WO2026002007A1

WO2026002007A1 - Complement factor b inhibitor, pharmaceutical composition thereof, and use thereof

Info

Publication number: WO2026002007A1
Application number: PCT/CN2025/103317
Authority: WO
Inventors: 谷正松; 陈照强; 秦丽; 张晓金; 赵岭; 邵顺杰; 周媛; 曹斌; 田野; 陈斌
Original assignee: Zhuhai United Laboratories Co Ltd
Current assignee: Zhuhai United Laboratories Co Ltd
Priority date: 2024-06-25
Filing date: 2025-06-25
Publication date: 2026-01-02
Anticipated expiration: 2026-12-25

Abstract

The present application relates to a complement factor B inhibitor of formula (I), a pharmaceutical composition thereof, and the use thereof.

Description

Complement factor B inhibitors, their pharmaceutical compositions and applications

Technical Field

本发明属于药物合成领域，具体涉及一种新型补体因子B抑制剂及其药物组合物和应用。This invention belongs to the field of drug synthesis, specifically relating to a novel complement factor B inhibitor, its pharmaceutical composition, and its applications.

Background Technology

补体系统是机体固有免疫的重要组成部分，在病原体免疫监测和维持组织稳态中起着重要作用。补体系统参与多种疾病的发生、发展，如神经系统疾病阿尔兹海默(AD)、视神经脊髓炎(NMO)、重症肌无力(gMG)等，眼病疾病老年性黄斑变性(AMD)、葡萄膜炎、青光眼，肾病如非典型溶血尿毒综合征(aHUS)、C3肾小球病(C3G)和IgA肾病等，以及血液病冷凝集素病、阵发性睡眠性血红蛋白尿(PNH)、血栓性微血管病(TMAs)等。The complement system is an important component of the body's innate immunity, playing a crucial role in pathogen immune surveillance and maintaining tissue homeostasis. The complement system is involved in the occurrence and development of various diseases, such as neurological disorders like Alzheimer's (AD), neuromyelitis optica (NMO), and myasthenia gravis (gMG); eye diseases like age-related macular degeneration (AMD), uveitis, and glaucoma; kidney diseases such as atypical hemolytic uremic syndrome (aHUS), C3 glomerulonephropathy (C3G), and IgA nephropathy; and hematological diseases such as cold agglutinin disorders, paroxysmal nocturnal hemoglobinuria (PNH), and thrombotic microangiopathy (TMAs).

补体系统通过三条既独立又交叉的途径被激活，即经典通路(classical pathway,CP)、旁路途径(alternative pathway,AP)和凝集素通路(lectin pathway,LP)。补体B因子(complement factor B，CFB)是补体旁路途径(AP)中的一个重要因子，主要由肝细胞和巨噬细胞合成，是补体旁路途径活化中的一个重要成分。CFB参与机体防御，在细胞损伤及炎症过程中均起重要作用。CFB是一种胰蛋白酶样丝氨酸蛋白酶，以酶原形式存在于血液循环中。FB是激活AP途径的主要成分，其被激活后与C3b结合，随后被FD裂解产生一种含FB催化亚基(Bb)的C3转化酶复合物(C3bBb)，C3bBb继续切割C3以产生更多的C3b，从而对整个补体系统激活起到扩增放大作用。由于C3的不受控制循环，产生大量活性C3b及末端补体因子沉积于肾小球，引起肾小球结构及功能的改变，进一步引发补体系统受累相关肾病。The complement system is activated through three independent yet overlapping pathways: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP). Complement factor B (CFB) is a key factor in the alternative pathway (AP), primarily synthesized by hepatocytes and macrophages, and is a crucial component in its activation. CFB participates in the body's defense mechanisms, playing a vital role in cell damage and inflammation. CFB is a trypsin-like serine protease, existing in the bloodstream as a zymogen. FB is a major component in activating the AP pathway; upon activation, it binds to C3b, which is subsequently cleaved by FD to produce a C3 convertase complex (C3bBb) containing the FB catalytic subunit (Bb). C3bBb further cleaves C3 to generate more C3b, thus amplifying the activation of the entire complement system. Uncontrolled circulation of C3 leads to the deposition of large amounts of active C3b and terminal complement factors in the glomeruli, causing changes in glomerular structure and function, and further triggering complement system-related nephropathy.

