acetic acid and NaBH₃ CN (189.11 mg, 3.01 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 93:7) to produce tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidine]-1'-carboxylate 7 (300 mg, 36% yield) as a white solid.

¹H NMR(400MHz,DMSO)δ12.40(s,1H),8.11(d,J＝7.2Hz,1H),7.81(s,1H),7.62(d,J＝7.8Hz,1H),7.51(s,1H),4.10-3.99(m,2H),3.53-3.44(m,1H),3.16 -3.04(m,1H),2.94-2.62(m,4H),1.99(d,J＝2.4Hz,4H),1.91(d,J＝2.4Hz,2H),1.82-1.53(m,4H),1.41(s,9H)。¹ H NMR (400MHz, DMSO) δ12.40(s,1H),8.11(d,J＝7.2Hz,1H),7.81(s,1H),7.62(d,J＝7.8Hz,1H),7.51( s,1H),4.10-3.99(m,2H),3.53-3.44(m,1H),3.16 -3.04(m,1H),2.94-2.62(m,4H),1.99(d,J＝2.4Hz, 4H), 1.91 (d, J = 2.4Hz, 2H), 1.82-1.53 (m, 4H), 1.41 (s, 9H).

2-([1,4'-联哌啶]-3-基)喹唑啉-4(3H)-酮(8)的制备Preparation of 2-([1,4'-bipiperidinyl]-3-yl)quinazolin-4(3H)-one (8)

将3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-甲酸叔丁酯7(300mg,0.65mmol)加入在二氧杂环己烷中的HCl(4M,10mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的2-([1,4'-联哌啶]-3-基)喹唑啉-4(3H)-酮8(200mg,88％收率)。Tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidin]-1'-carboxylate 7 (300 mg, 0.65 mmol) was added to HCl (4M, 10 mL) in dioxane, stirred at room temperature for 1 h, and the reaction mixture was concentrated under reduced pressure to give 2-([1,4'-bipiperidin]-3-yl)quinazolin-4(3H)-one 8 (200 mg, 88% yield) as a white solid.

C18H24N4O[M+H]⁺m/z的LCMS(ESI)计算值为313.20，实测值为313.15。LCMS (ESI) calcd for C18H24N4O[M+H]⁺ m/z 313.20, found 313.15.

N-甲基-5-(3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-基)吡啶酰胺(9)的制备Preparation of N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidinyl]-1'-yl)picolinamide (9)

向2-([1,4'-联哌啶]-3-基)喹唑啉-4(3H)-酮8(200.00mg,0.64mmol)在DMF(10mL)中的溶液中加入Cs₂CO₃(1042.94mg,3.20mmol)和5-氟-N-甲基吡啶酰胺(148.02mg,0.96mmol)。将混合物使用微波在150℃下搅拌6h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为黄色固体的N-甲基-5-(3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-基)吡啶酰胺9(100mg,95％纯度,33％收率)。To a solution of 2-([1,4'-bipiperidin]-3-yl)quinazolin-4(3H)-one 8 (200.00 mg, 0.64 mmol) in DMF (10 mL) was added Cs₂ CO₃ (1042.94 mg, 3.20 mmol) and 5-fluoro-N-methylpicolinamide (148.02 mg, 0.96 mmol). The mixture was stirred at 150 °C for 6 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 92:8) to give N-methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidin]-1'-yl)picolinamide 9 (100 mg, 95% purity, 33% yield) as a yellow solid.

C25H30N6O2[M+H]⁺m/z的LCMS(ESI)计算值为447.24，实测值为447.20。LCMS (ESI) calcd for C25H30N6O2[M+H]⁺ m/z 447.24, found 447.20.

N-甲基-5-(3-(4-氧代-3,4-二氢喹唑啉-2-基)-[1,4'-联哌啶]-1'-基)吡啶酰胺(化合物6a和化合物6b)的手性拆分Chiral Resolution of N-Methyl-5-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)-[1,4'-bipiperidinyl]-1'-yl)pyridineamide (Compound 6a and Compound 6b)

将化合物9通过SFC(柱：Daicel CHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝70/30)分离并在减压下浓缩以提供作为化合物6a的第一级分(40.6mg,100％纯度,ee％:100，白色固体)和作为化合物6b的第二级分(39.5mg,99％纯度,ee％:100，白色固体)Compound 9 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=70/30) and concentrated under reduced pressure to provide a first fraction as compound 6a (40.6 mg, 100% purity, ee%: 100, white solid) and a second fraction as compound 6b (39.5 mg, 99% purity, ee%: 100, white solid)

化合物6aCompound 6a

¹H NMR(400MHz,DMSO)δ12.25(s,1H),8.40(q,J＝4.8Hz,1H),8.29(d,J＝2.8Hz,1H),8.10(dd,J＝7.6,1.6Hz,1H),7.85-7.78(m,2H),7.63(d,J＝8.0Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(dd,J＝8.8,2.8Hz,1H),3.99(d,J＝12.8Hz,2H),3.08(d,J＝8.8Hz,1H),2.87-2.81(m,4H),2.80(d,J＝4.8Hz,3H),2.61-2.55(m,2H),2.32(t,J＝9.8Hz,1H),1.98-1.96(m,1H),1.87(d,J＝12.4Hz,2H),1.78-1.75(m,1H),1.69-1.55(m,4H)。¹ H NMR (400MHz, DMSO) δ12.25 (s, 1H), 8.40 (q, J = 4.8Hz, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.10 (dd, J = 7.6, 1.6 Hz,1H),7.85-7.78(m,2H),7.63(d,J＝8.0Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(dd,J＝8.8,2.8Hz,1H ),3.99 (d,J＝12.8Hz,2H),3.08(d,J＝8.8Hz,1H),2.87-2.81(m,4H),2.80(d,J＝4.8Hz,3H),2.61-2.55(m, 2H),2.32(t,J＝9.8Hz,1H),1.98-1.96(m,1H),1.87(d,J＝12.4Hz,2H),1.78-1.75(m,1H),1.69-1.55(m ,4H).

C25H30N6O2[M+H]⁺m/z的LCMS(ESI)计算值为447.24，实测值为447。LCMS (ESI) calcd. m/z for C25H30N6O2[M+H]⁺ 447.24, found 447.

化合物6bCompound 6b

¹H NMR(400MHz,DMSO)δ12.25(s,1H),8.39(q,J＝4.8Hz,1H),8.29(d,J＝2.8Hz,1H),8.10(dd,J＝7.6,1.6Hz,1H),7.84-7.78(m,2H),7.63(d,J＝8.0Hz,1H),7.50-7.47(m,1H),7.42(dd,J＝8.8,2.8Hz,1H),3.99(d,J＝12.8Hz,2H),3.08(d,J＝8.8Hz,1H),2.87-2.81(m,4H),2.80(d,J＝4.8Hz,3H),2.61-2.55(m,2H),2.31(t,J＝9.6Hz,1H),1.98-1.96(m,1H),1.87(d,J＝12.4Hz,2H),1.78-1.75(m,1H),1.63-1.55(m,4H)。¹ H NMR (400MHz, DMSO) δ12.25 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.10 (dd, J = 7.6, 1.6 Hz,1H),7.84-7.78(m,2H),7.63(d,J＝8.0Hz,1H),7.50-7.47(m,1H),7.42(dd,J＝8.8,2.8Hz,1H),3.99 ( d,J＝12.8Hz,2H),3.08(d,J＝8.8Hz,1H),2.87-2.81(m,4H),2.80(d,J＝4.8Hz,3H),2.61-2.55(m,2H ),2.31(t,J＝9.6Hz,1H),1.98-1.96(m,1H),1.87(d,J＝12.4Hz,2H),1.78-1.75(m,1H),1.63-1.55(m, 4H).

C25H30N6O2[M+H]⁺m/z的LCMS(ESI)计算值为447.24，实测值为447。LCMS (ESI) calcd. m/z for C25H30N6O2[M+H]⁺ 447.24, found 447.

实施例5-化合物8的合成Example 5-Synthesis of Compound 8

INT-5的合成Synthesis of INT-5

4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (3)

向2-氨基苯甲酰胺1(6.00g,44.10mmol)和1-(叔丁氧基羰基)哌啶-4-甲酸2(10.11g,44.10mmol)在吡啶(50mL)中的溶液中加入EDCI(8.45g,44.10mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯3(12.00g,79％收率)。To a solution of 2-aminobenzamide 1 (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 2 (10.11 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 3 (12.00 g, 79% yield) as a white solid.

C18H25N3O4[M+Na]⁺m/z的LCMS(ESI)计算值为370.42，实测值为370.15。LCMS (ESI) calculated value of m/z for C18H25N3O4[M+Na]⁺ is 370.42, found value is 370.15.

4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (4)

向4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯3(12.00g,34.50mmol)在二甘醇二甲醚(80mL)中的溶液中加入KOH(2.13g,37.95mmol)，加热至140℃搅拌2h，冷却至0℃，加入冰水(100mL)，然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯4(11.00g,97％收率)。To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 3 (12.00 g, 34.50 mmol) in diethylene glycol dimethyl ether (80 mL) was added KOH (2.13 g, 37.95 mmol), heated to 140 ° C and stirred for 2 h, cooled to 0 ° C, added ice water (100 mL), and then adjusted to pH <7 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 4 (11.00 g, 97% yield) as a white solid.

C18H23N3O3[M+H]⁺m/z的LCMS(ESI)计算值为330.17，实测值为330.20。LCMS (ESI) calcd for C18H23N3O3[M+H]⁺ m/z 330.17, found 330.20.

2-(哌啶-4-基)喹唑啉-4(3H)-酮(INT-5)的制备Preparation of 2-(piperidin-4-yl)quinazolin-4(3H)-one (INT-5)

向4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯4(3.30g,10.00mmol)在DCM(10mL)中的溶液中加入TFA(10mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(20mL)，然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物2-(哌啶-4-基)喹唑啉-4(3H)-酮INT-5(1.50g,66％收率)。To a solution of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 4 (3.30 g, 10.00 mmol) in DCM (10 mL) was added TFA (10 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (20 mL) was added, and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product 2-(piperidin-4-yl)quinazolin-4(3H)-one INT-5 (1.50 g, 66% yield) as a white solid.

C13H15N3O[M+H]⁺m/z的LCMS(ESI)计算值为230.12，实测值为230.20。LCMS (ESI) calcd for C13H15N3O[M+H]⁺ m/z 230.12, found 230.20.

化合物8合成Synthesis of compound 8

4-甲酰基哌啶-1-甲酸叔丁酯(2)的制备Preparation of tert-butyl 4-formylpiperidine-1-carboxylate (2)

向4-甲酰基哌啶-1-甲酸叔丁酯1(837.00mg,3.85mmol)在MeOH(50mL)中的溶液中加入2-(哌啶-4-基)喹唑啉-4(3H)-酮INT-5(300.00mg,1.31mmol)。然后在室温加入两滴乙酸和NaBH₃CN(400.00mg,6.37mmol)。然后将混合物在65℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为白色固体的4-((4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯2(500.00mg,90％收率)。To a solution of tert-butyl 4-formylpiperidine-1-carboxylate 1 (837.00 mg, 3.85 mmol) in MeOH (50 mL) was added 2-(piperidin-4-yl)quinazolin-4(3H)-one INT-5 (300.00 mg, 1.31 mmol). Two drops of acetic acid and NaBH₃ CN (400.00 mg, 6.37 mmol) were then added at room temperature. The mixture was then stirred at 65 ° C for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 92:8) to produce tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 2 (500.00 mg, 90% yield) as a white solid.

C24H34N4O3[M+H]⁺m/z的LCMS(ESI)计算值为427.26，实测值为427.30。LCMS (ESI) calcd for C24H34N4O3[M+H]⁺ m/z 427.26, found 427.30.

4-((4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (3)

在室温向4-((4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯2(500.00mg,1.17mmol)在MeOH(5mL)中的溶液中加入4M HCl-二氧杂环己烷(10mL)。将反应混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的2-(1-(哌啶-4-基甲基)哌啶-4-基)喹唑啉-4(3H)-酮3(350.00mg,87％收率)。To a solution of tert-butyl 4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 2 (500.00 mg, 1.17 mmol) in MeOH (5 mL) was added 4M HCl-dioxane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to yield 2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one 3 (350.00 mg, 87% yield) as a white solid.

C19H26N4O[M+H]⁺m/z的LCMS(ESI)计算值为327.21，实测值为327.15。LCMS (ESI) calcd for C19H26N4O[M+H]⁺ m/z 327.21, found 327.15.

N-甲基-5-(4-((4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-基)吡啶酰胺(化合物8)的制备Preparation of N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)picolinamide (Compound 8)

向2-(1-(哌啶-4-基甲基)哌啶-4-基)喹唑啉-4(3H)-酮3(300.00mg,0.92mmol)在DMF(5mL)中的溶液中加入5-氟-N-甲基吡啶酰胺4(354.14mg,2.30mmol)。然后在室温加入Cs₂CO₃(2994.20mg,9.19mmol)。将反应混合物在微波反应器中在150℃照射5h。将反应混合物在减压下浓缩。将残余物通过制备型HPLC(柱:Gemini 5um C18 150×21.2mm，流动相:ACN-H₂O(0.1％ FA)，梯度:15-25)纯化以产生作为白色固体的N-甲基-5-(4-((4-(4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-基)吡啶酰胺化合物8(100mg,98％纯度,24％收率)。To a solution of 2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one 3 (300.00 mg, 0.92 mmol) in DMF (5 mL) was added 5-fluoro-N-methylpicolinamide 4 (354.14 mg, 2.30 mmol). Then Cs₂ CO₃ (2994.20 mg, 9.19 mmol) was added at room temperature. The reaction mixture was irradiated at 150 °C for 5 h in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.1% FA), gradient: 15-25) to give N-methyl-5-(4-((4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)picolinamide Compound 8 (100 mg, 98% purity, 24% yield) as a white solid.

C26H32N6O2[M+H]⁺m/z的LCMS(ESI)计算值为461.26，实测值为461.20。LCMS (ESI) calcd for C26H32N6O2[M+H]⁺ m/z 461.26, found 461.20.

1H NMR(400MHz,DMSO)δ12.13(s,1H),8.37(d,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H),8.08(d,J＝7.6Hz,1H),7.82-7.76(m,2H),7.60(d,J＝8.0Hz,1H),7.50-7.35(m,2H),3.91(d,J＝12.4Hz,2H),2.95(d,J＝10.8Hz,2H),2.89-2.75(m,5H),2.62-2.53(m,1H),2.18(d,J＝6.4Hz,2H),1.98-1.73(m,9H),1.23-1.17(m,2H)。1H NMR (400MHz, DMSO) δ12.13(s,1H),8.37(d,J＝4.8Hz,1H),8.26(d,J＝2.8Hz,1H ),8.08(d,J＝7.6Hz,1H),7.82-7.76(m,2H),7.60(d,J＝8.0Hz,1H),7.50-7.35 (m,2H),3.91(d,J＝12.4Hz,2H),2.95(d,J＝10.8Hz,2H),2.89-2.75(m,5H),2. 62-2.53(m,1H),2.18(d,J＝6.4Hz,2H),1.98-1.73(m,9H),1.23-1.17(m,2H).

实施例6-化合物10的合成Example 6-Synthesis of Compound 10

化合物10合成Synthesis of compound 10

3-((2-氨甲酰基苯基)氨甲酰基)吡咯烷-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate (3)

向2-氨基苯甲酰胺1(6.00g,44.10mmol)和1-(叔丁氧基羰基)吡咯烷-3-甲酸2(9.49g,44.10mmol)在吡啶(50mL)中的溶液中加入EDCI(8.45g,44.10mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭并将水层用EtOAc(50mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的3-((2-氨甲酰基苯基)氨甲酰基)吡咯烷-1-甲酸叔丁酯3(12.00g,77％收率)。To a solution of 2-aminobenzamide 1 (6.00 g, 44.10 mmol) and 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid 2 (9.49 g, 44.10 mmol) in pyridine (50 mL) was added EDCI (8.45 g, 44.10 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate 3 (12.00 g, 77% yield) as a white solid.

C17H23N3O4[M+Na]⁺m/z的LCMS(ESI)计算值为356.17，实测值为356.00。LCMS (ESI) calcd for C17H23N3O4[M+Na]⁺ m/z 356.17, found 356.00.

3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4)

向3-((2-氨甲酰基苯基)氨甲酰基)吡咯烷-1-甲酸叔丁酯3(12.00g,36.04mmol)在二甘醇二甲醚(80mL)中的溶液中加入KOH(2.42g,43.25mmol)，加热至140℃搅拌0.5h，冷却至0℃，加入冰水(100mL)，然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯4(10.00g,83％收率)。To a solution of tert-butyl 3-((2-carbamoylphenyl)carbamoyl)pyrrolidine-1-carboxylate 3 (12.00 g, 36.04 mmol) in diethylene glycol dimethyl ether (80 mL) was added KOH (2.42 g, 43.25 mmol), heated to 140 ° C and stirred for 0.5 h, cooled to 0 ° C, added ice water (100 mL), and then adjusted to pH <7 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate 4 (10.00 g, 83% yield) as a white solid.

C17H21N3O3[M+H]⁺m/z的LCMS(ESI)计算值为316.16，实测值为316.05。LCMS (ESI) calcd for C17H21N3O3[M+H]⁺ m/z 316.16, found 316.05.

2-(吡咯烷-3-基)喹唑啉-4(3H)-酮(INT-5-2)的制备Preparation of 2-(Pyrrolidin-3-yl)quinazolin-4(3H)-one (INT-5-2)

向3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯4(10.00g,31.75mmol)在DCM(20mL)中的溶液中加入TFA(20mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(20mL)然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物2-(吡咯烷-3-基)喹唑啉-4(3H)-酮INT-5-2(8.00g,80％收率)。To a solution of tert-butyl 3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate 4 (10.00 g, 31.75 mmol) in DCM (20 mL) was added TFA (20 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (20 mL) was added and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product 2-(pyrrolidin-3-yl)quinazolin-4(3H)-one INT-5-2 (8.00 g, 80% yield) as a white solid.

1H NMR(400MHz,DMSO-d₆,ppm)δ8.14-8.07(m,1H),7.87-7.76(m,1H),7.64(d,J＝8.0Hz,1H),7.57-7.44(m,1H),3.76-3.61(m,1H),3.61-3.49(m,2H),3.43-3.33(m,1H),3.29(dt,J＝11.4,5.6Hz,1H),2.37(td,J＝14.0,7.1Hz,1H),2.21(td,J＝13.5,7.2Hz,1H)。1H NMR (400MHz, DMSO-d₆ ,ppm) δ8.14-8.07(m,1H),7.87-7.76(m,1H),7.64(d,J＝8.0Hz,1H),7.57-7.44(m, 1H),3.76-3.61(m,1H),3.61-3.49(m,2H),3.43-3.33(m,1H),3.29(dt,J＝11.4,5.6Hz,1H),2.37(td,J＝ 14.0,7.1Hz,1H),2.21(td,J＝13.5,7.2Hz,1H).

C12H13N3O[M-H]-m/z的LCMS(ESI)计算值为216.11，实测值为215.95。The LCMS (ESI) calculated value of C12H13N3O[M-H]-m/z is 216.11, and the found value is 215.95.

4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-甲酸叔丁酯(7)的制备Preparation of tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate (7)

向2-(吡咯烷-3-基)喹唑啉-4(3H)-酮INT-5-2(600.00mg,2.79mmol)在MeOH(30mL)中的溶液中加入4-氧代哌啶-1-甲酸叔丁酯6(1.67g,8.36mmol)，然后在室温加入两滴乙酸和NaBH₃CN(1.05g,16.72mmol)。将反应混合物在50℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至93:7洗脱)纯化以产生作为白色固体的4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-甲酸叔丁酯7(400mg,34％收率)。To a solution of 2-(pyrrolidin-3-yl)quinazolin-4(3H)-one INT-5-2 (600.00 mg, 2.79 mmol) in MeOH (30 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate 6 (1.67 g, 8.36 mmol), followed by two drops of acetic acid and NaBH₃ CN (1.05 g, 16.72 mmol) at room temperature. The reaction mixture was stirred at 50 ° C for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 93:7) to produce tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate 7 (400 mg, 34% yield) as a white solid.

C22H30N4O3[M+H]⁺m/z的LCMS(ESI)计算值为399.23，实测值为399.30。LCMS (ESI) calcd for C22H30N4O3[M+H]⁺ m/z was 399.23, found 399.30.

2-(1-(哌啶-4-基)吡咯烷-3-基)喹唑啉-4(3H)-酮(8)的制备Preparation of 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one (8)

将4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-甲酸叔丁酯7(400mg,0.81mmol)加入在二氧杂环己烷中的HCl(4M,10mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的2-(1-(哌啶-4-基)吡咯烷-3-基)喹唑啉-4(3H)-酮8(200.00mg,79％收率)。Tert-butyl 4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidine-1-carboxylate 7 (400 mg, 0.81 mmol) was added to HCl (4M, 10 mL) in dioxane, stirred at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one 8 (200.00 mg, 79% yield) as a white solid.

C17H22N4O[M+H]⁺m/z的LCMS(ESI)计算值为299.18，实测值为299.25。LCMS (ESI) calcd for C17H22N4O[M+H]⁺ m/z 299.18, found 299.25.

N-甲基-5-(4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(9)的制备Preparation of N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (9)

向2-(1-(哌啶-4-基)吡咯烷-3-基)喹唑啉-4(3H)-酮8(200.00mg,0.67mmol)在DMF(10mL)中的溶液中加入Cs₂CO₃(2.18g,6.70mmol)和5-氟-N-甲基吡啶酰胺9(432.44mg,2.01mmol)。将混合物使用微波在150℃下搅拌6h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为黄色固体的N-甲基-5-(4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺9(100mg,95％纯度,33％收率)。To a solution of 2-(1-(piperidin-4-yl)pyrrolidin-3-yl)quinazolin-4(3H)-one 8 (200.00 mg, 0.67 mmol) in DMF (10 mL) was added Cs₂ CO₃ (2.18 g, 6.70 mmol) and 5-fluoro-N-methylpicolinamide 9 (432.44 mg, 2.01 mmol). The mixture was stirred at 150 °C for 6 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 92:8) to give N-methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 9 (100 mg, 95% purity, 33% yield) as a yellow solid.

C24H28N6O2[M+H]⁺m/z的LCMS(ESI)计算值为433.23，实测值为433.25。LCMS (ESI) calcd for C24H28N6O2[M+H]⁺ m/z 433.23, found 433.25.

N-甲基-5-(4-(3-(4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(9)的手性拆分Chiral Resolution of N-Methyl-5-(4-(3-(4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (9)

将化合物9通过SFC(柱：Daicel CHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝70/30)分离并在减压下浓缩以提供作为化合物10a的第一级分(16.4.mg,100％纯度,ee％:100，灰白色固体)和作为化合物10b的第二级分(12.3mg,100％纯度,ee％:100，灰白色固体)Compound 9 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=70/30) and concentrated under reduced pressure to provide a first fraction as compound 10a (16.4. mg, 100% purity, ee%: 100, off-white solid) and a second fraction as compound 10b (12.3 mg, 100% purity, ee%: 100, off-white solid)

化合物10aCompound 10a

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.16(s,1H),8.40-8.37(m,1H),8.27(d,J＝2.8Hz,1H),8.07(dd,J＝7.6,1.6Hz,1H),7.82-7.75(m,2H),7.61(d,J＝8.0Hz,1H),7.48-7.44(m,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.82(d,J＝12.8Hz,2H),3.07(t,J＝8.6Hz,2H),2.95(t,J＝10.8Hz,2H),2.86-2.79(m,2H),2.78-2.77(m,3H),2.69-2.63(m,1H),2.33-2.32(m,1H),2.20-2.13(m,2H),1.96-1.93(m,2H),1.58-1.47(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.16 (s, 1H), 8.40-8.37 (m, 1H), 8.27 (d, J = 2.8Hz, 1H), 8.07 (dd, J = 7.6 ,1.6Hz,1H),7.82-7.75(m,2H),7.61(d,J＝8.0Hz,1H),7.48-7.44(m,1H),7.40(dd,J＝8.8,2.8Hz,1H) ,3.82(d,J＝ 12.8Hz,2H),3.07(t,J＝8.6Hz,2H),2.95(t,J＝10.8Hz,2H),2.86-2.79(m,2H),2.78-2.77(m,3H),2.69- 2.63(m,1H),2.33-2.32(m,1H),2.20-2.13(m,2H),1.96-1.93(m,2H),1.58-1.47(m,2H).

C24H28N6O2[M+H]⁺m/z的LCMS(ESI)计算值为433.23，实测值为433.20。LCMS (ESI) calcd for C24H28N6O2[M+H]⁺ m/z 433.23, found 433.20.

化合物10bCompound 10b

¹H NMR(400MHz,DMSO-d₆,ppm)δ8.39-8.38(m,1H),8.28(d,J＝3.2Hz,1H),8.08(dd,J＝7.6,1.6Hz,1H),7.83-7.76(m,2H),7.61(d,J＝8.0Hz,1H),7.47(t,J＝7.6Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.83(d,J＝12.8Hz,2H),3.09(d,J＝8.4Hz,2H),2.95(t,J＝12.4Hz,2H),2.88-2.79(m,2H),2.79(d,J＝4.8Hz,3H),2.68-2.66(m,1H),2.39-2.31(m,1H),2.21-2.14(m,2H),1.97-1.94(m,2H),1.59-1.47(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ8.39-8.38 (m, 1H), 8.28 (d, J = 3.2Hz, 1H), 8.08 (dd, J = 7.6, 1.6Hz, 1H), 7.83-7.76(m,2H),7.61(d,J＝8.0Hz,1H),7.47(t,J＝7.6Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.83(d ,J＝12.8Hz ,2H),3.09(d,J＝8.4Hz,2H),2.95(t,J＝12.4Hz,2H),2.88-2.79(m,2H),2.79(d,J＝4.8Hz,3H),2.68 -2.66(m,1H),2.39-2.31(m,1H),2.21-2.14(m,2H),1.97-1.94(m,2H),1.59-1.47(m,2H).

C24H28N6O2[M+H]⁺m/z的LCMS(ESI)计算值为433.23，实测值为433.20。LCMS (ESI) calcd for C24H28N6O2[M+H]⁺ m/z 433.23, found 433.20.

实施例7-化合物14的合成Example 7-Synthesis of Compound 14

INT5-3的制备Preparation ofINT5-3

3-(2-((2-氨甲酰基苯基)氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate (3)

向2-氨基苯甲酰胺1(2.80g,20.60mmol)和2-(1-(叔丁氧基羰基)哌啶-3-基)乙酸2(5.00g,20.60mmol)在吡啶(50mL)中的溶液中加入EDCI(3.95g,20.60mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物3-(2-((2-氨甲酰基苯基)氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯3(7.00g,94％收率)。To a solution of 2-aminobenzamide 1 (2.80 g, 20.60 mmol) and 2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid 2 (5.00 g, 20.60 mmol) in pyridine (50 mL) was added EDCI (3.95 g, 20.60 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate 3 (7.00 g, 94% yield) as a white solid.

C19H27N3O4[M+H]⁺m/z的LCMS(ESI)计算值为362.20，实测值为362.25。LCMS (ESI) calcd for C19H27N3O4[M+H]⁺ m/z 362.20, found 362.25.

3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate (4)

向3-(2-((2-氨甲酰基苯基)氨基)-2-氧代乙基)哌啶-1-甲酸叔丁酯3(7.60g,21.00mmol)在二甘醇二甲醚(80mL)中的溶液中加入KOH(1.18g,21.00mmol)，加热至140℃搅拌2h，冷却至0℃，加入冰水(100mL)然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-甲酸叔丁酯4(6.80g,94％收率)。To a solution of tert-butyl 3-(2-((2-carbamoylphenyl)amino)-2-oxoethyl)piperidine-1-carboxylate 3 (7.60 g, 21.00 mmol) in diethylene glycol dimethyl ether (80 mL) was added KOH (1.18 g, 21.00 mmol), heated to 140 ° C and stirred for 2 h, cooled to 0 ° C, added ice water (100 mL) and then adjusted to pH <7 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate 4 (6.80 g, 94% yield) as a white solid.

C19H25N3O3[M+H]⁺m/z的LCMS(ESI)计算值为344.19，实测值为344.15。LCMS (ESI) calcd for C19H25N3O3[M+H]⁺ m/z 344.19, found 344.15.

2-(哌啶-3-基甲基)喹唑啉-4(3H)-酮(INT-5-3)的制备Preparation of 2-(piperidin-3-ylmethyl)quinazolin-4(3H)-one (INT-5-3)

向3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-甲酸叔丁酯4(2.00g,5.80mmol)在DCM(10mL)中的溶液中加入TFA(10mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(20mL)然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物2-(哌啶-3-基甲基)喹唑啉-4(3H)-酮INT-5-3(1.20g,85％收率)。To a solution of tert-butyl 3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidine-1-carboxylate 4 (2.00 g, 5.80 mmol) in DCM (10 mL) was added TFA (10 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (20 mL) was added and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered and the filter cake was washed with ice water (50 mL*3) and then dried to give the product 2-(piperidin-3-ylmethyl)quinazolin-4(3H)-one INT-5-3 (1.20 g, 85% yield) as a white solid.

C14H17N3O[M+H]⁺m/z的LCMS(ESI)计算值为244.14，实测值为244.20。LCMS (ESI) calcd for C14H17N3O[M+H]⁺ m/z 244.14, found 244.20.

化合物14合成Synthesis of compound 14

4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯(2)的制备Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate (2)

向5-羟基-N-甲基吡啶酰胺1(500.00mg,3.29mmol)和Cs₂CO₃(3.22g,9.87mmol)在DMF(15mL)中的溶液中加入1-溴-2-氯乙烷2(943.64mg,6.58mmol)。然后将混合物在50℃搅拌3h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取，将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以产生作为无色油的4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯2(500.00mg,71％收率)。To a solution of 5-hydroxy-N-methylpicolinamide 1 (500.00 mg, 3.29 mmol) and Cs₂ CO₃ (3.22 g, 9.87 mmol) in DMF (15 mL) was added 1-bromo-2-chloroethane 2 (943.64 mg, 6.58 mmol). The mixture was then stirred at 50 °C for 3 h. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (50 mL x 3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc=100:0 to 80:20) to produce tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 2 (500.00 mg, 71% yield) as a colorless oil.

C9H11ClN2O2[M+H]⁺m/z的LCMS(ESI)计算值为215.05，实测值为215.00。LCMS (ESI) calcd for C9H11ClN2O2[M+H]⁺ m/z 215.05, found 215.00.

N-甲基-5-(2-(3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-基)乙氧基)吡啶酰胺(3)的制备Preparation of N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidin-1-yl)ethoxy)picolinamide (3)

向4-((2-氨甲酰基苯基)氨甲酰基)哌啶-1-甲酸叔丁酯2(500.00mg,2.33mmol)和Cs₂CO₃(2.28g,6.99mmol)在DMF(15mL)中的溶液中加入2-(哌啶-3-基甲基)喹唑啉-4(3H)-酮INT5-3(566.91mg,2.33mmol)和KI(1.16g,6.99mmol)。然后将混合物在80℃搅拌3h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取，将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为黄色固体的N-甲基-5-(2-(3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-基)乙氧基)吡啶酰胺3(200.00mg,20％收率)。To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)piperidine-1-carboxylate 2 (500.00 mg, 2.33 mmol) and Cs₂ CO₃ (2.28 g, 6.99 mmol) in DMF (15 mL) was added 2-(piperidin-3-ylmethyl)quinazolin-4(3H)-one INT5-3 (566.91 mg, 2.33 mmol) and KI (1.16 g, 6.99 mmol). The mixture was then stirred at 80° C. for 3 h. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (50 mL×3), and the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100:0 to 92:8) to give N-methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidin-1-yl)ethoxy)picolinamide 3 (200.00 mg, 20% yield) as a yellow solid.

C23H27N5O3[M+H]⁺m/z的LCMS(ESI)计算值为422.21，实测值为422.10。LCMS (ESI) calcd for C23H27N5O3[M+H]⁺ m/z 422.21, found 422.10.

N-甲基-5-(2-(3-((4-氧代-3,4-二氢喹唑啉-2-基)甲基)哌啶-1-基)乙氧基)吡啶酰胺(化合物14)的手性拆分Chiral Resolution of N-Methyl-5-(2-(3-((4-oxo-3,4-dihydroquinazolin-2-yl)methyl)piperidin-1-yl)ethoxy)picolinamide (Compound 14)

将化合物3通过SFC(柱：Daicel CHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(FA)]＝70/30)分离并在减压下浓缩以提供作为化合物14a的第一级分(31.6mg,100％纯度,ee％:100，白色固体)和作为化合物14b的第二级分(28.1mg,99％纯度,ee％:99，白色固体)Compound 3 was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (FA)]=70/30) and concentrated under reduced pressure to provide a first fraction as compound 14a (31.6 mg, 100% purity, ee%: 100, white solid) and a second fraction as compound 14b (28.1 mg, 99% purity, ee%: 99, white solid)

化合物14aCompound 14a

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.15(s,1H),8.53(q,J＝9.6,4.8Hz,1H),8.23(d,J＝2.8Hz,1H),8.07(dd,J＝8.0,1.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.79-7.73(m,1H),7.56(d,J＝8.0Hz,1H),7.49-7.42(m,2H),4.18(t,J＝5.6Hz,2H),2.90-2.81(m,2H),2.79(d,J＝4.8Hz,3H),2.73-2.65(m,2H),2.55-2.51(m,2H),2.17-2.00(m,2H),1.93-1.85(m,1H),1.70-1.59(m,2H),1.51-1.38(m,1H),1.02-0.99(m,1H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.15 (s, 1H), 8.53 (q, J＝9.6, 4.8Hz, 1H), 8.23 (d, J＝2.8Hz, 1H), 8.07 ( dd,J＝8.0,1.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.79-7.73(m,1H),7.56(d,J＝8.0Hz,1H),7.49-7.42(m ,2H),4.18(t ,J＝5.6Hz,2H),2.90-2.81(m,2H),2.79(d,J＝4.8Hz,3H),2.73-2.65(m,2H),2.55-2.51(m,2H),2.17- 2.00(m,2H),1.93-1.85(m,1H),1.70-1.59(m,2H),1.51-1.38(m,1H),1.02-0.99(m,1H).

C23H27N5O3[M+H]⁺m/z的LCMS(ESI)计算值为422.21，实测值为422.25。LCMS (ESI) calcd for C23H27N5O3[M+H]⁺ m/z 422.21, found 422.25.

化合物14bCompound 14b

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.15(s,1H),8.53(q,J＝9.6,4.8Hz,1H),8.23(d,J＝2.8Hz,1H),8.07(dd,J＝8.0,1.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.79-7.73(m,1H),7.56(d,J＝8.0Hz,1H),7.49-7.42(m,2H),4.18(t,J＝5.6Hz,2H),2.90-2.81(m,2H),2.79(d,J＝4.8Hz,3H),2.73-2.65(m,2H),2.55-2.51(m,2H),2.17-2.00(m,2H),1.93-1.85(m,1H),1.70-1.59(m,2H),1.51-1.38(m,1H),1.02-0.99(m,1H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.15 (s, 1H), 8.53 (q, J＝9.6, 4.8Hz, 1H), 8.23 (d, J＝2.8Hz, 1H), 8.07 ( dd,J＝8.0,1.2Hz,1H),7.92(d,J＝8.8Hz,1H),7.79-7.73(m,1H),7.56(d,J＝8.0Hz,1H),7.49-7.42(m ,2H),4.18(t ,J＝5.6Hz,2H),2.90-2.81(m,2H),2.79(d,J＝4.8Hz,3H),2.73-2.65(m,2H),2.55-2.51(m,2H),2.17- 2.00(m,2H),1.93-1.85(m,1H),1.70-1.59(m,2H),1.51-1.38(m,1H),1.02-0.99(m,1H).

C23H27N5O3[M+H]⁺m/z的LCMS(ESI)计算值为422.21，实测值为422.25。LCMS (ESI) calcd for C23H27N5O3[M+H]⁺ m/z 422.21, found 422.25.

实施例8-化合物17的合成Example 8-Synthesis of Compound 17

化合物17合成Synthesis of compound 17

4-(4-(乙氧基羰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (3)

向1H-吡唑-4-甲酸乙酯1(2.00g,14.30mmol)和4-((甲基磺酰基)氧基)哌啶-1-甲酸叔丁酯2(4.99g,17.87mmol)在DMF(60mL)中的溶液中加入Cs₂CO₃(10.02g,30.74mmol)。然后将混合物在120℃搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(200mL x 3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥，在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的产物4-(4-(乙氧基羰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯3(2.00g,41％收率)。To a solution of ethyl 1H-pyrazole-4-carboxylate 1 (2.00 g, 14.30 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate 2 (4.99 g, 17.87 mmol) in DMF (60 mL) was added Cs₂ CO₃ (10.02 g, 30.74 mmol). The mixture was then stirred at 120 °C for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na₂ SO₄ , and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 95:5) to yield the product tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 3 (2.00 g, 41% yield) as a white solid.

C₁₆H₂₅N₃O₄[M+H]⁺m/z的LCMS(ESI)计算值为324.18，实测值为324.20。LCMS (ESI) calcd for_C16H25N3O4 [M_+H ]⁺ m_/ z 324.18, found 324.20.

1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-甲酸(4)的制备Preparation of 1-(1-(tert-Butyloxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid (4)

向4-(4-(乙氧基羰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯3(1.50g,4.80mmol)在MeOH/H₂O＝1:1(40mL)中的溶液中加入LiOH(460.00mg,19.20mmol)。将混合物在室温搅拌1h。将反应混合物在减压下在40℃浓缩以得到残余物。在0℃向其中加入水并用1M的HCl水溶液酸化以调节pH＝4～5，将水层用EtOAc(200mL x 3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥，在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至95:5洗脱)纯化以产生作为白色固体的1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-甲酸4(1.00g,67％收率)。To a solution of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 3 (1.50 g, 4.80 mmol) in MeOH/H₂ O=1:1 (40 mL) was added LiOH (460.00 mg, 19.20 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure at 40° C. to obtain a residue. Water was added thereto at 0° C. and acidified with a 1M aqueous HCl solution to adjust pH=4-5, and the aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na₂ SO₄ , and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100:0 to 95:5) to give 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid 4 (1.00 g, 67% yield) as a white solid.

C₁₄H₂₁N₃O₄[M-56+H]⁺m/z的LCMS(ESI)计算值为240.15，实测值为240.20。LCMS (ESI) calcd for_C14H21N3O4 [M-₅₆ +H]⁺_m/ z 240.15, found 240.20.

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.29(s,1H),8.30(s,1H),7.81(s,1H),4.52-4.30(m,1H),4.03(d,J＝11.2Hz,2H),2.88(s,2H),1.99(d,J＝12.4Hz,2H),1.78(dt,J＝12.4,8.0Hz,2H),1.41(s,9H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.29(s,1H),8.30(s,1H),7.81(s,1H),4.52-4.30(m,1H),4.03(d,J =11.2Hz, 2H), 2.88 (s, 2H), 1.99 (d, J = 12.4Hz, 2H), 1.78 (dt, J = 12.4, 8.0Hz, 2H), 1.41 (s, 9H).

4-(4-((2-氨甲酰基苯基)氨甲酰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6)

向2-氨基苯甲酰胺5(299.66mg,2.20mmol)和1-(1-(叔丁氧基羰基)哌啶-4-基)-1H-吡唑-4-甲酸4(650.00mg,2.20mmol)在吡啶(25mL)中的溶液中加入EDCI(421.91mg,2.20mmol)。然后将混合物在室温搅拌12h。将反应混合物用水淬灭，将水层用EtOAc(50mL x3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物4-(4-((2-氨甲酰基苯基)氨甲酰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯6(720.00mg,71％收率)。To a solution of 2-aminobenzamide 5 (299.66 mg, 2.20 mmol) and 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazole-4-carboxylic acid 4 (650.00 mg, 2.20 mmol) in pyridine (25 mL) was added EDCI (421.91 mg, 2.20 mmol). The mixture was then stirred at room temperature for 12 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 6 (720.00 mg, 71% yield) as a white solid.

C₂₁H₂₇N₅O₄[M+H]⁺m/z的LCMS(ESI)计算值为414.21，实测值为414.25。LCMS (ESI) calcd for_C21H27N5O4 [M₊ H]⁺_m/ z 414.21, found 414.25.

4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯(7)的制备Preparation of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (7)

向4-(4-((2-氨甲酰基苯基)氨甲酰基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯6(700.00mg,1.69mmol)在二甘醇二甲醚(15mL)中的溶液中加入KOH(113.99mg,2.03mmol)，加热至140℃搅拌2h，冷却至0℃，加入冰水(10mL)然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯7(600mg,67％收率)。To a solution of tert-butyl 4-(4-((2-carbamoylphenyl)carbamoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 6 (700.00 mg, 1.69 mmol) in diethylene glycol dimethyl ether (15 mL) was added KOH (113.99 mg, 2.03 mmol), heated to 140 ° C and stirred for 2 h, cooled to 0 ° C, added ice water (10 mL) and then adjusted to pH <7 using 1M HCl solution to form a precipitate, filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 7 (600 mg, 67% yield) as a white solid.

C₂₁H₂₅N₅O₃[M+H]⁺m/z的LCMS(ESI)计算值为396.20，实测值为396.25。LCMS (ESI) calcd for_C21H25N5O3 [M₊ H]⁺_m/ z 396.20, found 396.25.

2-(1-(哌啶-4-基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮(8)的制备Preparation of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one (8)

在室温向4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡唑-1-基)哌啶-1-甲酸叔丁酯7(350.00mg,0.88mmol)的溶液中加入HCl-二氧杂环己烷(4M,40mL)。将反应混合物在室温搅拌1h。反应结束以后，将混合物在减压下浓缩以得到作为白色固体的粗制2-(1-(哌啶-4-基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮8(200mg,73％收率)。To a solution of tert-butyl 4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 7 (350.00 mg, 0.88 mmol) was added HCl-dioxane (4M, 40 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated under reduced pressure to give crude 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one 8 (200 mg, 73% yield) as a white solid.

C₁₆H₁₇N₅O[M+H]⁺m/z的LCMS(ESI)计算值为296.14，实测值为296.25。LCMS (ESI) calcd for_C16H17N5O [M₊ H]⁺ m_/ z 296.14, found 296.25.

N-甲基-5-(4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡唑-1-基)哌啶-1-基)吡啶酰胺(化合物17)的制备Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)picolinamide (Compound 17)

向2-(1-(哌啶-4-基)-1H-吡唑-4-基)喹唑啉-4(3H)-酮8(200.00mg,0.68mmol)在DMF(10mL)中的溶液中加入Cs₂CO₃(2.21g,6.77mmol)和5-氟-N-甲基吡啶酰胺INT-9-1(260.96mg,1.69mmol)。将混合物使用微波在150℃下搅拌6h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生粗制产物，将其通过制备型HPLC(Gemini 5um C18 150×21.2mm，流动相:ACN-H₂O(0.1％ FA)，梯度:25-75)纯化以产生作为白色固体的N-甲基-5-(4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-1H-吡唑-1-基)哌啶-1-基)吡啶酰胺化合物17(30mg,98％纯度,9％收率)。To a solution of 2-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one 8 (200.00 mg, 0.68 mmol) in DMF (10 mL) was added Cs₂ CO₃ (2.21 g, 6.77 mmol) and 5-fluoro-N-methylpicolinamide INT-9-1 (260.96 mg, 1.69 mmol). The mixture was stirred at 150° C. for 6 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to give a crude product, which was purified by preparative HPLC (Gemini 5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.1% FA), gradient: 25-75) to give N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazol-1-yl)piperidin-1-yl)picolinamide Compound 17 (30 mg, 98% purity, 9% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.30(s,1H),8.67(s,1H),8.43-8.40(m,1H),8.35(d,J＝2.8Hz,1H),8.26(s,1H),8.09(d,J＝8.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.80-7.76(m,1H),7.61(d,J＝8.0Hz,1H),7.50-7.42(m,2H),4.56-4.53(m,1H),4.08(d,J＝12.8Hz,2H),3.10(t,J＝11.6,10.8Hz,2H),2.79(d,J＝4.8Hz,3H),2.19-2.17(m,2H),2.06-1.98(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.30 (s, 1H), 8.67 (s, 1H), 8.43-8.40 (m, 1H), 8.35 (d, J = 2.8Hz, 1H), 8.26(s,1H),8.09(d,J＝8.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.80-7.76(m,1H),7.61(d,J＝ 8.0Hz,1H),7.50-7.42(m,2H),4.56-4.53(m,1H),4.08(d,J＝12.8Hz,2H),3.10(t,J＝11.6,10.8Hz,2H), 2.79(d,J=4.8Hz,3H),2.19-2.17(m,2H),2.06-1.98(m,2H).

C₂₃H₂₃N₇O₂[M+H]⁺m/z的LCMS(ESI)计算值为430.19，实测值为430.25。LCMS (ESI) calcd for_C23H23N7O2 [M+H]⁺_m/ z 430.19, found_430.25 .

实施例9-化合物40的合成Example 9-Synthesis of Compound 40

化合物40合成Synthesis of compound 40

8-氯喹唑啉-2,4(1H,3H)-二酮(2)的制备Preparation of 8-chloroquinazoline-2,4(1H,3H)-dione (2)

在室温向2-氨基-3-氯苯甲酸1(10.00g,58.30mmol)在HOAC(100mL)中的溶液中缓慢地加入KOCN(14.19g,174.90mmol)。将混合物加热至100℃搅拌15小时，冷却至0℃，加入冰水(30mL)。将沉淀物通过过滤进行收集，用石油醚:EtOAc＝5:1(100mL)洗涤，过滤以提供作为白色固体的8-氯喹唑啉-2,4(1H,3H)-二酮2(5.00g,40％收率)，将其不经进一步纯化直接用在下一步中。To a solution of 2-amino-3-chlorobenzoic acid 1 (10.00 g, 58.30 mmol) in HOAC (100 mL) was slowly added KOCN (14.19 g, 174.90 mmol) at room temperature. The mixture was heated to 100 ° C. and stirred for 15 hours, cooled to 0 ° C., and ice water (30 mL) was added. The precipitate was collected by filtration, washed with petroleum ether: EtOAc = 5: 1 (100 mL), and filtered to provide 8-chloroquinazoline-2,4 (1H, 3H) -dione 2 (5.00 g, 40% yield) as a white solid, which was used directly in the next step without further purification.

C₈H₅ClN₂O₂[M+H]⁺m/z的LCMS(ESI)计算值为197.00，实测值为196.95。LCMS (ESI) calcd for_C8H5ClN2O2 [M₊ H]⁺_m/ z 197.00, found 196.95.

2,4,8-三氯喹唑啉(3)的制备Preparation of 2,4,8-trichloroquinazoline (3)

在室温向8-氯喹唑啉-2,4(1H,3H)-二酮2(5.00g,25.40mmol)在POCl₃(45mL)中的溶液中缓慢地加入DMF(3mL)。将混合物加热至100℃保持12小时。将得到的混合物用冰水(200mL)稀释，并用EtOAc(400mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩并通过硅胶柱色谱法(用EtOAc/石油醚,100:0至50:50洗脱)纯化以产生作为白色固体的2,4,8-三氯喹唑啉3(2.00g,32％收率)。DMF (3 mL) was slowly added to a solution of 8-chloroquinazoline-2,4 (1H, 3H)-dione 2 (5.00 g, 25.40 mmol) in POCl₃ (45 mL) at room temperature. The mixture was heated to 100 ° C for 12 hours. The resulting mixture was diluted with ice water (200 mL) and extracted with EtOAc (400 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluted with EtOAc/petroleum ether, 100:0 to 50:50) to produce 2,4,8-trichloroquinazoline 3 (2.00 g, 32% yield) as a white solid.