目前已有多款靶向补体系统的药物获批上市，如C5抑制剂Culizumab和Ravulizumab，以及C3抑制剂Pegcetacoplan，适应证涉及非典型溶血性尿毒症综合征(aHUS)、重症肌无力和阵发性夜间血红蛋白尿(PNH)等。但临床发现大多使用C5或C3抑制剂的PNH患者未能完全阻断AP激活，仍存在轻中度的血管外溶血现象，补体受累相关疾病仍存在大量未满足的临床需求。Several drugs targeting the complement system have been approved for marketing, such as the C5 inhibitors Culizumab and Ravulizumab, and the C3 inhibitor Pegcetacoplan, with indications including atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria (PNH). However, clinical findings show that most PNH patients using C5 or C3 inhibitors do not completely block AP activation and still exhibit mild to moderate extravascular hemolysis, indicating a significant unmet clinical need for complement-related diseases.

LNP023(WO2015009616A1和WO2019043609A1)是Novartis开发的首个小分子FB靶向抑制剂，用于治疗补体系统受累相关的肾脏疾病，包括：阵发性睡眠性血红蛋白尿(PNH)、免疫球蛋白A肾病(IgAN)、C3肾小球疾病(C3G)、非典型溶血性尿毒症综合症(aHUS)等，其中PNH适应症已于2023年12月获批上市。
LNP023 (WO2015009616A1 and WO2019043609A1) is Novartis' first small molecule FB-targeting inhibitor for the treatment of kidney diseases related to complement system involvement, including paroxysmal nocturnal hemoglobinuria (PNH), immunoglobulin A nephropathy (IgAN), C3 glomerular disease (C3G), and atypical hemolytic uremic syndrome (aHUS). The PNH indication was approved for marketing in December 2023.

本领域仍然迫切需要开发新型补体系统FB小分子抑制剂，以增加临床研究并满足补体异常导致的各种疾病或病症的治疗。There remains an urgent need in this field to develop novel small molecule inhibitors of the complement system FB to increase clinical research and meet the treatment needs of various diseases or conditions caused by complement abnormalities.

Summary of the Invention

本发明提供调节并优选抑制补体旁路途径激活的化合物。在一些实施方案中，本发明提供调节并优选抑制补体因子B(FB)活性和/或FB介导的补体途径激活的化合物。This invention provides compounds that regulate and preferably inhibit activation of the complement bypass pathway. In some embodiments, this invention provides compounds that regulate and preferably inhibit complement factor B (FB) activity and/or FB-mediated complement pathway activation.

本发明的新型FB小分子抑制剂对FB具有高亲合力，能够抑制FB的催化活性，具有明显的对补体旁路途径激活的抑制作用，因此具有抑制由C3激活引起的补体系统扩增，预防和治疗由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症的潜力。本发明的化合物具有改善的药物代谢动力学性质(例如改善的生物利用度、改善的代谢稳定性、合适的半衰期和作用持续时间)、改善的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等更优异的性质。The novel small molecule inhibitors of FB of the present invention have a high affinity for FB, inhibit its catalytic activity, and exhibit significant inhibitory effects on complement bypass pathway activation. Therefore, they have the potential to inhibit complement system amplification caused by C3 activation, and to prevent and treat diseases, disorders, or conditions mediated by complement activation, particularly those mediated by complement bypass pathway activation. The compounds of the present invention possess superior properties such as improved pharmacokinetic properties (e.g., improved bioavailability, improved metabolic stability, suitable half-life and duration of action), improved safety (lower toxicity (e.g., reduced cardiotoxicity) and/or fewer side effects), and less likelihood of developing drug resistance.

在一个方面，本发明提供如下文所定义的式(I)的化合物：
In one aspect, the present invention provides compounds of formula (I) as defined below:

或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐。Or its stereoisomers, tautomers, diastereomers, racemic compounds, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts.

在另一个方面，本发明提供药物组合物，其包含根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，以及药学上可接受的载体。In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

在另一个方面，本发明提供药物组合，其包括根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，和另一种治疗活性剂。In another aspect, the present invention provides a pharmaceutical combination comprising a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and another therapeutically active agent.

在另一个方面，本发明提供调节个体的补体旁路途径活性的方法，其中所述方法包括：向所述个体施用治疗有效量的根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐；或者向所述个体施用治疗有效量的根据本发明的药物组合物；或者向所述个体施用治疗有效量的根据本发明的药物组合。In another aspect, the present invention provides a method for modulating the activity of the complement bypass pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the invention.

在另一个方面，本发明提供预防或治疗个体中由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症的方法，其中所述方法包括：向所述个体施用治疗有效量的根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐；或者向所述个体施用治疗有效量的根据本发明的药物组合物；或者向所述个体施用治疗有效量的根据本发明的药物组合。In another aspect, the present invention provides a method for preventing or treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the invention.