C₈H₃Cl₃N₂[M+H]⁺m/z的LCMS(ESI)计算值为232.94，实测值为232.90。LCMS (ESI) calcd for_C8H3Cl3N2 [M+_H ]⁺_m/ z 232.94, found 232.90.

2,8-二氯喹唑啉-4(3H)-酮(4)的制备Preparation of 2,8-dichloroquinazolin-4(3H)-one (4)

向2,4,8-三氯喹唑啉3(2.00g,8.60mmol)在THF/H₂O＝1:1(200mL)中的溶液中加入NaOH(690mg,17.20mmol)。将混合物在室温搅拌2h。将反应混合物在减压下在40℃浓缩以得到残余物。在0℃向其中加入水并用1M的HCl水溶液酸化以调节pH 4～5。将混合物用EtOAc(200mL x 3)萃取。将合并的有机相用盐水(100mL×3)洗涤，经无水硫酸钠干燥并在真空中浓缩。将残余物通过快速色谱法(洗脱液:DCM/MeOH＝100:0至95:5)纯化以提供作为白色固体的2,8-二氯喹唑啉-4(3H)-酮4(1.60g,82％收率)。To a solution of 2,4,8-trichloroquinazoline 3 (2.00 g, 8.60 mmol) in THF/H₂ O=1:1 (200 mL) was added NaOH (690 mg, 17.20 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure at 40° C. to give a residue. Water was added thereto at 0° C. and acidified with a 1M aqueous HCl solution to adjust pH 4 to 5. The mixture was extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (100 mL×3), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (eluent: DCM/MeOH=100:0 to 95:5) to provide 2,8-dichloroquinazoline-4(3H)-one 4 (1.60 g, 82% yield) as a white solid.

C₈H₄C_l2N₂O[M+H]⁺m/z的LCMS(ESI)计算值为214.97，实测值为214.95。LCMS^{(ESI) calcd for C8H4C12N2O [M+H]+}_m/z214.97 , found 214.95.

4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(5)的制备Preparation of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (5)

在室温向2,8-二氯喹唑啉-4(3H)-酮4(400mg,1.86mmol)在二氧杂环己烷/H₂O＝10:1(40mL)中的溶液中接连地加入4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(690mg,2.23mmol)、Pd(dppf)Cl₂(50mg,0.07mmol)和Na₂CO₃(591mg,5.58mmol)。将反应混合物在N₂下在80℃搅拌18h。将混合物用水(50mL)稀释，并用EtOAc(100mL×3)萃取。将合并的有机层用盐水(100mL×2)洗涤，经Na₂SO₄干燥，过滤并在真空中浓缩以得到粗产物，将其通过快速柱色谱法(PE/EtOAc＝100:0至20:80)纯化以提供作为黄色固体的4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯5(550mg,77％收率)。To a solution of 2,8-dichloroquinazolin-4(3H)-one 4 (400 mg, 1.86 mmol) in dioxane/H₂ O=10:1 (40 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (690 mg, 2.23 mmol), Pd(dppf)Cl₂ (50 mg, 0.07 mmol) and Na₂ CO₃ (591 mg, 5.58 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 18 h under N_2. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL x 2), dried_overNa2SO4 , filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (PE/EtOAc = 100:0 to 20:80) to afford tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 5 (550 mg, 77% yield) as a yellow solid.

C₁₈H₂₀ClN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为362.12，实测值为362.10。LCMS (ESI) calcd for_C18H20ClN3O3 [M+H]⁺_m/ z 362.12, found_362.10 .

4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate (6)

向4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯5(550mg,1.52mmol)在EtOAc(200mL)中的溶液中加入PtO₂(110mg)。将混合物抽真空并用氢气回填3次并然后用氢气填充。将得到的混合物在室温搅拌1小时。然后将混合物穿过硅藻土过滤并在真空下浓缩以产生粗产物，将其通过快速柱色谱法(PE/EtOAc＝100:0至50:50)纯化以提供作为黄色固体的4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯6(400mg,65％收率)。To a solution of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 5 (550 mg, 1.52 mmol) in EtOAc (200 mL) was added PtO₂ (110 mg). The mixture was evacuated and backfilled with hydrogen 3 times and then filled with hydrogen. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then filtered through celite and concentrated under vacuum to produce a crude product, which was purified by flash column chromatography (PE/EtOAc=100:0 to 50:50) to provide tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 6 (400 mg, 65% yield) as a yellow solid.

C₁₈H₂₂ClN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为364.13，实测值为364.10。LCMS (ESI) calcd for_C18H22ClN3O3 [M+H]⁺_m/ z 364.13, found_364.10 .

8-氯-2-(哌啶-4-基)喹唑啉-4(3H)-酮(7)的制备Preparation of 8-chloro-2-(piperidin-4-yl)quinazolin-4(3H)-one (7)

向4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-甲酸叔丁酯6(400mg,1.21mmol)在DCM(5mL)中的溶液中加入TFA(2mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(2mL)然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(5mL*3)洗涤，然后干燥以产生作为白色固体的产物8-氯-2-(哌啶-4-基)喹唑啉-4(3H)-酮7(300mg,89％收率)。To a solution of tert-butyl 4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidine-1-carboxylate 6 (400 mg, 1.21 mmol) in DCM (5 mL) was added TFA (2 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (2 mL) was added and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered, and the filter cake was washed with ice water (5 mL*3) and then dried to give the product 8-chloro-2-(piperidin-4-yl)quinazolin-4(3H)-one 7 (300 mg, 89% yield) as a white solid.

C₁₃H₁₄ClN₃O[M+H]⁺m/z的LCMS(ESI)计算值为264.08，实测值为264.10。LCMS (ESI) calcd for_C13H14ClN3O [M+H]⁺_m/ z 264.08, found 264.10.

4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate (8)

向8-氯-2-(哌啶-4-基)喹唑啉-4(3H)-酮7(300mg,1.14mmol)在MeOH(60mL)中的溶液中加入4-氧代哌啶-1-甲酸叔丁酯(727mg,3.41mmol)，然后在室温加入两滴乙酸和NaBH₃CN(428mg,6.82mmol)。将反应混合物在50℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯8(300mg,51％收率)。To a solution of 8-chloro-2-(piperidin-4-yl)quinazolin-4(3H)-one 7 (300 mg, 1.14 mmol) in MeOH (60 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (727 mg, 3.41 mmol), followed by two drops of acetic acid and NaBH₃ CN (428 mg, 6.82 mmol) at room temperature. The reaction mixture was stirred at 50 ° C for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to produce tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 8 (300 mg, 51% yield) as a white solid.

C₂₄H₃₃ClN₄O₃[M+H]⁺m/z的LCMS(ESI)计算值为361.17，实测值为361.05。LCMS (ESI) calcd for_C24H33ClN4O3 [M+H]⁺_m/ z 361.17, found_361.05 .

8-氯-2-(1-(哌啶-4-基甲基)哌啶-4-基)喹唑啉-4(3H)-酮(9)的制备Preparation of 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one (9)

将4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-甲酸叔丁酯8(300mg,0.65mmol)加入在二氧杂环己烷中的HCl(4M,30mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的8-氯-2-(1-(哌啶-4-基甲基)哌啶-4-基)喹唑啉-4(3H)-酮9(200mg,81％收率)。Tert-butyl 4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidine-1-carboxylate 8 (300 mg, 0.65 mmol) was added to HCl (4M, 30 mL) in dioxane, stirred at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one 9 (200 mg, 81% yield) as a white solid.

C₁₉H₂₅ClN₄O[M+H]⁺m/z的LCMS(ESI)计算值为361.17，实测值为361.05。LCMS (ESI) calcd for_C19H25ClN4O [M+H]⁺_m/ z 361.17, found 361.05.

5-(4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-基)-N-甲基吡啶酰胺(化合物40)的制备Preparation of 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide (Compound 40)

向8-氯-2-(1-(哌啶-4-基甲基)哌啶-4-基)喹唑啉-4(3H)-酮9(150mg,0.42mmol)在DMF(10mL)中的溶液中加入Cs₂CO₃(1.35g,4.16mmol)和5-氟-N-甲基吡啶酰胺INT-9-1(160mg,1.03mmol)。将混合物使用微波在150℃下搅拌6h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为黄色固体的粗制5-(4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-基)-N-甲基吡啶酰胺化合物40。将粗产物通过制备型HPLC(Gemini 5um C18 150×21.2mm，流动相:ACN-H₂O(0.1％ FA)，梯度:20-80)纯化以产生作为白色固体的5-(4-((4-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)哌啶-1-基)甲基)哌啶-1-基)-N-甲基吡啶酰胺化合物40(24.2mg,96％纯度,11％收率)。To a solution of 8-chloro-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)quinazolin-4(3H)-one 9 (150 mg, 0.42 mmol) in DMF (10 mL) was added Cs₂ CO₃ (1.35 g, 4.16 mmol) and 5-fluoro-N-methylpicolinamide INT-9-1 (160 mg, 1.03 mmol). The mixture was stirred at 150 °C for 6 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 90:10) to yield crude 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide compound 40 as a yellow solid. The crude product was purified by preparative HPLC (Gemini 5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.1% FA), gradient: 20-80) to give 5-(4-((4-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)piperidin-1-yl)methyl)piperidin-1-yl)-N-methylpicolinamide Compound 40 (24.2 mg, 96% purity, 11% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,ppm)δ12.39(s,1H),8.40-8.37(m,1H),8.26(d,J＝2.8Hz,1H),8.04(dd,J＝7.6,1.2Hz,1H),7.94(dd,J＝7.8,1.2Hz,1H),7.81(d,J＝8.8Hz,1H),7.46-7.36(m,2H),3.91(d,J＝12.8Hz,2H),2.97-2.94(m,2H),2.86-2.81(m,2H),2.77(d,J＝4.8Hz,3H),2.65-2.53(m,1H),2.18(d,J＝6.8Hz,2H),1.97-1.80(m,9H),1.23-1.17(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ12.39 (s, 1H), 8.40-8.37 (m, 1H), 8.26 (d, J = 2.8 Hz, 1H), 8.04 (dd, J = 7.6 ,1.2Hz,1H),7.94(dd,J＝7.8,1.2Hz,1H),7.81(d,J＝8.8Hz,1H),7.46-7.36(m,2H),3 .91(d,J＝12.8Hz,2H),2.97-2.94(m,2H),2.86-2.81(m,2H),2.77(d,J＝4.8Hz,3H),2.65-2.53(m,1H ), 2.18 (d, J = 6.8 Hz, 2H), 1.97-1.80 (m, 9H), 1.23-1.17 (m, 2H).

C₂₆H₃₁ClN₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为495.22，实测值为495.15。LCMS (ESI) calcd for_C26H31ClN6O2 [M+H]⁺_m/ z 495.22, found_495.15 .

实施例10-化合物52的合成Example 10 - Synthesis of Compound 52

化合物52合成Synthesis of compound 52

3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3)

在N₂下向2,8-二氯喹唑啉-4(3H)-酮1(500mg,2.35mmol)在1,4-二氧杂环己烷/H₂O＝5:1(60mL)中的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯2(900mg,3.00mmol)、Pd(dppf)Cl₂(170mg,0.23mmol)和Na₂CO₃(740mg,6.98mmol)。将反应混合物在80℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至91:9洗脱)纯化以产生作为白色固体的3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯3(400mg,40％收率)。_To a solution of 2,8-dichloroquinazolin-4(3H)-one 1 (500 mg, 2.35 mmol) in 1,4-dioxane/H₂ O=5:1 (60 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 2 (900 mg, 3.00 mmol), Pd(dppf)Cl₂ (170 mg, 0.23 mmol) and Na₂ CO₃ (740 mg, 6.98 mmol) under N 2. The reaction mixture was stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100:0 to 91:9) to give tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 3 (400 mg, 40% yield) as a white solid.

C17H18ClN3O3[M+H]⁺m/z的LCMS(ESI)计算值为348.10，实测值为348.17。LCMS (ESI) calcd for C17H18ClN3O3[M+H]⁺ m/z was 348.10, found 348.17.

3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate (4)

在H₂下向3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯3(400mg,1.15mmol)在EtOAc(50mL)中的溶液中加入PtO₂(80mg,0.35mmol)。将反应混合物在室温搅拌2h。将混合物穿过硅藻土垫过滤，并将滤液浓缩以产生作为白色固体的3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯4(200mg,50％收率)粗产物。To a solution of tert-_butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 3 (400 mg, 1.15 mmol) in EtOAc (50 mL) was added_PtO (80 mg, 0.35 mmol) under H. The reaction mixture was stirred at room temperature for 2 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated to yield tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate 4 (200 mg, 50% yield) crude product as a white solid.

C17H₂₀ClN3O3[M+H]⁺m/z的LCMS(ESI)计算值为350.12，实测值为350.18。LCMS (ESI) calcd for_C17H20ClN3O3 [M+H]⁺ m/z: 350.12, found: 350.18.

8-氯-2-(吡咯烷-3-基)喹唑啉-4(3H)-酮(5)的制备Preparation of 8-chloro-2-(pyrrolidin-3-yl)quinazolin-4(3H)-one (5)

将3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-甲酸叔丁酯4(200mg,0.57mmol)加入在二氧杂环己烷中的HCl(4M,5mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的产物8-氯-2-(吡咯烷-3-基)喹唑啉-4(3H)-酮5(130mg,82％收率)。Tert-butyl 3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidine-1-carboxylate 4 (200 mg, 0.57 mmol) was added to HCl (4M, 5 mL) in dioxane, stirred at room temperature for 1 h, the reaction mixture was concentrated under reduced pressure to give the product 8-chloro-2-(pyrrolidin-3-yl)quinazolin-4(3H)-one 5 (130 mg, 82% yield) as a white solid.

C12H12ClN3O[M+H]⁺m/z的LCMS(ESI)计算值为250.07，实测值为250.12。LCMS (ESI) calcd for C12H12ClN3O[M+H]⁺ m/z 250.07, found 250.12.

5-(4-(3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(7)的制备Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (7)

向8-氯-2-(吡咯烷-3-基)喹唑啉-4(3H)-酮5(80mg,0.32mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺6(50mg,0.21mmol)，然后在室温加入三滴乙酸和NaBH₃CN(15mg,0.24mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为白色固体的5-(4-(3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺7(40mg,40％收率)。To a solution of 8-chloro-2-(pyrrolidin-3-yl)quinazolin-4(3H)-one 5 (80 mg, 0.32 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide 6 (50 mg, 0.21 mmol), followed by three drops of acetic acid and NaBH₃ CN (15 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at 50 ° C for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to produce 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 7 (40 mg, 40% yield) as a white solid.

C24H27ClN6O2[M+H]⁺m/z的LCMS(ESI)计算值为467.19，实测值为467.28。LCMS (ESI) calcd for C24H27ClN6O2[M+H]⁺ m/z 467.19, found 467.28.

5-(4-(3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物52a和化合物52b)的制备Preparation of 5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 52a and Compound 52b)

将5-(4-(3-(8-氯-4-氧代-3,4-二氢喹唑啉-2-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺7通过SFC(柱：DAICEL AS-H4.6mmI.D.*250mmL 5μm；流动相:CO2/IPA[0.1％NH3(7M在MeOH中的溶液)]＝60/40)分离并在减压下浓缩以提供作为化合物52a的第一级分(14.4mg,97％纯度,ee％:100，白色固体)和作为化合物52b的第二级分(15.4mg,99％纯度,ee％:100，白色固体)5-(4-(3-(8-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 7 was separated by SFC (column: DAICEL AS-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO 2 /IPA [0.1% NH 3 (7 M solution in MeOH)]=60/40) and concentrated under reduced pressure to give a first fraction as compound 52a (14.4 mg, 97% purity, ee%: 100, white solid) and a second fraction as compound 52b (15.4 mg, 99% purity, ee%: 100, white solid)

化合物52aCompound 52a

¹H NMR(400MHz,DMSO)δ8.42(d,J＝4.8Hz,1H),8.27(d,J＝2.8Hz,1H),8.05(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.48-7.38(m,2H),3.83(d,J＝12.8Hz,2H),3.40-3.32(m,1H),3.06(t,J＝9.2Hz,1H),2.95(dd,J＝22.0,12.0Hz,3H),2.80-2.68(m,5H),2.38(t,J＝10.4Hz,1H),2.24-2.15(m,2H),1.96(d,J＝11.2Hz,2H),1.53(dd,J＝22.8,10.8Hz,2H)。¹ H NMR (400MHz, DMSO) δ8.42(d,J＝4.8Hz,1H),8.27(d,J＝2.8Hz,1H),8.05(d,J＝8.0Hz,1H),7.94(d, J＝8.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.48-7.38(m,2H),3.83(d,J＝12.8Hz,2H),3.40- 3.32(m,1H),3.06(t,J＝9.2Hz,1H),2.95(dd,J＝22.0,12.0Hz,3H),2.80-2.68(m,5H),2.38(t,J＝10.4Hz ,1H),2.24-2.15(m,2H),1.96(d,J＝11.2Hz,2H),1.53(dd,J＝22.8,10.8Hz,2H).

C24H27ClN6O2[M+H]⁺m/z的LCMS(ESI)计算值为467.19，实测值为467.28。LCMS (ESI) calcd for C24H27ClN6O2[M+H]⁺ m/z 467.19, found 467.28.

化合物52bCompound 52b

¹H NMR(400MHz,DMSO)δ8.49(d,J＝4.8Hz,1H),8.34(d,J＝2.4Hz,1H),8.11(d,J＝7.6Hz,1H),8.01(d,J＝7.6Hz,1H),7.89(d,J＝8.8Hz,1H),7.55-7.45(m,2H),3.90(d,J＝12.4Hz,2H),3.45-3.39(m,1H),3.13(t,J＝8.8Hz,1H),3.01(dd,J＝22.8,11.6Hz,3H),2.87-2.77(m,5H),2.43(d,J＝10.0Hz,1H),2.26(d,J＝6.4Hz,2H),2.02(d,J＝11.2Hz,2H),1.59(d,J＝12.0Hz,2H)。¹ H NMR (400MHz, DMSO) δ8.49(d,J＝4.8Hz,1H),8.34(d,J＝2.4Hz,1H),8.11(d,J＝7.6Hz,1H),8.01(d, J＝7.6Hz,1H),7.89(d,J＝8.8Hz,1H),7.55-7.45(m,2H),3.90(d,J＝12.4Hz,2H),3.45 -3.39(m,1H),3.13(t,J＝8.8Hz,1H),3.01(dd,J＝22.8,11.6Hz,3H),2.87-2.77(m,5H),2.43(d,J＝10.0 Hz, 1H), 2.26 (d, J = 6.4 Hz, 2H), 2.02 ( d, J = 11.2 Hz, 2H), 1.59 ( d, J = 12.0 Hz, 2H).

C24H27ClN6O2[M+H]⁺m/z的LCMS(ESI)计算值为467.19，实测值为467.28。LCMS (ESI) calcd for C24H27ClN6O2[M+H]⁺ m/z 467.19, found 467.28.

实施例11-化合物54的合成Example 11 - Synthesis of Compound 54

化合物54合成Synthesis of compound 54

4-{[(2-氨甲酰基苯基)氨甲酰基]甲基}哌啶-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate (3)

向2-氨基苯甲酰胺1(2.00g,14.70mmol)和{1-[(叔丁氧基)羰基]哌啶-4-基}乙酸2(3.58g,14.70mmol)在吡啶(50mL)中的溶液中加入EDCI(2.82g,14.70mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为黄色油的4-{[(2-氨甲酰基苯基)氨甲酰基]甲基}哌啶-1-甲酸叔丁酯3(5.76g,92％收率)。To a solution of 2-aminobenzamide 1 (2.00 g, 14.70 mmol) and {1-[(tert-butoxy)carbonyl]piperidin-4-yl}acetic acid 2 (3.58 g, 14.70 mmol) in pyridine (50 mL) was added EDCI (2.82 g, 14.70 mmol). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate 3 (5.76 g, 92% yield) as a yellow oil.

C19H27N3O4[M+H]⁺m/z的LCMS(ESI)计算值为362.20，实测值为262.30。LCMS (ESI) calcd for C19H27N3O4[M+H]⁺ m/z 362.20, found 262.30.

4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (4)

向4-{[(2-氨甲酰基苯基)氨甲酰基]甲基}哌啶-1-甲酸叔丁酯3(5.76g,15.90mmol)在二甘醇二甲醚(40mL)中的溶液中加入KOH(1.16g,20.67mmol)，加热至140℃搅拌2h，冷却至0℃，加入冰水(50mL)然后使用1M HCl溶液调节pH<7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-甲酸叔丁酯4(4.20g,73％收率)。To a solution of tert-butyl 4-{[(2-carbamoylphenyl)carbamoyl]methyl}piperidine-1-carboxylate 3 (5.76 g, 15.90 mmol) in diethylene glycol dimethyl ether (40 mL) was added KOH (1.16 g, 20.67 mmol), heated to 140 ° C. and stirred for 2 h, cooled to 0 ° C., ice water (50 mL) was added and then 1M HCl solution was used to adjust the pH <7 to form a precipitate, which was filtered and the filter cake was washed with ice water (50 mL*3) and then dried to give the product tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate 4 (4.20 g, 73% yield) as a white solid.

C19H25N3O3[M+H]⁺m/z的LCMS(ESI)计算值为344.19，实测值为344.25。LCMS (ESI) calcd for C19H25N3O3[M+H]⁺ m/z 344.19, found 344.25.

2-(哌啶-4-基甲基)-3H-喹唑啉-4-酮(5)的制备Preparation of 2-(piperidin-4-ylmethyl)-3H-quinazolin-4-one (5)

向4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-甲酸叔丁酯4(4.20g,10.00mmol)在DCM(13mL)中的溶液中加入TFA(13mL)，在室温搅拌1h，将混合物在减压下浓缩以产生粗产物，加入冰水(20mL)然后使用氢氧化铵溶液调节pH>7，形成沉淀物，过滤，将滤饼用冰水(50mL*3)洗涤，然后干燥以产生作为白色固体的产物2-(哌啶-4-基甲基)-3H-喹唑啉-4-酮5(2.32g,90％收率)。To a solution of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate 4 (4.20 g, 10.00 mmol) in DCM (13 mL) was added TFA (13 mL), stirred at room temperature for 1 h, and the mixture was concentrated under reduced pressure to give a crude product, ice water (20 mL) was added and then the pH was adjusted to >7 using ammonium hydroxide solution to form a precipitate, which was filtered, and the filter cake was washed with ice water (50 mL*3) and then dried to give the product 2-(piperidin-4-ylmethyl)-3H-quinazolin-4-one 5 (2.32 g, 90% yield) as a white solid.

C14H17N3O[M+H]⁺m/z的LCMS(ESI)计算值为244.14，实测值为244.25。LCMS (ESI) calcd for C14H17N3O[M+H]⁺ m/z 244.14, found 244.25.

4-{4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-基}哌啶-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidine-1-carboxylate (6)

向2-(哌啶-4-基甲基)-3H-喹唑啉-4-酮5(500mg,2.06mmol)在MeOH(50mL)中的溶液中加入4-氧代哌啶-1-甲酸叔丁酯(532mg,2.67mmol)，然后在室温加入两滴乙酸和NaBH₃CN(504mg,8.01mmol)。将反应混合物在50℃搅拌18h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至91:9洗脱)纯化以产生作为白色固体的4-{4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-基}哌啶-1-甲酸叔丁酯6(244mg,25％收率)。To a solution of 2-(piperidin-4-ylmethyl)-3H-quinazolin-4-one 5 (500 mg, 2.06 mmol) in MeOH (50 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (532 mg, 2.67 mmol), followed by two drops of acetic acid and NaBH₃ CN (504 mg, 8.01 mmol) at room temperature. The reaction mixture was stirred at 50 ° C for 18 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 91:9) to produce tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidine-1-carboxylate 6 (244 mg, 25% yield) as a white solid.

C24H34N4O3[M+H]⁺m/z的LCMS(ESI)计算值为427.26，实测值为427.40。LCMS (ESI) calcd for C24H34N4O3[M+H]⁺ m/z 427.26, found 427.40.

4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-甲酸叔丁酯(7)的制备Preparation of tert-butyl 4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidine-1-carboxylate (7)

将4-{4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-基}哌啶-1-甲酸叔丁酯6(244mg,0.57mmol)加入在二氧杂环己烷中的HCl(4M,8mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的2-{[1-(哌啶-4-基)哌啶-4-基]甲基}-3H-喹唑啉-4-酮7(187mg,90％收率)。Tert-butyl 4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidine-1-carboxylate 6 (244 mg, 0.57 mmol) was added to HCl (4M, 8 mL) in dioxane, stirred at room temperature for 1 h, and the reaction mixture was concentrated under reduced pressure to give 2-{[1-(piperidin-4-yl)piperidin-4-yl]methyl}-3H-quinazolin-4-one 7 (187 mg, 90% yield) as a white solid.

C19H26N4O[M+H]⁺m/z的LCMS(ESI)计算值为327.21，实测值为327.44。LCMS (ESI) calcd for C19H26N4O[M+H]⁺ m/z 327.21, found 327.44.

N-甲基-5-(4-{4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-基}哌啶-1-基)吡啶-2-甲酰胺(化合物54)的制备Preparation of N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidin-1-yl)pyridine-2-carboxamide (Compound 54)

向2-{[1-(哌啶-4-基)哌啶-4-基]甲基}-3H-喹唑啉-4-酮7(200mg,0.61mmol)在DMF(16mL)中的溶液中加入Cs₂CO₃(1.20g,3.68mmol)和5-氟-N-甲基吡啶-2-甲酰胺5(208mg,1.35mmol)。将混合物使用微波在150℃下搅拌5h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至91:9洗脱)纯化以产生作为白色固体的N-甲基-5-(4-{4-[(4-氧代-3H-喹唑啉-2-基)甲基]哌啶-1-基}哌啶-1-基)吡啶-2-甲酰胺化合物54(20.11mg,99％纯度,7％收率)。To a solution of 2-{[1-(piperidin-4-yl)piperidin-4-yl]methyl}-3H-quinazolin-4-one 7 (200 mg, 0.61 mmol) in DMF (16 mL) was added Cs₂ CO₃ (1.20 g, 3.68 mmol) and 5-fluoro-N-methylpyridine-2-carboxamide 5 (208 mg, 1.35 mmol). The mixture was stirred at 150 °C for 5 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 91:9) to give N-methyl-5-(4-{4-[(4-oxo-3H-quinazolin-2-yl)methyl]piperidin-1-yl}piperidin-1-yl)pyridine-2-carboxamide compound 54 (20.11 mg, 99% purity, 7% yield) as a white solid.

¹H NMR(400MHz,DMSO)δ12.16(s,1H),8.37(d,J＝4.8Hz,1H),8.25(d,J＝2.8Hz,1H),8.07(d,J＝8.0Hz,1H),7.83-7.74(m,2H),7.59(d,J＝8.0Hz,1H),7.45(t,J＝7.6Hz,1H),7.37(dd,J＝8.8,2.8Hz,1H),3.93(d,J＝12.4Hz,2H),2.90-2.74(m,8H),2.14(t,J＝10.8Hz,2H),1.81(d,J＝11.6Hz,3H),1.64(d,J＝10.8Hz,2H),1.49(d,J＝8.8Hz,2H),1.23(d,J＝9.2Hz,3H)。¹ H NMR (400MHz, DMSO) δ12.16 (s, 1H), 8.37 (d, J = 4.8Hz, 1H), 8.25 (d, J = 2.8Hz, 1H), 8.07 (d, J = 8.0Hz, 1H),7.83-7.74(m,2H),7.59(d,J＝8.0Hz,1H),7.45(t,J＝7.6Hz,1H),7.37(dd,J ＝8.8,2.8Hz,1H),3.93(d,J＝12.4Hz,2H),2.90-2.74(m,8H),2.14(t,J＝10.8Hz,2H),1.81(d,J＝11.6Hz ,3H), 1.64(d,J＝10.8Hz,2H), 1.49(d,J＝8.8Hz,2H), 1.23(d,J＝9.2Hz,3H).

C24H28N6O2[M+H]⁺m/z的LCMS(ESI)计算值为461.26，实测值为461.40。LCMS (ESI) calcd for C24H28N6O2[M+H]⁺ m/z 461.26, found 461.40.

实施例12-化合物136rac、136a和136b的合成化合物136rac、136a和136b的合成Example 12 - Synthesis of Compounds 136rac, 136a and 136b Synthesis of Compounds 136rac, 136a and 136b

N,N-二乙基-2-氟-6-甲基苯甲酰胺(3)的制备Preparation of N,N-diethyl-2-fluoro-6-methylbenzamide (3)

在室温向2-氟-6-甲基苯甲酸1(1.00g,6.50mmol)和二乙胺2(0.57g,7.80mmol)在DCM(50mL)中的溶液中加入三甲苯基膦(50％在EtOAc中)(3.10g,9.75mmol)和DIEA(4.20g,32.50mmol)。将混合物在室温搅拌1h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至90:10洗脱)纯化以产生作为白色固体的N,N-二乙基-2-氟-6-甲基苯甲酰胺3(0.90g,63％收率)。To a solution of 2-fluoro-6-methylbenzoic acid 1 (1.00 g, 6.50 mmol) and diethylamine 2 (0.57 g, 7.80 mmol) in DCM (50 mL) was added tritolylphosphine (50% in EtOAc) (3.10 g, 9.75 mmol) and DIEA (4.20 g, 32.50 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAC=100:0 to 90:10) to produce N,N-diethyl-2-fluoro-6-methylbenzamide 3 (0.90 g, 63% yield) as a white solid.

C12H16FNO[M+H]⁺m/z的LCMS(ESI)计算值为210.12，实测值为210.09。LCMS (ESI) calcd for C12H16FNO[M+H]⁺ m/z 210.12, found 210.09.

3-羟基-1-(1-甲基苯基)吡咯烷-3-甲酸(5)的制备Preparation of 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid (5)

在惰性气氛下在-78℃将无水THF(30ml)装入带有加料漏斗的干燥三颈圆底烧瓶中。逐滴加入LDA溶液(2.5M在THF中的溶液，0.9ml)。在整个添加过程中将内部温度维持在-70℃以下。在-78℃保持0.5h以后，逐滴加入N,N-二乙基-2-氟-6-甲基苯甲酰胺3(300mg,1.43mmol)在无水THF(10ml)中的溶液，并将混合物搅拌1h，然后在-78℃加入3-氰基吡咯烷-1-甲酸叔丁酯4(366mg,1.86mmol)。将混合物在室温搅拌18h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以产生作为白色固体的3-羟基-1-(1-甲基苯基)吡咯烷-3-甲酸5(160mg,32％收率)。Anhydrous THF (30 ml) was charged into a dry three-necked round bottom flask with an addition funnel at -78°C under an inert atmosphere. LDA solution (2.5M solution in THF, 0.9 ml) was added dropwise. The internal temperature was maintained below -70°C throughout the addition. After 0.5 h at -78°C, a solution of N,N-diethyl-2-fluoro-6-methylbenzamide 3 (300 mg, 1.43 mmol) in anhydrous THF (10 ml) was added dropwise, and the mixture was stirred for 1 h, then tert-butyl 3-cyanopyrrolidine-1-carboxylate 4 (366 mg, 1.86 mmol) was added at -78°C. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAc = 100:0 to 80:20) to give 3-hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid 5 (160 mg, 32% yield) as a white solid.

C18H21FN2O3[M+H]⁺m/z的LCMS(ESI)计算值为333.15，实测值为333.25。LCMS (ESI) calcd for C18H21FN2O3[M+H]⁺ m/z 333.15, found 333.25.

8-氟-3-(吡咯烷-3-基)-2H-异喹啉-1-酮(6)的制备Preparation of 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one (6)

将3-羟基-1-(1-甲基苯基)吡咯烷-3-甲酸5(160mg,0.48mmol)加入HCl-二氧杂环己烷(4M,10mL)中。将混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的8-氟-3-(吡咯烷-3-基)-2H-异喹啉-1-酮6(120mg,97％收率)。3-Hydroxy-1-(1-methylphenyl)pyrrolidine-3-carboxylic acid 5 (160 mg, 0.48 mmol) was added to HCl-dioxane (4M, 10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one 6 (120 mg, 97% yield) as a white solid.

C13H13FN2O[M+H]⁺m/z的LCMS(ESI)计算值为233.10，实测值为233.12。LCMS (ESI) calcd for C13H13FN2O [M+H]⁺ m/z 233.10, found 233.12.

5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(化合物136rac)的制备Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 136rac)

向8-氟-3-(吡咯烷-3-基)-2H-异喹啉-1-酮6(120mg,0.52mmol)在MeOH(15mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT(100mg,0.55mmol)，然后在室温加入两滴乙酸和NaBH₃CN(30mg,0.46mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为黄色固体的5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺化合物136rac(65mg,25％收率,99％纯度)。To a solution of 8-fluoro-3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one 6 (120 mg, 0.52 mmol) in MeOH (15 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT (100 mg, 0.55 mmol), followed by two drops of acetic acid and NaBH₃ CN (30 mg, 0.46 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to give 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide compound 136rac (65 mg, 25% yield, 99% purity) as a yellow solid.

化合物136racCompound 136rac

¹H NMR(400MHz,DMSO)δ11.10(s,1H),8.41-8.38(m,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.62-7.58(m,1H),7.45-7.36(m,2H),7.10(dd,J＝11.6,8.0Hz,1H),6.46(d,J＝1.6Hz,1H),3.84-3.80(m,2H),3.23-3.16(m,1H),3.00-2.92(m,3H),2.84-2.65(m,6H),2.38-2.33(m,1H),2.24-2.18(m,1H),1.97-1.97(m,2H),1.84-1.76(m,1H),1.60-1.49(m,2H)。¹ H NMR (400MHz, DMSO) δ11.10 (s, 1H), 8.41-8.38 (m, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.83 (d, J = 8.8Hz, 1H), 7.62-7.58(m,1H),7.45-7.36(m,2H),7.10(dd,J＝11.6,8.0Hz,1H),6.46(d,J＝1. 6Hz,1H),3.84-3.80(m,2H),3.23-3.16(m,1H),3.00-2.92(m,3H),2.84-2.65(m,6H),2.38-2.33(m,1H), 2.24-2.18(m,1H),1.97-1.97(m,2H),1.84-1.76(m,1H),1.60-1.49(m,2H).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.30。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.30.

5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(化合物136a和化合物136b)的制备Preparation of 5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (Compound 136a and Compound 136b)

将5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺136rac通过SFC(柱：Daicel CHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝70/30)分离并在减压下浓缩以提供作为化合物136a的第一级分(12.8mg,99％纯度,ee％:100，白色固体)和作为化合物136b的第二级分(13.8mg,99％纯度,ee％:97，白色固体)5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide 136rac was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=70/30) and concentrated under reduced pressure to give a first fraction as compound 136a (12.8 mg, 99% purity, ee%: 100, white solid) and a second fraction as compound 136b (13.8 mg, 99% purity, ee%: 97, white solid).

化合物136aCompound 136a

¹H NMR(400MHz,DMSO)δ11.10(s,1H),8.41(q,J＝4.4Hz,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.62-7.58(m,1H),7.42-7.36(m,2H),7.10(dd,J＝12.0,8.0Hz,1H),6.46(s,1H),3.84-3.80(m,2H),3.22-3.15(m,1H),3.00-2.90(m,3H),2.81-2.63(m,6H),2.36-2.31(m,1H),2.23-2.18(m,1H),1.97-1.93(m,2H),1.87-1.79(m,1H),1.56-1.52(m,2H)。¹ H NMR (400MHz, DMSO) δ11.10 (s, 1H), 8.41 (q, J = 4.4Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.83 (d, J = 8.8Hz, 1H),7.62-7.58(m,1H),7.42-7.36(m,2H),7.10(dd,J＝12.0,8.0Hz,1H),6.46(s ,1H),3.84-3.80(m,2H),3.22-3.15(m,1H),3.00-2.90(m,3H),2.81-2.63(m,6H),2.36-2.31(m,1H),2.23 -2.18(m,1H),1.97-1.93(m,2H),1.87-1.79(m,1H),1.56-1.52(m,2H).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.20。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.20.

化合物136bCompound 136b

¹H NMR(400MHz,DMSO)δ11.10(s,1H),8.40(q,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.61-7.58(m,1H),7.42-7.36(m,2H),7.10(dd,J＝11.6,8.0Hz,1H),6.46(s,1H),3.84-3.80(m,2H),3.22-3.15(m,1H),3.00-2.90(m,3H),2.81-2.63(m,6H),2.36-2.31(m,1H),2.25-2.18(m,1H),1.97-1.94(m,2H),1.87-1.79(m,1H),1.56-1.52(m,2H)。¹ H NMR (400MHz, DMSO) δ11.10 (s, 1H), 8.40 (q, J = 4.8Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.82 (d, J = 8.8Hz, 1H),7.61-7.58(m,1H),7.42-7.36(m,2H),7.10(dd,J＝11.6,8.0Hz,1H),6.46(s ,1H),3.84-3.80(m,2H),3.22-3.15(m,1H),3.00-2.90(m,3H),2.81-2.63(m,6H),2.36-2.31(m,1H),2.25 -2.18(m,1H),1.97-1.94(m,2H),1.87-1.79(m,1H),1.56-1.52(m,2H).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.25。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.25.

实施例13-化合物151rac、151a和151b的合成化合物151rac、151a和151b的合成Example 13 - Synthesis of Compounds 151rac, 151a and 151b Synthesis of Compounds 151rac, 151a and 151b

3-(5-氨基-6-甲氧基吡啶-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯(3)的制备Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate (3)

向6-溴-2-甲氧基吡啶-3-胺1(1.38g,6.80mmol)在1,4-二氧杂环己烷/H₂O＝4:1(20mL)中的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯2(2.01g,6.80mmol)，然后在室温加入Pd(dppf)Cl₂(0.50g,0.68mmol)和Na₂CO₃(2.23g,21.08mmol)。将反应混合物在氮气下在N₂下在80℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-氨基-6-甲氧基吡啶-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯3(1.50g,72％收率)。To a solution of 6-bromo-2-methoxypyridin-3-amine 1 (1.38 g, 6.80 mmol) in 1,4-dioxane/H₂ O=4:1 (20 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate 2 (2.01 g, 6.80 mmol), followed by addition of Pd(dppf)Cl₂ (0.50 g, 0.68 mmol) and Na₂ CO₃ (2.23 g, 21.08 mmol) at room temperature. The reaction mixture was stirred at 80° C. under nitrogen for 3 h under N_2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EA = 100:0 to 85:15) to give tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate 3 (1.50 g, 72% yield) as a white solid.

C15H21N3O3[M+H]⁺m/z的LCMS(ESI)计算值为292.16，实测值为292.19。LCMS (ESI) calcd for C15H21N3O3[M+H]⁺ m/z was 292.16, found 292.19.

3-(5-氨基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (4)

在室温向3-(5-氨基-6-甲氧基吡啶-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯3(1.50g,5.10mmol)在MeOH(20mL)中的溶液中加入Pd/C(0.54g,5.10mmol)。将反应混合物在氢气下在50℃搅拌2h。冷却至室温之后，将反应混合物过滤，将溶液在减压下浓缩以产生作为白色固体的产物3-(5-氨基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯4(1.20g,76％收率)。To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)-2,5-dihydropyrrole-1-carboxylate 3 (1.50 g, 5.10 mmol) in MeOH (20 mL) was added Pd/C (0.54 g, 5.10 mmol) at room temperature. The reaction mixture was stirred at 50 °C under hydrogen for 2 h. After cooling to room temperature, the reaction mixture was filtered and the solution was concentrated under reduced pressure to give the product tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 4 (1.20 g, 76% yield) as a white solid.

C15H23N3O3[M+H]⁺m/z的LCMS(ESI)计算值为294.17，实测值为294.18。LCMS (ESI) calcd for C15H23N3O3[M+H]⁺ m/z was 294.17, found 294.18.

3-(5-溴-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯(5)的制备Preparation of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (5)

向3-(5-氨基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯4(1.40g,4.80mmol)在ACN(20mL)中的溶液中加入亚硝酸叔丁酯(1.14g,11.04mmol)。然后在室温加入CuBr(1.38g,9.60mmol)。将反应混合物在50℃搅拌2h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-溴-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯5(0.65g,35％收率)。To a solution of tert-butyl 3-(5-amino-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 4 (1.40 g, 4.80 mmol) in ACN (20 mL) was added tert-butyl nitrite (1.14 g, 11.04 mmol). CuBr (1.38 g, 9.60 mmol) was then added at room temperature. The reaction mixture was stirred at 50 ° C for 2 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EA=100:0 to 85:15) to produce tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 5 (0.65 g, 35% yield) as a white solid.

C15H21BrN2O3[M+H]⁺m/z的LCMS(ESI)计算值为357.07，实测值为357.11。LCMS (ESI) calculated value of m/z for C15H21BrN2O3[M+H]⁺ is 357.07, found is 357.11.

3-(5-乙基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯(6)的制备Preparation of tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate (6)

向3-(5-溴-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯5(300mg,0.84mmol)在1,4-二氧杂环己烷(15mL)中的溶液中加入Pd(dppf)Cl₂(61mg,0.08mmol)。然后在室温加入Et₂Zn(5mL,0.14mml)。将反应混合物在氮气下在80℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EA＝100:0至85:15洗脱)纯化以产生作为白色固体的3-(5-乙基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯6(120mg,44％收率)。To a solution of tert-butyl 3-(5-bromo-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 5 (300 mg, 0.84 mmol) in 1,4-dioxane (15 mL) was added Pd(dppf)Cl₂ (61 mg, 0.08 mmol). Then Et₂ Zn (5 mL, 0.14 mml) was added at room temperature. The reaction mixture was stirred at 80 °C for 3 h under nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EA=100:0 to 85:15) to give tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 6 (120 mg, 44% yield) as a white solid.

C17H26N2O3[M+H]⁺m/z的LCMS(ESI)计算值为307.19，实测值为307.25。LCMS (ESI) calcd for C17H26N2O3[M+H]⁺ m/z 307.19, found 307.25.

3-乙基-6-(吡咯烷-3-基)-1H-吡啶-2-酮(7)的制备Preparation of 3-ethyl-6-(pyrrolidin-3-yl)-1H-pyridin-2-one (7)

将3-(5-乙基-6-甲氧基吡啶-2-基)吡咯烷-1-甲酸叔丁酯6(120mg,0.39mmol)加入HBr水溶液(48％,15mL)中。将反应混合物在100℃搅拌6h。冷却至室温之后，将反应混合物在减压下浓缩以产生作为白色固体的3-乙基-6-(吡咯烷-3-基)-1H-吡啶-2-酮7(70mg,88％收率)。Tert-butyl 3-(5-ethyl-6-methoxypyridin-2-yl)pyrrolidine-1-carboxylate 6 (120 mg, 0.39 mmol) was added to aqueous HBr solution (48%, 15 mL). The reaction mixture was stirred at 100 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give 3-ethyl-6-(pyrrolidin-3-yl)-1H-pyridin-2-one 7 (70 mg, 88% yield) as a white solid.

C11H16N2O[M+H]⁺m/z的LCMS(ESI)计算值为193.13，实测值为193.14。LCMS (ESI) calcd for C11H16N2O [M+H]⁺ m/z 193.13, found 193.14.

5-(4-(3-(5-乙基-6-氧代-1,6-二氢吡啶-2-基)吡咯烷-1-基)哌啶-1-基)-6-氟-N-甲基吡啶酰胺(151rac)的制备Preparation of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-6-fluoro-N-methylpicolinamide (151rac)

向6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT-2(100mg,0.40mmol)在MeOH(40mL)中的溶液中加入3-乙基-6-(吡咯烷-3-基)-1H-吡啶-2-酮7(115mg,0.60mmol)，然后在室温加入两滴乙酸和NaBH₃CN(38mg,0.61mmol)。将反应混合物在50℃搅拌12h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以提供作为白色固体的5-(4-(3-(5-乙基-6-氧代-1,6-二氢吡啶-2-基)吡咯烷-1-基)哌啶-1-基)-6-氟-N-甲基吡啶酰胺151rac(40mg,95％纯度,22.34％收率)。To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (100 mg, 0.40 mmol) in MeOH (40 mL) was added 3-ethyl-6-(pyrrolidin-3-yl)-1H-pyridin-2-one 7 (115 mg, 0.60 mmol), followed by two drops of acetic acid and NaBH₃ CN (38 mg, 0.61 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 90:10) to afford 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-6-fluoro-N-methylpicolinamide 151rac (40 mg, 95% purity, 22.34% yield) as a white solid.

C₂₃H₃₀FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为428.24，实测值为428.10。LCMS (ESI) calcd for_C23H30FN5O2 [M₊ H]⁺_m/ z 428.24, found 428.10.

5-(4-(3-(5-乙基-6-氧代-1,6-二氢吡啶-2-基)吡咯烷-1-基)哌啶-1-基)-6-氟-N-甲基吡啶酰胺(化合物151a和化合物151b)的手性拆分Chiral Resolution of 5-(4-(3-(5-ethyl-6-oxo-1,6-dihydropyridin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)-6-fluoro-N-methylpicolinamide (Compound 151a and Compound 151b)

将化合物151通过SFC(柱：Daicel Chiralpak AD-H SFC 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝80/20)分离并在减压下浓缩以提供作为化合物151a的第一级分(15.8mg,92％纯度,ee％:100，白色固体)和作为化合物151b的第二级分(15.9mg,95％纯度,ee％:100，白色固体)Compound 151 was separated by SFC (column: Daicel Chiralpak AD-H SFC 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=80/20) and concentrated under reduced pressure to provide a first fraction as Compound 151a (15.8 mg, 92% purity, ee%: 100, white solid) and a second fraction as Compound 151b (15.9 mg, 95% purity, ee%: 100, white solid)

化合物151aCompound 151a

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.28(s,1H),8.44-8.37(m,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.61-7.52(m,1H),7.17(d,J＝7.2Hz,1H),6.03(d,J＝6.4Hz,1H),3.56-3.43(m,2H),3.17-3.09(m,1H),2.90-2.74(m,7H),2.68-2.60(m,2H),2.35-2.17(m,4H),1.96(d,J＝12.0Hz,2H),1.79-1.70(m,1H),1.63-1.52(m,2H),1.06(t,J＝7.2Hz,3H)。¹ H NMR (400 MHz, DMSO-d₆ ,ppm)δ:11.28(s,1H),8.44-8.37(m,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.61-7.52(m,1H),7.17(d,J＝7.2Hz,1H),6.03(d,J＝6.4Hz,1H),3.56-3.43(m,2 H),3.17-3.09(m,1H),2.90-2.74(m,7H),2.68-2.60(m,2H),2.35-2.17(m,4H),1.96(d,J＝12.0Hz,2H),1.79-1.70(m,1H),1.63-1.52(m,2H),1.0 6(t,J=7.2Hz,3H).

C₂₃H₃₀FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为428.24，实测值为428.10。LCMS^{(ESI) calcd for C23H30FN5O2 [M+H]+}_m/z428.24 , found 428.10.

化合物151bCompound 151b

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.28(s,1H),8.45-8.35(m,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.64-7.51(m,1H),7.17(d,J＝6.8Hz,1H),6.03(d,J＝6.8Hz,1H),3.58-3.41(m,2H),3.17-3.09(m,1H),2.93-2.74(m,7H),2.68-2.60(m,2H),2.35-2.16(m,4H),2.01-1.92(m,2H),1.79-1.70(m,1H),1.64-1.52(m,2H),1.06(t,J＝7.2Hz,3H)。¹ H NMR (400 MHz, DMSO-d₆ ,ppm)δ:11.28(s,1H),8.45-8.35(m,1H),7.83(dd,J＝8.0,1.2Hz,1H),7.64-7.51(m,1H),7.17(d,J＝6.8Hz,1H),6.03(d,J＝6.8Hz,1H),3.58-3.41(m,2 H),3.17-3.09(m,1H),2.93-2.74(m,7H),2.68-2.60(m,2H),2.35-2.16(m,4H),2.01-1.92(m,2H),1.79-1.70(m,1H),1.64-1.52(m,2H),1.06(t ,J=7.2Hz,3H).

C₂₃H₃₀FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为428.24，实测值为428.20。LCMS^{(ESI) calcd for C23H30FN5O2 [M+H]+}_m/z428.24 , found 428.20.

INT-2的合成Synthesis of INT-2

6-氯-5-氟-N-甲基吡啶酰胺(2)的制备Preparation of 6-chloro-5-fluoro-N-methylpicolinamide (2)

在室温向6-氯-5-氟吡啶甲酸1(2.00g,11.40mmol)在DMF(50mL)中的溶液中接连地加入甲胺(420mg,13.68mmol)、DIEA(4.42g,34.20mmol)、HATU(6.50g,17.10mmol)。将混合物保持在室温搅拌1h。将得到的混合物用水稀释，并用EtOAc(200mL x 3)萃取。将合并的有机层经Na₂SO₄干燥并在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至70:30洗脱)纯化以提供作为白色固体的6-氯-5-氟-N-甲基吡啶酰胺2(2.00g,88％收率)。To a solution of 6-chloro-5-fluoropicolinic acid 1 (2.00 g, 11.40 mmol) in DMF (50 mL) were added methylamine (420 mg, 13.68 mmol), DIEA (4.42 g, 34.20 mmol), HATU (6.50 g, 17.10 mmol) successively at room temperature. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAc=100:0 to 70:30) to provide 6-chloro-5-fluoro-N-methylpicolinamide 2 (2.00 g, 88% yield) as a white solid.

C₇H₆ClFN₂O[M+H]⁺m/z的LCMS(ESI)计算值为189.02，实测值为188.90。LCMS (ESI) calcd for_C7H6ClFN2O [M+H]⁺_m/ z: 189.02, found: 188.90.

6-氯-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺(4)的制备Preparation of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)pyridineamide (4)

向6-氯-5-氟-N-甲基吡啶酰胺2(2.00g,10.60mmol)在DMF(20mL)中的溶液中加入Cs₂CO₃(6.91g,21.20mmol)和1,4-二氧杂-8-氮杂螺[4.5]癸烷3(3.04g,21.20mmol)。使用密闭试管将混合物在120℃下搅拌4h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以提供作为白色固体的6-氯-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺4(1.60g,42％收率)。To a solution of 6-chloro-5-fluoro-N-methylpicolinamide 2 (2.00 g, 10.60 mmol) in DMF (20 mL) was added Cs₂ CO₃ (6.91 g, 21.20 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane 3 (3.04 g, 21.20 mmol). The mixture was stirred at 120 °C for 4 h using a sealed test tube. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC=100:0 to 50:50) to provide 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide 4 (1.60 g, 42% yield) as a white solid.

C₁₄H₁₈ClN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为312.10，实测值为311.95。LCMS (ESI) calcd for_C14H18ClN3O3 [M+H]⁺_m/ z 312.10, found_311.95 .

6-氟-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺(5)的制备Preparation of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide (5)

向6-氯-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺4(300mg,0.96mmol)在DMF(20mL)中的溶液中加入CsF(293mg,1.93mmol)。将混合物使用微波在150℃下搅拌20h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至30:70洗脱)纯化以产生作为黄色固体的6-氟-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺5(200mg,69％收率)。To a solution of 6-chloro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide 4 (300 mg, 0.96 mmol) in DMF (20 mL) was added CsF (293 mg, 1.93 mmol). The mixture was stirred at 150 ° C for 20 h using microwaves. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAC=100:0 to 30:70) to produce 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide 5 (200 mg, 69% yield) as a yellow solid.

C₁₄H₁₈FN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为296.13，实测值为295.95。LCMS (ESI) calcd for_C14H18FN3O3 [_M +H]⁺_m/ z 296.13, found 295.95.

6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺(INT-2)的制备Preparation of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT-2)

向6-氟-N-甲基-5-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)吡啶酰胺5(200mg,0.68mmol)在H₂O(3mL)中的溶液中加入甲酸(2mL)，在50℃搅拌1h。将水溶液用NaHCO₃水溶液调节至pH 7-8。将混合物用水(50mL)稀释，并用EtOAc(100mL×3)萃取。将合并的有机层用盐水(100mL×2)洗涤，经Na₂SO₄干燥，浓缩以产生作为黄色固体的6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT-2(100mg,47％收率)的粗产物。To a solution of 6-fluoro-N-methyl-5-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)picolinamide 5 (200 mg, 0.68 mmol) in H₂ O (3 mL) was added formic acid (2 mL) and stirred at 50 ° C for 1 h. The aqueous solution was adjusted to pH 7-8 with aqueous NaHCO₃ solution. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na₂ SO₄ , and concentrated to give a crude product of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (100 mg, 47% yield) as a yellow solid.

C₁₂H₁₄FN₃O₂[M+H]⁺m/z的LCMS(ESI)计算值为252.11，实测值为251.90。LCMS^{(ESI) calcd for C12H14FN3O2 [M+H]+}_m/z252.11 , found 251.90.

实施例14-化合物154rac、154a和154b的合成化合物154rac、154a和154b的合成Example 14 - Synthesis of Compounds 154rac, 154a and 154b Synthesis of Compounds 154rac, 154a and 154b

3-氯-7-氟-1-甲氧基异喹啉(2)的制备Preparation of 3-chloro-7-fluoro-1-methoxyisoquinoline (2)

在室温向1,3-二氯-7-氟异喹啉1(500mg,2.32mmol)在MeOH(50mL)中的溶液中加入MeONa(150mg,2.78mmol)。将混合物在室温搅拌72h。将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至98:2洗脱)纯化以产生作为白色固体的3-氯-7-氟-1-甲氧基异喹啉2(160mg,33％收率)。To a solution of 1,3-dichloro-7-fluoroisoquinoline 1 (500 mg, 2.32 mmol) in MeOH (50 mL) was added MeONa (150 mg, 2.78 mmol) at room temperature. The mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC=100:0 to 98:2) to give 3-chloro-7-fluoro-1-methoxyisoquinoline 2 (160 mg, 33% yield) as a white solid.

C10H7ClFNO[M+H]⁺m/z的LCMS(ESI)计算值为212.02，实测值为211.90。LCMS (ESI) calcd for C10H7ClFNO[M+H]⁺ m/z 212.02, found 211.90.

3-(7-氟-1-甲氧基异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(4)的制备Preparation of tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (4)

在室温向3-氯-7-氟-1-甲氧基异喹啉2(160mg,0.76mmol)在二氧杂环己烷:H₂O＝5:1(20mL)中的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯3(270mg,0.92mmol)、Pd(dppf)Cl₂(50mg,0.07mmol)和K₂CO₃(250mg,1.81mmol)。将反应混合物在N₂下在90℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至95:5洗脱)纯化以提供作为白色固体的3-(7-氟-1-甲氧基异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯4(160mg,61％收率)。To a solution of 3-chloro-7-fluoro-1-methoxyisoquinoline 2 (160 mg, 0.76 mmol) in dioxane:H₂ O=5:1 (20 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 3 (270 mg, 0.92 mmol), Pd(dppf)Cl₂ (50 mg, 0.07 mmol) and K₂ CO₃ (250 mg, 1.81 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 h under N_2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 95:5) to afford tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 4 (160 mg, 61% yield) as a white solid.

C19H21FN2O3[M+H]⁺m/z的LCMS(ESI)计算值为345.15，实测值为345.11。LCMS (ESI) calcd for C19H21FN2O3[M+H]⁺ m/z 345.15, found 345.11.

3-(7-氟-1-甲氧基异喹啉-3-基)吡咯烷-1-甲酸叔丁酯(5)的制备Preparation of tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)pyrrolidine-1-carboxylate (5)

在H₂下向3-(7-氟-1-甲氧基异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯4(160g,0.46mmol)在MeOH(20mL)中的溶液中加入Pd/C(35mg,0.29mmol)。将反应混合物在室温搅拌5h。将混合物穿过硅藻土垫过滤并将滤液浓缩以产生作为白色固体的3-(7-氟-1-甲氧基异喹啉-3-基)吡咯烷-1-甲酸叔丁酯5(140mg,88％收率)。To a solution of tert-_butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 4 (160 g, 0.46 mmol) in MeOH (20 mL) was added Pd/C (35 mg, 0.29 mmol) under H. The reaction mixture was stirred at room temperature for 5 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to give tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)pyrrolidine-1-carboxylate 5 (140 mg, 88% yield) as a white solid.

C19H23FN2O3[M+H]⁺m/z的LCMS(ESI)计算值为347.17，实测值为347.18。LCMS (ESI) calcd for C19H23FN2O3[M+H]⁺ m/z was 347.17, found was 347.18.

7-氟-3-(吡咯烷-3-基)异喹啉-1(2H)-酮(6)的制备Preparation of 7-fluoro-3-(pyrrolidin-3-yl)isoquinolin-1(2H)-one (6)

将3-(7-氟-1-甲氧基异喹啉-3-基)吡咯烷-1-甲酸叔丁酯5(140mg,0.40mmol)加入HBr水溶液(48％,3mL)中。将混合物在100℃搅拌2h。将反应混合物在减压下浓缩以产生作为白色固体的7-氟-3-(吡咯烷-3-基)异喹啉-1(2H)-酮6(90mg,97％收率)。Tert-butyl 3-(7-fluoro-1-methoxyisoquinolin-3-yl)pyrrolidine-1-carboxylate 5 (140 mg, 0.40 mmol) was added to aqueous HBr solution (48%, 3 mL). The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give 7-fluoro-3-(pyrrolidin-3-yl)isoquinolin-1(2H)-one 6 (90 mg, 97% yield) as a white solid.

C13H13FN2O[M+H]⁺m/z的LCMS(ESI)计算值为233.10，实测值为232.95。LCMS (ESI) calcd for C13H13FN2O [M+H]⁺ m/z 233.10, found 232.95.

5-(4-(3-(7-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物154rac)的制备Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 154rac)

向7-氟-3-(吡咯烷-3-基)异喹啉-1(2H)-酮6(90mg,0.39mmol)在MeOH(15mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺(INT,100mg,0.43mmol)，然后在室温加入两滴乙酸和NaBH₃CN(25mg,0.40mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将残余物通过制备型HPLC(柱:Gemini 5um C18 150×21.2mm，流动相:ACN-H₂O(0.1％ FA)，梯度:10-25)纯化以产生作为白色固体的5-(4-(3-(7-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺154rac(35mg,99％纯度,20％收率)。To a solution of 7-fluoro-3-(pyrrolidin-3-yl)isoquinolin-1(2H)-one 6 (90 mg, 0.39 mmol) in MeOH (15 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT, 100 mg, 0.43 mmol), followed by two drops of acetic acid and NaBH₃ CN (25 mg, 0.40 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the residue was purified by preparative HPLC (column: Gemini 5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.1% FA), gradient: 10-25) to give 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 154rac (35 mg, 99% purity, 20% yield) as a white solid.

化合物154racCompound 154rac

1H NMR(400MHz,DMSO)δ11.35(s,1H),8.39(q,J＝4.8Hz,1H),8.30(d,J＝2.8Hz,1H),7.87-7.76(m,2H),7.70(dd,J＝8.8,5.2Hz,1H),7.59(td,J＝8.8,2.8Hz,1H),7.43(dd,J＝8.8,2.8Hz,1H),6.57(s,1H),4.02-3.85(m,2H),3.31-2.71(m,11H),2.40-2.25(m,1H),2.13-1.88(m,3H),1.68-1.52(m,2H)。1H NMR (400MHz, DMSO) δ11.35 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.30 (d, J = 2.8Hz, 1H), 7.87-7.76 (m, 2H), 7.70 (dd,J＝8.8,5.2Hz,1H),7.59(td,J＝8.8,2.8Hz,1H),7.43(dd,J＝8.8,2.8Hz,1H),6.57(s,1H),4.02- 3.85(m,2H),3.31-2.71(m,11H),2.40-2.25(m,1H),2.13-1.88(m,3H),1.68-1.52(m,2H).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.23。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.23.

5-(4-(3-(7-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(154a和154b)的制备Preparation of 5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (154a and 154b)

将5-(4-(3-(7-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺154rac通过SFC(柱：DAICEL OJ-H4.6mmI.D.*250mmL 5μm；流动相:CO2/MeOH[0.1％NH3(7M在MeOH中的溶液)]＝75/25)分离并在减压下浓缩以提供作为154a的第一级分(10mg,99％纯度,ee％:100，白色固体)和作为154b的第二级分(10mg,97％纯度,ee％:100，白色固体)5-(4-(3-(7-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 154rac was separated by SFC (column: DAICEL OJ-H 4.6 mm I.D.*250 mm L 5 μm; mobile phase: CO 2 /MeOH [0.1% NH 3 (7 M solution in MeOH)]=75/25) and concentrated under reduced pressure to give a first fraction as 154a (10 mg, 99% purity, ee%: 100, white solid) and a second fraction as 154b (10 mg, 97% purity, ee%: 100, white solid)

化合物154aCompound 154a

1H NMR(400MHz,DMSO)δ11.25(s,1H),8.39(d,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.4Hz,1H),7.77(dd,J＝9.2,2.8Hz,1H),7.68(dd,J＝8.8,5.6Hz,1H),7.56(td,J＝8.8,2.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),6.51(s,1H),3.87-3.77(m,2H),3.25-3.17(m,1H),3.03-2.91(m,3H),2.85-2.75(m,4H),2.74-2.66(m,2H),2.35-2.32(m,1H),2.28-2.17(m,1H),2.01-1.90(m,2H),1.88-1.78(m,1H),1.60-1.47(m,2H)。1H NMR (400MHz, DMSO) δ11.25(s,1H),8.39(d,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.4Hz,1H ),7.77(dd,J＝9.2,2.8Hz,1H),7.68(dd,J＝8.8,5.6Hz,1H),7.56(td,J＝8.8,2.8Hz,1H),7.40(dd,J＝ 8.8,2.8H z,1H),6.51(s,1H),3.87-3.77(m,2H),3.25-3.17(m,1H),3.03-2.91(m,3H),2.85-2.75(m,4H),2.74- 2.66(m,2H),2.35-2.32(m,1H),2.28-2.17(m,1H),2.01-1.90(m,2H),1.88-1.78(m,1H),1.60-1.47(m,2H ).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.20。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.20.

化合物154bCompound 154b

1H NMR(400MHz,DMSO)δ11.25(s,1H),8.39(d,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.77(dd,J＝9.2,2.8Hz,1H),7.68(dd,J＝8.8,5.2Hz,1H),7.56(td,J＝8.8,2.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),6.51(s,1H),3.88-3.78(m,2H),3.26-3.16(m,1H),3.03-2.91(m,3H),2.83-2.78(m,4H),2.74-2.66(m,2H),2.35-2.31(m,1H),2.28-2.17(m,1H),2.00-1.92(m,2H),1.89-1.79(m,1H),1.61-1.47(m,2H)。1H NMR (400MHz, DMSO) δ11.25(s,1H),8.39(d,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H ),7.77(dd,J＝9.2,2.8Hz,1H),7.68(dd,J＝8.8,5.2Hz,1H),7.56(td,J＝8.8,2.8Hz,1H),7.40(dd,J＝ 8.8,2.8H z,1H),6.51(s,1H),3.88-3.78(m,2H),3.26-3.16(m,1H),3.03-2.91(m,3H),2.83-2.78(m,4H),2.74- 2.66(m,2H),2.35-2.31(m,1H),2.28-2.17(m,1H),2.00-1.92(m,2H),1.89-1.79(m,1H),1.61-1.47(m,2H ).

C25H28FN5O2[M+H]⁺m/z的LCMS(ESI)计算值为450.22，实测值为450.20。LCMS (ESI) calcd for C25H28FN5O2[M+H]⁺ m/z 450.22, found 450.20.

实施例15-化合物162rac、162a和162b的合成化合物162rac、162a和162b的合成Example 15 - Synthesis of Compounds 162rac, 162a and 162b Synthesis of Compounds 162rac, 162a and 162b

4,6-二氯-3-碘-1H-吡唑并[3,4-d]嘧啶(2)的制备Preparation of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (2)

向4,6-二氯-1H-吡唑并[3,4-d]嘧啶1(5g,26.50mmol)在ACN/DMF＝1:1(100mL)中的溶液中加入NIS(8.9g,39.75mmol)。将得到的混合物在90℃搅拌3h。将残余物通过快速色谱法(用PE/EtOAc＝100:0至72:28洗脱)纯化以产生作为白色固体的4,6-二氯-3-碘-1H-吡唑并[3,4-d]嘧啶2(2.9g,35％收率)。To a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine 1 (5 g, 26.50 mmol) in ACN/DMF=1:1 (100 mL) was added NIS (8.9 g, 39.75 mmol). The resulting mixture was stirred at 90° C. for 3 h. The residue was purified by flash chromatography (eluted with PE/EtOAc=100:0 to 72:28) to give 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 2 (2.9 g, 35% yield) as a white solid.

C5HCl2IN4[M+H]⁺m/z的LCMS(ESI)计算值为314.86，实测值为314.85。LCMS (ESI) calcd for C5HCl2IN4[M+H]⁺ m/z: 314.86, found: 314.85.

4,6-二氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(3)的制备Preparation of 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (3)

在0℃向4,6-二氯-3-碘-1H-吡唑并[3,4-d]嘧啶2(2.9g,9.24mmol)在THF(40mL)中的溶液中加入NaH(290mg,11.96mmol)，搅拌10min，然后加入SEMCl(2.3g,13.80mmol)。将得到的混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的4,6-二氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶3(3.6g,88％收率)。To a solution of 4,6-dichloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine 2 (2.9 g, 9.24 mmol) in THF (40 mL) was added NaH (290 mg, 11.96 mmol) at 0°C, stirred for 10 min, and then SEMCl (2.3 g, 13.80 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to yield 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 3 (3.6 g, 88% yield) as a white solid.

C11H15Cl2IN4OSi[M+H]⁺m/z的LCMS(ESI)计算值为444.94，实测值为444.85。LCMS (ESI) calcd for C11H15Cl2IN4OSi[M+H]⁺ m/z 444.94, found 444.85.

6-氯-3-碘-4-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(4)的制备Preparation of 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (4)

向4,6-二氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶3(1.5g,3.39mmol)在MeOH(45mL)中的溶液中加入MeONa(183mg,3.39mmol)。将混合物在室温搅拌1h。将残余物通过快速色谱法(用PE/EtOAc＝100:0至95:5洗脱)纯化以产生作为白色固体的6-氯-3-碘-4-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶4(282mg,19％收率)。To a solution of 4,6-dichloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 3 (1.5 g, 3.39 mmol) in MeOH (45 mL) was added MeONa (183 mg, 3.39 mmol). The mixture was stirred at room temperature for 1 h. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 95:5) to give 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4 (282 mg, 19% yield) as a white solid.

C12H18ClIN4O2Si[M+H]⁺m/z的LCMS(ESI)计算值为440.99，实测值为441.01。LCMS (ESI) calculated value of C12H18ClIN4O2Si[M+H]⁺ m/z is 440.99, found value is 441.01.

6-氯-4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶(6)的制备Preparation of 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (6)

在N₂下向6-氯-3-碘-4-甲氧基-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶4(282mg,0.64mmol)和2,2-二氟-2-(氟磺酰基)乙酸甲酯5(491mg,2.56mmol)在DMF(15mL)中的溶液中加入CuCl₂(131mg,0.98mmol)。将反应混合物在100℃搅拌2h。将残余物通过快速色谱法(用PE/EtOAc＝100:0至96:4洗脱)纯化以产生作为白色固体的6-氯-4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶6(220mg,90％收率)。To a_solution of 6-chloro-3-iodo-4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 4 (282 mg, 0.64 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate 5 (491 mg, 2.56 mmol) in DMF (15 mL) was added CuCl (₁₃₁ mg, 0.98 mmol) under N2. The reaction mixture was stirred at 100 °C for 2 h. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 96:4) to give 6-chloro-4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine 6 (220 mg, 90% yield) as a white solid.

C13H18ClF3N4O2Si[M+H]+m/z的LCMS(ESI)计算值为383.08，实测值为383.08。The LCMS (ESI) calculated value of C13H18ClF3N4O2Si[M+H]+ m/z was 383.08 and the found value was 383.08.

3-(4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8)

在N₂下向3-(4-甲氧基-5-(三氟甲基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯6(200mg,0.52mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯7(154mg,0.52mmol)和Pd(dppf)Cl₂(23mg,0.031mmol)在1,4-二氧杂环己烷/H₂O＝10:1(11mL)中的溶液中加入Na₂CO₃(165mg,1.56mmol)。将反应混合物在100℃搅拌2h。将残余物通过快速色谱法(用PE/EtOAc＝100:0至93:7洗脱)纯化以产生作为橙色油的3-(4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯8(280mg,94％收率)。To a solution of tert-_butyl 3-(4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 6 (200 mg, 0.52 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 7 (154 mg, 0.52 mmol) and Pd(dppf)Cl₂ (23 mg, 0.031 mmol) in 1,4-dioxane/H₂ O=10:1 (11 mL) was added Na₂ CO₃ (165 mg, 1.56 mmol) under N 2. The reaction mixture was stirred at 100° C. for 2 h. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 93:7) to give tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8 (280 mg, 94% yield) as an orange oil.

C27H32F3N5O4Si[M+H]+m/z的LCMS(ESI)计算值为516.22，实测值为516.23。The LCMS (ESI) calculated value of C27H32F3N5O4Si[M+H]+ m/z was 516.22 and the found value was 516.23.

3-(4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-甲酸叔丁酯(9)的制备Preparation of tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate (9)

在H₂下向3-(4-甲氧基-5-(三氟甲基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)吡咯烷-1-甲酸叔丁酯8(280mg,0.54mmol)在MeOH(15mL)中的溶液中加入Pd/C(114mg,1.08mmol)。将反应混合物在室温搅拌2h。然后将混合物穿过硅藻土过滤并在真空下浓缩以产生作为白色固体的3-(4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-甲酸叔丁酯9(158mg,56％收率)。To a solution of tert-_butyl 3-(4-methoxy-5-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate 8 (280 mg, 0.54 mmol) in MeOH (15 mL) was added Pd/C (114 mg, 1.08 mmol) under H. The reaction mixture was stirred at room temperature for 2 h. The mixture was then filtered through celite and concentrated under vacuum to yield tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate 9 (158 mg, 56% yield) as a white solid.

C22H34F3N5O4Si[M+H]+m/z的LCMS(ESI)计算值为518.23，实测值为518.25。The LCMS (ESI) calculated value of C22H34F3N5O4Si[M+H]+ m/z is 518.23 and the found value is 518.25.

6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮(10)的制备Preparation of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (10)

将3-(4-甲氧基-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-甲酸叔丁酯9(158mg,0.31mmol)加入HBr水(5mL)中。将反应混合物在100℃搅拌2h。然后将混合物在真空下浓缩以产生作为白色固体的6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮10(80mg,96％收率)。Tert-butyl 3-(4-methoxy-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidine-1-carboxylate 9 (158 mg, 0.31 mmol) was added to HBr water (5 mL). The reaction mixture was stirred at 100 °C for 2 h. The mixture was then concentrated under vacuum to give 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 10 (80 mg, 96% yield) as a white solid.

C10H10F3N5O[M+H]+m/z的LCMS(ESI)计算值为274.08，实测值为274.00。LCMS (ESI) calculated value for C10H10F3N5O [M+H] + m/z is 274.08, found is 274.00.

N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(162rac)的制备Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (162rac)

向6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮10(80mg,0.29mmol)、N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(90mg,0.29mmol)和三乙酰氧基硼氢化钠(92mg,0.44mmol)在MeOH(10mL)中的溶液中加入两滴HOAc并将溶液在50℃搅拌0.5h。然后加入NaBH3CN(22mg,0.35mmol)。将混合物在50℃搅拌18h。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的产物N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺162rac(69mg,48％收率)。To a solution of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one 10 (80 mg, 0.29 mmol), N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (90 mg, 0.29 mmol) and sodium triacetoxyborohydride (92 mg, 0.44 mmol) in MeOH (10 mL) were added two drops of HOAc and the solution was stirred at 50° C. for 0.5 h. NaBH3CN (22 mg, 0.35 mmol) was then added. The mixture was stirred at 50° C. for 18 h. The residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 90:10) to give the product N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 162rac (69 mg, 48% yield) as a white solid.

C22H25F3N8O2[M+H]+m/z的LCMS(ESI)计算值为491.21，实测值为491.25。The LCMS (ESI) calculated value of C22H25F3N8O2[M+H]+ m/z is 491.21, the found value is 491.25.

N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(162a和162b)的手性拆分Chiral Resolution of N-Methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (162a and 162b)

将化合物162rac通过SFC(柱：DAICEL OJ-H 4.6mml.D.*250mmL,5μm；流动相:CO₂/MeOH[0.1％ NH₃(7M在MeOH中的溶液)]＝70/30)分离并在减压下浓缩以提供作为162a的第一级分(39mg,93％纯度,ee％:100，白色固体)和作为162b的第二级分(31mg,99％纯度,ee％:100，白色固体)Compound 162rac was separated by SFC (column: DAICEL OJ-H 4.6 mml.D.*250 mmL, 5 μm; mobile phase: CO₂ /MeOH [0.1% NH₃ (7M solution in MeOH)]=70/30) and concentrated under reduced pressure to give a first fraction as 162a (39 mg, 93% purity, ee%: 100, white solid) and a second fraction as 162b (31 mg, 99% purity, ee%: 100, white solid)

化合物162aCompound 162a

1H NMR(400MHz,DMSO)δ14.37(s,1H),12.27(s,1H),8.39(q,J＝4.4Hz,1H),8.27(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.40(dd,J＝8.4,2.8Hz,1H),3.83(d,J＝12.8Hz,2H),3.38-3.35(m,1H),3.06(t,J＝8.4Hz,1H),2.98-2.88(m,2H),2.83-2.73(m,5H),2.68-2.61(m,1H),2.39-2.29(m,1H),2.21-2.09(m,2H),1.93(d,J＝11.6Hz,2H),1.55-1.43(m,2H)。1H NMR (400MHz, DMSO) δ14.37(s,1H),12.27(s,1H),8.39(q,J＝4.4Hz,1H),8.27(d,J＝2.8Hz,1H),7.82(d ,J＝8.8Hz,1H),7.40(dd,J＝8.4,2.8Hz,1H),3.83(d,J＝12.8Hz,2H),3.38 -3.35(m,1H),3.06(t,J＝8.4Hz,1H),2.98-2.88(m,2H),2.83-2.73(m,5H),2.68-2.61(m,1H),2.39-2.29 (m,1H),2.21-2.09(m,2H),1.93(d,J=11.6Hz,2H),1.55-1.43(m,2H).

C22H25F3N8O2[M+H]+m/z的LCMS(ESI)计算值为491.21，实测值为491.26。The LCMS (ESI) calculated value of C22H25F3N8O2[M+H]+ m/z is 491.21 and the found value is 491.26.

化合物162bCompound 162b

1H NMR(400MHz,)δ14.41(s,1H),12.41(s,1H),8.39(q,J＝4.8Hz,1H),8.28(d,J＝2.0Hz,1H),7.82(d,J＝8.8Hz,1H),7.41(dd,J＝8.8,2.0Hz,1H),3.86(s,1H),3.30-3.27(m,1H),3.16-3.03(m,1H),2.96-2.58(m,8H),2.34-2.10(m,3H),2.03-1.88(m,2H),1.63-1.44(m,2H)。1H NMR(400MHz,)δ14.41(s,1H),12.41(s,1H),8.39(q,J＝4.8Hz,1H),8.28(d,J＝2.0Hz,1H),7.82(d, J＝8.8Hz,1H),7.41(dd,J＝8.8,2.0Hz,1H),3.86(s,1H),3.30-3.27(m,1H),3.16-3.03(m,1H),2.96-2.58 (m,8H),2.34-2.10(m,3H),2.03-1.88(m,2H),1.63-1.44(m,2H).

C22H25F3N8O2[M+H]+m/z的LCMS(ESI)计算值为491.21，实测值为491.25。The LCMS (ESI) calculated value of C22H25F3N8O2[M+H]+ m/z is 491.21, the found value is 491.25.

实施例16-化合物184rac、184a和184b的合成化合物184rac、184a和184b的合成Example 16 - Synthesis of Compounds 184rac, 184a and 184b Synthesis of Compounds 184rac, 184a and 184b

6-氟-5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(184rac)的制备Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184rac)

向6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT-1(92mg,0.40mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺2(在化合物136的合成中的中间体6)(100mg,0.40mmol)。然后在室温加入两滴乙酸和NaBH₃CN(25mg,0.26mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为无色油的产物6-氟-5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺184rac(60mg,27％收率)。To a solution of 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT-1 (92 mg, 0.40 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide 2 (Intermediate 6 in the synthesis of compound 136) (100 mg, 0.40 mmol). Two drops of acetic acid and NaBH₃ CN (25 mg, 0.26 mmol) were then added at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to give the product 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide 184rac (60 mg, 27% yield) as a colorless oil.

C25H27F2N5O2[M+H]⁺m/z的LCMS(ESI)计算值为468.21，实测值为468.26。LCMS (ESI) calcd for C25H27F2N5O2[M+H]⁺ m/z 468.21, found 468.26.

6-氟-5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺(184a和184b)的制备Preparation of 6-fluoro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide (184a and 184b)

将6-氯-5-{4-[3-(8-氟-1-氧代-2H-异喹啉-3-基)吡咯烷-1-基]哌啶-1-基}-N-甲基吡啶-2-甲酰胺184rac通过SFC(柱：Daicel CHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝80/20)分离并在减压下浓缩以提供作为184a的第一级分(24.5mg,98％纯度,ee％:100，白色固体)和作为184b的第二级分(24.4mg,99％纯度,ee％:97，白色固体)6-Chloro-5-{4-[3-(8-fluoro-1-oxo-2H-isoquinolin-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-N-methylpyridine-2-carboxamide 184rac was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=80/20) and concentrated under reduced pressure to give a first fraction as 184a (24.5 mg, 98% purity, ee%: 100, white solid) and a second fraction as 184b (24.4 mg, 99% purity, ee%: 97, white solid).

化合物184aCompound 184a

¹H NMR(400MHz,DMSO)δ11.10(s,1H),8.41(q,J＝5.2Hz,1H),7.85(d,J＝7.2Hz,1H),7.64-7.56(m,2H),7.39(d,J＝7.6Hz,1H),7.10(dd,J＝12.0,8.0Hz,1H),6.47(s,1H),3.52-3.51(m,2H),3.22-3.16(m,1H),2.91-2.73(m,8H),2.67-2.63(m,1H),2.30-2.22(m,2H),2.00-1.97(m,2H),1.86-1.79(m,1H),1.68-1.53(m,2H)。¹ H NMR (400MHz, DMSO) δ11.10 (s, 1H), 8.41 (q, J = 5.2Hz, 1H), 7.85 (d, J = 7.2Hz, 1H), 7.64-7.56 (m, 2H), 7.39(d,J＝7.6Hz,1H),7.10(dd,J＝12.0,8.0Hz,1H),6.47(s,1H),3.52-3.51(m,2H),3.22-3.16(m,1H) ,2.91-2.73(m,8H),2.67-2.63(m,1H),2.30-2.22(m,2H),2.00-1.97(m,2H),1.86-1.79(m,1H),1.68-1.53( m,2H).

C25H27F2N5O2[M+H]⁺m/z的LCMS(ESI)计算值为468.21，实测值为468.22。LCMS (ESI) calcd for C25H27F2N5O2[M+H]⁺ m/z 468.21, found 468.22.

化合物184bCompound 184b

¹H NMR(400MHz,DMSO)δ11.10(s,1H),8.41(q,J＝4.8Hz,1H),7.85(dd,J＝8.0,1.2Hz,1H),7.64-7.56(m,2H),7.39(d,J＝7.6Hz,1H),7.11(dd,J＝11.6,8.0Hz,1H),6.46(s,1H),3.53-3.49(m,2H),3.21-2.87(m,1H),2.93-2.71(m,8H),2.68-2.63(m,1H),2.28-2.19(m,2H),2.00-1.97(m,2H),1.88-1.79(m,1H),1.64-1.54(m,2H)。¹ H NMR (400MHz, DMSO) δ11.10(s,1H),8.41(q,J＝4.8Hz,1H),7.85(dd,J＝8.0,1.2Hz,1H),7.64-7.56(m,2H),7.39(d,J＝7.6Hz,1H),7.11(dd,J＝11.6,8.0Hz,1H),6 .46(s,1H),3.53-3.49(m,2H),3.21-2.87(m,1H),2.93-2.71(m,8H),2.68-2.63(m,1H),2.28-2.19(m,2H),2.00-1.97(m,2H),1.88-1.79(m,1H) ,1.64-1.54(m,2H).

C25H27F2N5O2[M+H]⁺m/z的LCMS(ESI)计算值为468.21，实测值为468.18。LCMS (ESI) calcd for C25H27F2N5O2[M+H]⁺ m/z 468.21, found 468.18.

实施例17-化合物192的合成Example 17-Synthesis of Compound 192

化合物192的合成Synthesis of compound 192

4-((2-氨甲酰基苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3)

向2-氨基苯甲酰胺1(360mg,2.64mmol)和2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酸2(500mg,2.20mmol)在吡啶(30mL)中的溶液中加入EDCI(422mg,2.20mmol)。然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(200mL x 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物4-((2-氨甲酰基苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(600mg,90％收率)。EDCI (422 mg, 2.20 mmol) was added to a solution of 2-aminobenzamide 1 (360 mg, 2.64 mmol) and 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 2 (500 mg, 2.20 mmol) in pyridine (30 mL). The mixture was then stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 3 (600 mg, 90% yield) as a white solid.

C₁₈H₂₃N₃O₄[M+Na]⁺m/z的LCMS(ESI)计算值为368.17，实测值为368.05。LCMS (ESI) calcd for_C18H23N3O4 [M₊ Na]⁺_m /_z : 368.17, found: 368.05.

4-(4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(4)的制备Preparation of tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4)

向4-((2-氨甲酰基苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(600mg,1.74mmol)在DME(60mL)中的溶液中加入KOH(195mg,3.47mmol)，加热至60℃搅拌2h，冷却至25℃，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的4-(4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(400mg,63％收率)。To a solution of tert-butyl 4-((2-carbamoylphenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (600 mg, 1.74 mmol) in DME (60 mL) was added KOH (195 mg, 3.47 mmol), heated to 60° C. with stirring for 2 h, cooled to 25° C., and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to give tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (400 mg, 63% yield) as a white solid.

C₁₈H₂₁N₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为328.16，实测值为328.05。LCMS (ESI) calcd for_C18H21N3O3 [M₊ H]⁺_m/ z 328.16, found 328.05.

2-(2-氮杂双环[2.1.1]己烷-4-基)喹唑啉-4(3H)-酮(5)的制备Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazolin-4(3H)-one (5)

将4-(4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(400mg,0.56mmol)加入在二氧杂环己烷中的HCl(4M,10mL)中。将混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的产物2-(2-氮杂双环[2.1.1]己烷-4-基)喹唑啉-4(3H)-酮5(320mg,93％收率)。Tert-butyl 4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (400 mg, 0.56 mmol) was added to HCl (4M, 10 mL) in dioxane. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give the product 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazolin-4(3H)-one 5 (320 mg, 93% yield) as a white solid.

C₁₃H₁₃N₃O[M+H]⁺m/z的LCMS(ESI)计算值为228.11，实测值为228.02。_{LCMS (ESI) calcd for C13H13N3O[} M+H]⁺ m_/ z 228.11, found 228.02.

N-甲基-5-(4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺(化合物192)的制备Preparation of N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (Compound 192)

向2-(2-氮杂双环[2.1.1]己烷-4-基)喹唑啉-4(3H)-酮5(80mg,0.35mmol)在MeOH(40mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺(INT,98mg,0.42mmol)，然后在室温加入两滴乙酸和NaBH(OAC)₃(149mg,0.70mmol)。将反应混合物在50℃搅拌1h。然后加入NaBH₃CN(11.06mg,0.176mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过C18柱(流动相:ACN-H₂O(0.1％ FA)，梯度:10-95)纯化以产生作为白色固体的N-甲基-5-(4-(4-(4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺192(25.6mg,99％纯度,16％收率)。To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)quinazolin-4(3H)-one 5 (80 mg, 0.35 mmol) in MeOH (40 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide (INT, 98 mg, 0.42 mmol), followed by two drops of acetic acid and NaBH(OAC)₃ (149 mg, 0.70 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. NaBH₃ CN (11.06 mg, 0.176 mmol) was then added. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by C18 column (mobile phase: ACN-_H2O (0.1% FA), gradient: 10-95) to give N-methyl-5-(4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide 192 (25.6 mg, 99% purity, 16% yield) as a white solid.

化合物192Compound 192

¹H NMR(400MHz,DMSO-d₆,ppm)δ:12.17(s,1H),8.43-8.36(m,1H),8.29(d,J＝2.8Hz,1H),8.17(s,1H),8.10(dd,J＝8.0,1.2Hz,1H),7.86-7.76(m,2H),7.62(d,J＝7.8Hz,1H),7.52-7.47(m,1H),7.42(dd,J＝8.8,2.9Hz,1H),3.93-3.86(m,2H),3.76(s,1H),3.12(s,2H),2.97-2.90(m,2H),2.78(d,J＝4.8Hz,3H),2.69-2.62(m,1H),2.19-2.14(m,2H),2.02-1.90(m,4H),1.54-1.44(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 12.17 (s, 1H), 8.43-8.36 (m, 1H), 8.29 (d, J = 2.8Hz, 1H), 8.17 (s, 1H), 8.10(dd,J＝8.0,1.2Hz,1H),7.86-7.76(m,2H),7.62(d,J＝7.8Hz,1H),7.52-7.47(m,1H),7.42(dd,J＝ 8.8,2.9Hz,1H),3.93-3.86(m,2H),3.76(s,1H),3.12(s,2H),2.97-2.90(m,2H),2.78(d,J＝4.8Hz,3H ),2.69-2.62(m,1H),2.19-2.14(m,2H),2.02-1.90(m,4H),1.54-1.44(m,2H).

C₂₅H₂₈N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为445.23，实测值为445.15。LCMS (ESI) calcd for_C25H28N6O2 [M₊ H]⁺_m/ z 445.23, found 445.15.

实施例18-化合物194a和194b的合成Example 18 - Synthesis of Compounds 194a and 194b

化合物194a和194b的合成Synthesis of compounds 194a and 194b

6-氯-3-碘-1H-吡唑并[4,3-c]吡啶(2)的制备Preparation of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (2)

向6-氯-1H-吡唑并[4,3-c]吡啶1(10.00g,0.06mol)在DMF(200mL)中的溶液中加入NIS(8.44g,0.08mol)。将混合物在60℃搅拌3h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至60:40洗脱)纯化以产生作为黄色固体的产物6-氯-3-碘-1H-吡唑并[4,3-c]吡啶2(10.5g,64％收率)。To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine 1 (10.00 g, 0.06 mol) in DMF (200 mL) was added NIS (8.44 g, 0.08 mol). The mixture was stirred at 60 ° C for 3 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAc=100:0 to 60:40) to produce the product 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine 2 (10.5 g, 64% yield) as a yellow solid.

C6H3ClIN3[M+H]⁺m/z的LCMS(ESI)计算值为279.91，实测值为280.00。LCMS (ESI) calcd for C6H3ClIN3[M+H]⁺ m/z 279.91, found 280.00.

6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶(3)的制备Preparation of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (3)

将6-氯-3-碘-1H-吡唑并[4,3-c]吡啶2(10.50g,0.04mol)和NaH(2.70g,0.11mol)在DMF(200mL)中的悬浮液在0℃搅拌30min，然后加入SEMCl(12.30g,0.08mol)。将混合物在室温搅拌3h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至70:30洗脱)纯化以产生作为黄色固体的产物6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶3(9.90g,61％收率)。A suspension of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine 2 (10.50 g, 0.04 mol) and NaH (2.70 g, 0.11 mol) in DMF (200 mL) was stirred at 0 ° C for 30 min, and then SEMCl (12.30 g, 0.08 mol) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAc=100:0 to 70:30) to produce the product 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 3 (9.90 g, 61% yield) as a yellow solid.

C12H17ClIN3OSi[M+H]⁺m/z的LCMS(ESI)计算值为409.99，实测值为410.05。LCMS (ESI) calcd for C12H17ClIN3OSi[M+H]⁺ m/z 409.99, found 410.05.

6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶(5)的制备Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine (5)

在室温向6-氯-3-碘-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶3(9.90g,0.02mol)和2,2-二氟-2-(氟磺酰基)乙酸甲酯4(23.04g,0.12mol)在DMF(80mL)中的溶液中加入CuI(9.15g,0.04mmol)和HMPA(21.35g,0.12mmol)。将混合物在110℃搅拌2h。将反应混合物用水淬灭，将水层用EtOAc(50mL x 3)萃取。将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以产生作为黄色固体的产物6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶5(3.30g,38％收率)。To a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 3 (9.90 g, 0.02 mol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester 4 (23.04 g, 0.12 mol) in DMF (80 mL) was added CuI (9.15 g, 0.04 mmol) and HMPA (21.35 g, 0.12 mmol) at room temperature. The mixture was stirred at 110 ° C for 2 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 80:20) to give the product 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5 (3.30 g, 38% yield) as a yellow solid.

C13H17ClF3N3OSi[M+H]⁺m/z的LCMS(ESI)计算值为352.08，实测值为352.20。LCMS (ESI) calcd for C13H17ClF3N3OSi[M+H]⁺ m/z 352.08, found 352.20.

6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶5-氧化物(6)的制备Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide (6)

向6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶5(3.30g,0.01mmol)在HOAc(20mL)中的溶液中加入H₂O₂(20mL)。将反应混合物在70℃搅拌5h。冷却至室温之后，将反应混合物用水淬灭，将水层用EtOAc(30mL x 3)萃取。将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至55:45洗脱)纯化以产生作为黄色油的产物6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶5-氧化物6(1.60g,48％收率)。To a solution of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5 (3.30 g, 0.01 mmol) in HOAc (20 mL) was added H₂ O₂ (20 mL). The reaction mixture was stirred at 70 °C for 5 h. After cooling to room temperature, the reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc=100:0 to 55:45) to give the product 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide 6 (1.60 g, 48% yield) as a yellow oil.

C13H17ClF3N3O2Si[M+H]⁺m/z的LCMS(ESI)计算值为368.07，实测值为367.97。LCMS (ESI) calculated value of m/z for C13H17ClF3N3O2Si[M+H]⁺ is 368.07, found value is 367.97.

6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮(7)的制备Preparation of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (7)

向6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶5-氧化物6(800mg,2.16mmol)在H₂O(15mL)中的溶液中加入MsCl(1.00g,8.62mmol)。将反应混合物在室温搅拌1h。将反应混合物用水淬灭，将水层用EtOAc(20mL x 3)萃取。将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至85:15洗脱)纯化以产生作为黄色油的产物6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮7(400mg,48％收率)。To a solution of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine 5-oxide 6 (800 mg, 2.16 mmol) in H₂ O (15 mL) was added MsCl (1.00 g, 8.62 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc=100:0 to 85:15) to give the product 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 7 (400 mg, 48% yield) as a yellow oil.

C13H17ClF3N3O2Si[M+H]⁺m/z的LCMS(ESI)计算值为368.07，实测值为368.01。LCMS (ESI) calculated value of m/z for C13H17ClF3N3O2Si[M+H]⁺ is 368.07, found value is 368.01.

6-氯-5-(4-甲氧基苄基)-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮(8)的制备Preparation of 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (8)

在室温向6-氯-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮7(400mg,1.07mmol)和Cs₂CO₃(1.25g,3.85mmol)在DMF(15mL)中的溶液中加入PMBCl(0.84g,5.35mmol)。将反应混合物在50℃搅拌2h。冷却至室温之后，将合并的有机层在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至85:15洗脱)纯化以产生作为黄色油的产物6-氯-5-(4-甲氧基苄基)-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮8(200mg,32％收率)。To a solution of 6-chloro-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 7 (400 mg, 1.07 mmol) and Cs₂ CO₃ (1.25 g, 3.85 mmol) in DMF (15 mL) was added PMBCl (0.84 g, 5.35 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 85:15) to give the product 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 8 (200 mg, 32% yield) as a yellow oil.

C21H25ClF3N3O3Si[M+H]⁺m/z的LCMS(ESI)计算值为488.13，实测值为488.15。LCMS (ESI) calcd for C21H25ClF3N3O3Si[M+H]⁺ m/z 488.13, found 488.15.

3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(10)的制备Preparation of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10)

在室温向6-氯-5-(4-甲氧基苄基)-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮8(200mg,0.48mmol)和3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢吡咯-1-甲酸叔丁酯9(150mg,0.50mmol)在二氧杂环己烷:H₂O＝5:1(15mL)中的溶液中加入Pd(dppf)Cl₂(50mg,0.07mmol)和Na₂CO₃(70mg,0.06mmol)。将反应混合物在氮气下在80℃搅拌3h。冷却至室温之后，将反应混合物在减压下浓缩并通过快速色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以产生作为黄色油的产物3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯10(140mg,60％收率)。To a solution of 6-chloro-5-(4-methoxybenzyl)-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 8 (200 mg, 0.48 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate 9 (150 mg, 0.50 mmol) in dioxane:H₂ O=5:1 (15 mL) was added Pd(dppf)Cl₂ (50 mg, 0.07 mmol) and Na₂ CO₃ (70 mg, 0.06 mmol) at room temperature. The reaction mixture was stirred at 80° C. for 3 h under nitrogen. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (eluting with PE/EtOAc=100:0 to 80:20) to give the product tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 10 (140 mg, 60% yield) as a yellow oil.

C30H39F3N4O5Si[M+H]⁺m/z的LCMS(ESI)计算值为621.26，实测值为621.30。LCMS (ESI) calcd for C30H39F3N4O5Si[M+H]⁺ m/z was 621.26, found 621.30.

3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-甲酸叔丁酯(11)的制备Preparation of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-1-carboxylate (11)

向3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯10(140mg,0.30mmol)在MeOH(15mL)中的溶液中加入Pd/C(60mg,0.57mmol)。将反应混合物在氢气下在室温搅拌2h。将反应混合物过滤，将溶液在减压下浓缩以产生作为无色油的产物3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-甲酸叔丁酯11(120mg,80％收率)。To a solution of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 10 (140 mg, 0.30 mmol) in MeOH (15 mL) was added Pd/C (60 mg, 0.57 mmol). The reaction mixture was stirred under hydrogen at room temperature for 2 h. The reaction mixture was filtered and the solution was concentrated under reduced pressure to give the product tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-1-carboxylate 11 (120 mg, 80% yield) as a colorless oil.