在另一个方面，本发明提供根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐、或者根据本发明的药物组合物、或者根据本发明的药物组合，其用作药物。In another aspect, the present invention provides a compound of formula (I) according to the invention, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, or a pharmaceutical composition according to the invention, or a pharmaceutical combination according to the invention, which are used as pharmaceuticals.

在另一个方面，本发明提供根据本发明的式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐、或者根据本发明的药物组合物、或者根据本发明的药物组合在制备用于治疗个体中由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症的药物中的用途。In another aspect, the present invention provides the use of a compound of formula (I) according to the invention, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical compositions according to the invention, or pharmaceutical combinations according to the invention, in the preparation of medicaments for treating diseases, disorders or conditions mediated by complement activation in an individual, particularly diseases, disorders or conditions mediated by activation of the complement alternative pathway.

在一些实施方案中所述疾病、障碍或病症选自与年龄相关的黄斑变性(AMD)、黄斑地图状萎缩、糖尿病视网膜病变、葡萄膜炎、视网膜色素变性、黄斑水肿、白塞氏葡萄膜炎、多灶性脉络膜炎、Vogt-Koyangi-Harada综合征、中间葡萄膜炎、鸟眼视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮，非动脉性缺血性视神经病变、术后炎症、视网膜静脉阻塞、神经系统疾病、多发性硬化、中风、格林-巴利综合征、创伤性脑损伤、帕金森氏病、不适当或不期望的补体激活导致的病症、血液透析并发症、超急性同种异体移植排斥、异种移植排斥、白细胞介素-2(IL-2)治疗期间IL-2诱导的毒性、炎症性疾病、自身免疫性疾病的炎症、克罗恩病、成人呼吸窘迫综合征、心肌炎、缺血后再灌注病症、心肌梗死、球囊血管成形术、心肺转流术或肾转流术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建后肠系膜动脉再灌注、感染性疾病或败血症、免疫复合物病症和自身免疫性疾病、类风湿性关节炎、系统性红斑狼疮(SLE)、狼疮肾炎(LN)、增生性肾炎、C3肾小球疾病(C3G)、免疫球蛋白A肾病(IgAN)或具有肾小球C3沉积证据的其他肾病(例如膜性肾病(MN)和大肠杆菌诱导的溶血性尿毒症综合征(HUS))、阵发性夜间血红蛋白尿(PNH)、非典型溶血性尿毒症综合征(aHUS)、免疫性血小板减少性紫癜(ITP)、冷凝集素疾病(CAD)、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、哮喘、慢性阻塞性肺病(COPD)、肺气肿、肺栓塞和梗塞、肺炎、纤维原性粉尘病、肺纤维化、过敏、支气管收缩、超敏性肺炎、寄生虫病、肺出血肾炎综合征、肺血管炎、Pauci免疫血管炎、免疫复合物相关炎症、抗磷脂综合征、肾小球肾炎或肥胖症。In some implementations, the diseases, disorders, or conditions described are selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, etc. Stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, symptoms caused by inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia Blood loss, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative glomerulonephritis, C3 glomerular disease (C3G), immunoglobulin A nephropathy (IgAN) or other nephropathy with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and Escherichia coli-induced hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), Immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrogenic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity.

Detailed Implementation

定义definition

除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤(即，这些术语也涵盖术语“基本上由……组成”和“由……组成”)。The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

如本文中所使用，术语“烷烃”意指直链或支链的饱和脂肪族烃。As used in this article, the term "alkane" refers to a straight-chain or branched saturated aliphatic hydrocarbon.

如本文中所使用，术语“烷基”意指直链或支链的单价饱和脂肪族烃，其可以看作由烷烃失去1个氢原子而得到的基团。在一些实施方案中，烷基具有1至12个，例如1至6个(例如1、2、3、4、5或6个)碳原子。例如，如本文中所使用，术语“C_1-6烷基”指1至6个碳原子的直链或支链的基团，包括“C_2-6烷基”、“C_2-5烷基”和“C_1-4烷基”。“C_1-6烷基”的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基和正己基。所述烷基任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”，例如CF₃、C₂F₅、CHF₂、CH₂F、CH₂CF₃、CH₂Cl或-CH₂CH₂CF₃等)。术语“C_1-4烷基”指具有1至4个碳原子的烷基(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。As used herein, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon, which can be considered as a group obtained by losing one hydrogen atom from an alkane. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term " _C1-6 alkyl" refers to a straight-chain or branched group with 1 to 6 carbon atoms, including " _C2-6 alkyl", " _C2-5 alkyl", and " _C1-4 alkyl". Examples of " _C1-6 alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The alkyl group is optionally substituted with one or more (such as one to three) suitable substituents such as halogens (in which case the group is called a "haloalkyl", for example _CF3 , _C2F5 , _CHF2 , _CH2F , _CH2CF3 , _CH2Cl , or _-CH2CH2CF3 , _etc. ). The term " _C1-4 alkyl" refers to an alkyl group having one _to _four carbon atoms (i.e., methyl, ethyl, n-propyl _, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