C30H41F3N4O5Si[M+H]⁺m/z的LCMS(ESI)计算值为623.28，实测值为623.30。LCMS (ESI) calculated value of C30H41F3N4O5Si[M+H]⁺ m/z is 623.28, found value is 623.30.

6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮(12)的制备Preparation of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one (12)

向3-(5-(4-甲氧基苄基)-4-氧代-3-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-甲酸叔丁酯11(120mg,0.19mmol)在TFA(5mL)中的溶液中加入两滴TfOH。将反应混合物在50℃搅拌1h。将反应混合物在减压下浓缩以产生作为黄色油的产物6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮12(50mg,90％收率)。To a solution of tert-butyl 3-(5-(4-methoxybenzyl)-4-oxo-3-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-1-carboxylate 11 (120 mg, 0.19 mmol) in TFA (5 mL) were added two drops of TfOH. The reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the product 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 12 (50 mg, 90% yield) as a yellow oil.

C11H11F3N4O[M+H]⁺m/z的LCMS(ESI)计算值为273.09，实测值为273.15。LCMS (ESI) calcd for C11H11F3N4O[M+H]⁺ m/z 273.09, found 273.15.

N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(194a和194b的外消旋混合物)的制备Preparation of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of 194a and 194b)

向6-(吡咯烷-3-基)-3-(三氟甲基)-1,5-二氢-4H-吡唑并[4,3-c]吡啶-4-酮12(50mg,0.18mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT(43mg,0.18mmol)。然后在室温加入两滴乙酸和NaBH₃CN(12mg,0.18mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至92:8洗脱)纯化以产生作为白色固体的N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺，即化合物194a和194b的外消旋混合物(30mg,32％收率)。To a solution of 6-(pyrrolidin-3-yl)-3-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one 12 (50 mg, 0.18 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT (43 mg, 0.18 mmol). Then two drops of acetic acid and NaBH₃ CN (12 mg, 0.18 mmol) were added at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 92:8) to give N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide, a racemic mixture of compounds 194a and 194b (30 mg, 32% yield) as a white solid.

C23H26F3N7O2[M+H]⁺m/z的LCMS(ESI)计算值为490.21，实测值为490.17。LCMS (ESI) calcd for C23H26F3N7O2[M+H]⁺ m/z 490.21, found 490.17.

N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(化合物194a和194b)的手性分离Chiral Separation of N-Methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (Compounds 194a and 194b)

将N-甲基-5-(4-(3-(4-氧代-3-(三氟甲基)-4,5-二氢-1H-吡唑并[4,3-c]吡啶-6-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺的外消旋混合物(194rac)通过SFC(柱：DaicelCHIRALPAK OJ-H 250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％(NH₃)]＝70/30)分离并在减压下浓缩以提供作为194a的第一级分(9.9mg,98％纯度,ee％:100，白色固体)和作为194b的第二级分(9.4mg,100％纯度,ee％:98，白色固体)The racemic mixture of N-methyl-5-(4-(3-(4-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (194rac) was separated by SFC (column: Daicel CHIRALPAK OJ-H 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% (NH₃ )]=70/30) and concentrated under reduced pressure to give a first fraction (9.9 mg, 98% purity, ee%: 100, white solid) as 194a and a second fraction (9.4 mg, 100% purity, ee%: 98, white solid) as 194b.

化合物194aCompound 194a

¹H NMR(400MHz,DMSO)δ13.82(s,1H),11.10(s,1H),8.39(q,J＝4.4Hz,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.41(dd,J＝8.8,2.8Hz,1H),6.39(s,1H),3.84-3.81(m,2H),3.29-3.25(m,1H),2.98(t,J＝11.2Hz,2H),2.89-2.85(m,1H),2.81-2.78(m,5H),2.60-2.56(m,1H),2.39-2.30(m,1H),2.30-2.17(m,1H),1.97(d,J＝12.0Hz,2H),1.83-1.77(m,1H),1.56-1.51(m,2H)。¹ H NMR (400MHz, DMSO) δ13.82 (s, 1H), 11.10 (s, 1H), 8.39 (q, J = 4.4Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.83 ( d,J＝8.8Hz,1H),7.41(dd,J＝8.8,2.8Hz,1H),6.39(s,1H),3.84-3.81(m,2H),3.29-3.25 (m,1H),2.98(t,J＝11.2Hz,2H),2.89-2.85(m,1H),2.81-2.78(m,5H),2.60-2.56(m,1H),2.39-2.30(m ,1H),2.30-2.17(m,1H),1.97(d,J＝12.0Hz,2H),1.83-1.77(m,1H),1.56-1.51(m,2H).

C23H26F3N7O2[M+H]⁺m/z的LCMS(ESI)计算值为490.21，实测值为490.20。LCMS (ESI) calcd for C23H26F3N7O2[M+H]⁺ m/z 490.21, found 490.20.

化合物194bCompound 194b

¹H NMR(400MHz,DMSO)δ13.81(s,1H),11.11(s,1H),8.39(q,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),6.40(s,1H),3.91-3.81(m,2H),3.27-3.23(m,1H),2.98(t,J＝11.6Hz,2H),2.90-2.86(m,1H),2.80-2.77(m,5H),2.60-2.54(m,1H),2.36-2.33(m,1H),2.25-2.19(m,1H),1.97(d,J＝11.2Hz,2H),1.86-1.75(m,1H),1.58-1.48(m,2H)。¹ H NMR (400MHz, DMSO) δ13.81 (s, 1H), 11.11 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.83 ( d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),6.40(s,1H),3.91-3.81(m,2H),3.27-3.23 (m,1H),2.98(t,J＝11.6Hz,2H),2.90-2.86(m,1H),2.80-2.77(m,5H),2.60-2.54(m,1H),2.36-2.33(m ,1H),2.25-2.19(m,1H),1.97(d,J＝11.2Hz,2H),1.86-1.75(m,1H),1.58-1.48(m,2H).

C23H26F3N7O2[M+H]⁺m/z的LCMS(ESI)计算值为490.21，实测值为490.16。LCMS (ESI) calcd for C23H26F3N7O2[M+H]⁺ m/z 490.21, found 490.16.

实施例19-化合物208a和208b的合成Example 19 - Synthesis of Compounds 208a and 208b

化合物208a和208b的合成Synthesis of compounds 208a and 208b

2-氯吡啶并[2,3-d]嘧啶-4(3H)-酮(2)的制备Preparation of 2-chloropyrido[2,3-d]pyrimidin-4(3H)-one (2)

向在室温的2,4-二氯吡啶并[2,3-d]嘧啶1(1.5g,0.0075mol)在EtOH(30mL)中的溶液中加入在室温的NaOH(0.66g,0.017mol)在H₂O(16.5mL)中的溶液。将反应混合物在室温搅拌1h。将反应溶液用水淬灭，然后用1M HCl调至pH＝4～5。将溶液过滤，并将滤饼收集并在真空压强下干燥以产生作为黄色固体的2-氯吡啶并[2,3-d]嘧啶-4(3H)-酮2(1.1g,90％纯度,73％收率)。To a solution of 2,4-dichloropyrido[2,3-d]pyrimidine 1 (1.5 g, 0.0075 mol) in EtOH (30 mL) at room temperature was added a solution of NaOH (0.66 g, 0.017 mol) in H₂ O (16.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with water and then adjusted to pH=4-5 with 1M HCl. The solution was filtered, and the filter cake was collected and dried under vacuum pressure to produce 2-chloropyrido[2,3-d]pyrimidin-4(3H)-one 2 (1.1 g, 90% purity, 73% yield) as a yellow solid.

C₇H₄ClN₃O[M+H]⁺m/z的LCMS(ESI)计算值为182.00，实测值为181.90。LCMS (ESI) calcd for_C7H4ClN3O [M₊ H]⁺_m /z 182.00, found 181.90.

2-氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮(3)的制备Preparation of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (3)

向2-氯吡啶并[2,3-d]嘧啶-4(3H)-酮2(1.1g,0.0061mol)在THF/H₂O＝4:1(50mL)中的溶液中加入PtO₂(0.14g)。然后将混合物在氢气下在室温搅拌18h。将混合物穿过硅藻土垫过滤，并将滤液在减压下浓缩以产生作为黄色固体的2-氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮3(1.1g,95％纯度,91％收率)。To a solution of 2-chloropyrido[2,3-d]pyrimidin-4(3H)-one 2 (1.1 g, 0.0061 mol) in THF/H₂ O=4:1 (50 mL) was added PtO₂ (0.14 g). The mixture was then stirred at room temperature for 18 h under hydrogen. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 3 (1.1 g, 95% purity, 91% yield) as a yellow solid.

C₇H₈ClN₃O[M+H]⁺m/z的LCMS(ESI)计算值为186.04，实测值为185.95。LCMS (ESI) calcd for_C7H8ClN3O [M₊ H]⁺_m /z: 186.04, found: 185.95.

2-氯-3-(4-甲氧基苄基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮(4)的制备Preparation of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (4)

在室温向2-氯-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮3(0.9g,4.85mmol)在DMSO(150mL)中的溶液中加入Cs₂CO₃(4.7g,14.5mmol)和PMBCl(1.52g,9.7mmol)。将反应混合物在50℃搅拌1h。将反应溶液用水淬灭，并用EtOAc(100mL×3)萃取。将合并的有机相用盐水洗涤3次并在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以产生作为白色固体的2-氯-3-(4-甲氧基苄基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮4(1.23g,90％纯度,74％收率)。To a solution of 2-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 3 (0.9 g, 4.85 mmol) in DMSO (150 mL) was added Cs₂ CO₃ (4.7 g, 14.5 mmol) and PMBCl (1.52 g, 9.7 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. The reaction solution was quenched with water and extracted with EtOAc (100 mL×3). The combined organic phase was washed 3 times with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC = 100:0 to 50:50) to give 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 4 (1.23 g, 90% purity, 74% yield) as a white solid.

C₁₅H₁₆ClN₃O₂[M+H]⁺m/z的LCMS(ESI)计算值为306.09，实测值为305.80。LCMS (ESI) calcd for_C15H16ClN3O2 [M+H]⁺_m/ z: 306.09, found:_305.80 .

2-氯-3-(4-甲氧基苄基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮(5)的制备Preparation of 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (5)

在0℃向2-氯-3-(4-甲氧基苄基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮4(1.2g,0.004mol)在DMF(50mL)中的溶液中加入MeI(3.05g,0.02mol)和NaH(60％在矿物油中,0.32g,0.008mol)。将反应混合物在室温搅拌2h。将反应溶液用水淬灭，并用EtOAc(100mL×3)萃取。将合并的有机相用盐水洗涤3次并在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以产生作为黄色油的2-氯-3-(4-甲氧基苄基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮5(450mg,90％纯度,33％收率)。To a solution of 2-chloro-3-(4-methoxybenzyl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 4 (1.2 g, 0.004 mol) in DMF (50 mL) was added MeI (3.05 g, 0.02 mol) and NaH (60% in mineral oil, 0.32 g, 0.008 mol) at 0°C. The reaction mixture was stirred at room temperature for 2 h. The reaction solution was quenched with water and extracted with EtOAc (100 mL×3). The combined organic phases were washed 3 times with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC = 100:0 to 50:50) to give 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 5 (450 mg, 90% purity, 33% yield) as a yellow oil.

C₁₆H₁₈ClN₃O₂[M+H]⁺m/z的LCMS(ESI)计算值为320.11，实测值为320.00。LCMS (ESI) calcd for_C16H18ClN3O2 [M+H]⁺_m/ z 320.11, found_320.00 .

3-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(7)的制备Preparation of tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (7)

在室温向2-氯-3-(4-甲氧基苄基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮5(450mg,1.41mmol)在二氧杂环己烷/H₂O＝5:1(30mL)中的溶液中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯6(500mg,1.69mmol)、Pd(dppf)Cl₂·DCM(115mg,0.14mmol)和K₂CO₃(587mg,4.22mmol)。将反应混合物在90℃搅拌3h。将反应溶液用水淬灭，并用EtOAc(50mL×3)萃取。将合并的有机相在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以产生作为白色固体的3-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯7(550mg,90％纯度,77％收率)。To a solution of 2-chloro-3-(4-methoxybenzyl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 5 (450 mg, 1.41 mmol) in dioxane/H₂ O=5:1 (30 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 6 (500 mg, 1.69 mmol), Pd(dppf)Cl₂ ·DCM (115 mg, 0.14 mmol) and K₂ CO₃ (587 mg, 4.22 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL×3). The combined organic phases were concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC = 100:0 to 50:50) to give tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 7 (550 mg, 90% purity, 77% yield) as a white solid.

C₂₅H₃₂N₄O₄[M+H]⁺m/z的LCMS(ESI)计算值为453.24，实测值为453.20。LCMS (ESI) calcd for_C25H32N4O4 [M₊ H]⁺_m/ z 453.24, found 453.20.

3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate (8)

在室温向3-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯7(550mg,1.2mmol)在MeOH(15mL)中的溶液中加入Pd/C(55mg)。将反应混合物在氢气气氛下在室温搅拌18h。将反应溶液过滤，并将滤饼用MeOH(5mL×2)洗涤。将滤液在减压下浓缩以产生作为黄色油的3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-甲酸叔丁酯8(400mg,90％纯度,88％收率)。To a solution of tert-butyl 3-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 7 (550 mg, 1.2 mmol) in MeOH (15 mL) was added Pd/C (55 mg) at room temperature. The reaction mixture was stirred at room temperature for 18 h under a hydrogen atmosphere. The reaction solution was filtered, and the filter cake was washed with MeOH (5 mL×2). The filtrate was concentrated under reduced pressure to produce tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate 8 (400 mg, 90% purity, 88% yield) as a yellow oil.

C₁₇H₂₆N₄O₃[M+H]⁺m/z的LCMS(ESI)计算值为335.20，实测值为335.30。LCMS (ESI) calcd for_C17H26N4O3 [M₊ H]⁺_m/ z 335.20, found 335.30.

8-甲基-2-(吡咯烷-3-基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮盐酸盐(9)的制备Preparation of 8-methyl-2-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride (9)

将3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-甲酸叔丁酯8(200mg,0.60mmol)在HCl-二氧杂环己烷(4M,10mL)中的溶液在N₂气氛下在室温搅拌2h。将形成的沉淀物用DCM(5mL×3)洗涤，收集并在减压下干燥以得到作为白色固体的8-甲基-2-(吡咯烷-3-基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮盐酸盐9(110mg,90％纯度,70％收率)。A solution of tert-butyl 3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidine-1-carboxylate 8 (200 mg, 0.60 mmol) in HCl-dioxane (4M, 10 mL) was stirred at room temperature for 2 h under_N2 atmosphere. The formed precipitate was washed with DCM (5 mL x 3), collected and dried under reduced pressure to give 8-methyl-2-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride 9 (110 mg, 90% purity, 70% yield) as a white solid.

C₁₂H₁₈N₄O[M+H]⁺m/z的LCMS(ESI)计算值为235.15，实测值为235.00。LCMS (ESI) calcd for_C12H18N4O [M₊ H]⁺ m_/ z 235.15, found 235.00.

N-甲基-5-(4-(3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(208a和208b)的制备Preparation of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (208a and 208b)

在室温向8-甲基-2-(吡咯烷-3-基)-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮盐酸盐9(110mg,0.46mmol)在MeOH(1mL)中的溶液中加入TEA(1mL)并搅拌5分钟，然后将反应物在减压下浓缩至干燥。在室温将残余物溶解在MeOH(15mL)和AcOH(0.01mL)中。加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(131mg,0.56mmol)和NaBH₃CN(88mg,1.40mmol)。将反应混合物在50℃搅拌1h。将反应溶液在减压下浓缩并将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的N-甲基-5-(4-(3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺208rac的外消旋混合物(120mg,99％纯度,55％收率)。To a solution of 8-methyl-2-(pyrrolidin-3-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one hydrochloride 9 (110 mg, 0.46 mmol) in MeOH (1 mL) was added TEA (1 mL) and stirred for 5 minutes at room temperature, and then the reactant was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (15 mL) and AcOH (0.01 mL) at room temperature. N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (131 mg, 0.56 mmol) and NaBH₃ CN (88 mg, 1.40 mmol) were added. The reaction mixture was stirred at 50° C. for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to give a racemic mixture of N-methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide 208rac as a white solid (120 mg, 99% purity, 55% yield).

C₂₄H₃₃N₇O₂[M+H]⁺m/z的LCMS(ESI)计算值为452.27，实测值为452.20。LCMS (ESI) calcd for_C24H33N7O2 [M₊ H]⁺_m/ z 452.27, found 452.20.

N-甲基-5-(4-(3-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(208rac)的手性拆分Chiral Resolution of N-Methyl-5-(4-(3-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (208rac)

将化合物208a和208b的外消旋混合物通过SFC(柱：Daicel Chiralpak IH SFC,250mm×20mm I.D.,5μmm；流动相:CO₂/MeOH[0.1％ NH₃]＝70/30)分离并在减压下浓缩以提供作为208a的第一级分(52.3mg,99％纯度,100％ee，白色固体)和作为208b的第二级分(54.2mg,100％纯度,98％ee，白色固体)。The racemic mixture of compounds 208a and 208b was separated by SFC (column: Daicel Chiralpak IH SFC, 250 mm×20 mm ID, 5 μmm; mobile phase: CO₂ /MeOH [0.1% NH₃ ]=70/30) and concentrated under reduced pressure to provide the first fraction as 208a (52.3 mg, 99% purity, 100% ee, white solid) and the second fraction as 208b (54.2 mg, 100% purity, 98% ee, white solid).

化合物208aCompound 208a

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.37(s,1H),8.43-8.34(m,1H),8.26(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.39(dd,J＝8.8,3.2Hz,1H),3.82-3.77(m,2H),3.23-3.20(m,2H),3.13-3.09(m,1H),3.03(s,3H),2.99-2.92(m,3H),2.78(d,J＝4.8Hz,3H),2.68-2.66(m,1H),2.59-2.57(m,1H),2.35-2.26(m,4H),2.07-2.00(m,2H),1.94-1.88(m,2H),1.78-1.72(m,2H),1.53-1.44(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 11.37 (s, 1H), 8.43-8.34 (m, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz,1H),7.39(dd,J＝8.8,3.2Hz,1H),3.82-3.77(m,2H),3.23-3.20(m,2H),3.13-3.09(m,1H),3.03(s ,3H),2.99-2.92(m,3H),2.78(d,J＝4.8Hz,3H),2.68-2.66(m,1H),2.59-2.57(m,1H),2.35-2.26(m,4H ),2.07-2.00(m,2H),1.94-1.88(m,2H),1.78-1.72(m,2H),1.53-1.44(m,2H).

C₂₄H₃₃N₇O₂[M+H]⁺m/z的LCMS(ESI)计算值为452.27，实测值为452.30。LCMS (ESI) calcd for_C24H33N7O2 [M₊ H]⁺_m/ z 452.27, found 452.30.

化合物208bCompound 208b

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.35(s,1H),8.41-8.33(m,1H),8.26(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),3.85-3.75(m,2H),3.24-3.19(m,2H),3.14-3.07(m,1H),3.03(s,3H),3.00-2.88(m,3H),2.77(d,J＝4.8Hz,3H),2.67-2.62(m,1H),2.61-2.56(m,1H),2.35-2.21(m,4H),2.09-1.99(m,2H),1.96-1.87(m,2H),1.79-1.70(m,2H),1.55-1.43(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 11.35 (s, 1H), 8.41-8.33 (m, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz,1H),7.39(dd,J＝8.8,2.8Hz,1H),3.85-3.75(m,2H),3.24-3.19(m,2H),3.14-3.07(m,1H),3.03(s ,3H),3.00-2.88(m,3H),2.77(d,J＝4.8Hz,3H),2.67-2.62(m,1H),2.61-2.56(m,1H),2.35-2.21(m,4H ),2.09-1.99(m,2H),1.96-1.87(m,2H),1.79-1.70(m,2H),1.55-1.43(m,2H).

C₂₄H₃₃N₇O₂[M+H]⁺m/z的LCMS(ESI)计算值为452.27，实测值为452.30。LCMS (ESI) calcd for_C24H33N7O2 [M₊ H]⁺_m/ z 452.27, found 452.30.

实施例20-INT-3的合成Example 20-Synthesis of INT-3

INT-3的合成Synthesis of INT-3

3-(4-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯(INT-3)的制备Preparation of tert-butyl 3-(4-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (INT-3)

在室温向3-(1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯1(500mg,1.59mmol)在DMAC(20mL)中的溶液中加入Selectfluor(563mg,1.59mmol)。将混合物在150℃搅拌10min。冷却至室温以后，将反应混合物加入冷水中并然后用EtOAc(100mL×3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥并在减压下浓缩。将残余物通过快速硅胶色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以产生作为黄色油的3-(4-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯INT-3(100mg,60％纯度,11％收率)。To a solution of tert-butyl 3-(1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidine-1-carboxylate 1 (500 mg, 1.59 mmol) in DMAC (20 mL) was added Selectfluor (563 mg, 1.59 mmol) at room temperature. The mixture was stirred at 150° C. for 10 min. After cooling to room temperature, the reaction mixture was added to cold water and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluting with PE/EtOAC=100:0 to 50:50) to produce tert-butyl 3-(4-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidine-1-carboxylate INT-3 (100 mg, 60% purity, 11% yield) as a yellow oil.

C₁₈H₂₁FN₂O₃[M+H]⁺m/z的LCMS(ESI)计算值为333.15，实测值为332.90。LCMS (ESI) calcd for_C18H21FN2O3 [_M +H]⁺_m/ z 333.15, found 332.90.

实施例21-化合物259的合成Example 21 - Synthesis of Compound 259

化合物259的合成Synthesis of compound 259

4-((2-氨甲酰基-4-氟苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3)

向2-氨基-5-氟苯甲酰胺1(30mg,2.21mmol)和2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酸2(520mg,2.20mmol)在吡啶(20mL)中的溶液中加入EDCI(423mg,2.21mmol)，然后将混合物在室温搅拌18h。将反应混合物用水淬灭，将水层用EtOAc(150mLx 3)萃取。将合并的有机层用1M HCl溶液和盐水洗涤，经Na₂SO₄干燥，在减压下浓缩以产生作为白色固体的产物4-((2-氨甲酰基-4-氟苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(500mg,56％收率)。EDCI (423 mg, 2.21 mmol) was added to a solution of 2-amino-5-fluorobenzamide 1 (30 mg, 2.21 mmol) and 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 2 (520 mg, 2.20 mmol) in pyridine (20 mL), and the mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water and the aqueous layer was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with 1 M HCl solution and brine, dried over Na₂ SO₄ , and concentrated under reduced pressure to produce the product 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 3 (500 mg, 56% yield) as a white solid.

C₁₈H₂₂FN₃O₄[M+Na]⁺m/z的LCMS(ESI)计算值为386.16，实测值为385.95。LCMS (ESI) calcd for_C18H22FN3O4 [_M +Na]⁺ m_/z : 386.16, found: 385.95.

4-(6-氟-4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(4)的制备Preparation of tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4)

向4-((2-氨甲酰基-4-氟苯基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(500mg,1.38mmol)在DME(50mL)中的溶液中加入KOH(154mg,2.75mmol)。将溶液在60℃搅拌2h，冷却至室温，然后将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的4-(6-氟-4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(400mg,76％收率)。To a solution of tert-butyl 4-((2-carbamoyl-4-fluorophenyl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (500 mg, 1.38 mmol) in DME (50 mL) was added KOH (154 mg, 2.75 mmol). The solution was stirred at 60 ° C for 2 h, cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to produce tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (400 mg, 76% yield) as a white solid.

C₁₈H₂₀FN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为346.15，实测值为345.85。LCMS (ESI) calcd for_C18H20FN3O3 [_M +H]⁺_m/ z 346.15, found 345.85.

2-(2-氮杂双环[2.1.1]己烷-4-基)-6-氟喹唑啉-4(3H)-酮(5)的制备Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazolin-4(3H)-one (5)

向4-(6-氟-4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(400mg,1.16mmol)在DCM(10mL)中的溶液中加入在二氧杂环己烷中的HCl(4M,20mL)。将混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的产物2-(2-氮杂双环[2.1.1]己烷-4-基)-6-氟喹唑啉-4(3H)-酮5(200mg,63％收率)。To a solution of tert-butyl 4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (400 mg, 1.16 mmol) in DCM (10 mL) was added HCl (4M, 20 mL) in dioxane. The mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to produce the product 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazolin-4(3H)-one 5 (200 mg, 63% yield) as a white solid.

C₁₅H₁₇N₃O[M+H]⁺m/z的LCMS(ESI)计算值为246.10，实测值为245.95。LCMS (ESI) calcd for_C15H17N3O [M₊ H]⁺ m_/ z 246.10, found 245.95.

6-氟-5-(4-(4-(6-氟-4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物259)的制备Preparation of 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 259)

向2-(2-氮杂双环[2.1.1]己烷-4-基)-6-氟喹唑啉-4(3H)-酮5(60mg,0.24mmol)在MeOH(20mL)中的溶液中加入6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT-2(61mg,0.24mmol)，然后在室温加入两滴乙酸和NaBH(OAC)₃(104mg,0.49mmol)。1h以后，加入NaBH₃CN(8mg,0.13mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过C₁₈柱(流动相:ACN-H₂O(0.1％ FA)，梯度:10-95)纯化以产生作为白色固体的6-氟-5-(4-(4-(6-氟-4-氧代-3,4-二氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)-N-甲基吡啶酰胺259(45.5mg,99％纯度,15％收率)。To a solution of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-6-fluoroquinazolin-4(3H)-one 5 (60 mg, 0.24 mmol) in MeOH (20 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (61 mg, 0.24 mmol), followed by two drops of acetic acid and NaBH(OAC)₃ (104 mg, 0.49 mmol) at room temperature. After 1 h, NaBH₃ CN (8 mg, 0.13 mmol) was added. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by_C18 column (mobile phase: ACN-_H2O (0.1% FA), gradient: 10-95) to give 6-fluoro-5-(4-(4-(6-fluoro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide 259 (45.5 mg, 99% purity, 15% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,ppm)δ:12.29(s,1H),8.40(q,1H),7.84(dd,J＝8.0,1.2Hz,1H),7.77(dd,J＝8.4,2.8Hz,1H),7.72-7.65(m,2H),7.62-7.56(m,1H),3.70(s,1H),3.59-3.53(m,2H),3.05(s,2H),2.86(t,J＝11.2Hz,2H),2.77(d,J＝4.8Hz,3H),2.57-2.52(m,1H),2.15-2.09(m,2H),1.99(d,J＝10.8Hz,2H),1.92-1.86(m,2H),1.58-1.47(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 12.29 (s, 1H), 8.40 (q, 1H), 7.84 (dd, J = 8.0, 1.2 Hz, 1H), 7.77 (dd, J = 8.4 ,2.8Hz,1H),7.72-7.65(m,2H),7.62-7.56(m,1H),3.70(s,1H),3.59-3.53(m,2H ),3.05(s,2H),2.86(t,J＝11.2Hz,2H),2.77(d,J＝4.8Hz,3H),2.57-2.52(m,1H),2.15-2.09(m,2H) ,1.99(d,J=10.8Hz,2H),1.92-1.86(m,2H),1.58-1.47(m,2H).

C₂₅H₂₆F₂N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为481.21，实测值为481.05。LCMS (ESI) calcd for_C25H26F2N6O2 [M₊ H]⁺_m/ z 481.21, found_481.05 .

实施例22-化合物299的合成Example 22-Synthesis of Compound 299

化合物299的合成Synthesis of compound 299

((1-(6-(甲基氨甲酰基)吡啶-3-基)哌啶-4-基)甲基)氨基甲酸叔丁酯(2)的制备Preparation of tert-butyl ((1-(6-(methylcarbamoyl)pyridin-3-yl)piperidin-4-yl)methyl)carbamate (2)

在室温向2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酸1(500mg,2.19mmol)在DCM(20mL)中的溶液中接连地加入NH₄Cl(234mg,4.38mmol)、DIPEA(1415mg,10.95mmol)和HATU(1249mg,3.28mmol)。将混合物保持在室温搅拌1h。将得到的混合物用水稀释，并用DCM(50mL×3)萃取。将合并的有机层经Na₂SO₄干燥并在减压下浓缩。将残余物通过快速色谱法(用3％至5％的MeOH/DCM洗脱)纯化以产生作为白色固体的4-氨甲酰基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯2(400mg,90％纯度,72％收率)。To a solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 1 (500 mg, 2.19 mmol) in DCM (20 mL) was added NH₄ Cl (234 mg, 4.38 mmol), DIPEA (1415 mg, 10.95 mmol) and HATU (1249 mg, 3.28 mmol) successively at room temperature. The mixture was kept stirring at room temperature for 1 h. The resulting mixture was diluted with water and extracted with DCM (50 mL×3). The combined organic layers were dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 3% to 5% MeOH/DCM) to produce tert-butyl 4-carbamoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate 2 (400 mg, 90% purity, 72% yield) as a white solid.

C₁₁H₁₈N₂O₃[M-56+H]⁺m/z的LCMS(ESI)计算值为171.13，实测值为171.10。_{LCMS (ESI) calcd for C11H18N2O3[} M-₅₆ +H]⁺ m/_z : 171.13, found: 171.10.

4-甲脒基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-carbamimidoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate (3)

将4-氨甲酰基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯2(400mg,1.76mmol)加入Me₃O⁺BF₄^-(312mg,2.1mmol)在无水DCM(10mL)中的悬浮液中。将混合物在氩气氛下在室温搅拌2h。然后除去溶剂以提供粗制的亚氨酸盐。将该粗制物溶解在NH₃/MeOH(7M,10mL)中并在室温搅拌16h。然后加入Boc₂O(1152mg,5.28mmol)。将混合物在室温搅拌10min并然后浓缩以产生作为白色固体的粗制4-甲脒基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(500mg,50％纯度,62％收率)。4-Carbamoyl-2-azabicyclo [2.1.1] hexane-2-carboxylic acid tert-butyl ester 2 (400 mg, 1.76 mmol) was added to a suspension of Me₃ O⁺ BF₄^- (312 mg, 2.1 mmol) in anhydrous DCM (10 mL). The mixture was stirred at room temperature for 2 h under an argon atmosphere. The solvent was then removed to provide a crude imidate. The crude was dissolved in NH₃ /MeOH (7M, 10 mL) and stirred at room temperature for 16 h. Boc₂ O (1152 mg, 5.28 mmol) was then added. The mixture was stirred at room temperature for 10 min and then concentrated to produce crude 4-carbamimidoyl-2-azabicyclo [2.1.1] hexane-2-carboxylic acid tert-butyl ester 3 (500 mg, 50% purity, 62% yield) as a white solid.

C₁₁H₁₉N₃O₂[M+H]⁺m/z的LCMS(ESI)计算值为226.15，实测值为226.05。LCMS (ESI) calcd for_C11H19N3O2 [M₊ H]⁺_m/ z 226.15, found 226.05.

4-(6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(5)的制备Preparation of tert-butyl 4-(6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5)

向4-甲脒基-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(500mg,2.21mmol)在DMF(20mL)中的溶液中一次性加入K₂CO₃(916mg,6.63mmol)和(E)-3-甲氧基丙烯酸甲酯4(770mg,6.63mmol)。将反应混合物加热并在120℃搅拌2h。将反应混合物浓缩并通过硅胶柱色谱法(用50％至100％的EtOAc/PE洗脱)纯化以得到作为白色固体的4-(6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(200mg,90％纯度,29％收率)。To a solution of tert-butyl 4-carbamimidoyl-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (500 mg, 2.21 mmol) in DMF (20 mL) was added K₂ CO₃ (916 mg, 6.63 mmol) and (E)-methyl 3-methoxyacrylate 4 (770 mg, 6.63 mmol) in one portion. The reaction mixture was heated and stirred at 120° C. for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (eluting with 50% to 100% EtOAc/PE) to give tert-butyl 4-(6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (200 mg, 90% purity, 29% yield) as a white solid.

C₁₄H₁₉N₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为278.15，实测值为277.95。LCMS (ESI) calcd for_C14H19N3O3 [M₊ H]⁺_m/ z 278.15, found 277.95.

4-(5-碘-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6)

向4-(6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(215mg,0.77mmol)在AcOH(5mL)中的溶液中一次性加入NIS(260mg,1.16mmol)。将反应混合物加热并在50℃搅拌2h。将反应混合物浓缩并通过硅胶柱色谱法(用50％至70％的EtOAc/PE洗脱)纯化以得到作为白色固体的4-(5-碘-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯6(180mg,90％纯度,51％收率)。To a solution of tert-butyl 4-(6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (215 mg, 0.77 mmol) in AcOH (5 mL) was added NIS (260 mg, 1.16 mmol) in one portion. The reaction mixture was heated and stirred at 50 °C for 2 h. The reaction mixture was concentrated and purified by silica gel column chromatography (eluting with 50% to 70% EtOAc/PE) to give tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 6 (180 mg, 90% purity, 51% yield) as a white solid.

C₁₄H₁₈IN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为404.04，实测值为403.85。LCMS (ESI) calcd for_C14H18IN3O3 [_M +H]⁺_m/ z 404.04, found 403.85.

4-(6-氧代-5-乙烯基-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(8)的制备Preparation of tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (8)

将4-(5-碘-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯6(180mg,0.44mmol)、三丁基(乙烯基)锡烷7(282mg,0.89mmol)和Pd(AMPHOS)Cl₂(32mg,0.04mmol)在ACN(10mL)中的溶液用N₂净化2min并然后在80℃搅拌1h。冷却至室温以后，将反应混合物浓缩并通过快速色谱法(用50％至70％的EtOAc/PE洗脱)纯化以产生作为白色固体的4-(6-氧代-5-乙烯基-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯8(120mg,90％纯度,79％收率)。A solution of tert-butyl 4-(5-iodo-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 6 (180 mg, 0.44 mmol), tributyl(vinyl)stannane 7 (282 mg, 0.89 mmol) and Pd(AMPHOS)Cl₂ (32 mg, 0.04 mmol) in ACN (10 mL) was purged with N₂ for 2 min and then stirred at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography (eluting with 50% to 70% EtOAc/PE) to give tert-butyl 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 8 (120 mg, 90% purity, 79% yield) as a white solid.

C₁₆H₂₁N₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为304.16，实测值为304.20。LCMS (ESI) calcd for_C16H21N3O3 [M₊ H]⁺_m/ z 304.16, found 304.20.

4-(5-乙基-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(9)的制备Preparation of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (9)

向4-(6-氧代-5-乙烯基-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯8(120mg,0.40mmol)在MeOH(5mL)中的溶液中加入10％ Pd/C(12mg)。将混合物抽真空并用氮气回填3次并然后用氢气填充。将得到的混合物在室温搅拌16小时。然后将混合物穿过硅藻土过滤并在真空下浓缩以产生作为白色固体的粗制4-(5-乙基-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯9(120mg,90％纯度,89％收率)，将其不经进一步纯化直接用在下一步中。10% Pd/C (12 mg) was added to a solution of 4-(6-oxo-5-vinyl-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 8 (120 mg, 0.40 mmol) in MeOH (5 mL). The mixture was evacuated and backfilled with nitrogen 3 times and then filled with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then filtered through diatomaceous earth and concentrated under vacuum to produce crude 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester 9 (120 mg, 90% purity, 89% yield) as a white solid, which was used directly in the next step without further purification.

C₁₆H₂₃N₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为306.18，实测值为306.00。LCMS (ESI) calcd for_C16H23N3O3 [M+H]⁺_m/ z 306.18, found 306.00_.

2-(2-氮杂双环[2.1.1]己烷-4-基)-5-乙基嘧啶-4(3H)-酮(10)的制备Preparation of 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-ethylpyrimidin-4(3H)-one (10)

在0℃向4-(5-乙基-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯9(120mg,0.39mmol)在DCM(4mL)中的溶液中逐滴加入TFA(1mL)。将反应溶液在室温搅拌1小时，然后在真空下浓缩。将得到的混合物用Et₃N淬灭并在真空下浓缩以提供2-(2-氮杂双环[2.1.1]己烷-4-基)-5-乙基嘧啶-4(3H)-酮10(120mg,50％纯度,74％收率)。To a solution of tert-butyl 4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 9 (120 mg, 0.39 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise at 0°C. The reaction solution was stirred at room temperature for 1 hour and then concentrated under vacuum. The resulting mixture was quenched with_Et3N and concentrated under vacuum to provide 2-(2-azabicyclo[2.1.1]hexane-4-yl)-5-ethylpyrimidin-4(3H)-one 10 (120 mg, 50% purity, 74% yield).

C₁₁H₁₅N₃O[M+H]⁺m/z的LCMS(ESI)计算值为206.12，实测值为206.00。LCMS (ESI) calcd for_C11H15N3O [M₊ H]⁺ m_/ z 206.12, found 206.00.

5-(4-(4-(5-乙基-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)-N-甲基吡啶酰胺(299)的制备Preparation of 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide (299)

向2-(2-氮杂双环[2.1.1]己烷-4-基)-5-乙基嘧啶-4(3H)-酮10(40mg,0.19mmol)在MeOH(5mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(68mg,0.29mmol)，然后在室温加入两滴乙酸和NaBH(OAc)₃(82mg,0.39mmol)。1h以后，加入NaBH₃CN(12mg,0.19mmol)。将反应混合物在50℃搅拌1h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过制备型HPLC(Gemini 5um C18 150×21.2mm，用含有0.1％ NH₃·H₂O的10％至40％ACN/H₂O洗脱)和制备型TLC(MeOH/DCM,1/20)纯化以产生作为白色固体的5-(4-(4-(5-乙基-6-氧代-1,6-二氢嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)-N-甲基吡啶酰胺299(3.2mg,99％纯度,3％收率)。To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5-ethylpyrimidin-4(3H)-one 10 (40 mg, 0.19 mmol) in MeOH (5 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (68 mg, 0.29 mmol), followed by two drops of acetic acid and NaBH(OAc)₃ (82 mg, 0.39 mmol) at room temperature. After 1 h, NaBH₃ CN (12 mg, 0.19 mmol) was added. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um C18 150x21.2 mm, eluting with 10% to 40% ACN/_H2O containing 0.1%_NH3 -_H2O ) and preparative TLC (MeOH/DCM, 1/20) to give 5-(4-(4-(5-ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)-N-methylpicolinamide 299 as a white solid (3.2 mg, 99% purity, 3% yield).

¹H NMR(400MHz,DMSO-d₆,ppm)δ:12.30(s,1H),8.39(q,J＝4.8Hz,1H),8.27(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.72(s,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.94-3.81(m,2H),3.64(s,1H),3.00-2.85(m,4H),2.78(d,J＝4.8Hz,3H),2.57-2.52(m,1H),2.40-2.27(m,2H),2.07-2.01(m,2H),1.96-1.91(m,2H),1.87-1.72(m,2H),1.50-1.36(m,2H),1.07(t,J＝7.6Hz,3H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 12.30 (s, 1H), 8.39 (q, J = 4.8Hz, 1H), 8.27 (d, J = 2.8Hz, 1H), 7.81 (d, J＝8.8Hz,1H),7.72(s,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.94-3.81(m,2H),3.64(s,1H),3.00-2 .85(m,4H),2.78(d,J＝4.8Hz,3H),2.57-2.52(m,1H),2.40-2.27(m,2H),2.07-2.01(m,2H),1.96-1.91 (m,2H),1.87-1.72(m,2H),1.50-1.36(m,2H),1.07(t,J=7.6Hz,3H).

C₂₃H₃₀N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为423.25，实测值为423.15LCMS (ESI) calcd for C₂₃ H₃₀ N₆ O₂ [M+H]⁺ m/z 423.25, found 423.15

实施例23-化合物309a和309b的合成Example 23 - Synthesis of Compounds 309a and 309b

化合物309a和309b的合成Synthesis of compounds 309a and 309b

2-氯-6-甲氧基吡啶-4-胺(2)的制备Preparation of 2-chloro-6-methoxypyridin-4-amine (2)

在室温向2,6-二氯吡啶-4-胺1(1.0g,6.1mmol)在二氧杂环己烷(15mL)中的溶液中加入MeONa(3.3g,61.0mmol)和TBAI(230mg,0.6mmol)。将反应混合物在密闭试管中在150℃搅拌15h。将反应溶液冷却至室温，并在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至95:5洗脱)纯化以提供作为白色固体的2-氯-6-甲氧基吡啶-4-胺2(880mg,90％纯度,81％收率)。MeONa (3.3 g, 61.0 mmol) and TBAI (230 mg, 0.6 mmol) were added to a solution of 2,6-dichloropyridine-4-amine 1 (1.0 g, 6.1 mmol) in dioxane (15 mL) at room temperature. The reaction mixture was stirred at 150 ° C for 15 h in a sealed test tube. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE/EtOAc=100:0 to 95:5) to provide 2-chloro-6-methoxypyridine-4-amine 2 (880 mg, 90% purity, 81% yield) as a white solid.

C₆H₇ClN₂O[M+H]⁺m/z的LCMS(ESI)计算值为159.02，实测值为158.93。LCMS (ESI) calcd for_C6H7ClN2O [M₊ H]⁺_m /z: 159.02, found: 158.93.

3-溴-6-氯-2-甲氧基吡啶-4-胺(3)的制备Preparation of 3-bromo-6-chloro-2-methoxypyridin-4-amine (3)

在室温向2-氯-6-甲氧基吡啶-4-胺2(880mg,5.5mmol)在DMF(40mL)中的溶液中加入NBS(1.2g,6.7mmol)。将反应混合物在室温搅拌1h。将反应混合物倒入水中。将水层用EtOAc(100mL×3)萃取。将合并的有机层用盐水(100mL×3)洗涤，经Na₂SO₄干燥并在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至70:30洗脱)纯化以提供作为白色固体的3-溴-6-氯-2-甲氧基吡啶-4-胺3(950mg,90％纯度,64％收率)。To a solution of 2-chloro-6-methoxypyridine-4-amine 2 (880 mg, 5.5 mmol) in DMF (40 mL) was added NBS (1.2 g, 6.7 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water. The aqueous layer was extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL × 3), dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE/EtOAc=100:0 to 70:30) to provide 3-bromo-6-chloro-2-methoxypyridine-4-amine 3 (950 mg, 90% purity, 64% yield) as a white solid.

C₆H₆BrClN₂O[M+H]⁺m/z的LCMS(ESI)计算值为236.94，实测值为236.87。LCMS (ESI) calcd for_C6H6BrClN2O [_M +H]⁺ m_/ z 236.94, found 236.87.

(3-溴-6-氯-2-甲氧基吡啶-4-基)氨基甲酸叔丁酯(4)的制备Preparation of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate (4)

在室温向3-溴-6-氯-2-甲氧基吡啶-4-胺3(950mg,4.0mmol)在DCM(30mL)中的溶液中接连地加入Boc₂O(1.31g,6.0mmol)、Et₃N(810mg,8.0mmol)和DMAP(244mg,2.0mmol)。将反应混合物在室温搅拌1h。将反应溶液在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以提供作为白色固体的(3-溴-6-氯-2-甲氧基吡啶-4-基)氨基甲酸叔丁酯4和(3-溴-6-氯-2-甲氧基吡啶-4-基)(叔丁氧基羰基)氨基甲酸叔丁酯4a的混合物(750mg,90％纯度,49％收率)。To a solution of 3-bromo-6-chloro-2-methoxypyridin-4-amine 3 (950 mg, 4.0 mmol) in DCM (30 mL) was added Boc₂ O (1.31 g, 6.0 mmol), Et₃ N (810 mg, 8.0 mmol) and DMAP (244 mg, 2.0 mmol) successively at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE/EtOAc=100:0 to 80:20) to provide a mixture of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate 4 and tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate 4a as a white solid (750 mg, 90% purity, 49% yield).

C₁₁H₁₄BrClN₂O₃[M+H]⁺m/z的LCMS(ESI)计算值为336.99，实测值为336.92。LCMS (ESI) calcd for_{C11H14BrClN2O3} [M+H]⁺_m/ z: 336.99, found:_336.92 .

(E)-3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙烯酸乙酯(6)的制备Preparation of ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate (6)

在室温向(3-溴-6-氯-2-甲氧基吡啶-4-基)氨基甲酸叔丁酯4和(3-溴-6-氯-2-甲氧基吡啶-4-基)(叔丁氧基羰基)氨基甲酸叔丁酯4a的混合物(750mg,2.2mmol)在二氧杂环己烷/H₂O(25mL,10:1)中的溶液中接连地加入(E)-3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)丙烯酸乙酯5(751mg,3.3mmol)、Pd(dppf)Cl₂·DCM(181mg,0.22mmol)和K₃PO₄·H₂O(1.5g,6.6mmol)。将反应混合物在N₂下在100℃搅拌6h。将反应溶液冷却至室温，并在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至70:30洗脱)纯化以提供作为白色固体的(E)-3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙烯酸乙酯6和(E)-3-(4-(双(叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙烯酸乙酯6a的混合物(410mg,90％纯度,46％收率)。To a solution of a mixture of tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)carbamate 4 and tert-butyl (3-bromo-6-chloro-2-methoxypyridin-4-yl)(tert-butoxycarbonyl)carbamate 4a (750 mg, 2.2 mmol) in dioxane/H₂ O (25 mL, 10:1) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate 5 (751 mg, 3.3 mmol), Pd(dppf)Cl₂ ·DCM (181 mg, 0.22 mmol) and K₃ PO₄ ·H₂ O (1.5 g, 6.6 mmol) successively at room temperature. The reaction mixture was stirred at 100° C. for 6 h under N_2. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE/EtOAc=100:0 to 70:30) to afford a mixture of ethyl (E)-3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate 6 and ethyl (E)-3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate 6a as a white solid (410 mg, 90% purity, 46% yield).

C₁₆H₂₁ClN₂O₅[M+H]⁺m/z的LCMS(ESI)计算值为357.11，实测值为357.00。LCMS (ESI) calcd for_C16H21ClN2O5 [M+H]⁺_m/ z 357.11, found_357.00 .

3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙酸乙酯(7)的制备Preparation of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate (7)

将(E)-3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙烯酸乙酯6和(E)-3-(4-(双(叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙烯酸乙酯6a的混合物(410mg,0.9mmol)和PtO₂(50mg)在EtOAc(10mL)中的溶液在H₂气氛下在室温搅拌1h。将得到的溶液穿过硅藻土过滤并将滤饼用DCM(20mL)洗涤。将滤液在减压下浓缩以产生作为无色油的3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙酸乙酯7和3-(4-(双(叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙酸乙酯7a的混合物(210mg,90％纯度,45％收率)。A mixture of (E)-ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate 6 and (E)-ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)acrylate 6a (410 mg, 0.9 mmol) and_PtO2 (50 mg) in EtOAc (10 mL) was stirred at room temperature for 1 h under_H2 atmosphere. The resulting solution was filtered through celite and the filter cake was washed with DCM (20 mL). The filtrate was concentrated under reduced pressure to give a mixture of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate 7 and ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate 7a as a colorless oil (210 mg, 90% purity, 45% yield).

C₁₆H₂₃ClN₂O₅[M+H]⁺m/z的LCMS(ESI)计算值为359.13，实测值为359.08。LCMS (ESI) calcd for_C16H23ClN2O5 [M+H]⁺_m/ z: 359.13, found:_359.08 .

7-氯-5-甲氧基-3,4-二氢-1,6-萘啶-2(1H)-酮(8)的制备Preparation of 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one (8)

将3-(4-((叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙酸乙酯7和3-(4-(双(叔丁氧基羰基)氨基)-6-氯-2-甲氧基吡啶-3-基)丙酸乙酯7a的混合物(210mg,0.6mmol)在HCl-二氧杂环己烷(10mL,4M)中的溶液在室温搅拌2h。将反应混合物在减压下浓缩以产生作为白色固体的7-氯-5-甲氧基-3,4-二氢-1,6-萘啶-2(1H)-酮8(110mg,90％纯度,79％收率)。A solution of a mixture of ethyl 3-(4-((tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate 7 and ethyl 3-(4-(bis(tert-butoxycarbonyl)amino)-6-chloro-2-methoxypyridin-3-yl)propanoate 7a (210 mg, 0.6 mmol) in HCl-dioxane (10 mL, 4 M) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one 8 (110 mg, 90% purity, 79% yield) as a white solid.

C₉H₉ClN₂O₂[M+H]⁺m/z的LCMS(ESI)计算值为213.04，实测值为212.92。LCMS (ESI) calcd for_C9H9ClN2O2 [_M +H]⁺_m/ z 213.04, found 212.92.

3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(10)的制备Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (10)

在室温向7-氯-5-甲氧基-3,4-二氢-1,6-萘啶-2(1H)-酮8(110mg,0.5mmol)在二氧杂环己烷/H₂O(10mL,10:1)中的溶液中接连地加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯9(184mg,0.6mmol)、Pd(dppf)Cl₂(42mg,0.06mmol)和K₃PO₄·H₂O(357mg,1.6mmol)。将反应混合物在N₂气氛下在100℃搅拌6h。将反应溶液冷却至室温，并在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至20:80洗脱)纯化以提供作为白色固体的3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯10(150mg,90％纯度,75％收率)。To a solution of 7-chloro-5-methoxy-3,4-dihydro-1,6-naphthyridin-2(1H)-one 8 (110 mg, 0.5 mmol) in dioxane/H₂ O (10 mL, 10:1) were added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 9 (184 mg, 0.6 mmol), Pd(dppf)Cl₂ (42 mg, 0.06 mmol) and K₃ PO₄ ·H₂ O (357 mg, 1.6 mmol) successively at room temperature. The reaction mixture was stirred at 100° C. for 6 h under N₂ atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluting with PE/EtOAc = 100:0 to 20:80) to afford tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 10 (150 mg, 90% purity, 75% yield) as a white solid.

C₁₈H₂₃N₃O₄[M+H]⁺m/z的LCMS(ESI)计算值为346.17，实测值为346.05。LCMS (ESI) calcd for_C18H23N3O4 [M₊ H]⁺_m/ z 346.17, found 346.05.

3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯(11)的制备Preparation of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (11)

将3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯10(150mg,0.4mmol)和Pd/C(20mg)在MeOH(10mL)中的溶液在H₂气氛下在室温搅拌2h。将得到的溶液穿过硅藻土过滤并将滤饼用DCM(20mL×3)洗涤。将滤液在减压下浓缩以产生作为无色油的3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯11(140mg,90％纯度,83％收率)。A solution of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 10 (150 mg, 0.4 mmol) and Pd/C (20 mg) in MeOH (10 mL) was stirred at room temperature for 2 h under H₂ atmosphere. The resulting solution was filtered through celite and the filter cake was washed with DCM (20 mL×3). The filtrate was concentrated under reduced pressure to produce tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate 11 (140 mg, 90% purity, 83% yield) as a colorless oil.

C₁₈H₂₅N₃O₄[M+H]⁺m/z的LCMS(ESI)计算值为348.18，实测值为347.95。LCMS (ESI) calcd for_C18H25N3O4 [M+_H ]⁺_m/ z 348.18, found 347.95.

7-(吡咯烷-3-基)-4,6-二氢-1,6-萘啶-2,5(1H,3H)-二酮(12)的制备Preparation of 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione (12)

将3-(5-甲氧基-2-氧代-1,2,3,4-四氢-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯11(120mg,0.34mmol)在HBr(48％在H₂O中,5mL)中的溶液在110℃搅拌2h。将反应溶液冷却至室温，并在减压下浓缩。将残余物溶解在MeOH(5mL)中并逐滴加入Et₃N(1mL)。将反应混合物在室温搅拌5min。将反应溶液在减压下浓缩以产生作为棕色固体的7-(吡咯烷-3-基)-4,6-二氢-1,6-萘啶-2,5(1H,3H)-二酮12(65mg,90％纯度,72％收率)。A solution of tert-butyl 3-(5-methoxy-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate 11 (120 mg, 0.34 mmol) in HBr (48% in H₂ O, 5 mL) was stirred at 110° C. for 2 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and Et₃ N (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 min. The reaction solution was concentrated under reduced pressure to produce 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridin-2,5(1H,3H)-dione 12 (65 mg, 90% purity, 72% yield) as a brown solid.

C₁₂H₁₅N₃O₂[M+H]⁺m/z的LCMS(ESI)计算值为234.12，实测值为234.06。LCMS (ESI) calcd for_C12H15N3O2 [M₊ H]⁺_m/ z 234.12, found 234.06.

5-(4-(3-(2,5-二氧代-1,2,3,4,5,6-六氢-1,6-萘啶-7-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物309a和309b的外消旋混合物)的制备Preparation of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture ofcompounds 309a and 309b )

在室温向7-(吡咯烷-3-基)-4,6-二氢-1,6-萘啶-2,5(1H,3H)-二酮12(65mg,0.3mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(78mg,0.3mmol)、AcOH(2滴)和NaBH₃CN(35mg,0.6mmol)。将反应混合物在50℃搅拌1h。将反应混合物用水(2mL)淬灭并将反应溶液在减压下浓缩。将残余物通过快速柱色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以提供作为白色固体的5-(4-(3-(2,5-二氧代-1,2,3,4,5,6-六氢-1,6-萘啶-7-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺，即化合物309a和309b的外消旋混合物(35mg,98％纯度,27％收率)。To a solution of 7-(pyrrolidin-3-yl)-4,6-dihydro-1,6-naphthyridine-2,5(1H,3H)-dione 12 (65 mg, 0.3 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (78 mg, 0.3 mmol), AcOH (2 drops) and NaBH₃ CN (35 mg, 0.6 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. The reaction mixture was quenched with water (2 mL) and the reaction solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with DCM/MeOH=100:0 to 90:10) to afford 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide, a racemic mixture of compounds 309a and 309b (35 mg, 98% purity, 27% yield) as a white solid.

5-(4-(3-(2,5-二氧代-1,2,3,4,5,6-六氢-1,6-萘啶-7-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物309a和309b的外消旋混合物)的手性拆分Chiral Resolution of 5-(4-(3-(2,5-dioxo-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 309a and 309b)

将化合物309a和309b的外消旋混合物通过SFC(柱：Daicel Chiralpak IH SFC；20mm I.D.×250mm,5μmm；流动相:CO₂/MeOH[0.1％ NH₃(7M在MeOH中的溶液)]＝60/40)分离并在减压下浓缩以提供作为309a的第一级分(4.8mg,95％纯度,100％ee，白色固体)和作为309b的第二级分(8.7mg,95％纯度,100％ee，白色固体)。The racemic mixture of compounds 309a and 309b was separated by SFC (column: Daicel Chiralpak IH SFC; 20 mm ID×250 mm, 5 μmm; mobile phase: CO₂ /MeOH [0.1% NH₃ (7 M solution in MeOH)]=60/40) and concentrated under reduced pressure to give a first fraction (4.8 mg, 95% purity, 100% ee, white solid) as 309a and a second fraction (8.7 mg, 95% purity, 100% ee, white solid) as 309b.

化合物309aCompound 309a

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.08(s,1H),10.04(s,1H),8.43-8.34(m,1H),8.27(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.48-7.36(m,1H),5.83(s,1H),3.89-3.76(m,2H),3.14-3.07(m,1H),3.01-2.91(m,2H),2.84-2.72(m,5H),2.60-2.56(m,3H),2.43-2.41(m,3H),2.24-2.10(m,2H),1.96-1.88(m,2H),1.72-1.62(m,1H),1.55-1.46(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 11.08 (s, 1H), 10.04 (s, 1H), 8.43-8.34 (m, 1H), 8.27 (d, J = 2.8Hz, 1H), 7.81(d,J＝8.8Hz,1H),7.48-7.36(m,1H),5.83(s,1H),3.89-3.76(m,2H),3.14-3.0 7(m,1H),3.01-2.91(m,2H),2.84-2.72(m,5H),2.60-2.56(m,3H),2.43-2.41(m,3H),2.24-2.10(m,2H ),1.96-1.88(m,2H),1.72-1.62(m,1H),1.55-1.46(m,2H).

C₂₄H₃₀N₆O₃[M+H]⁺m/z的LCMS(ESI)计算值为451.24，实测值为451.40。LCMS (ESI) calcd for_C24H30N6O3 [M₊ H]⁺_m/ z 451.24, found 451.40.

化合物309bCompound 309b

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.07(s,1H),10.04(s,1H),8.46-8.32(m,1H),8.27(d,J＝2.8Hz,1H),7.81(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),5.83(s,1H),3.87-3.76(m,2H),3.14-3.04(m,1H),3.02-2.91(m,2H),2.84-2.75(m,5H),2.58-2.54(m,3H),2.44-2.37(m,3H),2.30-2.24(m,1H),2.23-2.12(m,1H),1.97-1.90(m,2H),1.75-1.63(m,1H),1.59-1.44(m,2H)。¹ H NMR (400MHz, DMSO-d₆ , ppm) δ: 11.07 (s, 1H), 10.04 (s, 1H), 8.46-8.32 (m, 1H), 8.27 (d, J = 2.8Hz, 1H), 7.81(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),5.83(s,1H),3.87-3.76(m,2H),3.14-3.04(m, 1H),3.02-2.91(m,2H),2.84-2.75(m,5H),2.58-2.54(m,3H),2.44-2.37(m,3H),2.30-2.24(m,1H),2.23- 2.12(m,1H),1.97-1.90(m,2H),1.75-1.63(m,1H),1.59-1.44(m,2H).

C₂₄H₃₀N₆O₃[M+H]⁺m/z的LCMS(ESI)计算值为451.24，实测值为451.20。LCMS (ESI) calcd for_C24H30N6O3 [M₊ H]⁺_m/ z 451.24, found 451.20.

实施例24-化合物324rac的合成Example 24 - Synthesis of Compound 324rac

化合物324rac的合成Synthesis of compound 324rac

2-(2-乙氧基-2-氧代乙基)-5-氟吡啶-3-甲酸(3)的制备Preparation of 2-(2-ethoxy-2-oxoethyl)-5-fluoropyridine-3-carboxylic acid (3)

向3-氧代丁酸乙酯2(4.57g,0.0351mol)在DME(250mL)中的溶液中加入t-BuOK(5.25g,0.0468mol)。将混合物在室温搅拌1小时。加入Cu(OAc)₂(1.70g,0.00936mol)和2-氯-5-氟吡啶-3-甲酸1(4.1g,0.0234mol)并将得到的混合物在氮气气氛下在100℃搅拌24小时。将混合物用水稀释，用1M HCl酸化至pH＝2，并用乙酸乙酯萃取。将合并的有机层经硫酸钠干燥，过滤，并在减压下浓缩。将残余物通过硅胶上的柱色谱法(DCM/MeOH＝100:0至90:10)纯化以提供作为白色固体的2-(2-乙氧基-2-氧代乙基)-5-氟吡啶-3-甲酸3(2.4g,90％纯度,40％收率)。To a solution of ethyl 3-oxobutanoate 2 (4.57 g, 0.0351 mol) in DME (250 mL) was added t-BuOK (5.25 g, 0.0468 mol). The mixture was stirred at room temperature for 1 hour. Cu(OAc)₂ (1.70 g, 0.00936 mol) and 2-chloro-5-fluoropyridine-3-carboxylic acid 1 (4.1 g, 0.0234 mol) were added and the resulting mixture was stirred at 100 °C under nitrogen atmosphere for 24 hours. The mixture was diluted with water, acidified to pH = 2 with 1M HCl, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM/MeOH=100:0 to 90:10) to afford 2-(2-ethoxy-2-oxoethyl)-5-fluoropicolinic acid 3 (2.4 g, 90% purity, 40% yield) as a white solid.

C₁₀H₁₀FNO₄[M+H]⁺m/z的LCMS(ESI)计算值为228.06，实测值为228.00。LCMS (ESI) calcd for_C10H10FNO4 [M+H]⁺_m/ z 228.06, found 228.00.

3-氟-6,8-二氢-1,6-萘啶-5,7-二酮(4)的制备Preparation of 3-fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione (4)

在N₂气氛下在0℃向2-(2-乙氧基-2-氧代乙基)-5-氟吡啶-3-甲酸3(2400mg,10.56mmol)和TEA(2137mg,21.12mmol)在THF(40mL)中的溶液中逐滴加入氯甲酸乙酯(2281mg,21.12mmol)。将混合物在该温度搅拌1小时，然后逐滴加入NH₃·H₂O(28％,1285mg)并将得到的混合物在室温搅拌1小时。将混合物用水稀释，并用乙酸乙酯萃取。将合并的有机层用盐水洗涤，经硫酸钠干燥，过滤并浓缩。将残余物通过Biotage Isolera One(C₁₈柱，用含有0.1％ FA的5％至90％ MeCN/H₂O洗脱)纯化以提供作为白色固体的3-氟-6,8-二氢-1,6-萘啶-5,7-二酮4(505mg,90％纯度,23％收率)。To a solution of 2-(₂ -ethoxy-2-oxoethyl)-5-fluoropicolinic acid 3 (2400 mg, 10.56 mmol) and TEA (2137 mg, 21.12 mmol) in THF (40 mL) was added ethyl chloroformate (2281 mg, 21.12 mmol) dropwise at 0°C under N2 atmosphere. The mixture was stirred at this temperature for 1 hour, then_NH3.H2O (28%, 1285 mg) was added dropwise and the resulting mixture was stirred at room temperature for₁ hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage Isolera One (_C18 column, eluting with 5% to 90% MeCN/_H20 containing 0.1% FA) to afford 3-fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione 4 (505 mg, 90% purity, 23% yield) as a white solid.

C₈H₅FN₂O₂[M+H]⁺m/z的LCMS(ESI)计算值为181.03，实测值为180.90。LCMS (ESI) calcd for_C8H5FN2O2 [M₊ H]⁺_m/ z: 181.03, found: 180.90.

5,7-二氯-3-氟-1,6-萘啶(5)的制备Preparation of 5,7-dichloro-3-fluoro-1,6-naphthyridine (5)

将3-氟-6,8-二氢-1,6-萘啶-5,7-二酮4(300mg,1.66mmol)在PhPOCl₂(3mL)中的溶液在氮气气氛下在110℃搅拌12小时。将混合物冷却并用KOH水溶液(5重量％)调至pH＝9～10并用乙酸乙酯稀释。将混合物用盐水洗涤，经无水硫酸钠干燥，过滤，并在减压下浓缩。将残余物通过硅胶柱色谱法(PE/EtOAc＝100:0至50:50)纯化以提供作为白色固体的5,7-二氯-3-氟-1,6-萘啶5(125mg,90％纯度,31％收率)。A solution of 3-fluoro-6,8-dihydro-1,6-naphthyridine-5,7-dione 4 (300 mg, 1.66 mmol) in PhPOCl₂ (3 mL) was stirred at 110° C. for 12 hours under a nitrogen atmosphere. The mixture was cooled and adjusted to pH=9-10 with aqueous KOH (5 wt %) and diluted with ethyl acetate. The mixture was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EtOAc=100:0 to 50:50) to provide 5,7-dichloro-3-fluoro-1,6-naphthyridine 5 (125 mg, 90% purity, 31% yield) as a white solid.

C₈H₃C₂FN₂[M+H]⁺m/z的LCMS(ESI)计算值为216.97，实测值为216.90。LCMS^{(ESI) calcd for C8H3C2FN2 [M+H]+}_m/z216.97 , found 216.90.

7-氯-3-氟-5-甲氧基-1,6-萘啶(6)的制备Preparation of 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine (6)

向5,7-二氯-3-氟-1,6-萘啶5(195mg,0.8985mmol)在MeOH(20mL)中的溶液中加入MeONa(48mg,0.8985mmol)，然后在室温搅拌2h。将反应混合物用EtOAc(20mL×3)和盐水分离。将合并的有机相在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至95:5洗脱)纯化以产生作为白色固体的7-氯-3-氟-5-甲氧基-1,6-萘啶6(135mg,90％纯度,63％收率)。MeONa (48 mg, 0.8985 mmol) was added to a solution of 5,7-dichloro-3-fluoro-1,6-naphthyridine 5 (195 mg, 0.8985 mmol) in MeOH (20 mL), and then stirred at room temperature for 2 h. The reaction mixture was separated with EtOAc (20 mL×3) and brine. The combined organic phases were concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with PE/EtOAc=100:0 to 95:5) to produce 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine 6 (135 mg, 90% purity, 63% yield) as a white solid.

C₉H₆ClFN₂O[M+H]⁺m/z的LCMS(ESI)计算值为213.02，实测值为212.90。LCMS (ESI) calcd for_C9H6ClFN2O [M₊ H]⁺_m /z 213.02, found 212.90.

3-(3-氟-5-甲氧基-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8)

将7-氯-3-氟-5-甲氧基-1,6-萘啶6(100mg,0.470mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯7(167mg,0.564mmol)、Pd(dppf)Cl₂(38mg,0.047mmol)和Na₂CO₃(306mg,0.941mmol)在二氧杂环己烷和H₂O(3:1,2mL)中的混合物用N₂脱气并在N₂气氛下在80℃加热3h。将反应混合物浓缩并通过快速硅胶色谱法纯化以得到作为无色油的3-(3-氟-5-甲氧基-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯8(100mg,90％纯度,24％收率)。A mixture of 7-chloro-3-fluoro-5-methoxy-1,6-naphthyridine 6 (100 mg, 0.470 mmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 7 (167 mg, 0.564 mmol), Pd(dppf)_Cl2 (38 mg, 0.047 mmol) and_Na2CO3 (306 mg, 0.941 mmol) in dioxane and_H2O (3:1, 2 mL) was degassed with_N2 and heated at 80 °_C under_N2 atmosphere for 3 h. The reaction mixture was concentrated and purified by flash silica gel chromatography to give tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8 (100 mg, 90% purity, 24% yield) as a colorless oil.

C₁₈H₂₀FN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为346.15，实测值为346.15。LCMS (ESI) calcd for_C18H20FN3O3 [_M +H]⁺_m/ z: 346.15, found: 346.15.

3-(3-氟-5-甲氧基-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯(9)的制备Preparation of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate (9)

将3-(3-氟-5-甲氧基-1,6-萘啶-7-基)-2,5-二氢-1H-吡咯-1-甲酸酯8(100mg,0.289mmol)和Pd/C(31mg)在MeOH(2mL)中的混合物用H₂脱气并在H₂气氛下在室温搅拌2h。将反应混合物过滤。将滤液在减压下浓缩以得到作为黄色油的3-(3-氟-5-甲氧基-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯9(100mg,60％纯度,59％收率)。A mixture of 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8 (100 mg, 0.289 mmol) and Pd/C (31 mg) in MeOH (2 mL) was degassed with_H and stirred at room temperature for 2 h under_H atmosphere. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate 9 (100 mg, 60% purity, 59% yield) as a yellow oil.

C₁₈H₂₂FN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为348.16，实测值为348.05。LCMS (ESI) calcd for_C18H22FN3O3 [_M +H]⁺_m/ z 348.16, found 348.05.

3-氟-7-(吡咯烷-3-基)-1,6-萘啶-5(6H)-酮氢溴酸盐(10)的制备Preparation of 3-fluoro-7-(pyrrolidin-3-yl)-1,6-naphthyridin-5(6H)-one hydrobromide (10)

将3-(3-氟-5-甲氧基-1,6-萘啶-7-基)吡咯烷-1-甲酸叔丁酯9(100mg,0.287mmol)在HBr-水(48％,10mL)中的溶液在100℃加热2h。将混合物在减压下浓缩以得到作为白色固体的3-氟-7-(吡咯烷-3-基)-1,6-萘啶-5(6H)-酮氢溴酸盐10(80mg,90％纯度,79％收率)。A solution of tert-butyl 3-(3-fluoro-5-methoxy-1,6-naphthyridin-7-yl)pyrrolidine-1-carboxylate 9 (100 mg, 0.287 mmol) in HBr-water (48%, 10 mL) was heated at 100° C. for 2 h. The mixture was concentrated under reduced pressure to give 3-fluoro-7-(pyrrolidin-3-yl)-1,6-naphthyridin-5(6H)-one hydrobromide 10 (80 mg, 90% purity, 79% yield) as a white solid.

C₁₂H₁₂FN₃O[M+H]⁺m/z的LCMS(ESI)计算值为234.10，实测值为233.95。LCMS (ESI) calcd for_C12H12FN3O [M₊ H]⁺ m_/ z 234.10, found 233.95.

6-氟-5-(4-(3-(3-氟-5-氧代-5,6-二氢-1,6-萘啶-7-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物324rac)的制备Preparation of 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 324rac)

向3-氟-7-(吡咯烷-3-基)-6H-1,6-萘啶-5-酮氢溴酸盐10(40mg,0.127mmol)在MeOH(10mL)中的溶液中加入6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT-2(32mg,0.127mmol)，然后在室温加入两滴乙酸和NaBH₃CN(40mg,0.636mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法纯化以产生作为白色固体的6-氟-5-(4-(3-(3-氟-5-氧代-5,6-二氢-1,6-萘啶-7-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺外消旋物324rac(13.2mg,95％纯度,21％收率)。To a solution of 3-fluoro-7-(pyrrolidin-3-yl)-6H-1,6-naphthyridin-5-one hydrobromide 10 (40 mg, 0.127 mmol) in MeOH (10 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT-2 (32 mg, 0.127 mmol), followed by two drops of acetic acid and NaBH₃ CN (40 mg, 0.636 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography to give 6-fluoro-5-(4-(3-(3-fluoro-5-oxo-5,6-dihydro-1,6-naphthyridin-7-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide racemate 324rac (13.2 mg, 95% purity, 21% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆ ppm)δ11.56(s,1H),8.92(d,J＝2.8Hz,1H),8.42-8.35(m,1H),8.23-8.17(m,1H),8.16(s,1H),7.84(d,J＝8.0Hz,1H),7.62-7.54(m,1H),6.61(s,1H),3.54-3.49(m,2H),3.31-3.27(m,1H),2.97-2.84(m,4H),2.83-2.79(m,1H),2.77(d,J＝4.8Hz,3H),2.70-2.64(m,1H),2.38-2.31(m,1H),2.30-2.23(m,1H),1.99(d,J＝12.4Hz,2H),1.92-1.81(m,1H),1.67-1.55(m,2H)。¹ H NMR (400MHz, DMSO-d₆ ppm) δ11.56 (s, 1H), 8.92 (d, J = 2.8Hz, 1H), 8.42-8.35 (m, 1H), 8.23-8.17 (m, 1H) ,8.16(s,1H),7.84(d,J＝8.0Hz,1H),7.62-7.54(m,1H),6.61(s,1H),3.54-3.49(m,2H),3.31-3.27(m ,1 H),2.97-2.84(m,4H),2.83-2.79(m,1H),2.77(d,J＝4.8Hz,3H),2.70-2.64(m,1H),2.38-2.31(m,1H) ,2.30-2.23(m,1H),1.99(d,J＝12.4Hz,2H),1.92-1.81(m,1H),1.67-1.55(m,2H).

C₂₄H₂₆F₂N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为469.21，实测值为469.10。LCMS (ESI) calcd for_C24H26F2N6O2 [M₊ H]⁺_m/ z 469.21, found_469.10 .

实施例25-化合物337a和337b的合成Example 25 - Synthesis of Compounds 337a and 337b

化合物337a和337b的合成Synthesis of compounds 337a and 337b

5,6,7,8-四氢异喹啉-1(2H)-酮(2)的制备Preparation of 5,6,7,8-tetrahydroisoquinolin-1(2H)-one (2)

将2H-异喹啉-1-酮(8g,0.05mol)和PtO₂(0.9g,0.003mol)加入TFA(80mL)中，在H₂(1Mpa)下在100℃搅拌12h。将沉淀物通过过滤进行收集，用EtOAc(400mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩，并通过硅胶柱色谱法(洗脱液:PE/EtOAC＝100:0至80:20)纯化以产生作为黑色油的5,6,7,8-四氢异喹啉-1(2H)-酮2(7.00g,77％收率)。2H-isoquinolin-1-one (8 g, 0.05 mol) and PtO₂ (0.9 g, 0.003 mol) were added to TFA (80 mL) and stirred at 100° C. for 12 h under H₂ (1 MPa). The precipitate was collected by filtration and extracted with EtOAc (400 mL×3). The combined organic phase was washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE/EtOAC=100:0 to 80:20) to give 5,6,7,8-tetrahydroisoquinolin-1(2H)-one 2 (7.00 g, 77% yield) as a black oil.

C₉H₁₁NO[M+H]⁺m/z的LCMS(ESI)计算值为150.08，实测值为150.00LCMS (ESI) calculated for C₉ H₁₁ NO [M+H]⁺ m/z: 150.08, found: 150.00

1-氯-5,6,7,8-四氢异喹啉(3)的制备Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline (3)

将5,6,7,8-四氢-2H-异喹啉-1-酮钠2(7g,0.047mmol)在POCl₃(100mL)中的溶液在110℃搅拌3h。反应结束以后，将混合物冷却至室温，放入冰水中，在冷却下用NH₃.H₂O中和，用EtOAc(300mLx3)萃取。将合并的有机层用盐水洗涤，经无水Na₂SO₄干燥并浓缩。将反应混合物在减压下浓缩。将残余物通过快速柱色谱法(用PE/EtOAc＝100:0至80:20洗脱)纯化以提供作为无色油的1-氯-5,6,7,8-四氢异喹啉3(5g,90％纯度,57％收率)。A solution of sodium 5,6,7,8-tetrahydro-2H-isoquinolin-1-one 2 (7 g, 0.047 mmol) in POCl₃ (100 mL) was stirred at 110° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature, put into ice water, neutralized with NH₃ .H₂ O under cooling, and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na₂ SO₄ and concentrated. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (eluted with PE/EtOAc=100:0 to 80:20) to provide 1-chloro-5,6,7,8-tetrahydroisoquinoline 3 (5 g, 90% purity, 57% yield) as a colorless oil.

C₉H₁₀ClN[M+H]⁺m/z的LCMS(ESI)计算值为168.05，实测值为168.00。LCMS (ESI) calcd for_C9H10C1N [M+H]⁺_m /z: 168.05, found: 168.00.

1-氯-5,6,7,8-四氢异喹啉2-氧化物(4)的制备Preparation of 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide (4)

将1-氯-5,6,7,8-四氢异喹啉3(5g,0.029mol)加入AcOH/H₂O₂(100mL)中。将反应混合物在70℃搅拌2h。将沉淀物通过过滤进行收集，用EtOAc(200mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩，并通过硅胶柱色谱法(洗脱液:DCM/MeOH＝100:0至90:10)纯化以产生作为黄色油的1-氯-5,6,7,8-四氢异喹啉2-氧化物4(2.00g,73％收率)。1-Chloro-5,6,7,8-tetrahydroisoquinoline 3 (5 g, 0.029 mol) was added to AcOH/H₂ O₂ (100 mL). The reaction mixture was stirred at 70° C. for 2 h. The precipitate was collected by filtration and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: DCM/MeOH=100:0 to 90:10) to give 1-chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide 4 (2.00 g, 73% yield) as a yellow oil.

C₉H₁₀ClNO[M+H]⁺m/z的LCMS(ESI)计算值为184.05，实测值为184.00。LCMS (ESI) calcd for_C9H10ClNO [M+H]⁺_m /z: 184.05, found: 184.00.

1,3-二氯-5,6,7,8-四氢异喹啉(5)的制备Preparation of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline (5)

在室温将1-氯-5,6,7,8-四氢异喹啉2-氧化物4(2.00g,0.019mmol)缓慢地加入POCl₃(50mL)中。将混合物加热至110℃搅拌3h。将得到的混合物用冰水(200mL)稀释，并用EtOAc(400mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩，并通过硅胶柱色谱法(洗脱液:PE/EtOAc＝100:0至70:30)纯化以产生作为黄色油的1,3-二氯-5,6,7,8-四氢异喹啉5(370mg,15％收率)。1-Chloro-5,6,7,8-tetrahydroisoquinoline 2-oxide 4 (2.00 g, 0.019 mmol) was slowly added to POCl₃ (50 mL) at room temperature. The mixture was heated to 110° C. and stirred for 3 h. The resulting mixture was diluted with ice water (200 mL) and extracted with EtOAc (400 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE/EtOAc=100:0 to 70:30) to produce 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline 5 (370 mg, 15% yield) as a yellow oil.

C₉H₉Cl₂N[M+H]⁺m/z的LCMS(ESI)计算值为202.01，实测值为201.95。LCMS (ESI) calcd for_C9H9Cl2N [M+H_]⁺_m /z 202.01, found 201.95.

3-氯-1-甲氧基-5,6,7,8-四氢异喹啉(6)的制备Preparation of 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline (6)

向1,3-二氯-5,6,7,8-四氢异喹啉5(350mg,1.73mmol)在MeOH(15mL)中的溶液中加入MeONa(280mg,5.20mmol)，将混合物在搅拌下加热至60℃保持3h。将沉淀物通过过滤进行收集，用EtOAc(100mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩，并通过硅胶柱色谱法(洗脱液:PE/EtOAC＝100:0至90:10)纯化以提供作为白色固体的3-氯-1-甲氧基-5,6,7,8-四氢异喹啉6(250mg,66％收率)。To a solution of 1,3-dichloro-5,6,7,8-tetrahydroisoquinoline 5 (350 mg, 1.73 mmol) in MeOH (15 mL) was added MeONa (280 mg, 5.20 mmol), and the mixture was heated to 60 ° C. for 3 h with stirring. The precipitate was collected by filtration and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: PE/EtOAC=100:0 to 90:10) to provide 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline 6 (250 mg, 66% yield) as a white solid.

C₁₀H₁₂ClNO[M+H]⁺m/z的LCMS(ESI)计算值为198.06，实测值为197.95。LCMS (ESI) calcd for_C10H12ClNO [M+H]⁺_m /z: 198.06, found: 197.95.

3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (8)

在室温向3-氯-1-甲氧基-5,6,7,8-四氢异喹啉6(240mg,1.21mmol)在二氧杂环己烷/H₂O＝10:1(60mL)中的溶液中接连地加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯7(394mg,1.33mmol)、Pd(dppf)Cl₂(88mg,0.12mmol)和Na₂CO₃(503mg,3.64mmol)。将反应混合物在N₂下在90℃搅拌3h。将混合物用水(50mL)稀释，并用EtOAc(100mL×3)萃取。将合并的有机层用盐水(100mL×2)洗涤，经Na₂SO₄干燥，过滤并在真空中浓缩以得到粗产物，将其通过快速柱色谱法(PE/EtOAc＝100:0至85:15)纯化以提供作为黄色固体的3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯8(140mg,31％收率)。To a solution of 3-chloro-1-methoxy-5,6,7,8-tetrahydroisoquinoline 6 (240 mg, 1.21 mmol) in dioxane/H₂ O=10:1 (60 mL) were added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 7 (394 mg, 1.33 mmol), Pd(dppf)Cl₂ (88 mg, 0.12 mmol) and Na₂ CO₃ (503 mg, 3.64 mmol) successively at room temperature. The reaction mixture was stirred at 90° C. for 3 h under N_2. The mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL x 2), dried_overNa2SO4 , filtered and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (PE/EtOAc = 100:0 to 85:15) to afford tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8 (140 mg, 31% yield) as a yellow solid.

C₁₉H₂₆N₂O₃[M+H]⁺m/z的LCMS(ESI)计算值为331.19，实测值为331.15。LCMS (ESI) calcd for_C19H26N2O3 [M+H]⁺_m/ z 331.19, found_331.15 .

3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯(9)的制备Preparation of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)pyrrolidine-1-carboxylate (9)

向3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)-2,5-二氢-1H-吡咯-1-甲酸叔丁酯8(130mg,0.39mmol)在MeOH(50mL)中的溶液中加入Pd/C(30mg)。将混合物抽真空并用氢气回填3次并然后用氢气填充。将得到的混合物在室温搅拌5h。然后将混合物穿过硅藻土过滤并在真空下浓缩以产生粗产物，将其通过快速柱色谱法(PE/EtOAc＝100:0至50:50)纯化以提供作为黄色固体的3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯9(130mg,89％收率)。To a solution of tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 8 (130 mg, 0.39 mmol) in MeOH (50 mL) was added Pd/C (30 mg). The mixture was evacuated and backfilled with hydrogen 3 times and then filled with hydrogen. The resulting mixture was stirred at room temperature for 5 h. The mixture was then filtered through celite and concentrated under vacuum to give a crude product, which was purified by flash column chromatography (PE/EtOAc=100:0 to 50:50) to provide tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)pyrrolidine-1-carboxylate 9 (130 mg, 89% yield) as a yellow solid.

C₁₉H₂₈N₂O₃[M+H]⁺m/z的LCMS(ESI)计算值为333.21，实测值为333.10。LCMS (ESI) calcd for_C19H28N2O3 [M₊ H]⁺_m/ z 333.21, found 333.10.

3-(吡咯烷-3-基)-5,6,7,8-四氢异喹啉-1(2H)-酮(10)的制备Preparation of 3-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one (10)

将3-(1-甲氧基-5,6,7,8-四氢异喹啉-3-基)吡咯烷-1-甲酸叔丁酯9(115mg,0.71mmol)加入HBr水溶液(10mL)中。将混合物在100℃搅拌2h。将反应混合物在减压下浓缩以产生作为白色固体的产物3-(吡咯烷-3-基)-5,6,7,8-四氢异喹啉-1(2H)-酮10(80mg,95％收率)。Tert-butyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)pyrrolidine-1-carboxylate 9 (115 mg, 0.71 mmol) was added to aqueous HBr solution (10 mL). The mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the product 3-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one 10 (80 mg, 95% yield) as a white solid.

C₁₃H₁₈N₂O[M+H]⁺m/z的LCMS(ESI)计算值为219.14，实测值为219.05。_{LCMS (ESI) calcd for C13H18N2O[} M+H]⁺ m_/ z 219.14, found 219.05.

6-氟-N-甲基-5-(4-(3-(1-氧代-1,2,5,6,7,8-六氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(化合物337a和337b的外消旋混合物)的制备Preparation of 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of compounds 337a and 337b)

向3-(吡咯烷-3-基)-5,6,7,8-四氢异喹啉-1(2H)-酮10(60mg,0.27mmol)、6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶-2-甲酰胺INT-2(69mg,0.27mmol)和AcOH(两滴)在MeOH(5mL)中的溶液中加入三乙酰氧基硼氢化钠(146mg,0.69mmol)并然后在50℃搅拌1h，然后加入NaBH₃CN(21mg,0.33mmol)并搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的6-氟-N-甲基-5-(4-(3-(1-氧代-1,2,5,6,7,8-六氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺，即化合物337a和337b的外消旋混合物(22mg,18％收率)。To a solution of 3-(pyrrolidin-3-yl)-5,6,7,8-tetrahydroisoquinolin-1(2H)-one 10 (60 mg, 0.27 mmol), 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)pyridine-2-carboxamide INT-2 (69 mg, 0.27 mmol) and AcOH (two drops) in MeOH (5 mL) was added sodium triacetoxyborohydride (146 mg, 0.69 mmol) and then stirred at 50° C. for 1 h, then NaBH₃ CN (21 mg, 0.33 mmol) was added and stirred for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to give 6-fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide, a racemic mixture of compounds 337a and 337b (22 mg, 18% yield) as a white solid.

C₂₅H₃₂FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为454.25，实测值为454.15。LCMS (ESI) calcd for_C25H32FN5O2 [_M +H]⁺_m/ z 454.25, found 454.15.

6-氟-N-甲基-5-(4-(3-(1-氧代-1,2,5,6,7,8-六氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)吡啶酰胺(化合物337a和337b的外消旋混合物)的手性拆分Chiral Resolution of 6-Fluoro-N-methyl-5-(4-(3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)picolinamide (racemic mixture of compounds 337a and 337b)

将化合物337a和337b的外消旋混合物通过SFC(柱：DAICEL OD-H 4.6mmI.D.*250mmL 5μm；流动相:CO2/MeOH[0.1％NH3(7M在MeOH中的溶液)]＝70/30)分离并在减压下浓缩以提供作为337a的第一级分(7mg,95％纯度,ee％:100，白色固体)和作为337b的第二级分(5mg,92％纯度,ee％:100，白色固体)。The racemic mixture of compounds 337a and 337b was separated by SFC (column: DAICEL OD-H 4.6 mmI.D.*250 mmL 5 μm; mobile phase: CO2/MeOH [0.1% NH3 (7 M solution in MeOH)] = 70/30) and concentrated under reduced pressure to give a first fraction (7 mg, 95% purity, ee%: 100, white solid) as 337a and a second fraction (5 mg, 92% purity, ee%: 100, white solid) as 337b.

化合物337aCompound 337a

1H NMR(400MHz,DMSO)δ11.03(s,1H),8.40(d,J＝4.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.57(dd,J＝10.6,8.4Hz,1H),5.83(s,1H),3.55-3.44(m,2H),3.14-3.04(m,1H),2.86(t,J＝11.6Hz,3H),2.75(t,J＝6.4Hz,4H),2.63(dd,J＝14.8,8.0Hz,2H),2.44(s,2H),2.27(s,3H),2.21-2.10(m,1H),1.95(d,J＝13.2Hz,2H),1.73(dd,J＝12.8,8.4Hz,1H),1.58(dd,J＝22.4,12.0Hz,6H)。1H NMR (400MHz, DMSO) δ11.03(s,1H),8.40(d,J＝4.8Hz,1H),7.83(d,J＝7.8Hz,1H),7.57(dd,J＝10.6,8.4Hz ,1H),5.83(s,1H),3.55-3.44(m,2H),3.14-3.04(m,1H),2.86(t,J＝11.6Hz,3H) ,2.75(t,J＝6.4Hz,4H),2.63(dd,J＝14.8,8.0Hz,2H),2.44(s,2H),2.27(s,3H),2.21-2.10(m,1H), 1.95(d,J＝13.2Hz,2H), 1.73(dd,J＝12.8,8.4Hz,1H), 1.58(dd,J＝22.4,12.0Hz,6H).

C₂₅H₃₂FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为454.25，实测值为454.20。LCMS (ESI) calcd for_C25H32FN5O2 [_M +H]⁺_m/ z 454.25, found 454.20.

化合物337bCompound 337b

1H NMR(400MHz,DMSO)δ11.03(s,1H),8.40(d,J＝4.4Hz,1H),7.83(d,J＝8.0Hz,1H),7.70-7.45(m,1H),5.83(s,1H),3.49(d,J＝11.2Hz,2H),3.08(d,J＝6.4Hz,1H),2.85(t,J＝11.2Hz,3H),2.76(d,J＝4.4Hz,4H),2.69-2.57(m,2H),2.44(s,2H),2.27(s,3H),2.20-2.10(m,1H),1.95(d,J＝12.4Hz,2H),1.80-1.68(m,1H),1.68-1.51(m,6H)。1H NMR (400MHz, DMSO) δ11.03 (s, 1H), 8.40 (d, J = 4.4Hz, 1H), 7.83 (d, J = 8.0Hz, 1H), 7.70-7.45 (m, 1H), 5.83 (s,1H),3.49(d,J＝11.2Hz,2H),3.08(d,J＝6.4Hz,1H),2.85(t ,J＝11.2Hz,3H),2.76(d,J＝4.4Hz,4H),2.69-2.57(m,2H),2.44(s,2H),2.27(s,3H),2.20-2.10(m, 1H), 1.95 (d, J = 12.4Hz, 2H), 1.80-1.68 (m, 1H), 1.68-1.51 (m, 6H).

C₂₅H₃₂FN₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为454.25，实测值为454.15。LCMS (ESI) calcd for_C25H32FN5O2 [_M +H]⁺_m/ z 454.25, found 454.15.

实施例26-化合物343a和343b的合成Example 26 - Synthesis of Compounds 343a and 343b

化合物343a和343b的合成Synthesis of compounds 343a and 343b

4-氯-5-氟烟酸(2)的制备Preparation of 4-chloro-5-fluoronicotinic acid (2)

将N-BuLi(2.4M在己烷类中，10mL,23.9mmol)加入THF(100mL)中并冷却至-78℃。向该溶液中缓慢地加入i-PrNH₂(2.54g,25.0mmol)，随后加入4-氯-3-氟吡啶1(3g,22.8mmol)。在-78℃搅拌2h以后，一次性加入碎干冰。将反应混合物保持搅拌直到将反应混合物温热至室温。将反应物通过加入氯化铵水溶液淬灭并使用浓HCl酸化至pH＝2，并用乙酸乙酯(3x 200mL)萃取。将合并的有机层用盐水(10mL)洗涤，经Na₂SO₄干燥并在减压下浓缩以提供作为黄色固体的4-氯-5-氟烟酸2(2.2g,70％纯度,36％收率)。N-BuLi (2.4M in hexanes, 10 mL, 23.9 mmol) was added to THF (100 mL) and cooled to -78 °C. To the solution was slowly added i-PrNH₂ (2.54 g, 25.0 mmol) followed by 4-chloro-3-fluoropyridine 1 (3 g, 22.8 mmol). After stirring at -78 °C for 2 h, crushed dry ice was added in one portion. The reaction mixture was kept stirring until the reaction mixture was warmed to room temperature. The reaction was quenched by the addition of aqueous ammonium chloride solution and acidified to pH=2 using concentrated HCl and extracted with ethyl acetate (3 x 200 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂ SO₄ and concentrated under reduced pressure to provide 4-chloro-5-fluoronicotinic acid 2 (2.2 g, 70% purity, 36% yield) as a yellow solid.

C₆H₃ClFNO₂[M+H]⁺m/z的LCMS(ESI)计算值为175.99，实测值为175.80。LCMS (ESI) calcd for_C6H3ClFNO2 [_M +H]⁺_m /z 175.99, found 175.80.

4-氯-5-氟烟酸甲酯(3)的制备Preparation of 4-chloro-5-fluoronicotinate methyl ester (3)

在0℃向4-氯-5-氟烟酸2(2.2g,11.6mmol)在ACN(100mL)中的溶液中逐滴加入DBU(5.29g,34.8mmol)和CH₃I(8.2g,58.0mmol)。将混合物在室温搅拌5小时。将得到的混合物用水(300mL)稀释，并用EtOAc(100mL x 3)萃取。将合并的有机相用盐水洗涤，经硫酸钠干燥，浓缩，并通过硅胶柱色谱法(用20％至50％的EtOAc/PE洗脱)纯化以产生作为白色固体的4-氯-5-氟烟酸甲酯3(1.5g,90％纯度,63％收率)。To a solution of 4-chloro-5-fluoronicotinic acid 2 (2.2 g, 11.6 mmol) in ACN (100 mL) was added DBU (5.29 g, 34.8 mmol) and CH₃ I (8.2 g, 58.0 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 5 hours. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluted with 20% to 50% EtOAc/PE) to produce 4-chloro-5-fluoronicotinic acid methyl ester 3 (1.5 g, 90% purity, 63% yield) as a white solid.

C₇H₅ClFNO₂[M+H]⁺m/z的LCMS(ESI)计算值为190.00，实测值为189.95。LCMS (ESI) calcd for_C7H5ClFNO2 [_M +H]⁺_m /z 190.00, found 189.95.

4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸甲酯(5)的制备Preparation of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate (5)

将4-氯-5-氟烟酸甲酯3(150mg,0.79mmol)、3-乙炔基吡咯烷-1-甲酸叔丁酯4(233mg,1.19mmol)、PdCl₂(PPh₃)₂(55mg,0.079mmol)和DIPEA(511mg,3.96mmol)在ACN(15mL)中的混合物在N₂气氛下在85℃加热5小时。冷却至环境温度以后，将混合物穿过硅藻土过滤，并将滤液在真空下浓缩。将残余物用水稀释，并用EtOAc萃取。将合并的有机相用水和盐水洗涤，经硫酸钠干燥，在减压下浓缩，并通过快速色谱法(用20％至40％的EtOAc/PE洗脱)纯化以得到作为黄色固体的4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸甲酯5(150mg,90％纯度,48％收率)。A mixture of methyl 4-chloro-5-fluoronicotinate 3 (150 mg, 0.79 mmol), tert-butyl 3-ethynylpyrrolidine-1-carboxylate 4 (233 mg, 1.19 mmol), PdCl₂ (PPh₃ )₂ (55 mg, 0.079 mmol) and DIPEA (511 mg, 3.96 mmol) in ACN (15 mL) was heated at 85° C. for 5 h under N₂ atmosphere. After cooling to ambient temperature, the mixture was filtered through celite and the filtrate was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated under reduced pressure, and purified by flash chromatography (eluting with 20% to 40% EtOAc/PE) to give methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate 5 (150 mg, 90% purity, 48% yield) as a yellow solid.

C₁₈H₂₁FN₂O₄[M+H]⁺m/z的LCMS(ESI)计算值为349.15，实测值为348.95。LCMS (ESI) calcd for_C18H21FN2O4 [_M +H]⁺_m/ z 349.15, found 348.95.

4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸(6)的制备Preparation of 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid (6)

向4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸甲酯5(150mg,0.43mmol)在THF/H₂O(3/1,10mL)中的溶液中加入LiOH(31mg,1.29mmol)。将混合物在室温搅拌2h。然后在减压下除去有机溶剂。将水溶液用1M HCl调节至pH 3-4，并用DCM(50mL×3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥并在减压下浓缩以产生作为黄色油的4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸6(120mg,90％纯度,75％收率)。To a solution of methyl 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinate 5 (150 mg, 0.43 mmol) in THF/H₂ O (3/1, 10 mL) was added LiOH (31 mg, 1.29 mmol). The mixture was stirred at room temperature for 2 h. The organic solvent was then removed under reduced pressure. The aqueous solution was adjusted to pH 3-4 with 1M HCl and extracted with DCM (50 mL×3). The combined organic layers were washed with brine, dried over Na₂ SO₄ and concentrated under reduced pressure to give 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid 6 (120 mg, 90% purity, 75% yield) as a yellow oil.

C₁₇H₁₉FN₂O₄[M+H]⁺m/z的LCMS(ESI)计算值为335.14，实测值为335.00。LCMS^{(ESI) calcd for C17H19FN2O4 [M+H]+}_m/z335.14 , found 335.00.

3-(5-氟-1-氧代-1H-吡喃并[3,4-c]吡啶-3-基)吡咯烷-1-甲酸叔丁酯(7)的制备Preparation of tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate (7)

在0℃向4-((1-(叔丁氧基羰基)吡咯烷-3-基)乙炔基)-5-氟烟酸6(120mg,0.36mmol)在DCM(10mL)中的溶液中逐滴加入TfOH(161mg,1.07mmol)。将混合物在室温搅拌16小时。将反应物用DIPEA(231mg,1.79mmol)淬灭，然后加入Boc₂O(156mg,0.716mmol)。在室温搅拌1h以后，将得到的混合物在减压下浓缩并将残余物通过硅胶柱色谱法(用20％至40％的EtOAc/PE洗脱)纯化以产生作为白色固体的3-(5-氟-1-氧代-1H-吡喃并[3,4-c]吡啶-3-基)吡咯烷-1-甲酸叔丁酯7(70mg,90％纯度,52％收率)。To a solution of 4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)ethynyl)-5-fluoronicotinic acid 6 (120 mg, 0.36 mmol) in DCM (10 mL) was added TfOH (161 mg, 1.07 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with DIPEA (231 mg, 1.79 mmol) and then Boc₂ O (156 mg, 0.716 mmol) was added. After stirring at room temperature for 1 h, the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with 20% to 40% EtOAc/PE) to produce tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate 7 (70 mg, 90% purity, 52% yield) as a white solid.