如本文中所使用，术语“亚烷基”表示直链或支链的二价饱和脂肪族烃。在一些实施方案中，亚烷基具有1至12个碳原子，优选具有1、2、3、4、5或6个碳原子，例如亚甲基、亚乙基、亚丙基或亚丁基。As used herein, the term "alkylene" refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon. In some embodiments, the alkylene has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

如本文中所使用，术语“杂烷基”意指如本文所定义的烷基，其骨架中的一个或多个CH₂被杂原子代替，所述杂原子各自独立地选自O、S、S(O)、S(O)₂、NR’及其组合，其中R’为氢原子或C_1-6烷基或卤代-C_1-6烷基。如本文中所使用，与杂烷基结合的前缀“x元”或“x至y元”表示所述杂烷基骨架链中C原子和杂原子成员的总数。在一些实施方案中，亚杂烷基可以是例如2至6元亚杂烷基、2至5元亚杂烷基、或2至4元亚杂烷基(例如，-CH₂OCH₂CH₃、-CH₂N(CH₃)CH₂CH₃)。杂烷基可以通过骨架链中的杂原子或碳原子与分子的其余部分连接。As used herein, the term "heteroalkyl" means an alkyl group as defined herein, in which one or more _CH2 atoms in the skeleton are replaced by heteroatoms, each independently selected from O, S, S(O), S(O) ₂ , NR', and combinations thereof, wherein R' is a hydrogen atom or a _C1-6 alkyl or a halo- _C1-6 alkyl. As used herein, the prefix "x-membered" or "x to y-membered" associated with a heteroalkyl group indicates the total number of C atoms and heteroatom members in the heteroalkyl skeleton chain. In some embodiments, the heteroalkylene group may be, for example, a 2- to 6-membered heteroalkylene group, a 2- to 5-membered heteroalkylene group, or _a _2- to 4-membered heteroalkylene group (e.g., _-CH2OCH2CH3 , _-CH2N ( _CH3 ) _CH2CH3 ₎ . The heteroalkyl group may be attached to the remainder of the molecule via heteroatoms or carbon atoms in the skeleton chain.

如本文中所使用，术语“烯基”意指直链或支链的单价脂肪族烃基，其包含一个或多个双键。在一些实施方案中，烯基具有2-6个碳原子(“C_2-6烯基”)。所述烯基为例如-CH＝CH₂、-CH₂CH＝CH₂、-C(CH₃)＝CH₂、-CH₂-CH＝CH-CH₃、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”为相应的二价基团，包括例如“C_2-6亚烯基”、“C_2-4亚烯基”等，其具体实例包括但不限于：-CH＝CH-、-CH₂CH＝CH-、-C(CH₃)＝CH-、亚丁烯基、亚戊烯基、亚己烯基等。As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2-6 carbon atoms (" _C2-6 alkenyl"). The alkenyl group is, for example, -CH= _CH2 , _-CH2CH =CH2, -C( _CH3 )= _CH2 , _-CH2 _- CH=CH-CH3, ₂ -pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof. The term "alkenyl" refers to the corresponding divalent group, including, for example, " _C2-6 alkenyl", " _C2-4 alkenyl", etc. Specific examples include, but are not limited to: -CH=CH-, _-CH2CH =CH-, -C( _CH3 )=CH-, buteneyl, pentenyl, hexeneyl, etc.

如本文中所使用，术语“炔基”意指直链或支链的单价脂肪族烃基，其包含一个或多个三键。在一些实施方案中，炔基具有2、3、4、5或6个碳原子(“C_2-6炔基”)，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。术语“亚炔基”为相应的二价基团，包括例如“C_2-6亚炔基”、“C_2-4亚炔基”等。其实例包括但不限于等。所述亚炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C _2-6 alkynyl"), such as ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted by one or more (such as 1 to 3) identical or different substituents. The term "ynynyl" refers to a corresponding divalent group, including, for example, "C _2-6 ynynyl,""C _2-4 ynynyl," etc. Examples include, but are not limited to, [examples not included in the text]. The alynyl group may optionally be substituted by one or more (such as 1 to 3) identical or different substituents.