C₁₇H₁₉FN₂O₄[M-t-Bu+H]⁺m/z的LCMS(ESI)计算值为279.14，实测值为278.85。LCMS (_ESI ) calcd for_C17H19FN2O4 [Mt-Bu+H]⁺_m /_z 279.14, found 278.85.

3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-甲酸叔丁酯(8)的制备Preparation of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate (8)

将3-(5-氟-1-氧代-1H-吡喃并[3,4-c]吡啶-3-基)吡咯烷-1-甲酸叔丁酯7(70mg,0.21mmol)在NH₃-MeOH(7M,5mL)中的溶液在密闭试管中在90℃搅拌1h。然后将反应物在减压下浓缩以提供作为黄色固体的3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-甲酸叔丁酯8(70mg,90％纯度,90％收率)。A solution of tert-butyl 3-(5-fluoro-1-oxo-1H-pyrano[3,4-c]pyridin-3-yl)pyrrolidine-1-carboxylate 7 (70 mg, 0.21 mmol) in NH₃ -MeOH (7M, 5 mL) was stirred in a sealed tube at 90° C. for 1 h. The reaction was then concentrated under reduced pressure to afford tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate 8 (70 mg, 90% purity, 90% yield) as a yellow solid.

C₁₇H₂₀FN₃O₃[M+H]⁺m/z的LCMS(ESI)计算值为334.15，实测值为333.95。LCMS (ESI) calcd for_C17H20FN3O3 [_M +H]⁺_m/ z 334.15, found 333.95.

5-氟-3-(吡咯烷-3-基)-2,7-萘啶-1(2H)-酮(9)的制备Preparation of 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one (9)

将3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-甲酸叔丁酯8(70mg,0.44mmol)在HCl二氧杂环己烷溶液(4M,5mL)中的混合物在室温搅拌1小时。将混合物在减压下浓缩然后用Et₃N淬灭。将得到的溶液在真空下浓缩以产生作为黄色油的5-氟-3-(吡咯烷-3-基)-2,7-萘啶-1(2H)-酮9(50mg,90％纯度,92％收率)。A mixture of tert-butyl 3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidine-1-carboxylate 8 (70 mg, 0.44 mmol) in HCl dioxane solution (4M, 5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and then quenched with Et₃ N. The resulting solution was concentrated under vacuum to give 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one 9 (50 mg, 90% purity, 92% yield) as a yellow oil.

C₁₂H₁₂FN₃O[M+H]⁺m/z的LCMS(ESI)计算值为234.10，实测值为234.05。LCMS (ESI) calcd for_C12H12FN3O [M₊ H]⁺ m_/ z 234.10, found 234.05.

6-氟-5-(4-(3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物343a和343b的外消旋混合物)的制备Preparation of 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 343a and 343b)

向5-氟-3-(吡咯烷-3-基)-2,7-萘啶-1(2H)-酮9(70mg,0.30mmol)在MeOH(10mL)中的溶液中加入6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT-2(113mg,0.45mmol)，然后在室温加入两滴乙酸、NaBH₃CN(19mg,0.30mmol)和NaBH(OAc)₃(191mg,0.90mmol)。将反应混合物在50℃搅拌1h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的6-氟-5-(4-(3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺，即化合物343a和343b的外消旋混合物(50mg,95％纯度,33％收率)。To a solution of 5-fluoro-3-(pyrrolidin-3-yl)-2,7-naphthyridin-1(2H)-one 9 (70 mg, 0.30 mmol) in MeOH (10 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (113 mg, 0.45 mmol), followed by two drops of acetic acid, NaBH₃ CN (19 mg, 0.30 mmol) and NaBH(OAc)₃ (191 mg, 0.90 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) to give 6-fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide, a racemic mixture of compounds 343a and 343b (50 mg, 95% purity, 33% yield) as a white solid.

6-氟-5-(4-(3-(5-氟-1-氧代-1,2-二氢-2,7-萘啶-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物343a和343b的外消旋混合物)的手性拆分Chiral Resolution of 6-Fluoro-5-(4-(3-(5-fluoro-1-oxo-1,2-dihydro-2,7-naphthyridin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (racemic mixture of compounds 343a and 343b)

将化合物343a和343b的外消旋混合物通过SFC(柱：Daicel Chiralpak IH 20mmI.D.×250mm,5μm；流动相:CO₂/MeOH[0.1％(NH₃)]＝70/30)分离并在减压下浓缩以提供作为343a的第一级分(19.7mg,99％纯度,100％ee，白色固体)和作为343b的第二级分(24.7mg,98％纯度,90％ee，白色固体)The racemic mixture of compounds 343a and 343b was separated by SFC (column: Daicel Chiralpak IH 20 mm I.D.×250 mm, 5 μm; mobile phase: CO₂ /MeOH [0.1% (_{NH 3} )]=70/30) and concentrated under reduced pressure to give a first fraction (19.7 mg, 99% purity, 100% ee, white solid) as 343a and a second fraction (24.7 mg, 98% purity, 90% ee, white solid) as 343b.

化合物343aCompound 343a

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.74(s,1H),9.09(s,1H),8.68(d,J＝2.0Hz,1H),8.40(d,J＝4.8Hz,1H),7.87-7.80(m,1H),7.58(dd,J＝10.6,8.2Hz,1H),6.54(s,1H),3.58-3.47(m,2H),3.29-3.16(m,1H),2.91-2.83(m,5H),2.77(d,J＝4.8Hz,3H),2.72-2.58(m,1H),2.47-2.23(m,2H),2.10-1.96(m,2H),1.95-1.81(m,1H),1.77-1.50(m,2H)。¹ H NMR (400 MHz, DMSO-d₆ ,ppm)δ:11.74(s,1H),9.09(s,1H),8.68(d,J＝2.0Hz,1H),8.40(d,J＝4.8Hz,1H),7.87-7.80(m,1H),7.58(dd,J＝10.6,8.2Hz,1H),6.54(s,1H),3.58-3. 47(m,2H),3.29-3.16(m,1H),2.91-2.83(m,5H),2.77(d,J＝4.8Hz,3H),2.72-2.58(m,1H),2.47-2.23(m,2H),2.10-1.96(m,2H),1.95-1.81(m,1H), 1.77-1.50(m,2H).

C₂₄H₂₆F₂N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为469.21，实测值为469.07。LCMS (ESI) calcd for_C24H26F2N6O2 [M₊ H]⁺_m/ z 469.21, found_469.07 .

化合物343aCompound 343a

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.77(s,1H),9.09(s,1H),8.68(d,J＝2.0Hz,1H),8.45-8.31(m,1H),7.89-7.76(m,1H),7.58(dd,J＝10.6,8.2Hz,1H),6.55(s,1H),3.54-3.46(m,2H),3.29-3.23(m,1H),2.94-2.82(m,5H),2.77(d,J＝4.8Hz,3H),2.69-2.58(m,1H),2.36-2.25(m,2H),2.02-1.94(m,2H),1.91-1.78(m,1H),1.67-1.56(m,2H)。¹ H NMR (400 MHz, DMSO-d₆ ,ppm)δ:11.77(s,1H),9.09(s,1H),8.68(d,J＝2.0Hz,1H),8.45-8.31(m,1H),7.89-7.76(m,1H),7.58(dd,J＝10.6,8.2Hz,1H),6.55(s,1H),3.54-3.4 6(m,2H),3.29-3.23(m,1H),2.94-2.82(m,5H),2.77(d,J＝4.8Hz,3H),2.69-2.58(m,1H),2.36-2.25(m,2H),2.02-1.94(m,2H),1.91-1.78(m,1H), 1.67-1.56(m,2H).

C₂₄H₂₆F₂N₆O₂[M+H]⁺m/z的LCMS(ESI)计算值为469.21，实测值为469.10。LCMS (ESI) calcd for_C24H26F2N6O2 [M₊ H]⁺_m/ z 469.21, found_469.10 .

实施例27-化合物361的合成Example 27-Synthesis of Compound 361

化合物361的合成Synthesis of compound 361

4-((2-(乙氧基羰基)环己-1-烯-1-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((2-(ethoxycarbonyl)cyclohex-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3)

在室温向2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酸1(110mg,0.48mmol)在吡啶(10mL)中的溶液中加入2-氨基环己-1-烯-1-甲酸乙酯2(160mg,0.95mmol)，然后加入10滴POCl₃。将反应混合物在室温搅拌3h。冷却至室温之后，将反应混合物倒入水中，将水相用有机溶剂(50mL)萃取3次。将合并的有机层用盐水(50mL)洗涤并经Na₂SO₄干燥，然后在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAc＝100:0至85:15洗脱)纯化以产生作为白色固体的4-((2-(乙氧基羰基)环己-1-烯-1-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(100mg,55％收率)。To a solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 1 (110 mg, 0.48 mmol) in pyridine (10 mL) was added 2-aminocyclohex-1-ene-1-carboxylic acid ethyl ester 2 (160 mg, 0.95 mmol) at room temperature, followed by 10 drops of POCl₃ . The reaction mixture was stirred at room temperature for 3 h. After cooling to room temperature, the reaction mixture was poured into water, and the aqueous phase was extracted 3 times with an organic solvent (50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na₂ SO₄ , then concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 85:15) to give tert-butyl 4-((2-(ethoxycarbonyl)cyclohex-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (100 mg, 55% yield) as a white solid.

C20H30N2O5[M-56+H]⁺m/z的LCMS(ESI)计算值为323.22，实测值为323.05。LCMS (ESI) calculated value of m/z for C20H30N2O5[M-56+H]⁺ is 323.22, found is 323.05.

2-(2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酰氨基)环己-1-烯-1-甲酸(4)的制备Preparation of 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)cyclohex-1-ene-1-carboxylic acid (4)

向4-((2-(乙氧基羰基)环己-1-烯-1-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(100mg,0.26mmol)在MeOH:H2O＝1:1(10mL)中的溶液中加入LiOH(30mg,1.25mmol)。将反应混合物在室温搅拌1h。将反应混合物在减压下浓缩以产生作为白色固体的2-(2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酰氨基)环己-1-烯-1-甲酸4(80mg,88％收率)。To a solution of tert-butyl 4-((2-(ethoxycarbonyl)cyclohex-1-en-1-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (100 mg, 0.26 mmol) in MeOH:HO=1:1 (10 mL) was added LiOH (30 mg, 1.25 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)cyclohex-1-ene-1-carboxylic acid 4 (80 mg, 88% yield) as a white solid.

C18H26N2O5[M-56+H]⁺m/z的LCMS(ESI)计算值为295.18，实测值为295.05。LCMS (ESI) calcd. m/z for C18H26N2O5[M-56+H]⁺ 295.18, found 295.05.

4-(4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(5)的制备Preparation of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5)

在室温向2-(2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酰氨基)环己-1-烯-1-甲酸4(80mg,0.23mmol)在ACN(10mL)中的溶液中加入N,N,N',N'-四甲基氯甲脒鎓六氟磷酸盐/TCFH(150mg,0.54mmol)和N-甲基咪唑/NMI(50mg,0.61mmol)。10分钟以后，在50℃加入过量的NH₃-MeOH(7M,5mL)。将混合物在50℃搅拌18h。将残余物在减压下浓缩，然后通过快速色谱法(用DCM/MeOH＝100:0至96:4洗脱)纯化以产生作为白色固体的4-(4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(60mg,79％收率)。To a solution of 2-(2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxamido)cyclohex-1-ene-1-carboxylic acid 4 (80 mg, 0.23 mmol) in ACN (10 mL) was added N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate/TCFH (150 mg, 0.54 mmol) and N-methylimidazole/NMI (50 mg, 0.61 mmol) at room temperature. After 10 minutes, excess NH₃ -MeOH (7M, 5 mL) was added at 50° C. The mixture was stirred at 50° C. for 18 h. The residue was concentrated under reduced pressure and then purified by flash chromatography (eluted with DCM/MeOH=100:0 to 96:4) to give tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (60 mg, 79% yield) as a white solid.

C18H25N3O3[M+H]⁺m/z的LCMS(ESI)计算值为332.19，实测值为332.10。LCMS (ESI) calcd for C18H25N3O3[M+H]⁺ m/z 332.19, found 332.10.

2-(2-氮杂双环[2.1.1]己烷-4-基)-5,6,7,8-四氢喹唑啉-4(3H)-酮(6)的制备Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (6)

将4-(4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(60mg,0.18mmol)加入在二氧杂环己烷中的HCl(4M,3mL)中，在室温搅拌1h，将反应混合物在减压下浓缩以产生作为白色固体的2-(2-氮杂双环[2.1.1]己烷-4-基)-5,6,7,8-四氢喹唑啉-4(3H)-酮6(40mg,96％收率)。Tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (60 mg, 0.18 mmol) was added to HCl (4M, 3 mL) in dioxane, stirred at room temperature for 1 h, and the reaction mixture was concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one 6 (40 mg, 96% yield) as a white solid.

C13H17N3O[M+H]⁺m/z的LCMS(ESI)计算值为232.14，实测值为232.05。LCMS (ESI) calcd for C13H17N3O[M+H]⁺ m/z 232.14, found 232.05.

N-甲基-5-(4-(4-(4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺(化合物361)的制备Preparation of N-methyl-5-(4-(4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (Compound 361)

向2-(2-氮杂双环[2.1.1]己烷-4-基)-5,6,7,8-四氢喹唑啉-4(3H)-酮6(40mg,0.17mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(40mg,0.17mmol)和3滴HOAc，然后加入NaBH₃CN(10mg,0.16mmol)。将反应混合物在50℃搅拌4h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过制备型HPLC(柱:Gemini5um C18 150×21.2mm，流动相:ACN-H₂O(0.1％ FA)，梯度:10-25)纯化以产生作为白色固体的N-甲基-5-(4-(4-(4-氧代-3,4,5,6,7,8-六氢喹唑啉-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺361(30mg,97％纯度,38％收率)。To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one 6 (40 mg, 0.17 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (40 mg, 0.17 mmol) and 3 drops of HOAc, followed by NaBH₃ CN (10 mg, 0.16 mmol). The reaction mixture was stirred at 50° C. for 4 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.1% FA), gradient: 10-25) to give N-methyl-5-(4-(4-(4-oxo-3,4,5,6,7,8-hexahydroquinazolin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide 361 (30 mg, 97% purity, 38% yield) as a white solid.

化合物361Compound 361

¹H NMR(400MHz,DMSO)δ12.11(s,1H),8.38(q,J＝4.8Hz,1H),8.28(d,J＝2.8Hz,1H),7.82(d,J＝8.8Hz,1H),7.40(dd,J＝8.8,2.8Hz,1H),3.87(d,J＝12.8Hz,2H),3.69(s,1H),2.98(s,2H),2.91(t,J＝11.2Hz,2H),2.78(d,J＝4.8Hz,3H),2.61-2.54(m,1H),2.48-2.44(m,2H),2.31(t,J＝6.0Hz,2H),2.09-2.02(m,2H),1.99-1.92(m,2H),1.84-1.78(m,2H),1.72-1.59(m,4H),1.51-1.41(m,2H)。¹ H NMR (400MHz, DMSO) δ12.11 (s, 1H), 8.38 (q, J = 4.8Hz, 1H), 8.28 (d, J = 2.8Hz, 1H), 7.82 (d, J = 8.8Hz, 1H),7.40(dd,J＝8.8,2.8Hz,1H),3.87(d,J＝12.8Hz,2H),3.69(s,1H),2.98(s,2H),2.91(t,J＝ 11.2Hz,2H),2.78(d,J＝4.8Hz,3H),2.61-2.54(m,1H),2.48-2.44(m,2H),2.31(t,J＝6.0Hz,2H),2.09- 2.02(m,2H),1.99-1.92(m,2H),1.84-1.78(m,2H),1.72-1.59(m,4H),1.51-1.41(m,2H).

C25H32N6O2[M+H]⁺m/z的LCMS(ESI)计算值为449.26，实测值为449.20。LCMS (ESI) calcd for C25H32N6O2[M+H]⁺ m/z 449.26, found 449.20.

实施例28-化合物375的合成Example 28 - Synthesis of Compound 375

化合物375的合成Synthesis of compound 375

4-((3-氨甲酰基吡啶-2-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(3)的制备Preparation of tert-butyl 4-((3-carbamoylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (3)

在室温向2-(叔丁氧基羰基)-2-氮杂双环[2.1.1]己烷-4-甲酸2(500mg,2.19mmol)在DCM(15mL)中的溶液中接连地加入2-氨基烟酰胺1(330mg,2.41mmol)、T3P(50重量％在EtOAc中,4.18g,6.57mmol)和DIPEA(850mg,6.57mmol)。将混合物保持在室温搅拌1h。将反应溶液在减压下浓缩并将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的4-((3-氨甲酰基吡啶-2-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(330mg,90％纯度,39％收率)。To a solution of 2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid 2 (500 mg, 2.19 mmol) in DCM (15 mL) were added 2-aminonicotinamide 1 (330 mg, 2.41 mmol), T3P (50 wt% in EtOAc, 4.18 g, 6.57 mmol) and DIPEA (850 mg, 6.57 mmol) successively at room temperature. The mixture was kept stirring at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with DCM/MeOH=100:0 to 90:10) to produce tert-butyl 4-((3-carbamoylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (330 mg, 90% purity, 39% yield) as a white solid.

C₁₇H₂₂N₄O₄[M+H]⁺m/z的LCMS(ESI)计算值为347.16，实测值为346.85。LCMS (ESI) calcd for_C17H22N4O4 [M₊ H]⁺_m/ z 347.16, found 346.85.

4-(4-氧代-3,4-二氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(4)的制备Preparation of tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (4)

在室温向4-((3-氨甲酰基吡啶-2-基)氨甲酰基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯3(330mg,0.95mmol)在DME(20mL)中的溶液中加入KOH(160mg,2.85mmol)。将反应混合物在60℃搅拌6h。将反应溶液过滤以除去KOH。将滤液用水稀释，并用EtOAc(10mL×3)萃取。将水相通过硅胶C18柱(用含有0.1％甲酸的10％至50％MeCN/H₂O洗脱)纯化以产生作为白色固体的4-(4-氧代-3,4-二氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(220mg,80％纯度,56％收率)。To a solution of tert-butyl 4-((3-carbamoylpyridin-2-yl)carbamoyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 3 (330 mg, 0.95 mmol) in DME (20 mL) was added KOH (160 mg, 2.85 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 6 h. The reaction solution was filtered to remove KOH. The filtrate was diluted with water and extracted with EtOAc (10 mL x 3). The aqueous phase was purified by silica gel C18 column (eluted with 10% to 50% MeCN/H₂ O containing 0.1% formic acid) to produce tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (220 mg, 80% purity, 56% yield) as a white solid.

C₁₇H₂₀N₄O₃[M+H]⁺m/z的LCMS(ESI)计算值为329.15，实测值为329.00。LCMS (ESI) calcd for_C17H20N4O3 [M+_H ]⁺_m/ z 329.15, found 329.00.

4-(4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(5)的制备Preparation of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (5)

向4-(4-氧代-3,4-二氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯4(200mg,0.607mmol)在THF/H₂O＝4:1(20mL)中的溶液中加入PtO₂(41mg)。然后将混合物在室温在氢气下搅拌18h。将混合物穿过硅藻土垫过滤，并将滤液在减压下浓缩以产生作为黄色固体的4-(4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(200mg,90％纯度,88％收率)。To a solution of tert-butyl 4-(4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 4 (200 mg, 0.607 mmol) in THF/H₂ O=4:1 (20 mL) was added PtO₂ (41 mg). The mixture was then stirred at room temperature under hydrogen for 18 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (200 mg, 90% purity, 88% yield) as a yellow solid.

C₁₇H₂₄N₄O₃[M+H]⁺m/z的LCMS(ESI)计算值为333.18，实测值为333.25。LCMS (ESI) calcd for_C17H24N4O3 [M₊ H]⁺_m/ z 333.18, found 333.25.

4-(3-(4-甲氧基苄基)-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(6)的制备Preparation of tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (6)

在室温向4-(4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯5(200mg,0.6mmol)在DMSO(10mL)中的溶液中加入Cs₂CO₃(586mg,1.8mmol)和PMBCl(188mg,1.2mmol)。将反应混合物在50℃搅拌1h。将反应溶液用水淬灭，并用EtOAc(30mL×3)萃取。将合并的有机相用盐水洗涤3次并在减压下浓缩。将残余物通过快速色谱法(用PE/EtOAC＝100:0至50:50洗脱)纯化以产生作为白色固体的4-(3-(4-甲氧基苄基)-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯6(150mg,90％纯度,49％收率)。To a solution of tert-butyl 4-(4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 5 (200 mg, 0.6 mmol) in DMSO (10 mL) was added Cs₂ CO₃ (586 mg, 1.8 mmol) and PMBCl (188 mg, 1.2 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. The reaction solution was quenched with water and extracted with EtOAc (30 mL×3). The combined organic phase was washed 3 times with brine and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with PE/EtOAC = 100:0 to 50:50) to give tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 6 (150 mg, 90% purity, 49% yield) as a white solid.

C₂₅H₃₂N₄O₄[M+H]⁺m/z的LCMS(ESI)计算值为453.24，实测值为453.05。LCMS (ESI) calcd for_C25H32N4O4 [M₊ H]⁺_m/ z 453.24, found 453.05.

4-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯(7)的制备Preparation of tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (7)

在0℃向4-(3-(4-甲氧基苄基)-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯6(50mg,0.11mmol)在DMF(10mL)中的溶液中加入NaH(7mg,0.17mmol,60重量％)和MeI(24mg,0.17mmol)。将反应混合物在室温搅拌1h。将反应溶液用水淬灭，并用EtOAc(50mL×3)萃取。将有机相在减压下浓缩并将残余物通过快速色谱法(用PE/EtOAc＝100:0至70:30洗脱)纯化以产生作为白色固体的4-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯7(30mg,90％纯度,52％收率)。To a solution of tert-butyl 4-(3-(4-methoxybenzyl)-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 6 (50 mg, 0.11 mmol) in DMF (10 mL) was added NaH (7 mg, 0.17 mmol, 60 wt%) and MeI (24 mg, 0.17 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The reaction solution was quenched with water and extracted with EtOAc (50 mL×3). The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with PE/EtOAc = 100:0 to 70:30) to give tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 7 (30 mg, 90% purity, 52% yield) as a white solid.

C₂₆H₃₄N₄O₄[M+H]⁺m/z的LCMS(ESI)计算值为467.26，实测值为467.30。LCMS (ESI) calcd for_C26H34N4O4 [M₊ H]⁺_m/ z 467.26, found 467.30.

2-(2-氮杂双环[2.1.1]己烷-4-基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮(8)的制备Preparation of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one (8)

向4-(3-(4-甲氧基苄基)-8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-甲酸叔丁酯7(30mg,0.064mmol)在TFA(5mL)中的溶液中加入TfOH(0.2mL)。将反应物在室温搅拌0.5h。在0℃将反应溶液用饱和NaHCO₃水溶液调至pH 8。将碱化的溶液用DCM(10mL×3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥并在减压下浓缩以产生作为黄色油的2-(2-氮杂双环[2.1.1]己烷-4-基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮8(25mg,60％纯度,94％收率)。To a solution of tert-butyl 4-(3-(4-methoxybenzyl)-8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate 7 (30 mg, 0.064 mmol) in TFA (5 mL) was added TfOH (0.2 mL). The reactants were stirred at room temperature for 0.5 h. The reaction solution was adjusted to pH 8 with saturated aqueous NaHCO₃ at 0 ° C. The basified solution was extracted with DCM (10 mL×3). The combined organic layers were washed with_brine , dried over_Na2SO4 and concentrated under reduced pressure to give 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 8 (25 mg, 60% purity, 94% yield) as a yellow oil.

C₁₃H₁₈N₄O[M+H]⁺m/z的LCMS(ESI)计算值为247.15，实测值为247.25。LCMS (ESI) calcd for_C13H18N4O [M₊ H]⁺ m_/ z 247.15, found 247.25.

6-氟-N-甲基-5-(4-(4-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺(化合物375)的制备Preparation of 6-fluoro-N-methyl-5-(4-(4-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide (Compound 375)

在室温向2-(2-氮杂双环[2.1.1]己烷-4-基)-8-甲基-5,6,7,8-四氢吡啶并[2,3-d]嘧啶-4(3H)-酮8(25mg,0.10mmol)在MeOH(15mL)和AcOH(0.01mL)中的溶液中加入6-氟-N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT-2(31mg,0.12mmol)和NaBH₃CN(10mg,0.15mmol)。将反应混合物在50℃搅拌1h。将反应溶液在减压下浓缩并将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)和制备型HPLC(Gemini 5um C18 150×21.2mm，流动相:ACN-H₂O(0.05％NH₃)，梯度:25-95)纯化以产生作为白色固体的6-氟-N-甲基-5-(4-(4-(8-甲基-4-氧代-3,4,5,6,7,8-六氢吡啶并[2,3-d]嘧啶-2-基)-2-氮杂双环[2.1.1]己烷-2-基)哌啶-1-基)吡啶酰胺375(5.0mg,97％纯度,10％收率)。To a solution of 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-methyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one 8 (25 mg, 0.10 mmol) in MeOH (15 mL) and AcOH (0.01 mL) was added 6-fluoro-N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT-2 (31 mg, 0.12 mmol) and NaBH₃ CN (10 mg, 0.15 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. The reaction solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluted with DCM/MeOH=100:0 to 90:10) and preparative HPLC (Gemini 5um C18 150×21.2 mm, mobile phase: ACN—H₂ O (0.05% NH₃ ), gradient: 25-95) to give 6-fluoro-N-methyl-5-(4-(4-(8-methyl-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-2-yl)-2-azabicyclo[2.1.1]hexan-2-yl)piperidin-1-yl)picolinamide 375 (5.0 mg, 97% purity, 10% yield) as a white solid.

¹H NMR(400MHz,DMSO-d₆,ppm)δ:11.32(s,1H),8.43-8.35(m,1H),7.83(d,J＝8.0Hz,1H),7.63-7.53(m,1H),3.61(s,1H),3.57-3.50(m,2H),3.25-3.18(m,2H),3.03(s,3H),2.91(s,2H),2.84(t,J＝11.2Hz,2H),2.76(d,J＝4.8Hz,3H),2.47-2.42(m,1H),2.37-2.31(m,2H),2.03-1.90(m,4H),1.80-1.71(m,4H),1.55-1.42(m,2H)。¹ H NMR (400 MHz, DMSO-d₆ ,ppm)δ:11.32(s,1H),8.43-8.35(m,1H),7.83(d,J＝8.0Hz,1H),7.63-7.53(m,1H),3.61(s,1H),3.57-3.50(m,2H),3.25-3.18(m,2H),3.03(s,3H), 2.91(s,2H),2.84(t,J＝11.2Hz,2H),2.76(d,J＝4.8Hz,3H),2.47-2.42(m,1H),2.37-2.31(m,2H),2.03-1.90(m,4H),1.80-1.71(m,4H),1.55-1.42 (m,2H).

C₂₅H₃₂FN₇O₂[M+H]⁺m/z的LCMS(ESI)计算值为482.26，实测值为482.15。LCMS (ESI) calcd for_C25H32FN7O2 [_M +H]⁺_m/ z 482.26, found 482.15.

实施例29-化合物393rac的合成Example 29-Synthesis of Compound 393rac

化合物393rac的合成Synthesis of compound 393rac

8-氟-2-(4-甲氧基苄基)-3-乙烯基异喹啉-1(2H)-(3)的制备Preparation of 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinoline-1(2H)-(3)

向3-氯-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮1(2000mg,6.294mmol)和Pd(AMPHOS)Cl₂(445mg,0.6294mmol)在ACN(30mL)中的溶液中加入三丁基(乙烯基)锡烷2(1995mg,6.294mmol)。将混合物在密闭试管中在100℃加热5h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用0至15％的EtOAc/PE洗脱)纯化以产生作为白色固体的8-氟-2-(4-甲氧基苄基)-3-乙烯基异喹啉-1(2H)-酮3(1500mg,90％纯度,69％收率)。To a solution of 3-chloro-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 1 (2000 mg, 6.294 mmol) and Pd(AMPHOS)Cl₂ (445 mg, 0.6294 mmol) in ACN (30 mL) was added tributyl(vinyl)stannane 2 (1995 mg, 6.294 mmol). The mixture was heated at 100° C. for 5 h in a sealed test tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0 to 15% EtOAc/PE) to give 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinolin-1(2H)-one 3 (1500 mg, 90% purity, 69% yield) as a white solid.

C₁₉H₁₆FNO₂[M+H]⁺m/z的LCMS(ESI)计算值为310.12，实测值为309.90。LCMS (ESI) calcd for_C19H16FNO2 [M+H]⁺_m/ z 310.12, found 309.90.

8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-甲醛(4)的制备Preparation of 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde (4)

向8-氟-2-(4-甲氧基苄基)-3-乙烯基异喹啉-1(2H)-酮3(1500mg,4.85mmol)在MeOH/H₂O(3:1,80mL)中的溶液中加入NaIO₄(4150mg,19.40mmol)和K₂OsO₄·2H₂O(178mg,0.48mmol)。将反应物在室温搅拌1h。将反应混合物用水稀释，并用EtOAc(200mL x 3)萃取。将合并的有机层用盐水洗涤，经Na₂SO₄干燥并在减压下浓缩。将残余物通过硅胶上的快速色谱法(用0至25％的EtOAc/PE洗脱)纯化以产生作为黄色固体的8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-甲醛4(430mg,90％纯度,25％收率)。To a solution of 8-fluoro-2-(4-methoxybenzyl)-3-vinylisoquinolin-1(2H)-one 3 (1500 mg, 4.85 mmol) in MeOH/H₂ O (3:1, 80 mL) was added NaIO₄ (4150 mg, 19.40 mmol) and K₂ OsO₄ ·2H₂ O (178 mg, 0.48 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with 0 to 25% EtOAc/PE) to give 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde 4 (430 mg, 90% purity, 25% yield) as a yellow solid.

C₁₈H₁₄FNO₃[M+H]⁺m/z的LCMS(ESI)计算值为312.10，实测值为311.90。LCMS (ESI) calcd for_C18H14FNO3 [M+H]⁺_m/ z 312.10, found 311.90.

3-(2,2-二氟乙烯基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮(5)的制备Preparation of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (5)

向8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-甲醛4(430mg,1.38mmol)、PPh₃(724mg,2.76mmol)和LiI(369mg,2.76mmol)在DMF/二氧杂环己烷(8％,10mL)中的溶液中加入TMSCF₃(491mg,3.45mmol)。将混合物在密闭试管中在130℃加热3h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用0至15％的EtOAc/PE洗脱)纯化以产生作为白色固体的3-(2,2-二氟乙烯基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮5(200mg,60％纯度,25％收率)。To a solution of 8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinoline-3-carbaldehyde 4 (430 mg, 1.38 mmol), PPh₃ (724 mg, 2.76 mmol) and LiI (369 mg, 2.76 mmol) in DMF/dioxane (8%, 10 mL) was added TMSCF₃ (491 mg, 3.45 mmol). The mixture was heated at 130° C. for 3 h in a sealed tube. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0 to 15% EtOAc/PE) to give 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 5 (200 mg, 60% purity, 25% yield) as a white solid.

C₁₉H₁₄F₃NO₂[M+H]⁺m/z的LCMS(ESI)计算值为346.10，实测值为346.00。LCMS (ESI) calcd for_C19H14F3NO2 [M+H]⁺_m/ z_346.10 , found 346.00.

3-(1-苄基-4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮(7)的制备Preparation of 3-(1-benzyl-4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (7)

向3-(2,2-二氟乙烯基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮5(260mg,0.75mmol)和LiF(39mg,1.51mmol)在ACN(50mL)中的溶液中加入N-苄基-1-甲氧基-N-((三甲基甲硅烷基)甲基)甲胺6(357mg,1.51mmol)。将混合物保持在60℃搅拌16h。将得到的混合物用水稀释，并用DCM(30mL×3)萃取。将合并的有机层经Na₂SO₄干燥并在减压下浓缩。将残余物通过快速色谱法(用0至15％的EtOAc/PE洗脱)纯化以产生作为白色固体的3-(1-苄基-4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮7(25mg,90％纯度,6％收率)。To a solution of 3-(2,2-difluorovinyl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 5 (260 mg, 0.75 mmol) and LiF (39 mg, 1.51 mmol) in ACN (50 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine 6 (357 mg, 1.51 mmol). The mixture was stirred at 60 °C for 16 h. The resulting mixture was diluted with water and extracted with DCM (30 mL x 3). The combined organic layers were dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0 to 15% EtOAc/PE) to give 3-(1-benzyl-4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 7 (25 mg, 90% purity, 6% yield) as a white solid.

C₂₈H₂₅F₃N₂O₂[M+H]⁺m/z的LCMS(ESI)计算值为479.19，实测值为479.20。LCMS (ESI) calcd for_C28H25F3N2O2 [M+_H ]⁺_m/ z 479.19, found_479.20 .

3-(4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮(7)的制备Preparation of 3-(4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one (7)

向3-(1-苄基-4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮7(130mg,0.271mmol)在MeOH(5mL)中的溶液中加入一滴浓HCl、10％ Pd/C(20mg)和10％ Pd(OH)₂/C(20mg)。将混合物抽真空并用氢气回填3次并然后用氢气填充。将得到的混合物在室温搅拌16小时。然后将混合物穿过硅藻土过滤并在真空下浓缩以产生作为白色固体的粗制3-(4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮8(100mg,50％纯度,47％收率)，将其不经进一步纯化直接用在下一步中。To a solution of 3-(1-benzyl-4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 7 (130 mg, 0.271 mmol) in MeOH (5 mL) was added one drop of concentrated HCl, 10% Pd/C (20 mg) and 10% Pd(OH)₂ /C (20 mg). The mixture was evacuated and backfilled with hydrogen three times and then filled with hydrogen. The resulting mixture was stirred at room temperature for 16 hours. The mixture was then filtered through celite and concentrated under vacuum to give crude 3-(4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 8 (100 mg, 50% purity, 47% yield) as a white solid, which was used directly in the next step without further purification.

C₂₁H₁₉F₃N₂O₂[M+H]⁺m/z的LCMS(ESI)计算值为389.14，实测值为389.00。LCMS (ESI) calcd for_C21H19F3N2O2 [M_+H ]⁺_m /z 389.14, found_389.00 .

5-(4-(3,3-二氟-4-(8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(10)的制备Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (10)

向3-(4,4-二氟吡咯烷-3-基)-8-氟-2-(4-甲氧基苄基)异喹啉-1(2H)-酮8(100mg,0.257mmol)在MeOH(10mL)中的溶液中加入N-甲基-5-(4-氧代哌啶-1-基)吡啶酰胺INT(90mg,0.386mmol)，然后在室温加入两滴乙酸和NaBH₃CN(24mg,0.386mmol)。将反应混合物在50℃搅拌1h。冷却至室温之后，将反应混合物在减压下浓缩。将残余物通过快速色谱法(用DCM/MeOH＝100:0至90:10洗脱)纯化以产生作为白色固体的5-(4-(3,3-二氟-4-(8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺10(80mg,50％纯度,25％收率)。To a solution of 3-(4,4-difluoropyrrolidin-3-yl)-8-fluoro-2-(4-methoxybenzyl)isoquinolin-1(2H)-one 8 (100 mg, 0.257 mmol) in MeOH (10 mL) was added N-methyl-5-(4-oxopiperidin-1-yl)picolinamide INT (90 mg, 0.386 mmol), followed by two drops of acetic acid and NaBH₃ CN (24 mg, 0.386 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 1 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with DCM/MeOH = 100:0 to 90:10) to give 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 10 (80 mg, 50% purity, 25% yield) as a white solid.

C₃₃H₃₄F₃N₅O₃[M+H]⁺m/z的LCMS(ESI)计算值为606.26，实测值为606.20。_LCMS (ESI) calcd for_C33H34F3N5O3 [M_+H ]⁺_m /z: 606.26, found: 606.20.

5-(4-(3,3-二氟-4-(8-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺(化合物393rac)的制备Preparation of 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide (Compound 393rac)

在室温向5-(4-(3,3-二氟-4-(8-氟-2-(4-甲氧基苄基)-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺10(80mg,0.13mmol)在TFA(5mL)中的溶液中逐滴加入TfOH(1mL)。将反应混合物在100℃搅拌5min。通过逐渐加入饱和NaHCO₃溶液将得到的混合物的pH调至约8.0，并然后用DCM(50mL×3)萃取。将合并的有机层经Na₂SO₄干燥并在减压下浓缩。将残余物通过制备型HPLC(Gemini 5um C18 150×21.2mm，用含有0.1％ FA的35％至40％ ACN/H₂O洗脱)纯化以产生作为棕色固体的5-(4-(3,3-二氟-4-(8-氟-1-氧代-1,2-二氢异喹啉-3-基)吡咯烷-1-基)哌啶-1-基)-N-甲基吡啶酰胺393rac(6.2mg,93％纯度,9％收率)。To a solution of 5-(4-(3,3-difluoro-4-(8-fluoro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 10 (80 mg, 0.13 mmol) in TFA (5 mL) was added TfOH (1 mL) dropwise at room temperature. The reaction mixture was stirred at 100 °C for 5 min. The pH of the resulting mixture was adjusted to about 8.0 by gradually adding saturated NaHCO₃ solution, and then extracted with DCM (50 mL×3). The combined organic layers were dried over Na₂ SO₄ and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gemini 5um C18 150x21.2 mm, eluting with 35% to 40% ACN/_H20 containing 0.1% FA) to give 5-(4-(3,3-difluoro-4-(8-fluoro-1-oxo-1,2-dihydroisoquinolin-3-yl)pyrrolidin-1-yl)piperidin-1-yl)-N-methylpicolinamide 393rac (6.2 mg, 93% purity, 9% yield) as a brown solid.

¹H NMR(400MHz,CD₃OD_SPE,ppm)δ:8.31(d,J＝2.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.72-7.65(m,1H),7.57-7.47(m,1H),7.43(d,J＝8.0Hz,1H),7.17(dd,J＝11.8,8.2Hz,1H),6.76-6.68(m,1H),4.10-3.94(m,2H),3.85-3.50(m,5H),3.28-3.25(m,1H),3.07(t,J＝12.4Hz,2H),2.96-2.90(m,3H),2.24-2.09(m,2H),1.84-1.66(m,2H)。¹ H NMR (400 MHz, CD₃ OD_SPE,ppm)δ:8.31(d,J＝2.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.72-7.65(m,1H),7.57-7.47(m,1H),7.43(d,J＝8.0Hz,1H),7.17(dd,J＝11.8,8.2Hz,1H),6. 76-6.68(m,1H),4.10-3.94(m,2H),3.85-3.50(m,5H),3.28-3.25(m,1H),3.07(t,J＝12.4Hz,2H),2.96-2.90(m,3H),2.24-2.09(m,2H),1.84-1.66 (m,2H).

C₂₅H₂₆F₃N₅O₂[M+H]⁺m/z的LCMS(ESI)计算值为486.21，实测值为486.40。LCMS (ESI) calcd for_C25H26F3N5O2 [M+_H ]⁺_m/ z 486.21, found_486.40 .

测定Determination

制备了本发明的示例性化合物并试验以确定其作为PARP1和PARP2抑制剂的效果。下面描述了典型测定。Exemplary compounds of the invention were prepared and tested to determine their effectiveness as inhibitors of PARP1 and PARP2. A typical assay is described below.

PARP1生化解离-增强的镧系元素荧光免疫测定(DELFIA测定)PARP1 Biolysis-Enhanced Lanthanide Fluorescence Immunoassay (DELFIA Assay)

将Optiplate HB 384-孔平板使用在pH 9.6的Na₂CO₃/HCO₃包被缓冲液用抗-FLAG抗体(作为4mg/ml溶液供给)在4℃包被过夜，以达到每孔0.3μg的最终固定化。然后将孔在包被洗涤缓冲液(PBS/0.05％吐温(v/v))中洗涤3x 5min，并在4℃用在包被洗涤缓冲液中的2％ BSA(w/v)封闭过夜。在测定之前，将孔在包被洗涤缓冲液中洗涤3x 5min。为了测定，将20μl的2.5nM重组全长人N端FLAG-标记的PARP1加入384-孔平板的每个孔中在室温保持30分钟，随后使用pintool技术加入50nL的在DMSO中的化合物溶液。在室温温育30min以后，将5μl的10μM生物素-NAD⁺和10nM活化DNA(序列如下所示)溶解于20mM HEPES(pH 7.5)、100mM NaCl、2mM DTT、0.1％ BSA(w/v)、0.02％吐温(v/v)测定缓冲液中。在室温进行自身聚ADP核糖基化2h，然后加入5μl的12mM NAD⁺淬灭溶液。在室温30分钟以后，除去测定溶液并在洗涤5次各3min以后，加入100μl的DELFIA Eu-N1抗生蛋白链菌素试剂的1:1000稀释液。然后将平板在室温温育30min。除去反应混合物并将平板洗涤5次各3min，然后加入25μlDELFIA增强溶液。在室温温育30min以后，在Pherastar FS(Ex337 nm,Em620 nm；积分开始60μs；积分时间400μs)上测量荧光。Optiplate HB 384-well plates were coated with anti-FLAG antibody (supplied as a 4 mg/ml solution) using Na₂ CO₃ /HCO₃ coating buffer at pH 9.6 overnight at 4°C to achieve a final immobilization of 0.3 μg per well. The wells were then washed 3x 5 min in coating wash buffer (PBS/0.05% Tween (v/v)) and blocked with 2% BSA (w/v) in coating wash buffer overnight at 4°C. Prior to the assay, the wells were washed 3x 5 min in coating wash buffer. For the assay, 20 μl of 2.5 nM recombinant full-length human N-terminally FLAG-tagged PARP1 was added to each well of the 384-well plate for 30 minutes at room temperature, followed by the addition of 50 nL of compound solution in DMSO using the pintool technique. After incubation at room temperature for 30 min, 5 μl of 10 μM biotin-NAD⁺ and 10 nM activated DNA (sequence as shown below) were dissolved in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w/v), 0.02% Tween (v/v) assay buffer. Autopoly ADP ribosylation was performed at room temperature for 2 h, and then 5 μl of 12 mM NAD⁺ quenching solution was added. After 30 minutes at room temperature, the assay solution was removed and after washing 5 times for 3 min each, 100 μl of a 1:1000 dilution of DELFIA Eu-N1 streptavidin reagent was added. The plate was then incubated at room temperature for 30 min. The reaction mixture was removed and the plate was washed 5 times for 3 min each, and then 25 μl of DELFIA enhancement solution was added. After incubation at room temperature for 30 min, fluorescence was measured on a Pherastar FS (Ex 337 nm, Em 620 nm; integration start 60 μs; integration time 400 μs).

通常在12点浓度-应答曲线中以3倍稀释间隔从20μM开始试验化合物，以确定IC₅₀值。使用ActivityBase软件分析数据，并对低(无酶，0.2％ DMSO)和高(0.2％ DMSO)％对照的重复值取平均值，并使用以下公式将从试验化合物获得的数据表示为100％的百分比：Compounds were typically tested in 12-point concentration-response curves at 3-fold dilution intervals starting at 20 μM to determine IC₅₀ values. Data were analyzed using ActivityBase software and replicates of low (no enzyme, 0.2% DMSO) and high (0.2% DMSO) % controls were averaged and data obtained from test compounds were expressed as a percentage of 100% using the following formula:

％值＝100-(100*((高对照-未知)/(高对照-低对照))% value = 100 - (100 * ((high control - unknown) / (high control - low control))

将％数据拟合至非线性回归方程式(log抑制剂相对于应答-变量斜率4-参数)以得到IC₅₀值。The % data were fit to a non-linear regression equation (log inhibitor vs. response - variable slope 4-parameter) to give_IC50 values.

多种试验化合物的IC₅₀值显示在表1中。The_IC50 values of various test compounds are shown in Table 1.

活化DNA序列：Activating DNA sequence:

双链体序列Duplex sequence

PARP1探针替代均相时间分辨荧光测定(HTRF测定)PARP1 probe replacement homogeneous time-resolved fluorescence assay (HTRF assay)

将10nM全长N端FLAG-标记的PARP1与2nM抗-FLAG Tb-穴状化合物抗体和PARP1/2Cy5荧光染料-标记的结合探针(10倍探针K_d＝270nM)一起在20mM HEPES(pH 7.5)、100mMNaCl、2mM DTT、0.1％ BSA(w/v)、0.02％吐温(v/v)测定缓冲液中在室温温育40min。Cy5-标记的结合探针如下所示，并描述在Papeo,G.等人.J.Biomol.Screen.2014；19:1212-1219中。然后将6μl该反应混合物转移至黑色非结合表面384-孔平板的每个孔中，并然后使用pintool技术添加35nl的在DMSO中的化合物溶液。在室温温育1h以后，在Pherastar FS(Ex337nm,Em620 nm,em665 nm；积分开始60μs；积分时间400μs)上使用HTRF模块测量荧光。10 nM full-length N-terminally FLAG-tagged PARP1 was incubated with 2 nM anti-FLAG Tb-cryptate antibody and PARP1/2 Cy5 fluorescent dye-labeled binding probe (10x probe_Kd = 270 nM) in 20 mM HEPES (pH 7.5), 100 mM NaCl, 2 mM DTT, 0.1% BSA (w/v), 0.02% Tween (v/v) assay buffer at room temperature for 40 min. The Cy5-labeled binding probe is shown below and described in Papeo, G. et al. J. Biomol. Screen. 2014; 19: 1212-1219. 6 μl of this reaction mixture was then transferred to each well of a black non-binding surface 384-well plate and then 35 nl of compound solution in DMSO was added using pintool technology. After incubation at room temperature for 1 h, fluorescence was measured using a HTRF module on a Pherastar FS (Ex 337 nm, Em 620 nm, em 665 nm; integration start 60 μs; integration time 400 μs).

通常在12-点浓度-应答曲线中以3倍稀释间隔从58.5μM开始试验化合物以确定IC₅₀值。使用ActivityBase软件分析数据，并对低(不含酶但含探针和Tb-穴状化合物抗体，0.6％ DMSO)和高(0.6％DMSO)％对照的重复值取平均值，并使用以下公式将从试验化合物获得的数据表示为100％的百分比：Compounds were typically tested in 12-point concentration-response curves at 3-fold dilution intervals starting at 58.5 μM to determine IC₅₀ values. Data were analyzed using ActivityBase software and replicates of low (no enzyme but with probe and Tb-cryptate antibody, 0.6% DMSO) and high (0.6% DMSO) % controls were averaged and data obtained from test compounds were expressed as a percentage of 100% using the following formula:

％活性＝100*(值-低对照)/(高对照-低对照)% Activity = 100*(value - low control)/(high control - low control)

将％活性数据拟合至非线性回归方程式以得到IC50值The % activity data were fitted to a nonlinear regression equation to obtain IC50 values

使用Cheng-Prussoff公式计算K_d值：The_Kd value was calculated using the Cheng-Prussoff formula:

IC₅₀＝(1+([探针浓度]/[Km_探针]))*K_dIC50 = (1 + ([probe concentration] / [_Kmprobe ])) *_Kd

因此，K_d＝IC₅₀/(1+[[探针浓度]/[Km_探针]))；使用在10x K_m的探针，这相当于K_d＝IC₅₀/11Therefore,_Kd =_IC50 /(1 + [[probe concentration]/[_Kmprobe ])); using the probe at 10 x_Km , this is equivalent to_Kd =_IC50 /11

PARP2探针替代均相时间分辨荧光测定(HTRF测定)PARP2 probe replacement homogeneous time-resolved fluorescence assay (HTRF assay)

在与PARP1相同的条件下进行该测定，但使用N端FLAG-标记的PARP2(氨基酸1-583)代替PARP1，并且在10倍探针K_d＝540nM下使用PARP1/2结合探针。与PARP1相同地进行数据分析。The assay was performed under the same conditions as for PARP1, but N-terminally FLAG-tagged PARP2 (amino acids 1-583) was used instead of PARP1, and the PARP1/2 binding probe was used at 10-fold probe_Kd = 540 nM. Data analysis was performed identically to PARP1.