如本文中所使用，术语“环烃基”、“烃环”和“亚环烃基”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-7、3-6、4-6或5-6个)环碳原子的饱和(即，“环烷基”和“亚环烷基”)或部分不饱和的(即在环内具有一个或多个双键(即，“环烯基”和“亚环烯基”)和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环丁烯基(环)、(亚)环戊烯基(环)、(亚)环己烯基(环)、(亚)环庚烯基(环)、(亚)环辛烯基(环)、(亚)环壬烯基(环)等。As used herein, the terms “cycloalkyl,” “cycloalkyl,” and “cycloalkylene-subcycloalkyl” refer to a monocyclic or polycyclic hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 7, 3 to 6, 4 to 6, or 5 to 6) cyclic carbon atoms, either saturated (i.e., “cycloalkyl” and “cycloalkylene-subcycloalkyl”) or partially unsaturated (i.e., having one or more double bonds (i.e., “cycloalkenyl” and “cycloalkenylene”) and/or triple bonds within the ring. These include, but are not limited to, (cyclo-propyl), (cyclo-butyl), (cyclo-pentyl), (cyclo-hexyl), (cyclo-heptyl), (cyclo-octyl), (cyclo-nonyl), (cyclo-butenyl), (cyclo-pentenyl), (cyclo-hexenyl), (cyclo-heptenyl), (cyclo-octenyl), and (cyclo-nonenyl).

如本文中所使用，术语“稠合”意指两个或两个以上环状结构彼此共用两个相邻的原子。As used in this article, the term "fusion" means that two or more ring structures share two adjacent atoms with each other.

如本文中所使用，术语“桥”或“桥接”或“桥连”意指两个或两个以上环状结构彼此共用两个不相邻的原子。As used in this article, the term “bridge” or “bridging” or “bridge connection” means that two or more ring structures share two non-adjacent atoms.

如本文中所使用，术语“螺”或“螺接”意指两个或两个以上环状结构彼此共用1个原子。As used in this article, the term "screw" or "screwed connection" refers to two or more ring structures sharing one atom with each other.

如本文中所使用，术语“环烷基”或“亚环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子，适合地具有3至10个碳原子。例如，术语“C_3-6环烷基”指3至6个成环碳原子的饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)。所述环烷基任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。As used herein, the term "cycloalkyl" or "cycloalkylene" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms, suitably 3 to 10 carbon atoms. For example, the term "C _"3-6 cycloalkyl" refers to a saturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms. The cycloalkyl group is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

如本文中所使用，术语“杂环基”、“杂环”和“亚杂环基”指饱和(即，“杂环烷基”和“亚杂环烷基”)或部分不饱和(例如，在环内具有一个或多个双键(即，“杂环烯基”和“亚杂环烯基”))的单环、稠环、螺环或桥环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自C(＝O)、O、S、S(＝O)、S(＝O)₂和NR^a’的含杂原子的基团，其中R^a’表示氢原子或C_1-6烷基或C_1-6卤代烷基。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。所述“杂环基”可以是单环或多环体系(多环体系包括但不限于双环、三环、四环或五环体系基团)。例如，3-12元杂环基为在环中具有3-12个(例如3-7、4-6或5-6个)碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、硫杂环丁烷、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。As used herein, the terms “heterocyclic group,” “heterocyclic,” and “hemiecyclic group” refer to a monocyclic, fused-ring, spirocyclic, or bridged ring group that is saturated (i.e., “hemiecyclic alkyl” and “hemiecyclic alkyl”) or partially unsaturated (e.g., having one or more double bonds (i.e., “hemiecyclic alkenyl” and “hemiecyclic alkenyl”) within the ring) and has 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O) ₂ , and NR ^a' , where Ra ^' represents a hydrogen atom or a _C1-6 alkyl or _C1-6 haloalkyl. The heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). The “heterocyclic group” can be a monocyclic or polycyclic system (polycyclic systems include, but are not limited to, bicyclic, tricyclic, tetracyclic, or pentacyclic groups). For example, a 3-12 membered heterocyclic group is a group having 3-12 (e.g., 3-7, 4-6, or 5-6) carbon atoms and heteroatoms in a ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, thioheterocyclic butane, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

如本文中所使用，术语“芳基”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C_6-10芳基”意指含有6至10个碳原子的芳族基团，诸如苯基或萘基。芳基任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO₂、C_1-6烷基等)取代。As used herein, the term "aryl" refers to a monocyclic or fused-ring aromatic group having a conjugated π-electron system. For example, as used herein, the term " _C6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group may optionally be substituted with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, _{-NO2, C1-6} _alkyl , etc.).

如本文中所使用，术语“杂芳基”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基(包括1,2,3-三唑基、1,2,4-三唑基)、噻二唑基等，以及它们的苯并衍生物；或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等，以及它们的苯并衍生物。As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom (which may be the same or different, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl), thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].

如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br or I.

术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form a stable compound.

如果基团被描述为“任选地被……取代”或“任选取代的”，则该基团可以是：(1)未被取代或(2)被取代。如果基团的碳被描述为任选地被取代基列表中的一个或多个取代，则该碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果基团的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。任选的取代基可以选自：氘、卤素、OH、SH、CN、NO₂、C_1-6烷基、C_1-6卤代烷基、C_2-6烯基、C_2-6炔基、-O-C_1-6烷基、-O-卤代C_1-6烷基、-O-C_2-6烯基、-O-C_2-6炔基、-S-C_1-6烷基、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH、-C_1-6亚烷基-CN、-C_1-6亚烷基-NH₂、-C_1-6亚烷基-NH(C_1-6烷基)、-C_1-6亚烷基-N(C_1-6烷基)₂、-C_1-6烷基-O-C_1-6烷基、-C_0-6亚烷基-C(O)OH、-C_0-6亚烷基-C(O)OC_1-6烷基、-C_0-6亚烷基-C(O)NH₂、-C_0-6亚烷基-C(O)NH(C_1-6烷基)、-C_0-6亚烷基-C(O)N(C_1-6烷基)₂、-C_0-6亚烷基-S(O)₂C_1-6烷基、-C_0-6亚烷基-S(O)₂NH₂、-C_0-6亚烷基-S(O)₂NH(C_1-6烷基)、-C_0-6亚烷基-S(O)₂N(C_1-6烷基)₂、-NH-C(O)C_1-6烷基、-N(C_1-6烷基)-C(O)C_1-6烷基、-NH-C(＝O)OH、-NH-C(＝O)OC_1-6烷基、-N(C_1-6烷基)-C(＝O)OC_1-6烷基、-NH-C(O)NH₂、-NH-C(O)NH(C_1-6烷基)、-NH-C(O)N(C_1-6烷基)₂、-NH-S(O)₂-C_1-6烷基、-N(C_1-6烷基)-S(O)₂-C_1-6烷基、-C_0-6亚烷基-C_3-10环烷基、-C_0-6亚烷基-(3-10元杂环基)、-C_0-6亚烷基-苯基和-C_0-6亚烷基-(5-10元杂芳基)。If a group is described as “optionally substituted” or “optionally substituted”, then the group may be: (1) unsubstituted or (2) substituted. If the carbon of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and/or together with independently selected optional substituents. If the nitrogen of the group is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents. Optional substituents may be selected from: deuterium, halogen, OH, SH, CN, _NO₂ , C₁ _-6 alkyl, C₁ _- 6 haloalkyl, C₂ _- 6 alkenyl, C₂-6 ynyl, -OC₁ _-6 alkyl, -O-haloC₁-6 alkyl, _-OC₂- 6 alkenyl, -OC₂- ₆ ynyl, -SC₁- ₆ alkyl, NH₂, -NH(C₁ _-6 alkyl), -N(C₁ _- 6 alkyl) _₂ , -C₁-6 alkylene-OH, -C₁-6 alkylene-SH, -C₁ _-6 alkylene-CN, -C₁- ₆ alkylene-NH₂, -C₁- ₆ alkylene-NH(C₁ _-6 alkyl), -C₁-6 alkylene-N(C₁-6 alkyl) _₂ , -C₁-6 alkyl-OC₁ _-6 alkyl, -C₁- _{6 alkyl-OC₁-6} alkyl, -C₁- ₆ alkyl-NH₂, -C₁-6 alkyl-NH(C₁- ₆ alkyl), -C₁-6 alkylene-N(C₁- ₆ alkyl) _₂ , -C₁ _-6 alkyl-OC₁ _-6 alkyl, -C₁-6 alkyl-NH₂, -C₁ _-6 alkyl-NH(C₁ _-6 alkyl), ... -C _0-6 alkylene-C(O)OH, -C _ _0-6 alkylene-C(O)OC _1-6 alkyl, -C _0-6 alkylene-C(O)NH ₂ , -C _0-6 alkylene-C(O)NH(C_{1-6alkyl),-C0-6}alkylene-C(O)N(C_1-6alkyl) ₂ , -C _0-6 alkylene-S(O) ₂ C1-6 _ alkyl, -C _0-6 alkylene-S(O) ₂ NH ₂ , -C0-6alkylene-S(O) _ ₂ NH(C _1-6 alkyl), -C _ _0-6 alkylene-S(O) ₂ N(C1-6alkyl) ₂ , -NH-C(O)C _1-6 alkyl, -N(C _1-6 alkyl)-C(O)C1-6alkyl _1-6 alkyl, -NH-C(＝O)OH, -NH-C(＝O)OC _1-6 alkyl, -N(C _1-6 alkyl)-C(＝O)OC _1-6 alkyl, -NH-C(O)NH ₂ , -NH-C(O)NH(C _1-6 alkyl), -NH-C(O)N(C _1-6 alkyl) ₂ , -NH-S(O) ₂ -C _1-6 alkyl, -N(C _1-6 alkyl)-S(O) ₂ -C _1-6 alkyl, -C _0-6 alkylene-C _3-10 cycloalkyl, -C _0-6 alkylene-(3-10 heterocyclic group), -C _0-6 alkylene-phenyl and -C _0-6 alkylene-(5-10 heteroaryl group).