Cy5探针结构：Cy5 probe structure:

NanoBRET细胞靶标占据测定NanoBRET Cellular Target Occupancy Assay

采用NanoBRET测定来证明在PARP1和PARP2处的细胞靶标参与度和选择性。这些测定是基于Nano-luc-标记的蛋白(例如PARP1或PARP2)与高亲和力NAD⁺竞争性结合探针上的荧光基团之间的生物发光共振能量转移(BRET)。这样的细胞探针替代测定可以用于测量在PARP1和2处的抑制剂亲和力和选择性比率。NanoBRET assays were employed to demonstrate cellular target engagement and selectivity at PARP1 and PARP2. These assays are based on bioluminescence resonance energy transfer (BRET) between Nano-luc-tagged proteins (e.g., PARP1 or PARP2) and fluorophores on high-affinity NAD⁺ competitive binding probes. Such cellular probe surrogate assays can be used to measure inhibitor affinity and selectivity ratios at PARP1 and 2.

将用融合体或融合构建体(Promega)瞬时转染的冷冻HEK293细胞解冻并作为悬浮液分配到每个384-孔微量培养板中，密度为每个孔1750个细胞。然后将NanoBRET^TM TE PARP Tracer-01加入，对于PARP1和PARP2测定的终浓度分别为11和2nM。在12-点浓度-应答曲线中以3倍稀释间隔从25μM开始添加化合物，并将平板在37℃温育2小时。然后根据制造商的说明书添加NanoBRET^TM底物和细胞外抑制剂，然后使用NanoBRET模块(LUM 610-LP 450-80)和PHERAstar FS或FSX读数器测量BRET比率。使用Cheng-Prussoff公式计算Kd值：Will use Fusion or Frozen HEK293 cells transiently transfected with the fusion construct (Promega) were thawed and dispensed as a suspension into each 384-well microplate at a density of 1750 cells per well. NanoBRET^™ TE PARP Tracer-01 was then added at final concentrations of 11 and 2 nM for PARP1 and PARP2 assays, respectively. Compounds were added starting at 25 μM in a 12-point concentration-response curve at 3-fold dilution intervals, and the plates were incubated at 37°C for 2 hours. NanoBRET^™ was then added according to the manufacturer's instructions. Substrate and extracellular The inhibitor was then added and the BRET ratio was measured using a NanoBRET module (LUM 610-LP 450-80) and a PHERAstar FS or FSX reader. The Kd value was calculated using the Cheng-Prussoff formula:

IC50＝(1+([示踪剂浓度]/[Km_示踪剂]))*KdIC50 = (1 + ([tracer concentration] / [_Kmtracer ])) * Kd

表1显示了各种试验化合物的分档(Binned)效能、亲和力和选择性数据，其中使用了DELFIA和探针替代HTRF测定。表2显示了试验化合物子集的分档(Binned)效能、亲和力和选择性数据，其中使用了NanoBRET测定。Table 1 shows the binned potency, affinity and selectivity data for various test compounds using DELFIA and probe displacement HTRF assays. Table 2 shows the binned potency, affinity and selectivity data for a subset of test compounds using the NanoBRET assay.

表1选定化合物的Parp 1/2测定的结果(DELFIA和探针替代HTRF)Table 1 Results of Parp 1/2 assays for selected compounds (DELFIA and probe replacement HTRF)

表2Table 2

选定化合物的Parp 1/2测定的结果(NanoBRET)Results of Parp 1/2 assay for selected compounds (NanoBRET)

符号说明Explanation of symbols

DELFIA、探针替代HTRF和NanoBRET测定分类：DELFIA, Probe Replacement HTRF and NanoBRET Assay Categories:

-指示高于10μM的IC₅₀或K_d值- Indicates_IC50 or_Kd values above 10 μM

+指示高于1μM直到10μM的IC₅₀或K_d值+ indicates_IC50 or_Kd values above 1 μM up to 10 μM

++指示高于100nM直到1μM的IC₅₀或K_d值++ indicates_IC50 or_Kd values above 100 nM up to 1 μM

+++指示高于10nM直到100nM的IC₅₀或K_d值+++ indicates_IC50 or_Kd values above 10 nM up to 100 nM

++++指示10nM或更低的IC₅₀或K_d值++++ indicates_IC50 or_Kd values of 10 nM or lower

选择性分类：Selective classification:

-指示小于10的值- indicates a value less than 10

+指示10至小于50的值+ indicates a value from 10 to less than 50

++指示50至小于100的值++ indicates a value from 50 to less than 100

+++指示至少100的值+++ indicates a value of at least 100

选择性值与PARP1相对于PARP2的选择性偏好有关。它们是从PARP1和PARP2抑制的K_d值比率K_d(PARP2)/K_d(PARP1)计算得出。Selectivity values are related to the selective preference of PARP1 over PARP2. They are calculated from the ratio of_Kd values for PARP1 and PARP2 inhibition,_Kd (PARP2)/_Kd (PARP1).

Claims (69)