如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, six, seven, eight, nine, or ten.

除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

当取代基的键显示为穿过环中连接两个原子的键(“漂浮键”)时，则这样的取代基可键连至该可取代的环中的任一成环原子，除非另有说明。在显示可用环成员携带可取代的氢原子的情况下，当该漂浮键键连至该可用环成员时，该可取代氢原子实质上已被取代(即，不存在)。When a substituent is shown to be a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent may be bonded to any cyclic atom in the substituted ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present) when the floating bond is bonded to that substituted ring member.

本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D，²H)、氚(T，³H))；碳的同位素(例如¹¹C、¹³C及¹⁴C)；氯的同位素(例如³⁶Cl)；氟的同位素(例如¹⁸F)；碘的同位素(例如¹²³I及¹²⁵I)；氮的同位素(例如¹³N及¹⁵N)；氧的同位素(例如¹⁵O、¹⁷O及¹⁸O)；磷的同位素(例如³²P)；及硫的同位素(例如³⁵S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即³H)及碳-14(即¹⁴C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如¹¹C、¹⁸F、¹⁵O及¹³N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D₂O、丙酮-d₆或DMSO-d₆。在一些实施方案中，本发明的同位素标记化合物是氘代物。This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium (D, ^2H ), tritium (T, ^3H )); isotopes of carbon (e.g., ^11C , ^13C , and ^14C ); isotopes of chlorine (e.g., ^36Cl ); isotopes of fluorine (e.g., ^18F ); isotopes of iodine (e.g., ^123I and ^125I ); isotopes of nitrogen (e.g., ^13N and ^15N ); isotopes of oxygen (e.g., ^15O , ^17O , and ^18O ); isotopes of phosphorus (e.g., ^32P ); and isotopes of sulfur (e.g., ^35S ). Certain isotopically labeled compounds of the present invention (e.g., those incorporating radioactive isotopes) can be used in pharmaceutical and/or substrate tissue distribution studies (e.g., analysis). Radioactive isotopes tritium (i.e., ^3H ) and carbon-14 (i.e., ^14C ) are particularly suitable for this purpose due to their ease of incorporation and detection. Substitution with positron-emitting isotopes (e.g., ^11C , ^18F , ^15O , and ^13N ) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and/or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, _D₂O , acetone- _d₆ , or DMSO- _d₆ . In some embodiments, the isotopically labeled compounds of the present invention are deuterated.

术语“立体异构体”表示由于至少一个不对称中心形成的异构体，其具有相同的化学组成但原子或基团的空间排列不同。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。The term "stereoisomer" refers to isomers formed due to at least one asymmetric center, having the same chemical composition but different spatial arrangements of atoms or groups. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can occur. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It should be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

术语“非对映异构体”是指具有两个或多个手性中心并且其分子彼此不互为镜像的立体异构体。非对映异构体具有不同的物理性质，例如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可通过高分辨率的分析方法例如电泳法和色谱法进行分离。The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography.

术语“对映异构体”是指化合物的彼此呈不可重叠的镜像的两种立体异构体。The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

术语“手性”是指具有镜像对的不可重叠性的分子，而术语“非手性”是指可在它们的镜像对上重叠的分子。The term "chirality" refers to molecules that have mirror pairs that are not overlapping, while the term "chirality" refers to molecules that can overlap on their mirror pairs.