Translated fromChinese

1.用于用在药物中的PARP1抑制剂化合物，所述化合物包含以下结构：1. A PARP1 inhibitor compound for use in medicine, the compound comprising the following structure:其中R¹选自H和被取代的或未被取代的有机基团；R²可以存在或不存在并且独立地选自H和被取代的或未被取代的有机基团；R¹和R²可以一起形成环；R³独立地选自H和被取代的或未被取代的有机基团；R⁶可以存在或不存在并且独立地选自H和被取代的或未被取代的有机基团；Z¹和Z²独立地选自C和N；且L包含具有以下结构的基团：wherein R¹ is selected from H and a substituted or unsubstituted organic group; R² may be present or absent and is independently selected from H and a substituted or unsubstituted organic group; R¹ and R² may form a ring together; R³ is independently selected from H and a substituted or unsubstituted organic group; R⁶ may be present or absent and is independently selected from H and a substituted or unsubstituted organic group; Z¹ and Z² are independently selected from C and N; and L comprises a group having the following structure:其中，n是独立地选自0、1、2、3、4、5和6的数字；m是独立地选自0、1、2、3、4、5和6的数字；且m+n是选自2、3、4、5和6的数字；优选地其中n和m都至少是1；wherein n is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; m is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and m+n is a number selected from 2, 3, 4, 5 and 6; preferably wherein both n and m are at least 1;其中，r是独立地选自0、1、2、3、4和5的数字；s是独立地选自0、1、2、3、4和5的数字；且r+s是选自1、2、3、4和5的数字；优选地其中r和s都至少是1；wherein r is a number independently selected from 0, 1, 2, 3, 4 and 5; s is a number independently selected from 0, 1, 2, 3, 4 and 5; and r+s is a number selected from 1, 2, 3, 4 and 5; preferably wherein both r and s are at least 1;并且其中，每个X¹可以相同或不同并且独立地选自C、N、O和S；每个X³可以相同或不同并且独立地选自C、N、O和S；每个X⁶可以相同或不同并且独立地选自C和N；每个R⁴¹可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；每个R⁴³可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；且R⁴⁴可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；and wherein each X¹ may be the same or different and is independently selected from C, N, O and S; each X³ may be the same or different and is independently selected from C, N, O and S; each X⁶ may be the same or different and is independently selected from C and N; each R⁴¹ may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group; each R⁴³ may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group; and R⁴⁴ may be present or absent and is selected from H and a substituted or unsubstituted organic group;并且其中，虚线指示：环A可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；且独立地环C可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；and wherein the dashed lines indicate: Ring A may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic; and independently Ring C may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic;并且其中，R⁵选自H和被取代的或未被取代的有机基团；And wherein, R⁵ is selected from H and substituted or unsubstituted organic groups;并且其中每个Q¹可以相同或不同，并且可以存在或不存在，并且包含独立地选自以下结构的基团：And wherein each Q¹ may be the same or different, and may be present or absent, and comprises a group independently selected from the following structures:其中t独立地是选自0、1、2、3、4和5的数字；u独立地是选自0、1、2、3、4和5的数字；且t+u是选自0、1、2、3、4、5和6的数字(优选选自0、1、2和3的数字)；每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团；wherein t is independently a number selected from 0, 1, 2, 3, 4 and 5; u is independently a number selected from 0, 1, 2, 3, 4 and 5; and t+u is a number selected from 0, 1, 2, 3, 4, 5 and 6 (preferably a number selected from 0, 1, 2 and 3); each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group;并且其中Q²可以存在或不存在并且是具有以下结构的基团：And wherein^Q2 may be present or absent and is a group having the following structure:其中，p是独立地选自0、1、2、3、4、5和6的数字；q是独立地选自0、1、2、3、4、5和6的数字；且p+q是选自2、3、4、5和6的数字；wherein p is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; q is a number independently selected from 0, 1, 2, 3, 4, 5 and 6; and p+q is a number selected from 2, 3, 4, 5 and 6;并且其中，每个X²可以相同或不同并且独立地选自C、N、O和S；X⁵独立地选自C和N；每个R⁴²可以相同或不同，并且可以存在或不存在，并且选自H和被取代的或未被取代的有机基团；and wherein each X² may be the same or different and is independently selected from C, N, O and S; X⁵ is independently selected from C and N; each R⁴² may be the same or different and may be present or absent and is selected from H and a substituted or unsubstituted organic group;并且其中，虚线指示：环B可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；and wherein the dashed line indicates: Ring B may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic;并且其中Q³可以存在或不存在并且包含独立地选自以下结构的基团：And wherein Q³ may be present or absent and comprises a group independently selected from the following structures:其中v独立地是选自0、1、2、3、4和5的数字；w独立地是选自0、1、2、3、4和5的数字；且v+w是选自0、1、2、3、4、5和6的数字(优选选自0、1和2的数字)。wherein v is independently a number selected from 0, 1, 2, 3, 4 and 5; w is independently a number selected from 0, 1, 2, 3, 4 and 5; and v+w is a number selected from 0, 1, 2, 3, 4, 5 and 6 (preferably a number selected from 0, 1 and 2).2.根据权利要求1所述的化合物，其中Q³不存在或者是独立地选自以下结构的基团：2. The compound according to claim 1, wherein Q³ is absent or is a group independently selected from the following structures:其中每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团。wherein each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group.3.根据任何前述权利要求所述的化合物，其中R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁴⁵各自独立地选自H和选自下述基团的基团：3. A compound according to any preceding claim, wherein R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁴⁵ are each independently selected from H and a group selected from the following groups:-氘；-deuterium;-卤素(诸如-F、-Cl、-Br和-I)；- halogen (such as -F, -Cl, -Br and -I);-腈基团；- nitrile group;-被取代的或未被取代的直链或支链C₁-C₆烷基基团(诸如Me、Et、Pr、i-Pr、n-Bu、i-Bu、t-Bu、戊基和己基)；- substituted or unsubstituted straight or branched C₁ -C₆ alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl);-被取代的或未被取代的直链或支链C₁-C₆烷基-芳基基团(诸如-CH₂Ph、-CH₂(2、3或4)F-Ph、-CH₂(2、3或4)Cl-Ph、-CH₂(2、3或4)Br-Ph、-CH₂(2、3或4)I-Ph、-CH₂CH₂Ph、-CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂CH₂Ph和-CH₂CH₂CH₂CH₂CH₂CH₂Ph)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ alkyl-aryl groups (such as -CH₂ Ph, -CH₂ (2, 3, or 4)F-Ph, -CH₂ (2, 3, or 4)Cl-Ph, -CH₂ (2, 3, or 4)Br-Ph, -CH₂ (2, 3, or 4)I-Ph, -CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH 2 CH₂ CH₂ CH 2 Ph, -CH₂ CH₂ CH₂ CH₂ Ph, and -CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ Ph);-被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(诸如-CH₂F、-CH₂Cl、-CH₂Br、-CH₂I、-CHF₂、-CF₃、-CCl₃-CBr₃、-CI₃、-CH₂CH₂F、-CH₂CF₃、-CH₂CCl₃、-CH₂CBr₃和-CH₂CI₃)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ haloalkyl groups (such as -CH₂ F, -CH₂ Cl, -CH₂ Br, -CH₂ I, -CHF₂ , -CF₃ , -CCl₃ -CBr₃ , -CI₃ , -CH₂ CH₂ F, -CH₂ CF₃ , -CH₂ CCl₃ , -CH₂ CBr₃ and -CH₂ CI₃ );--NH₂或被取代的或未被取代的直链或支链伯、仲或叔C₁-C₆胺基团(诸如-NMeH、-NMe₂、-NEtH、-NEtMe、-NEt₂、-NPrH、-NPrMe、-NPrEt、-NPr₂、-NBuH、-NBuMe、-NBuEt、-CH₂-NH₂、-CH₂-NMeH、-CH₂-NMe₂、-CH₂-NEtH、-CH₂-NEtMe、-CH₂-NEt₂、-CH₂-NPrH、-CH₂-NPrMe和-CH₂-NPrEt)；_-NH2 or a substituted or unsubstituted linear or branched primary, secondary or tertiary_C1 -_C6 amine group (such as -NMeH,_-NMe2 , -NEtH, -NEtMe,_-NEt2 , -NPrH, -NPrMe, -NPrEt, -NPr2, -NBuH, -NBuMe, -NBuEt,_-CH2-NH2 , -CH2_-NMeH ,_-CH2 -NMe2, -CH2_- NEtH,_-CH2- NEtMe,_-CH2 -_NEt2 ,_-CH2- NPrH, -CH2_- NPrMe and_-CH2- NPrEt);-被取代的或未被取代的氨基-芳基基团(诸如-NH-Ph、-NH-(2、3或4)F-Ph、-NH-(2、3或4)Cl-Ph、-NH-(2、3或4)Br-Ph、-NH-(2、3或4)I-Ph、-NH-(2、3或4)Me-Ph、-NH-(2、3或4)Et-Ph、-NH-(2、3或4)Pr-Ph、-NH-(2、3或4)Bu-Ph、NH-(2、3或4)OMe-Ph、-NH-(2、3或4)OEt-Ph、-NH-(2、3或4)OPr-Ph、-NH-(2、3或4)OBu-Ph、-NH-2,(3、4、5或6)F₂-Ph、-NH-2,(3、4、5或6)Cl₂-Ph、-NH-2,(3、4、5或6)Br₂-Ph、-NH-2,(3、4、5或6)I₂-Ph、-NH-2,(3、4、5或6)Me₂-Ph、-NH-2,(3、4、5或6)Et₂-Ph、-NH-2,(3,4,5,或6)Pr₂-Ph、-NH-2,(3、4、5或6)Bu₂-Ph，-substituted or unsubstituted amino-aryl groups (such as -NH-Ph, -NH-(2, 3, or 4)F-Ph, -NH-(2, 3, or 4)Cl-Ph, -NH-(2, 3, or 4)Br-Ph, -NH-(2, 3, or 4)I-Ph, -NH-(2, 3, or 4)Me-Ph, -NH-(2, 3, or 4)Et-Ph, -NH-(2, 3, or 4)Pr-Ph, -NH-(2, 3, or 4)Bu-Ph, NH-(2, 3, or 4)OMe-Ph, -NH-(2, 3, or 4)OEt-Ph, -NH-(2, 3, or 4)OPr-Ph, -NH-(2, 3, or 4)OBu-Ph, -NH-2,(3, 4, 5, or 6)_F2 -Ph, -NH-2,(3, 4, 5, or₆ )Cl2 -Ph, -NH-2, (3, 4, 5, or 6)_Br2- Ph, -NH-2, (3, 4, 5, or 6)_I2 -Ph, -NH-2, (3, 4, 5, or 6)_Me2- Ph, -NH-2, (3, 4, 5, or 6)Et2-Ph, -NH-2, (3, 4, 5, or 6)Pr2_- Ph, -NH-2, (3, 4, 5, or 6)_Bu2 -Ph,-被取代的或未被取代的环状的胺或酰氨基基团(诸如吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、吗啉-2-基、吗啉-3-基、吗啉-4-基、2-酮-吡咯烷基、3-酮-吡咯烷基、2-酮-哌啶基、3-酮-哌啶基和4-酮-哌啶基)；- substituted or unsubstituted cyclic amine or amido groups (such as pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);-被取代的或未被取代的环状C₃-C₈烷基基团(诸如环丙基、环丁基、环戊基、环己基、环庚基和环辛基)；- substituted or unsubstituted cyclic C₃ -C₈ alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl);--OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团(诸如-CH₂OH、-CH₂CH₂OH、-CH(CH₃)CH₂OH、-C(CH₃)₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂CH₂OH、-CH(CH₃)CH₂CH₂OH、-CH(CH₃)CH(CH₃)OH、-CH(CH₂CH₃)CH₂OH、-C(CH₃)₂CH₂OH、-CH₂CH₂CH₂CH₂CH₂OH和-CH₂CH₂CH₂CH₂CH₂CH₂OH)；- an OH group or_a substituted or unsubstituted linear or branched_C1 -_C6 alcohol group (such as_-CH2OH , -CH2CH2OH,_-CH (_CH3 )_CH2OH , -C(CH3)2OH, -CH2CH2CH2OH_, -CH2CH2CH2CH2OH,_{-CH(CH3)CH2CH2OH} , -CH_{(CH3)CH(CH3)OH,-CH(CH2CH3} )_{CH2OH,-C(CH3)2CH2OH,-CH2CH2CH2CH2CH2OH,and-CH2CH2CH2CH2CH2CH2OH} )_;-被取代的或未被取代的直链或支链C₁-C₆羧酸基团(诸如-COOH、-CH₂COOH、-CH₂CH₂COOH、-CH₂CH₂CH₂COOH、-CH₂CH₂CH₂CH₂COOH和-CH₂CH₂CH₂CH₂CH₂COOH)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ carboxylic acid groups (such as -COOH, -CH₂ COOH, -CH₂ CH₂ COOH, -CH₂ CH₂ CH₂ COOH, -CH₂ CH₂ CH₂ CH₂ COOH, and -CH₂ CH₂ CH₂ CH₂ CH₂ COOH);-被取代的或未被取代的直链或支链羰基基团(诸如-(CO)Me、-(CO)Et、-(CO)Pr、-(CO)iPr、-(CO)nBu、-(CO)iBu、-(CO)tBu、-(CO)Ph、-(CO)CH₂Ph、-(CO)CH₂OH、-(CO)CH₂OCH₃、-(CO)CH₂NH₂、-(CO)CH₂NHMe、-(CO)CH₂NMe₂、-(CO)-环丙基、-(CO)-1,3-环氧丙烷-2-基；-(CO)NH₂、-(CO)NHMe、-(CO)NMe₂、-(CO)NHEt、-(CO)NEt₂、-(CO)-吡咯烷-N-基、-(CO)-吗啉-N-基、-(CO)-哌嗪-N-基、-(CO)-N-甲基-哌嗪-N-基、-(CO)NHCH₂CH₂OH、-(CO)NHCH₂CH₂OMe、-(CO)NHCH₂CH₂NH₂、-(CO)NHCH₂CH₂NHMe和-(CO)NHCH₂CH₂NMe₂；- substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)iPr, -(CO)_nBu , -(CO)iBu, -(CO)tBu, -(CO)Ph_, -(CO)_CH2Ph , -(CO)_CH2OH , -(CO)_CH2OCH3 , -(CO)_CH2NH2 , -(CO)_CH2NHMe ,_- (CO)_CH2NMe2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropane-2-yl; -(CO)_NH2 , -(CO)_NHMe , -(CO)NMe2, -(CO)NHEt, -(CO)_NEt2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH₂ CH₂ OH, -(CO)NHCH₂ CH₂ OMe, -(CO)NHCH₂ CH₂ NH₂ , -(CO)NHCH₂ CH₂ NHMe, and -(CO)NHCH₂ CH₂ NMe₂ ;-被取代的或未被取代的直链或支链C₁-C₆羧酸酯基团(诸如-COOMe、-COOEt、-COOPr、-COO-i-Pr、-COO-n-Bu、-COO-i-Bu、-COO-t-Bu、-CH₂COOMe、-CH₂CH₂COOMe、-CH₂CH₂CH₂COOMe和-CH₂CH₂CH₂CH₂COOMe)；- substituted or unsubstituted linear or branched C₁ -C₆ carboxylate groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH₂ COOMe, -CH₂ CH₂ COOMe_, -CH₂ CH₂ CH₂ COOMe, and -CH₂ CH 2 CH₂ CH₂ COOMe);-被取代的或未被取代的直链或支链C₁-C₆酰胺基团(诸如-CO-NH₂、-CO-NMeH、-CO-NMe₂、-CO-NEtH、-CO-NEtMe、-CO-NEt₂、-CO-NPrH、-CO-NPrMe和-CO-NPrEt)；- substituted or unsubstituted straight or branched C₁ -C₆ amide groups (such as -CO-NH₂ , -CO-NMeH, -CO-NMe₂ , -CO-NEtH, -CO-NEtMe, -CO-NEt₂ , -CO-NPrH, -CO-NPrMe and -CO-NPrEt);-被取代的或未被取代的直链或支链C₁-C₇氨基羰基基团(诸如-NH-CO-Me、-NH-CO-Et、-NH-CO-Pr、-NH-CO-Bu、-NH-CO-戊基、-NH-CO-己基、-NH-CO-Ph、-NMe-CO-Me、-NMe-CO-Et、-NMe-CO-Pr、-NMe-CO-Bu、-NMe-CO-戊基、-NMe-CO-己基、-NMe-CO-Ph；- substituted or unsubstituted straight-chain or branched C₁ -C₇ aminocarbonyl groups (such as -NH-CO-Me, -NH-CO-Et, -NH-CO-Pr, -NH-CO-Bu, -NH-CO-pentyl, -NH-CO-hexyl, -NH-CO-Ph, -NMe-CO-Me, -NMe-CO-Et, -NMe-CO-Pr, -NMe-CO-Bu, -NMe-CO-pentyl, -NMe-CO-hexyl, -NMe-CO-Ph;-被取代的或未被取代的直链或支链C₁-C₇烷氧基或芳氧基基团(诸如-OMe、-OEt、-OPr、-O-i-Pr、-O-n-Bu、-O-i-Bu、-O-t-Bu、-O-戊基、-O-己基、-OCH₂F、-OCHF₂、-OCF₃、-OCH₂Cl、-OCHCl₂、-OCCl₃、-O-Ph、-O-CH₂-Ph、-O-CH₂-(2、3或4)-F-Ph、-O-CH₂-(2、3或4)-Cl-Ph、-CH₂OMe、-CH₂OEt、-CH₂OPr、-CH₂OBu、-CH₂CH₂OMe、-CH₂CH₂CH₂OMe、-CH₂CH₂CH₂CH₂OMe和-CH₂CH₂CH₂CH₂CH₂OMe)；- substituted or unsubstituted straight or branched C₁ -C₇ alkoxy or aryloxy groups (such as -OMe, -OEt, -OPr, -Oi-Pr, -On-Bu, -Oi-Bu, -Ot-Bu, -O-pentyl, -O-hexyl, -OCH₂ F, -OCHF₂ , -OCF₃ , -OCH₂ Cl, -OCHCl₂ , -OCCl₃ , -O-Ph, -O-CH₂ -Ph, -O-CH₂ -(2, 3 or 4)-F-Ph, -O-CH₂ -(2, 3 or 4)-Cl-Ph, -CH₂ OMe, -CH₂ OEt, -CH₂ OPr, -CH₂ OBu, -CH₂ CH₂ OMe, -CH₂ CH₂ CH₂ OMe, -CH₂ CH_2CH2 OMe and -CH₂ CH₂ CH₂ CH₂ CH₂ OMe);-被取代的或未被取代的直链或支链氨基烷氧基基团(诸如-OCH₂NH₂、-OCH₂NHMe、-OCH₂NMe₂、-OCH₂NHEt、-OCH₂NEt₂、-OCH₂CH₂NH₂、-OCH₂CH₂NHMe、-OCH₂CH₂NMe₂、-OCH₂CH₂NHEt和-OCH₂CH₂NEt₂；- substituted or unsubstituted straight-_chain or branched aminoalkoxy groups₍ such_as-OCH2NH2 ,_{-OCH2NHMe,-OCH2NMe2,-OCH2NHHEt,-OCH2NEt2,-OCH2CH2NH2,-OCH2CH2NHMe} ,_{-OCH2CH2NMe2,-OCH2CH2NHHEtand-OCH2CH2NEt2;}-被取代的或未被取代的磺酰基基团(诸如-SO₂Me、-SO₂Et、-SO₂Pr、-SO₂iPr、-SO₂Ph、-SO₂-(2、3或4)-F-Ph、-SO₂-环丙基、-SO₂CH₂CH₂OCH₃)、-SO₂NH₂、-SO₂NHMe、-SO₂NMe₂、-SO₂NHEt、-SO₂NEt₂、-SO2-吡咯烷-N-基、-SO₂-吗啉-N-基、-SO₂NHCH₂OMe和-SO₂NHCH₂CH₂OMe；- substituted or unsubstituted sulfonyl groups (such as_-SO2Me ,_{-SO2Et, -SO2Pr} ,_-SO2iPr ,_-SO2Ph ,_-SO2- (2,₃ or₄ )-F-Ph,_-SO2- cyclopropyl,_{-SO2CH2CH2OCH3} ), -SO2NH2, -SO2NHMe,_-SO2NMe2, -SO2NHEt,_{-SO2NEt2,-SO2-} pyrrolidin-N-_yl ,_-SO2- morpholin-_N-yl ,_-SO2NHCH2OMe and_{-SO2NHCH2CH2OMe;}-被取代的或未被取代的氨基磺酰基基团(诸如-NHSO₂Me、-NHSO₂Et、-NHSO₂Pr、-NHSO₂iPr、-NHSO₂Ph、-NHSO₂-(2、3或4)-F-Ph、-NHSO₂-环丙基、-NHSO₂CH₂CH₂OCH₃)；- substituted or unsubstituted aminosulfonyl groups (such as_-NHSO2Me , -NHSO2Et,_-NHSO2Pr ,_-NHSO2iPr ,_-NHSO2Ph ,_-NHSO2- (₂ , 3 or 4)-F-Ph,_{-NHSO2-cyclopropyl,-NHSO2CH2CH2OCH3} );-被取代的或未被取代的芳族基团(诸如Ph-、2-F-Ph-、3-F-Ph-、4-F-Ph-、2-Cl-Ph-、3-Cl-Ph-、4-Cl-Ph-、2-Br-Ph-、3-Br-Ph-、4-Br-Ph-、2-I-Ph-、3-I-Ph、4-I-Ph-、2,(3、4、5或6)-F₂-Ph-、2,(3、4、5或6)-Cl₂-Ph-、2,(3、4、5或6)-Br₂-Ph-、2,(3、4、5或6)-I₂-Ph-、2,(3、4、5或6)-Me₂-Ph-、2,(3、4、5或6)-Et₂-Ph-、2,(3、4、5或6)-Pr₂-Ph-、2,(3、4、5或6)-Bu₂-Ph-、2,(3、4、5或6)-(CN)₂-Ph-、2,(3、4、5或6)-(NO₂)₂-Ph-、2,(3、4、5或6)-(NH₂)₂-Ph-、2,(3、4、5或6)-(MeO)₂-Ph-、2,(3、4、5或6)-(CF₃)₂-Ph-、3,(4或5)-F₂-Ph-、3,(4或5)-Cl₂-Ph-、3,(4或5)-Br₂-Ph-、3,(4或5)-I₂-Ph-、3,(4或5)-Me₂-Ph-、3,(4或5)-Et₂-Ph-、3,(4或5)-Pr₂-Ph-、3,(4或5)-Bu₂-Ph-、3,(4或5)-(CN)₂-Ph-、3,(4或5)-(NO₂)₂-Ph-、3,(4或5)-(NH₂)₂-Ph-、3,(4或5)-(MeO)₂-Ph-、3,(4或5)-(CF₃)₂-Ph-、2-Me-Ph-、3-Me-Ph-、4-Me-Ph-、2-Et-Ph-、3-Et-Ph-、4-Et-Ph-、2-Pr-Ph-、3-Pr-Ph-、4-Pr-Ph-、2-Bu-Ph-、3-Bu-Ph-、4-Bu-Ph-、2-(CN)-Ph-、3-(CN)-Ph-、4-(CN)-Ph-、2-(NO₂)-Ph-、3-(NO₂)-Ph-、4-(NO₂)-Ph-、2-(NH₂)-Ph-、3-(NH₂)-Ph-、4-(NH₂)-Ph-、2-MeO-Ph-、3-MeO-Ph-、4-MeO-Ph-、2-(NH₂-CO)-Ph-、3-(NH₂-CO)-Ph-、4-(NH₂-CO)-Ph-、2-CF₃-Ph-、3-CF₃-Ph-、4-CF₃-Ph-、2-CF₃O-Ph-、3-CF₃O-Ph-和4-CF₃O-Ph-)；-substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3, 4, 5, or 6)-F₂ -Ph-, 2,(3, 4, 5, or 6)-Cl₂ -Ph-, 2,(3, 4, 5, or 6)-Br₂ -Ph-, 2,(3, 4, 5, or 6)-I₂ -Ph-, 2,(3, 4, 5, or 6)-Me₂ -Ph-, 2,(3, 4, 5, or 6)-Et₂ -Ph-, 2,(3,4,5 or 6)-Pr₂ -Ph-, 2,(3,4,5 or 6)-Bu₂ -Ph-, 2,(3,4,5 or 6)-(CN)₂ -Ph-, 2,(3,4,5 or 6)-(NO₂ )₂ -Ph-, 2,(3,4,5 or 6)-(NH₂ )₂ -Ph-, 2,(3,4,5 or 6)-(MeO)₂ -Ph-, 2,(3,4,5 or 6)-(CF₃ )₂ -Ph-, 3,(4 or 5)-F₂ -Ph-, 3,(4 or 5)-Cl₂ -Ph-, 3,(4 or 5)-Br₂ -Ph-, 3,(4 or 5)-I₂ -Ph-, 3,(4 or 5)-Me₂ -Ph-, 3,(4 or 5)-Et₂ -Ph-, 3,(4 or 5)-Pr₂ -Ph-, 3,(4 or 5)-Bu₂ -Ph-, 3,(4 or 5)-(CN)₂ -Ph-, 3,(4 or 5)-(NO₂ )₂ -Ph-, 3,(4 or 5)-(NH₂ )₂ -Ph-, 3,(4 or 5)-(MeO)₂ -Ph-, 3,(4 or 5)-(CF₃ )₂ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO₂ )-Ph-, 3-(NO₂ )-Ph-, 4-(NO₂ )-Ph-, 2-(NH₂ )-Ph-, 3-(NH₂ )-Ph-, 4-(NH₂ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH₂ -CO)-Ph-, 3-(NH₂ -CO)-Ph-, 4-(NH₂ -CO)-Ph-, 2-CF₃ -Ph-, 3-CF₃ -Ph-, 4-CF₃ -Ph-, 2-CF₃ O-Ph-, 3-CF₃ O-Ph-, and 4-CF₃ O-Ph-);-饱和的或不饱和的被取代的或未被取代的杂环基团，包括芳族杂环基团和/或非芳族杂环基团(诸如吡咯-1-基、吡咯-2-基、吡咯-3-基、吡唑-1-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、咪唑-1-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、1,2,3-三唑-1-基、1,2,3-三唑-4-基、1,2,3-三唑-5-基、1,2,4-三唑-1-基、1,2,4-三唑-3-基、1,2,4-三唑-5-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、嘧啶-6-基、吡嗪-2-基、吡咯烷-1-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2-氮杂哌啶-1-基、2-氮杂哌啶-3-基、2-氮杂哌啶-4-基、3-氮杂哌啶-1-基、3-氮杂哌啶-2-基、3-氮杂哌啶-4-基、3-氮杂哌啶-5-基、哌嗪-1-基、哌嗪-2-基、呋喃-2-基、呋喃-3-基、吡喃-2-基、吡喃-3-基、吡喃-4-基、2-氮杂吡喃-2-基、2-氮杂吡喃-3-基、2-氮杂吡喃-4-基、2-氮杂吡喃-5-基、2-氮杂吡喃-6-基、3-氮杂吡喃-2-基、3-氮杂吡喃-4-基、3-氮杂吡喃-5-基、3-氮杂吡喃-6-基、4-氮杂吡喃-2-基、4-氮杂吡喃-3-基、4-氮杂吡喃-4-基、4-氮杂吡喃-5-基、4-氮杂吡喃-6-基、氧杂环丁烷-2-基、氧杂环丁烷-3-基、四氢呋喃-2-基、四氢呋喃-3-基、2-氮杂-四氢呋喃-2-基、2-氮杂-四氢呋喃-3-基、2-氮杂-四氢呋喃-4-基、2-氮杂-四氢呋喃-5-基、3-氮杂-四氢呋喃-2-基、3-氮杂-四氢呋喃-3-基、3-氮杂-四氢呋喃-4-基、3-氮杂-四氢呋喃-5-基、四氢吡喃-2-基、四氢吡喃-3-基、四氢吡喃-4-基、2-氮杂-四氢吡喃-2-基、2-氮杂-四氢吡喃-3-基、2-氮杂-四氢吡喃-4-基、2-氮杂-四氢吡喃-5-基、2-氮杂-四氢吡喃-6-基、3-氮杂-四氢吡喃-2-基、3-氮杂-四氢吡喃-3-基、3-氮杂-四氢吡喃-4-基、3-氮杂-四氢吡喃-5-基、3-氮杂-四氢吡喃-6-基、吗啉-2-基、吗啉-3-基、吗啉-4-基、噻吩-2-基、噻吩-3-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、噻喃-2-基、噻喃-3-基、噻喃-4-基、2-氮杂噻喃-2-基、2-氮杂噻喃-3-基、2-氮杂噻喃-4-基、2-氮杂噻喃-5-基、2-氮杂噻喃-6-基、3-氮杂噻喃-2-基、3-氮杂噻喃-4-基、3-氮杂噻喃-5-基、3-氮杂噻喃-6-基、4-氮杂噻喃-2-基、4-氮杂噻喃-3-基、4-氮杂噻喃-4-基、4-氮杂噻喃-5-基、4-氮杂噻喃-6-基、硫杂环戊烷-2-基、硫杂环戊烷-3-基、硫杂环己烷-2-基、硫杂环己烷-3-基、硫杂环己烷-4-基、噁唑-2-基、噁唑-4-基、噁唑-5-基、异噁唑-3-基、异噁唑-4-基、异噁唑-5-基、呋咱-3-基、(1,3,4-噁二唑)-2-基、(1,3,4-噁二唑)-5-基、(1,2,4-噁二唑)-3-基、(1,2,4-噁二唑)-5-基；和四唑-1-基、四唑-2-基、四唑-5-基)；- saturated or unsaturated substituted or unsubstituted heterocyclic groups, including aromatic heterocyclic groups and/or non-aromatic heterocyclic groups (such as pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol- 1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-1-yl, 2-azapiperidin- 3-yl, 2-azapiperidin-4-yl, 3-azapiperidin-1-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-1-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-2-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran- 2-yl, 3-azapyran-4-yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-4-yl, 4-azapyran-5-yl, 4-azepan-6-yl, oxetan-2-yl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-2-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl , 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3-aza-tetrahydrofuran-3-yl, 3-aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-2-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3- aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-3-yl, 3-aza-tetrahydropyran-4-yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2- Azathiopyran-2-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-4-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolane-2-yl, thiolane-3-yl, yl, thiin-2-yl, thiin-3-yl, thiin-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl);-在两个R基团连接至同一个原子的情况下，它们可以一起形成与该原子双键键合的基团(诸如羰基基团(＝O)或烯烃基团(＝C(R’)₂)，其中每个R’基团相同或不同，并且是H或有机基团，优选H或直链或支链C₁-C₆烷基基团)；- in case two R groups are attached to the same atom, they may together form a group doubly bonded to that atom (such as a carbonyl group (═O) or an olefin group (═C(R′)₂ ), wherein each R′ group is identical or different and is H or an organic group, preferably H or a linear or branched C₁ -C₆ alkyl group);-其中，连接至不同原子的一对R⁴¹基团可以与环A原子一起形成环，和/或连接至不同原子的一对R⁴²基团可以与环B原子一起形成环，任选地其中一对R⁴¹基团和/或一对R⁴²基团中的每一个独立地包含(X⁷)_1或2，其中每个X⁷可以相同或不同并且独立地选自C、N、O和S；并且其中每个X⁷独立地是未被取代的或(i)当X⁷是C时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团、卤素(诸如F)或羟基的有机基团取代；且(ii)当X⁷是N时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团或C₁-C₆酰胺基团的有机基团取代；并且- wherein a pair of R⁴¹ groups attached to different atoms may form a ring together with the ring A atom, and/or a pair of R⁴² groups attached to different atoms may form a ring together with the ring B atom, optionally wherein each of a pair of R⁴¹ groups and/or a pair of R⁴² groups independently comprises (X⁷ )_{1 or 2} , wherein each X⁷ may be the same or different and is independently selected from C, N, O and S; and wherein each X⁷ is independently unsubstituted or (i) when X⁷ is C, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group, a halogen (such as F) or a hydroxyl group; and (ii) when X⁷ is N, is independently substituted with H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group or a C₁ -C₆ amide group; and-其中基团R⁵和R⁴⁴可以与它们所连接的环C的原子X⁶和X³一起形成环，任选地其中R⁵和R⁴⁴基团一起包含(X⁸)_3、4或5，其中每个X⁸可以相同或不同并且独立地选自C、N、O和S；且其中每个X⁸独立地是未被取代的或(i)当X⁸是C时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团、卤素(诸如F)或羟基的有机基团取代；且(ii)当X⁸是N时，独立地被H或选自C₁-C₆烷基基团、C₁-C₆卤代烷基基团或C₁-C₆酰胺基团的有机基团取代。- wherein the groups R⁵ and R⁴⁴ may form a ring together with the atoms X⁶ and X³ of the ring C to which they are attached, optionally wherein the R⁵ and R⁴⁴ groups together comprise (X⁸ )_{3, 4 or 5} , wherein each X⁸ may be identical or different and is independently selected from C, N, O and S; and wherein each X⁸ is independently unsubstituted or (i) when X⁸ is C, is independently substituted by H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group, a halogen (such as F) or a hydroxyl group; and (ii) when X⁸ is N, is independently substituted by H or an organic group selected from a C₁ -C₆ alkyl group, a C₁ -C₆ haloalkyl group or a C₁ -C₆ amide group.4.根据权利要求3所述的化合物，其中R⁴¹、R⁴²、R⁴³和R⁴⁴各自独立地选自H、氘、卤素(诸如-F、-Cl、-Br和-I，优选F或Cl)、腈基团、被取代的或未被取代的C₁-C₆烷基基团、被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(优选CF₃或CHF₂)、环丙基基团、-OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团、被取代的或未被取代的直链或支链C₁-C₇氨基羰基基团(诸如-NH-CO-Me)、-NH₂基团或被取代的或未被取代的C₁-C₆氨基基团和被取代的或未被取代的C₁-C₆烷氧基基团；其中，当连接至不同原子的一对R⁴¹基团与环A原子一起形成环和/或连接至不同原子的一对R⁴²基团与环B原子一起形成环时，所述一对R⁴¹基团和/或一对R⁴²基团中的每一个独立地包含-CH₂-或-CH₂CH₂-；且其中，当基团R⁵和R⁴⁴与环C的原子一起形成环时，R⁵和R⁴⁴一起包含-CH＝CH-CH＝CH-或-NH-CO-NH-。4. The compound according to claim 3, wherein R⁴¹ , R⁴² , R⁴³ and R⁴⁴ are each independently selected from H, deuterium, halogen (such as -F, -Cl, -Br and -I, preferably F or Cl), a nitrile group, a substituted or unsubstituted C₁ -C₆ alkyl group, a substituted or unsubstituted straight or branched C₁ -C 6 haloalkyl group (preferably CF₃ or CHF₂ ), a cyclopropyl group, an -OH group or a substituted or unsubstituted straight or branched C₁ -C₆ alcohol group, a substituted or unsubstituted straight or branched C 1 -C₇ aminocarbonyl group (such as -NH-CO-Me), a -NH₂ group or a substituted or unsubstituted C₁ -C₆ amino group and a substituted or unsubstituted C₁ -C₆ alkoxy group; wherein, when a pair of R 41 , R 42 ,_R43 and R 44 are attached to different atoms, the two groups are independently selected from the group consisting of: When a pair of R⁴¹ groups are taken together with the ring A atoms to form a ring and/or a pair of R⁴² groups attached to different atoms are taken together with the ring B atoms to form a ring, each of the pair of R⁴¹ groups and/or the pair of R⁴² groups independently comprises -CH₂ - or -CH₂ CH₂ -; and wherein, when groups R⁵ and R⁴⁴ are taken together with the atoms of the ring C to form a ring, R⁵ and R⁴⁴ together comprise -CH=CH-CH=CH- or -NH-CO-NH-.5.根据权利要求3或权利要求4所述的化合物，其中R⁴⁵选自H、卤素(诸如-F、-Cl、-Br和-I，优选-F)、被取代的或未被取代的C₁-C₆烷基基团、被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(优选CF₃)、-NH₂基团或被取代的或未被取代的C₁-C₆氨基基团、-OH基团或被取代的或未被取代的直链或支链C₁-C₆醇基团和被取代的或未被取代的C₁-C₆烷氧基基团。5. The compound according to claim 3 or claim 4, wherein R⁴⁵ is selected from H, halogen (such as -F, -Cl, -Br and -I, preferably -F), a substituted or unsubstituted C₁ -C₆ alkyl group, a substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl group (preferably CF₃ ), a -NH₂ group or a substituted or unsubstituted C₁ -C₆ amino group, a -OH group or a substituted or unsubstituted straight or branched C₁ -C₆ alcohol group and a substituted or unsubstituted C₁ -C₆ alkoxy group.6.根据任何前述权利要求所述的化合物，其中R⁴⁶选自H和选自下述基团的基团：6. A compound according to any preceding claim, wherein R⁴⁶ is selected from H and a group selected from the following groups:-被取代的或未被取代的直链或支链C₁-C₆烷基基团(诸如Me、Et、Pr、i-Pr、n-Bu、i-Bu、t-Bu、戊基和己基)；- substituted or unsubstituted straight or branched C₁ -C₆ alkyl groups (such as Me, Et, Pr, i-Pr, n-Bu, i-Bu, t-Bu, pentyl and hexyl);-被取代的或未被取代的直链或支链C₁-C₆烷基-芳基基团(诸如-CH₂Ph、-CH₂(2、3或4)F-Ph、-CH₂(2、3或4)Cl-Ph、-CH₂(2、3或4)Br-Ph、-CH₂(2、3或4)I-Ph、-CH₂CH₂Ph、-CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂Ph、-CH₂CH₂CH₂CH₂CH₂Ph和-CH₂CH₂CH₂CH₂CH₂CH₂Ph)；- substituted or unsubstituted straight-chain or branched C₁ -C₆ alkyl-aryl groups (such as -CH₂ Ph, -CH₂ (2, 3, or 4)F-Ph, -CH₂ (2, 3, or 4)Cl-Ph, -CH₂ (2, 3, or 4)Br-Ph, -CH₂ (2, 3, or 4)I-Ph, -CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH₂ CH₂ CH₂ Ph, -CH 2 CH₂ CH₂ CH 2 Ph, -CH₂ CH₂ CH₂ CH₂ Ph, and -CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ Ph);-被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团(诸如-CH₂F、-CF3、-CH₂CH₂F和-CH₂CF₃)；- substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl groups (such as -CH₂ F, -CF 3 , -CH₂ CH₂ F and -CH₂ CF₃ );-被取代的或未被取代的环状的胺或酰氨基基团(诸如吡咯烷-3-基、哌啶-3-基、哌啶-4-基、2-酮-吡咯烷基、3-酮-吡咯烷基、2-酮-哌啶基、3-酮-哌啶基和4-酮-哌啶基)；- substituted or unsubstituted cyclic amine or amido groups (such as pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl, 2-keto-pyrrolidinyl, 3-keto-pyrrolidinyl, 2-keto-piperidinyl, 3-keto-piperidinyl and 4-keto-piperidinyl);-被取代的或未被取代的环状C₃-C₈烷基基团(诸如环丙基、环丁基、环戊基、环己基、环庚基和环辛基)；- substituted or unsubstituted cyclic C₃ -C₈ alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl);-被取代的或未被取代的直链或支链C₂-C₆醇基团(诸如-CH₂CH₂OH、-CH(CH₃)CH₂OH、-C(CH₃)₂OH、-CH₂CH₂CH₂OH、-CH₂CH₂CH₂CH₂OH、-CH(CH₃)CH₂CH₂OH、-CH(CH₃)CH(CH₃)OH、-CH(CH₂CH₃)CH₂OH、-C(CH₃)₂CH₂OH、-CH₂CH₂CH₂CH₂CH₂OH和-CH₂CH₂CH₂CH₂CH₂CH₂OH)；-_a substituted or unsubstituted linear or branched_C2 -_C6 alcohol group (such_as-CH2CH2OH , -CH(_CH3)CH2OH , -C(_CH3)2OH, -CH2CH2CH2OH_, -CH2CH2CH2CH2OH_, -CH(_CH3 )_CH2CH2OH , -CH(_CH3) CH_(CH3 )_{OH,-CH(CH2CH3)CH2OH,-C(CH3)2CH2OH,-CH2CH2CH2CH2CH2OH,and-CH2CH2CH2CH2CH2CH2CH2OH} );-被取代的或未被取代的直链或支链C₂-C₆羧酸基团(诸如-CH₂COOH、-CH₂CH₂COOH、-CH₂CH₂CH₂COOH、-CH₂CH₂CH₂CH₂COOH和-CH₂CH₂CH₂CH₂CH₂COOH)；- substituted or unsubstituted linear or branched C₂ -C₆ carboxylic acid groups (such as -CH₂ COOH, -CH₂ CH₂ COOH, -CH₂ CH_2CH2 COOH, -CH₂ CH 2 CH₂ CH₂ COOH, and -CH₂ CH₂ CH₂ CH₂ CH₂ COOH);-被取代的或未被取代的直链或支链羰基基团(诸如-(CO)Me、-(CO)Et、-(CO)Pr、-(CO)-i-Pr、-(CO)-n-Bu、-(CO)-i-Bu、-(CO)-t-Bu、-(CO)Ph、-(CO)CH₂Ph、-(CO)CH₂OH、-(CO)CH₂OCH₃、-(CO)CH₂NH₂、-(CO)CH₂NHMe、-(CO)CH₂NMe₂、-(CO)-环丙基、-(CO)-1,3-环氧丙烷-2-基；-(CO)NH₂、-(CO)NHMe、-(CO)NMe₂、-(CO)NHEt、-(CO)NEt₂、-(CO)-吡咯烷-N-基、-(CO)-吗啉-N-基、-(CO)-哌嗪-N-基、-(CO)-N-甲基-哌嗪-N-基、-(CO)NHCH₂CH₂OH、-(CO)NHCH₂CH₂OMe、-(CO)NHCH₂CH₂NH₂、-(CO)NHCH₂CH₂NHMe和-(CO)NHCH₂CH₂NMe₂；- substituted or unsubstituted straight-chain or branched carbonyl groups (such as -(CO)Me, -(CO)Et, -(CO)Pr, -(CO)-i-Pr, -(CO)-n-Bu, -(CO)-i-Bu, -(CO)_-t -Bu_, -(CO)_Ph , -(CO)_CH2Ph , -(CO)CH2OH, -(CO)_{CH2OCH3, -(CO)CH2NH2,} -(CO)_CH2NHMe , -(CO)_CH2NMe2 , -(CO)-cyclopropyl, -(CO)-1,3-epoxypropan-2-yl; -(CO)_NH2, -(CO)NHMe, -(CO)_NMe2 , -(CO)NHEt, -(CO)_NEt2 , -(CO)-pyrrolidin-N-yl, -(CO)-morpholin-N-yl, -(CO)-piperazin-N-yl, -(CO)-N-methyl-piperazin-N-yl, -(CO)NHCH₂ CH₂ OH, -(CO)NHCH₂ CH₂ OMe, -(CO)NHCH₂ CH₂ NH₂ , -(CO)NHCH₂ CH₂ NHMe, and -(CO)NHCH₂ CH₂ NMe₂ ;-被取代的或未被取代的直链或支链C₁-C₆羧酸酯基团(诸如-COOMe、-COOEt、-COOPr、-COO-i-Pr、-COO-n-Bu、-COO-i-Bu、-COO-t-Bu、-CH₂COOMe、-CH₂CH₂COOMe、-CH₂CH₂CH₂COOMe和-CH₂CH₂CH₂CH₂COOMe)；- substituted or unsubstituted linear or branched C₁ -C₆ carboxylate groups (such as -COOMe, -COOEt, -COOPr, -COO-i-Pr, -COO-n-Bu, -COO-i-Bu, -COO-t-Bu, -CH₂ COOMe, -CH₂ CH₂ COOMe_, -CH₂ CH₂ CH₂ COOMe, and -CH₂ CH 2 CH₂ CH₂ COOMe);-被取代的或未被取代的直链或支链C₁-C₆酰胺基团(诸如-CO-NH₂、-CO-NMeH、-CO-NMe₂、-CO-NEtH、-CO-NEtMe、-CO-NEt₂、-CO-NPrH、-CO-NPrMe和-CO-NPrEt)；- substituted or unsubstituted straight or branched C₁ -C₆ amide groups (such as -CO-NH₂ , -CO-NMeH, -CO-NMe₂ , -CO-NEtH, -CO-NEtMe, -CO-NEt₂ , -CO-NPrH, -CO-NPrMe and -CO-NPrEt);-被取代的或未被取代的磺酰基基团(诸如-SO₂Me、-SO₂Et、-SO₂Pr、-SO₂iPr、-SO₂Ph、-SO₂-(2、3或4)-F-Ph、-SO₂-环丙基、-SO₂CH₂CH₂OCH₃)、-SO₂NH₂、-SO₂NHMe、-SO₂NMe₂、-SO₂NHEt、-SO₂NEt₂、-SO₂-吡咯烷-N-基、-SO₂-吗啉-N-基、-SO₂NHCH₂OMe和-SO₂NHCH₂CH₂OMe；- substituted or unsubstituted sulfonyl groups (such as_-SO2Me ,_{-SO2Et, -SO2Pr} ,_-SO2iPr ,_-SO2Ph ,_-SO2- (2,₃ or₄ )-F-Ph,_-SO2- cyclopropyl,_{-SO2CH2CH2OCH3} ), -SO2NH2, -SO2NHMe,_-SO2NMe2, -SO2NHEt,_{-SO2NEt2,-SO2-} pyrrolidin-N-_yl ,_-SO2- morpholin-_N-yl ,_-SO2NHCH2OMe and_{-SO2NHCH2CH2OMe);}-被取代的或未被取代的芳族基团(诸如Ph-、2-F-Ph-、3-F-Ph-、4-F-Ph-、2-Cl-Ph-、3-Cl-Ph-、4-Cl-Ph-、2-Br-Ph-、3-Br-Ph-、4-Br-Ph-、2-I-Ph-、3-I-Ph、4-I-Ph-、2,(3、4、5或6)-F₂-Ph-、2,(3、4、5或6)-Cl₂-Ph-、2,(3、4、5或6)-Br₂-Ph-、2,(3、4、5或6)-I₂-Ph-、2,(3、4、5或6)-Me₂-Ph-、2,(3、4、5或6)-Et₂-Ph-、2,(3、4、5或6)-Pr₂-Ph-、2,(3、4、5或6)-Bu₂-Ph-、2,(3、4、5或6)-(CN)₂-Ph-、2,(3、4、5或6)-(NO₂)₂-Ph-、2,(3、4、5或6)-(NH₂)₂-Ph-、2,(3、4、5或6)-(MeO)₂-Ph-、2,(3、4、5或6)-(CF₃)₂-Ph-、3,(4或5)-F₂-Ph-、3,(4或5)-Cl₂-Ph-、3,(4或5)-Br₂-Ph-、3,(4或5)-I₂-Ph-、3,(4或5)-Me₂-Ph-、3,(4或5)-Et₂-Ph-、3,(4或5)-Pr₂-Ph-、3,(4或5)-Bu₂-Ph-、3,(4或5)-(CN)₂-Ph-、3,(4或5)-(NO₂)₂-Ph-、3,(4或5)-(NH₂)₂-Ph-、3,(4或5)-(MeO)₂-Ph-、3,(4或5)-(CF₃)₂-Ph-、2-Me-Ph-、3-Me-Ph-、4-Me-Ph-、2-Et-Ph-、3-Et-Ph-、4-Et-Ph-、2-Pr-Ph-、3-Pr-Ph-、4-Pr-Ph-、2-Bu-Ph-、3-Bu-Ph-、4-Bu-Ph-、2-(CN)-Ph-、3-(CN)-Ph-、4-(CN)-Ph-、2-(NO₂)-Ph-、3-(NO₂)-Ph-、4-(NO₂)-Ph-、2-(NH₂)-Ph-、3-(NH₂)-Ph-、4-(NH₂)-Ph-、2-MeO-Ph-、3-MeO-Ph-、4-MeO-Ph-、2-(NH₂-CO)-Ph-、3-(NH₂-CO)-Ph-、4-(NH₂-CO)-Ph-、2-CF₃-Ph-、3-CF₃-Ph-、4-CF₃-Ph-、2-CF₃O-Ph-、3-CF₃O-Ph-、和4-CF₃O-Ph-)；和-substituted or unsubstituted aromatic groups (such as Ph-, 2-F-Ph-, 3-F-Ph-, 4-F-Ph-, 2-Cl-Ph-, 3-Cl-Ph-, 4-Cl-Ph-, 2-Br-Ph-, 3-Br-Ph-, 4-Br-Ph-, 2-I-Ph-, 3-I-Ph, 4-I-Ph-, 2,(3, 4, 5, or 6)-F₂ -Ph-, 2,(3, 4, 5, or 6)-Cl₂ -Ph-, 2,(3, 4, 5, or 6)-Br₂ -Ph-, 2,(3, 4, 5, or 6)-I₂ -Ph-, 2,(3, 4, 5, or 6)-Me₂ -Ph-, 2,(3, 4, 5, or 6)-Et₂ -Ph-, 2,(3,4,5 or 6)-Pr₂ -Ph-, 2,(3,4,5 or 6)-Bu₂ -Ph-, 2,(3,4,5 or 6)-(CN)₂ -Ph-, 2,(3,4,5 or 6)-(NO₂ )₂ -Ph-, 2,(3,4,5 or 6)-(NH₂ )₂ -Ph-, 2,(3,4,5 or 6)-(MeO)₂ -Ph-, 2,(3,4,5 or 6)-(CF₃ )₂ -Ph-, 3,(4 or 5)-F₂ -Ph-, 3,(4 or 5)-Cl₂ -Ph-, 3,(4 or 5)-Br₂ -Ph-, 3,(4 or 5)-I₂ -Ph-, 3,(4 or 5)-Me₂ -Ph-, 3,(4 or 5)-Et₂ -Ph-, 3,(4 or 5)-Pr₂ -Ph-, 3,(4 or 5)-Bu₂ -Ph-, 3,(4 or 5)-(CN)₂ -Ph-, 3,(4 or 5)-(NO₂ )₂ -Ph-, 3,(4 or 5)-(NH₂ )₂ -Ph-, 3,(4 or 5)-(MeO)₂ -Ph-, 3,(4 or 5)-(CF₃ )₂ -Ph-, 2-Me-Ph-, 3-Me-Ph-, 4-Me-Ph-, 2-Et-Ph-, 3-Et-Ph-, 4-Et-Ph-, 2-Pr-Ph-, 3-Pr-Ph -, 4-Pr-Ph-, 2-Bu-Ph-, 3-Bu-Ph-, 4-Bu-Ph-, 2-(CN)-Ph-, 3-(CN)-Ph-, 4-(CN)-Ph-, 2-(NO₂ )-Ph-, 3-(NO₂ )-Ph-, 4-(NO₂ )-Ph-, 2-(NH₂ )-Ph-, 3-(NH₂ )-Ph-, 4-(NH₂ )-Ph-, 2-MeO-Ph-, 3-MeO-Ph-, 4-MeO-Ph-, 2-(NH_{and​​​​​​​​}-被取代的或未被取代的饱和的或不饱和的被取代的或未被取代的杂环基团，包括芳族杂环基团和/或非芳族杂环基团(诸如吡咯-2-基、吡咯-3-基、吡唑-3-基、吡唑-4-基、吡唑-5-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、1,2,3-三唑-4-基、1,2,3-三唑-5-基、1,2,4-三唑-3-基、1,2,4-三唑-5-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哒嗪-3-基、哒嗪-4-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、嘧啶-6-基、吡嗪-2-基、吡咯烷-2-基、吡咯烷-3-基、哌啶-2-基、哌啶-3-基、哌啶-4-基、2-氮杂哌啶-3-基、2-氮杂哌啶-4-基、3-氮杂哌啶-2-基、3-氮杂哌啶-4-基、3-氮杂哌啶-5-基、哌嗪-2-基、呋喃-2-基、呋喃-3-基、吡喃-2-基、吡喃-3-基、吡喃-4-基、2-氮杂吡喃-3-基、2-氮杂吡喃-4-基、2-氮杂吡喃-5-基、2-氮杂吡喃-6-基、3-氮杂吡喃-2-基、3-氮杂吡喃-4-基、3-氮杂吡喃-5-基、3-氮杂吡喃-6-基、4-氮杂吡喃-2-基、4-氮杂吡喃-3-基、4-氮杂吡喃-5-基、4-氮杂吡喃-6-基、四氢呋喃-2-基、四氢呋喃-3-基、2-氮杂-四氢呋喃-3-基、2-氮杂-四氢呋喃-4-基、2-氮杂-四氢呋喃-5-基、3-氮杂-四氢呋喃-2-基、3-氮杂-四氢呋喃-4-基、3-氮杂-四氢呋喃-5-基、四氢吡喃-2-基、氧杂环丁烷-3-基、四氢吡喃-3-基、四氢吡喃-4-基、2-氮杂-四氢吡喃-3-基、2-氮杂-四氢吡喃-4-基、2-氮杂-四氢吡喃-5-基、2-氮杂-四氢吡喃-6-基、3-氮杂-四氢吡喃-2-基、3-氮杂-四氢吡喃-4-基、3-氮杂-四氢吡喃-5-基、3-氮杂-四氢吡喃-6-基、吗啉-2-基、吗啉-3-基、噻吩-2-基、噻吩-3-基、异噻唑-3-基、异噻唑-4-基、异噻唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、噻喃-2-基、噻喃-3-基、噻喃-4-基、2-氮杂噻喃-3-基、2-氮杂噻喃-4-基、2-氮杂噻喃-5-基、2-氮杂噻喃-6-基、3-氮杂噻喃-2-基、3-氮杂噻喃-4-基、3-氮杂噻喃-5-基、3-氮杂噻喃-6-基、4-氮杂噻喃-2-基、4-氮杂噻喃-3-基、4-氮杂噻喃-5-基、4-氮杂噻喃-6-基、硫杂环戊烷-2-基、硫杂环戊烷-3-基、硫杂环己烷-2-基、硫杂环己烷-3-基、硫杂环己烷-4-基、噁唑-2-基、噁唑-4-基、噁唑-5-基、异噁唑-3-基、异噁唑-4-基、异噁唑-5-基、呋咱-3-基、(1,3,4-噁二唑)-2-基、(1,3,4-噁二唑)-5-基、(1,2,4-噁二唑)-3-基、(1,2,4-噁二唑)-5-基；和四唑-5-基)。- substituted or unsubstituted saturated or unsaturated substituted or unsubstituted heterocyclic groups, including aromatic heterocyclic groups and/or non-aromatic heterocyclic groups (such as pyrrol-2-yl, pyrrol-3-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4- triazol-3-yl, 1,2,4-triazol-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, pyrazin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2-azapiperidin-3-yl, 2-azapiperidin -4-yl, 3-azapiperidin-2-yl, 3-azapiperidin-4-yl, 3-azapiperidin-5-yl, piperazin-2-yl, furan-2-yl, furan-3-yl, pyran-2-yl, pyran-3-yl, pyran-4-yl, 2-azapyran-3-yl, 2-azapyran-4-yl, 2-azapyran-5-yl, 2-azapyran-6-yl, 3-azapyran-2-yl, 3-azapyran-4-yl, yl, 3-azapyran-5-yl, 3-azapyran-6-yl, 4-azapyran-2-yl, 4-azapyran-3-yl, 4-azapyran-5-yl, 4-azapyran-6-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-3-yl, 2-aza-tetrahydrofuran-4-yl, 2-aza-tetrahydrofuran-5-yl, 3-aza-tetrahydrofuran-2-yl, 3- Aza-tetrahydrofuran-4-yl, 3-aza-tetrahydrofuran-5-yl, tetrahydropyran-2-yl, oxetane-3-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, 2-aza-tetrahydropyran-3-yl, 2-aza-tetrahydropyran-4-yl, 2-aza-tetrahydropyran-5-yl, 2-aza-tetrahydropyran-6-yl, 3-aza-tetrahydropyran-2-yl, 3-aza-tetrahydropyran-4-yl -yl, 3-aza-tetrahydropyran-5-yl, 3-aza-tetrahydropyran-6-yl, morpholin-2-yl, morpholin-3-yl, thiophen-2-yl, thiophen-3-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, thiopyran-2-yl, thiopyran-3-yl, thiopyran-4-yl, 2-azathiopyran-3-yl, 2-azathiopyran-4-yl -yl, 2-azathiopyran-5-yl, 2-azathiopyran-6-yl, 3-azathiopyran-2-yl, 3-azathiopyran-4-yl, 3-azathiopyran-5-yl, 3-azathiopyran-6-yl, 4-azathiopyran-2-yl, 4-azathiopyran-3-yl, 4-azathiopyran-5-yl, 4-azathiopyran-6-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-2-yl, thiolan-3-yl, thiolan-5-yl, thiolan-6-yl, heterocyclohexan-3-yl, thioxan-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, furazan-3-yl, (1,3,4-oxadiazole)-2-yl, (1,3,4-oxadiazole)-5-yl, (1,2,4-oxadiazole)-3-yl, (1,2,4-oxadiazole)-5-yl; and tetrazol-5-yl).7.根据权利要求6所述的化合物，其中R⁴⁶选自H、被取代的或未被取代的C₁-C₆烷基基团或被取代的或未被取代的直链或支链C₁-C₆卤代烷基基团。The compound according to claim 6, wherein R⁴⁶ is selected from H, a substituted or unsubstituted C₁ -C₆ alkyl group, or a substituted or unsubstituted straight or branched C₁ -C₆ haloalkyl group.8.根据任何前述权利要求所述的化合物，其中基团L的环A包含以下结构中的任一种：8. A compound according to any preceding claim, wherein Ring A of group L comprises any one of the following structures:其中R⁴¹如在任何前述权利要求中所定义。wherein R⁴¹ is as defined in any preceding claim.9.根据权利要求8所述的化合物，其中基团L的环A包含以下结构中的任一种：9. The compound according to claim 8, wherein the ring A of the group L comprises any one of the following structures:10.根据任何前述权利要求所述的化合物，其中基团L的环C包含以下结构中的任一种：10. A compound according to any preceding claim, wherein Ring C of group L comprises any one of the following structures:其中R⁵、R⁴³、R⁴⁴和R⁴⁶如在任何前述权利要求中所定义。wherein R⁵ , R⁴³ , R⁴⁴ and R⁴⁶ are as defined in any preceding claim.11.根据权利要求10所述的化合物，其中基团L的环C包含以下结构中的任一种：11. The compound according to claim 10, wherein the ring C of the group L comprises any one of the following structures:其中R⁵和R⁴³如在权利要求10中所定义。wherein R⁵ and R⁴³ are as defined in claim 10.12.根据任何前述权利要求所述的化合物，其中R⁵是被取代的或未被取代的有机基团。12. A compound according to any preceding claim, wherein R⁵ is a substituted or unsubstituted organic group.13.根据权利要求1至11中的任一项所述的化合物，其中所述基团R⁵选自H、-F、-Cl、-Br、-I、-CN、-CONR⁵¹R⁵¹、-NR⁵¹COR⁵²、-SO₂NR⁵¹R⁵¹、-NR⁵¹SO₂R⁵³、-O-CR⁵²R⁵²R⁵²、-CR⁵²R⁵²NR⁵¹R⁵¹和以下结构中的任一种：13. The compound according to any one of claims 1 to 11, wherein the group R⁵ is selected from H, -F, -Cl, -Br, -I, -CN, -CONR⁵¹ R⁵¹ , -NR⁵¹ COR⁵² , -SO₂ NR⁵¹ R⁵¹ , -NR⁵¹ SO₂ R⁵³ , -O-CR⁵² R⁵² R⁵² , -CR⁵² R⁵² NR⁵¹ R⁵¹ and any one of the following structures:其中，R⁵¹、R⁵²和R⁵³中的每一个可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团。Wherein, each of R⁵¹ , R⁵² and R⁵³ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group.14.根据权利要求13所述的化合物，其中所述基团R⁵选自-F、-Cl、-CN、-CONH₂、-CONHMe、-CONHEt、-CONMe₂、-CONHCOMe、-CONHCH₂-CH₂OMe、-CONH-CH₂-CH₂F、-CONH-CH₂-CF₃、-CONH-CH₂-CHF₂、-OCHF₂、-NHCOMe、-NHSO₂Me、-SO₂NHMe、-CONHSO₂Me、14. The compound according to claim 13, wherein the group^R5 is selected from -F, -Cl, -CN,_-CONH2 , -CONHMe, -CONHEt, -CONMe2, -CONHCOMe, -CONHCH2-_CH2OMe , -CONH-_CH2-CH2F, -CONH-_CH2 -_CF3 , -CONH-_CH2-CHF2 ,_-OCHF2 , -NHCOMe,_-NHSO2Me ,_-SO2NHMe ,_-CONHSO2Me ,15.根据任何前述权利要求所述的化合物，其中Q²存在并且每个Q¹独立地不存在或者是独立地选自以下结构的基团：15. A compound according to any preceding claim, wherein Q² is present and each Q¹ is independently absent or is independently selected from a group of the following structures:其中每个R⁴⁵可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；并且R⁴⁶选自H和被取代的或未被取代的有机基团。wherein each R⁴⁵ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and R⁴⁶ is selected from H and a substituted or unsubstituted organic group.16.根据权利要求15所述的化合物，其中基团L的基团Q²存在，其中X⁵是N。16. The compound according to claim 15, wherein the group Q² of the group L is present, wherein X⁵ is N.17.根据权利要求16所述的化合物，其中基团L的Q²包含以下结构中的任一种：17. The compound according to claim 16, wherein Q² of the group L comprises any one of the following structures:其中R⁴²如在任何前述权利要求中所定义。wherein R⁴² is as defined in any preceding claim.18.根据权利要求17所述的化合物，其中基团L的Q²包含以下结构中的任一种：18. The compound according to claim 17, wherein Q² of the group L comprises any one of the following structures:19.根据权利要求15至18中的任一项所述的化合物，其中所述基团L包含具有以下结构的基团：19. The compound according to any one of claims 15 to 18, wherein the group L comprises a group having the following structure:其中Q¹不存在或者是如在权利要求3中所定义的基团，Q³不存在或者是如在权利要求2中所定义的基团，并且n、m、p、q、r、s、X¹、X²、X³、X⁵、X⁶、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、以及环A、B和C如在任何前述权利要求中所定义。wherein^Q1 is absent or is a group as defined in claim 3,^Q3 is absent or is a group as defined in claim 2, and n, m, p, q, r, s,^X1 ,^X2 ,^X3 , X5,^X6 ,^R41 ,^R42 ,^R43 ,^R44,R5 , and rings A, B and C are as defined in any preceding claim.20.根据权利要求19所述的化合物，其中所述基团L包含具有以下结构的基团：20. The compound according to claim 19, wherein the group L comprises a group having the following structure:其中n、m、p、q、r、s、X¹、X²、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、Q¹、Q³以及环A、B和C如在权利要求19中所定义。wherein n, m, p, q, r, s, X¹ , X² , X³ , X⁵ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ , R⁵ , Q¹ , Q³ and rings A, B and C are as defined in claim 19.21.根据权利要求20所述的化合物，其中所述基团L包含具有以下结构的基团：21. The compound of claim 20, wherein the group L comprises a group having the following structure:其中n、m、p、q、r、s、X¹、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、Q¹、Q³以及环A、B和C如在权利要求20中所定义。wherein n, m, p, q, r, s, X¹ , X³ , X⁵ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ , R⁵ , Q¹ , Q³ and rings A, B and C are as defined in claim 20.22.根据权利要求21所述的化合物，其中所述基团L包含具有以下结构的基团：22. The compound of claim 21, wherein the group L comprises a group having the following structure:其中n、m、p、q、r、s、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵、以及环A、B和C如在权利要求21中所定义。wherein n, m, p, q, r, s, X³ , X⁵ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ , R⁵ , and rings A, B and C are as defined in claim 21 .23.根据权利要求22所述的化合物，其中所述基团L包含具有以下结构的基团：23. The compound of claim 22, wherein the group L comprises a group having the following structure:其中n、m、p、q、r、s、X³、X⁵、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵和环C如在权利要求22中所定义。wherein n, m, p, q, r, s, X³ , X⁵ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ , R⁵ and Ring C are as defined in claim 22.24.根据权利要求19所述的化合物，其中所述基团L包含具有以下结构的基团：24. The compound of claim 19, wherein the group L comprises a group having the following structure:其中n、m、p、q、r、s、X¹、X²、X³、X⁵、X⁶、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁵和环C如在权利要求19中所定义。wherein n, m, p, q, r, s, X¹ , X² , X³ , X⁵ , X⁶ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ , R⁵ and Ring C are as defined in claim 19.25.根据权利要求24所述的化合物，其中所述基团L包含选自以下结构的基团：25. The compound according to claim 24, wherein the group L comprises a group selected from the following structures:其中n、m、p、q、X³、R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁵如在权利要求24中所定义。wherein n, m, p, q, X³ , R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁵ are as defined in claim 24.26.根据权利要求15至25中的任一项所述的化合物，其中m选自1或2，n选自2或3，p选自1、2或3，且q选自1或2。26. The compound according to any one of claims 15 to 25, wherein m is selected from 1 or 2, n is selected from 2 or 3, p is selected from 1, 2 or 3, and q is selected from 1 or 2.27.根据权利要求25或权利要求26所述的化合物，其中所述基团L包含具有任何以下结构的基团：27. A compound according to claim 25 or claim 26, wherein the group L comprises a group having any of the following structures:其中，R⁴¹、R⁴²、R⁴³、R⁴⁴和R⁵如在权利要求25中所定义。wherein R⁴¹ , R⁴² , R⁴³ , R⁴⁴ and R⁵ are as defined in claim 25 .28.根据权利要求1至14中的任一项所述的化合物，其中基团L的基团Q²不存在且仅一个Q¹基团存在，且其中所述Q¹基团在线性方向上将环A与环C分隔3或4个原子。28. The compound according to any one of claims 1 to 14, wherein the group Q² of the group L is absent and only one Q¹ group is present, and wherein the Q¹ group separates ring A from ring C by 3 or 4 atoms in a linear direction.29.根据权利要求28所述的化合物，其中所述Q¹基团包含以下结构中的任一种：29. The compound of claim 28, wherein the^Q1 group comprises any one of the following structures:其中R⁴⁵和R⁴⁶如在任何前述权利要求中所定义。wherein R⁴⁵ and R⁴⁶ are as defined in any preceding claim.30.根据权利要求29所述的化合物，其中所述Q¹基团包含以下结构中的任一种：30. The compound of claim 29, wherein the^Q1 group comprises any one of the following structures:31.根据权利要求1至11、或13至14中的任一项所述的化合物，其中所述基团L包含具有任何以下结构的基团：31. A compound according to any one of claims 1 to 11, or 13 to 14, wherein the group L comprises a group having any of the following structures:32.根据任何前述权利要求所述的化合物，所述化合物包含以下结构中的任一种：32. A compound according to any preceding claim, comprising any of the following structures:其中，虚线指示，环D可以包含单键，或单键和双键的组合，并且可以是脂族或芳族；每个X⁴可以相同或不同并且独立地选自C、N、O和S；每个R¹¹可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；且其中Z¹、R³、R⁶和L如在任何前述权利要求中所定义。wherein the dashed line indicates that ring D may contain a single bond, or a combination of single and double bonds, and may be aliphatic or aromatic; each X⁴ may be the same or different and is independently selected from C, N, O and S; each R¹¹ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and wherein Z¹ , R³ , R⁶ and L are as defined in any preceding claim.33.根据权利要求32所述的化合物，所述化合物包含以下结构中的任一种：33. The compound according to claim 32, comprising any one of the following structures:其中所述环D、X⁴、R¹¹、R³、R⁶和L如在权利要求32中所定义，优选地其中至少一个X⁴是C。wherein said ring D, X⁴ , R¹¹ , R³ , R⁶ and L are as defined in claim 32, preferably wherein at least one X⁴ is C.34.根据权利要求33所述的化合物，所述化合物包含以下结构中的任一种：34. The compound according to claim 33, comprising any one of the following structures:其中R¹⁴可以存在或不存在并且如果存在的话选自H、C₁至C₃烷基或C₁至C₃氟代烷基；且R¹¹、环D、R³、R⁶和L如在权利要求33中所定义。wherein R¹⁴ may be present or absent and if present is selected from H, C₁ to C₃ alkyl or C₁ to C₃ fluoroalkyl; and R¹¹ , Ring D, R³ , R⁶ and L are as defined in claim 33.35.根据权利要求34所述的化合物，所述化合物包含以下结构中的任一种：35. The compound of claim 34, comprising any one of the following structures:其中R³、R¹¹、R¹⁴、R⁶和L如在权利要求34中所定义。wherein R³ , R¹¹ , R¹⁴ , R⁶ and L are as defined in claim 34.36.根据权利要求32至35中的任一项所述的化合物，其中每个R¹¹独立地选自H、卤素、腈基团、直链或支链C₁-C₃烷基基团、直链或支链C₁-C₃卤代烷基基团(优选氟代烷基)、-OH基团、直链或支链C₁-C₃醇基团、卤代(优选氟-)直链或支链C₁-C₃醇基团、-NH₂、直链或支链伯、仲或叔C₁-C₃胺基团、卤代(优选氟-)直链或支链伯、仲或叔C₁-C₃胺基团、直链或支链C₁-C₃烷氧基基团、直链或支链C₁-C₃卤代烷氧基基团(优选氟代烷氧基)，和/或一对R¹¹基团连接至同一原子以形成＝O；且独立地，和/或当一对连接至不同原子的R¹¹基团与环D原子一起形成环时，这一对R¹¹基团包含-CH₂CH₂CH₂-。36. The compound according to any one of claims 32 to 35, wherein each R¹¹ is independently selected from H, halogen, a nitrile group, a straight or branched C₁ -C₃ alkyl group, a straight or branched C 1 -C₃ haloalkyl group (preferably fluoroalkyl), an -OH group, a straight or branched C_1-C3 alcohol group, a halogenated (preferably fluoro-) straight or branched C₁ -C₃ alcohol group, -NH₂ , a straight or branched primary, secondary or tertiary C₁ -C₃ amine group, a halogenated (preferably fluoro-) straight or branched primary, secondary or tertiary C₁ -C₃ amine group, a straight or branched C₁ -C₃ alkoxy group, a straight or branched C₁ -C₃ haloalkoxy group (preferably fluoroalkoxy), and/or a pair of R¹¹ groups are attached to the same atom to form =0; and independently, and/or when a pair of R 11 groups are attached to different atoms When the^{R 11} group and the ring D atom form a ring together, the pair of R¹¹ groups include -CH₂ CH₂ CH₂ -.37.根据权利要求36所述的化合物，其中每个R¹¹独立地选自H、Cl、F、CHF₂、CF₃、CH₃、OH、CH₃O和NH₂，和/或一对R¹¹基团连接至同一原子以形成＝O；且独立地，当一对连接至不同原子的R¹¹基团与环D原子一起形成环时，这一对R¹¹基团包含-CH₂CH₂CH₂-。37. The compound of claim 36, wherein each R¹¹ is independently selected from H, Cl, F,_CHF2 ,_CF3 ,_CH3 , OH,_CH3O and_NH2 , and/or a pair of R¹¹ groups are attached to the same atom to form =0; and independently, when a pair of_R¹¹ groups attached to different atoms form a ring together with the ring D atom, the pair of_R¹¹ groups comprises_-CH2CH2CH2- .38.根据权利要求37所述的化合物，所述化合物包含以下结构中的任一种：38. The compound of claim 37, comprising any one of the following structures:39.根据权利要求1至31中的任一项所述的化合物，所述化合物包含以下结构中的任一种：39. A compound according to any one of claims 1 to 31 comprising any one of the following structures:其中每个R¹²独立地选自H和被取代的或未被取代的有机基团，优选低级(C₁至C₆)烷基、烷氧基或卤代烷基基团、被取代的或未被取代的C₃至C₆环烷基或杂环基团和卤素基团，其中至少一个R¹²不是H；且其中每个R¹³可以相同或不同并且独立地选自H和被取代的或未被取代的有机基团；且其中R³、R⁶和L如在任何前述权利要求中所定义。wherein each R¹² is independently selected from H and a substituted or unsubstituted organic group, preferably a lower (C₁ to C₆ ) alkyl, alkoxy or haloalkyl group, a substituted or unsubstituted C₃ to C₆ cycloalkyl or heterocyclic group and a halogen group, wherein at least one R¹² is not H; and wherein each R¹³ may be the same or different and is independently selected from H and a substituted or unsubstituted organic group; and wherein R³ , R⁶ and L are as defined in any preceding claim.40.根据权利要求39所述的化合物，其中至少一个R¹²选自-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH₂F、-CHF₂、-CF₃、-F、-Cl、-CH₂CF₃、-CH₂CH₂F、-CH₂CH₂OH、甲氧基、甲氧基甲基、甲氧基乙基、异丙基、环丙基或环丙基甲基。40. The compound of claim 39, wherein at least one^R12 is selected from_-CH3,-CH2CH3 ,_-CH2CH2CH3 ,_-CH2F,-CHF2 ,_-CF3,-F , -Cl_,-CH2CF3 ,_-CH2CH2F ,_-CH2CH2OH , methoxy, methoxymethyl, methoxyethyl, isopropyl,_cyclopropyl , or cyclopropylmethyl.41.根据权利要求39或权利要求40所述的化合物，其中R¹³选自H、F、C₁至C₃烷基或C₁至C₃氟代烷基。41. A compound according to claim 39 or claim 40, wherein R¹³ is selected from H, F, C₁ to C₃ alkyl or C₁ to C₃ fluoroalkyl.42.根据权利要求39至41中的任一项所述的化合物，所述化合物包含以下结构中的任一种：42. A compound according to any one of claims 39 to 41, comprising any one of the following structures:43.根据权利要求32至37或39至41中的任一项所述的化合物，其中R³是H。43. A compound according to any one of claims 32 to 37 or 39 to 41, wherein R³ is H.44.根据权利要求32至37或39至41中的任一项所述的化合物，其中R⁶选自H、卤素、C₁至C₃烷基、C₁至C₃卤代烷基、C₁至C₃醇或C₁至C₃氨基烷基。44. A compound according to any one of claims 32 to 37 or 39 to 41, wherein^R6 is selected from H, halogen,_C1 to_C3 alkyl,_C1 to_C3 haloalkyl,_C1 to_C3 alcohol or_C1 to_C3 aminoalkyl.45.根据任何前述权利要求所述的用于用在药物中的化合物，所述化合物包含选自下述之一的式：45. A compound for use in medicine according to any preceding claim, said compound comprising a formula selected from one of the following:46.根据任何前述权利要求所述的用于用在药物中的化合物，所述化合物包含：46. A compound for use in medicine according to any preceding claim, comprising:-分离的对映异构体，或- separated enantiomers, or-两种或更多种对映异构体的混合物，或- a mixture of two or more enantiomers, or-两种或更多种非对映异构体和/或差向异构体的混合物，或- a mixture of two or more diastereomers and/or epimers, or-外消旋混合物，或- a racemic mixture, or-所述化合物的互变异构体。- tautomers of said compounds.47.根据任何前述权利要求所述的化合物，所述化合物相对于PARP2对PARP1具有选择性。47. A compound according to any preceding claim, which is selective for PARP1 over PARP2.48.用于治疗癌症的化合物，所述化合物是如在任何前述权利要求中所定义的化合物。48. A compound for use in the treatment of cancer, said compound being a compound as defined in any preceding claim.49.根据权利要求48所述的化合物，其中所述癌症是选自以下的癌症：实体肿瘤或液体肿瘤，包括眼癌、脑癌(诸如神经胶质瘤、胶质母细胞瘤、髓母细胞瘤、颅咽管瘤、室管膜瘤和星形细胞瘤)、脊髓癌、肾癌、口癌、唇癌、喉癌、口腔癌、鼻腔癌、小肠癌、结肠癌、甲状旁腺癌、胆囊癌、头颈癌、乳癌、骨癌、胆管癌、子宫颈癌、心脏癌、咽下腺癌、肺癌、支气管癌、肝癌、皮肤癌、输尿管癌、尿道癌、睾丸癌、阴道癌、肛门癌、喉腺癌、卵巢癌、甲状腺癌、食道癌、鼻咽腺癌、垂体癌、唾液腺癌、前列腺癌、胰腺癌、肾上腺癌；子宫内膜癌、口癌、黑素瘤、神经母细胞瘤、胃癌、血管瘤病、血管母细胞瘤、嗜铬细胞瘤、胰腺囊肿、肾细胞癌、威尔曼瘤、鳞状细胞癌、肉瘤、骨肉瘤、卡波西肉瘤、横纹肌肉瘤、肝细胞癌、PTEN错构瘤-肿瘤综合征(PHTS)(诸如Lhermitte-Duclos病、Cowden综合征、Proteus综合征和Proteus样综合征)、白血病和淋巴瘤(诸如急性成淋巴细胞性白血病、慢性淋巴细胞性白血病、急性髓性白血病、慢性髓性白血病、毛细胞白血病、T-细胞幼淋巴细胞性白血病(T-PLL)、大颗粒淋巴细胞白血病、成人T-细胞白血病、幼年型粒单核细胞性白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、套淋巴瘤、滤泡性淋巴瘤、原发性渗出性淋巴瘤、AIDS-有关的淋巴瘤、弥散性B细胞淋巴瘤、伯基特淋巴瘤、皮肤T-细胞淋巴瘤、鼻咽癌和胃肠癌。49. The compound of claim 48, wherein the cancer is a cancer selected from the group consisting of solid tumors or liquid tumors, including eye cancer, brain cancer (such as glioma, glioblastoma, medulloblastoma, craniopharyngioma, ependymoma and astrocytoma), spinal cord cancer, kidney cancer, mouth cancer, lip cancer, larynx cancer, oral cancer, nasal cancer, small intestine cancer, colon cancer, parathyroid cancer, gallbladder cancer, head and neck cancer, breast cancer, bone cancer, bile duct cancer, cervix cancer Cancer, heart cancer, hypopharyngeal cancer, lung cancer, bronchial cancer, liver cancer, skin cancer, ureter cancer, urethral cancer, testicular cancer, vaginal cancer, anal cancer, laryngeal cancer, ovarian cancer, thyroid cancer, esophageal cancer, nasopharyngeal cancer, pituitary cancer, salivary gland cancer, prostate cancer, pancreatic cancer, adrenal cancer; endometrial cancer, oral cancer, melanoma, neuroblastoma, gastric cancer, angiomatosis, hemangioblastoma, pheochromocytoma, pancreatic cyst, renal cell carcinoma, Wilman tumor, squamous cell carcinoma The invention relates to malignant cell carcinoma, sarcoma, osteosarcoma, Kaposi's sarcoma, rhabdomyosarcoma, hepatocellular carcinoma, PTEN hamartoma-tumor syndrome (PHTS) (such as Lhermitte-Duclos disease, Cowden syndrome, Proteus syndrome and Proteus-like syndrome), leukemias and lymphomas (such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, adult T-cell leukemia, juvenile myelomonocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle lymphoma, follicular lymphoma, primary effusion lymphoma, AIDS-related lymphoma, diffuse B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, nasopharyngeal carcinoma and gastrointestinal cancer.50.根据权利要求48或权利要求49所述的化合物，其中所述癌症缺乏DNA损伤应答修复途径，诸如同源重组依赖性DNA双链断裂DNA修复活性。50. A compound according to claim 48 or claim 49, wherein the cancer is deficient in DNA damage response repair pathways, such as homologous recombination dependent DNA double strand break DNA repair activity.51.根据权利要求48至50中的任一项所述的化合物，其中所述癌症缺乏BRCA1和/或BRCA2功能。51. The compound of any one of claims 48 to 50, wherein the cancer lacks BRCA1 and/or BRCA2 function.52.一种药物组合物，其包含如在权利要求1至47中的任一项中所定义的化合物。52. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 47.53.根据权利要求52所述的药物组合物，所述药物组合物进一步包含药学上可接受的添加剂和/或赋形剂，和/或其中所述化合物呈药学上可接受的盐、水合物、酸、酯的形式或所述化合物的其它替代形式。53. The pharmaceutical composition of claim 52, further comprising a pharmaceutically acceptable additive and/or excipient, and/or wherein the compound is in the form of a pharmaceutically acceptable salt, hydrate, acid, ester or other alternative form of the compound.54.根据权利要求52或权利要求53所述的药物组合物，所述组合物用于治疗如在权利要求48至51中的任一项中所定义的癌症。54. A pharmaceutical composition according to claim 52 or claim 53 for use in treating a cancer as defined in any one of claims 48 to 51.55.用于治疗癌症的根据权利要求54所述的药物组合物，所述药物组合物进一步包含用于治疗癌症的其它药剂；优选地其中所述用于治疗癌症的其它药剂选自抗微管剂、铂配位络合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、senolytic剂、激素和激素类似物、信号转导途径抑制剂、其它DNA损伤修复途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、抗体-药物偶联物、免疫治疗剂、激素剥夺疗法、促细胞凋亡剂和细胞周期信号传递抑制剂。55. A pharmaceutical composition according to claim 54 for treating cancer, further comprising other agents for treating cancer; preferably wherein the other agents for treating cancer are selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, immunotherapeutics, hormone deprivation therapy, pro-apoptotic agents and cell cycle signaling inhibitors.56.用于治疗癌症的根据权利要求55所述的药物组合物，其中所述其它药剂是选自抗肿瘤疫苗、溶瘤病毒、免疫刺激性抗体诸如抗-CTLA4、抗-PD1、抗-PDL-1、抗-OX40、抗-41BB、抗-CD27、抗-CD40、抗-LAG3、抗-TIM3和抗-GITR、模式识别受体激动剂诸如STING、TLR-9或RIG-I解螺旋酶激动剂、IDO或TDO抑制剂、新颖佐剂、肽、细胞因子、嵌合抗原受体T细胞疗法(CAR-T)、小分子免疫调节剂、肿瘤微环境调节剂和抗血管生成剂的免疫治疗剂。56. A pharmaceutical composition according to claim 55 for treating cancer, wherein the other agent is an immunotherapeutic agent selected from anti-tumor vaccines, oncolytic viruses, immunostimulatory antibodies such as anti-CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR, pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists, IDO or TDO inhibitors, novel adjuvants, peptides, cytokines, chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulators, tumor microenvironment modulators and anti-angiogenic agents.57.用于治疗癌症的药物试剂盒，所述药物试剂盒包含：57. A drug kit for treating cancer, the drug kit comprising:(a)如在权利要求1至47中的任一项中所定义的化合物；和(a) a compound as defined in any one of claims 1 to 47; and(b)用于治疗癌症的其它药剂；优选地其中所述用于治疗癌症的其它药剂选自抗微管剂、铂配位络合物、烷化剂、抗生素剂、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、senolytic剂、激素和激素类似物、信号转导途径抑制剂、其它DNA损伤修复途径抑制剂、非受体酪氨酸激酶血管生成抑制剂、抗体-药物偶联物、激素剥夺疗法、免疫治疗剂(诸如选自抗肿瘤疫苗、溶瘤病毒、免疫刺激性抗体诸如抗-CTLA4、抗-PD1、抗-PDL-1、抗-OX40、抗-41BB、抗-CD27、抗-CD40、抗-LAG3、抗-TIM3和抗-GITR、模式识别受体激动剂诸如STING、TLR-9或RIG-I解螺旋酶激动剂、IDO或TDO抑制剂、新颖佐剂、肽、细胞因子、嵌合抗原受体T细胞疗法(CAR-T)、小分子免疫调节剂、肿瘤微环境调节剂和抗血管生成剂)、促细胞凋亡剂和细胞周期信号传递抑制剂；(b) other agents for treating cancer; preferably wherein the other agents for treating cancer are selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, senolytic agents, hormones and hormone analogs, signal transduction pathway inhibitors, other DNA damage repair pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, antibody-drug conjugates, hormone deprivation therapy, immunotherapeutic agents (such as selected from anti-tumor vaccines, oncolytic viruses, immunostimulatory antibodies such as anti- CTLA4, anti-PD1, anti-PDL-1, anti-OX40, anti-41BB, anti-CD27, anti-CD40, anti-LAG3, anti-TIM3 and anti-GITR, pattern recognition receptor agonists such as STING, TLR-9 or RIG-I helicase agonists, IDO or TDO inhibitors, novel adjuvants, peptides, cytokines, chimeric antigen receptor T cell therapy (CAR-T), small molecule immunomodulators, tumor microenvironment modulators and anti-angiogenic agents), pro-apoptotic agents and cell cycle signaling inhibitors;其中所述化合物和所述其它药剂适合于同时、依次或单独施用。The compound and the other agent are suitable for simultaneous, sequential or separate administration.58.治疗疾病和/或病症和/或障碍的方法，所述方法包括向患者施用如在任何前述权利要求中所定义的化合物或组合物或试剂盒。58. A method of treating a disease and/or condition and/or disorder, the method comprising administering to a patient a compound or composition or kit as defined in any preceding claim.59.根据权利要求58所述的方法，其中所述疾病或病症或障碍是如在权利要求48至51中的任一项中所定义的疾病或病症或障碍。59. The method of claim 58, wherein the disease or condition or disorder is a disease or condition or disorder as defined in any one of claims 48 to 51.60.用于治疗癌症的根据权利要求59所述的方法，所述方法包括向患者施用如在权利要求1至50中的任一项中所定义的化合物或组合物以及如在权利要求55或权利要求56中所定义的用于治疗癌症的其它药剂；优选地其中同时、依次或单独施用所述化合物或组合物和所述其它药剂。60. A method according to claim 59 for treating cancer, the method comprising administering to a patient a compound or composition as defined in any one of claims 1 to 50 and other agents for treating cancer as defined in claim 55 or claim 56; preferably wherein the compound or composition and the other agent are administered simultaneously, sequentially or separately.61.根据权利要求58至60中的任一项所述的方法，其中所述患者是动物，优选哺乳动物，包括犬科动物、马科动物和猫科动物，且更优选人。61. The method of any one of claims 58 to 60, wherein the patient is an animal, preferably a mammal, including canines, equines and felines, and more preferably a human.62.化合物，其选自在权利要求45中定义的化合物中的任一种。62. A compound selected from any one of the compounds defined in claim 45.63.根据权利要求62所述的化合物，所述化合物包含：63. The compound of claim 62, comprising:-分离的对映异构体，或- separated enantiomers, or-两种或更多种对映异构体的混合物，或- a mixture of two or more enantiomers, or-两种或更多种非对映异构体和/或差向异构体的混合物，或- a mixture of two or more diastereomers and/or epimers, or-外消旋混合物，或- a racemic mixture, or-所述化合物的互变异构体。- tautomers of said compounds.64.如在权利要求1至47中的任一项中所定义的PARP1抑制剂化合物的合成方法，所述方法包括进行(i)包含带有取代基L的一部分的环E的第一反应物与(ii)包含取代基L的剩余部分的第二反应物之间的反应，从而形成所述PARP1抑制剂化合物。64. A method for synthesizing a PARP1 inhibitor compound as defined in any one of claims 1 to 47, the method comprising carrying out a reaction between (i) a first reactant comprising ring E bearing a portion of a substituent L and (ii) a second reactant comprising the remaining portion of the substituent L, thereby forming the PARP1 inhibitor compound.65.根据权利要求64所述的方法，其中所述第一反应物包含环E和环A，并且所述第二反应物包含带有反应基团的Q1或Q2前体，所述方法包括将环A的N原子连接至所述Q1或Q2前体。65. The method of claim 64, wherein the first reactant comprises ring E and ring A, and the second reactant comprises a Q1 or Q2 precursor bearing a reactive group, the method comprising attaching the N atom of ring A to the Q1 or Q2 precursor.66.根据权利要求65所述的方法，其中所述Q1或Q2前体的反应基团包含羰基基团、烷基卤化物或烷基磺酸酯。66. The method of claim 65, wherein the reactive group of the Q1 or Q2 precursor comprises a carbonyl group, an alkyl halide, or an alkyl sulfonate.67.根据权利要求64至66中的任一项所述的方法，其中所述反应包含烷基化、还原胺化或酰胺形成，从而形成基团L。67. The method according to any one of claims 64 to 66, wherein the reaction comprises alkylation, reductive amination or amide formation to form group L.68.根据权利要求64所述的方法，其中所述第一反应物包含环E、环A以及Q1和Q2中的至少一个，并且所述第二反应物包含带有离去基团(诸如卤化物或磺酸酯)的环C衍生物。68. The method of claim 64, wherein the first reactant comprises ring E, ring A, and at least one of Q1 and Q2, and the second reactant comprises a ring C derivative with a leaving group such as a halide or sulfonate.69.根据权利要求68所述的方法，其中所述反应包含亲核取代反应，诸如亲核芳族取代反应，从而形成基团L。69. The method of claim 68, wherein the reaction comprises a nucleophilic substitution reaction, such as a nucleophilic aromatic substitution reaction, thereby forming group L.