本发明的化合物可以制备成外消旋的形式，或者，通过对映体选择性合成或者通过拆分可以制备单一的对映异构体。The compounds of the present invention can be prepared in racemic form, or a single enantiomer can be prepared by enantioselective synthesis or by resolution.

术语“消旋体”、“外消旋物”或“外消旋混合物”是指缺少光学活性的两个对映异构体的等摩尔混合物。The terms “racemate,” “racemic mixture,” or “racemic mixture” refer to an equimolar mixture of two enantiomers that lack optical activity.

如本文中所使用，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。本文所提供的化合物包括所有顺式、反式、顺(syn)、反(anti)、entgegen(E)和zusammen(Z)异构体以及其相应的混合物。As used herein, the terms “cis-trans isomers” or “geometric isomers” arise from the fact that the single bonds of double or cyclic carbon atoms cannot rotate freely. The compounds presented herein include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and their corresponding mixtures.

本文中可使用实线实楔形或虚楔形描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键旨在表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键旨在表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。当化合物包含两个手性中心时，可使用粗实线和粗虚线描绘所述化合物中的化学键，来显示两个手性中心的相对关系，但不意指任何绝对立体化学。例如，表示环上连接R^a的键与连接R^b的键互相为顺式，并且涵盖和两种对应异构体。Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate that all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) are included at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs). Thick solid lines may be used when the compound contains two chiral centers. and thick dashed lines The chemical bonds in the compound are depicted to show the relative relationship between the two chiral centers, but do not imply any absolute stereochemistry. For example, This indicates that the key connecting ^Ra on the ring and the key connecting ^Rb are in sequence with each other, and Coverage and Two corresponding isomers.

还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向有需要的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to cover the various derivative forms of the compounds described above.

术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with other components constituting the formulation and/or the mammals treated with it.

本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucohepanoate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydroiodate/iodide, maleate, malonate, methyl sulfate, naphthylcarbamate, nicotinate, nitrate, orotate, oxalate, palmitate, and other similar salts.

适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.

适合的盐的综述参见Stahl及Wermuth的“Handbook ofPharmaceutical Salts:Properties,Selection,andUse”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts, see Stahl and Wermuth's "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W.H. Cheeseman and E.S.G. Werstiuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

术语“N-氧化物”又称氧化胺，是一类通式为R₃N+-O-(也写作R₃N＝O或R₃N→O)的有机化合物。The term "N-oxide" is also known as amine oxide, which is a class of organic compounds with the general formula _R3N +-O- (also written as _R3N ＝O or _R3N →O).

在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American PharmaceuticalAssociation)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design ofProdrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the desired therapeutically active compounds. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (edited by E.B. Roche, American Pharmaceutical Association). The prodrug of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., “Design of Prodrugs”, as described in H. Bundgaard (Elsevier, 1985)).

本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and/or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。As used herein, the term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

化合物compound

在一个方面，本发明提供式(I)的化合物：
In one aspect, the present invention provides compounds of formula (I):

或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，Or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts.

其中：in:

R¹各自独立地选自氘、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_1-6卤代烷基、C_1-6卤代烷氧基、-NH(C_1-6氘代烷基)、-N(C_1-6氘代烷基)₂、C_1-6氘代烷基、C_1-6氘代烷氧基、C_3-6环烷基或4-7元杂环基； ^R1 is independently selected from deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 alkoxy, -NH ( _{C1-6 haloalkyl), -N (C1-6} _haloalkyl ) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterated alkyl), -N ( _C1-6 deuterated alkyl) ₂ , _C1-6 deuterated alkyl, _C1-6 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

R²选自氢、氘、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_1-6卤代烷基、C_1-6卤代烷氧基、-NH(C_1-6氘代烷基)、-N(C_1-6氘代烷基)₂、C_1-6氘代烷基、C_1-6氘代烷氧基、C_3-6环烷基或4-7元杂环基； ^R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterated alkyl), -N ( _C1-6 deuterated alkyl) ₂ , _C1-6 deuterated alkyl, _C1-6 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

R³选自氢、氘、卤素、OH、SH、CN、-NR^3aR^3b、C_1-6烷基、C_1-6卤代烷基、C_1-6氘代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6氘代烷氧基、-S(C_1-6烷基)、C_3-6环烷基、4-7元杂环基、C_6-10芳基、5-10元杂芳基、-C_1-6亚烷基-OC_1-6烷基、-OC_1-6亚烷基-OC_1-6烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-CN或-C_1-6亚烷基-NR^3aR^3b； ^R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, ^-NR3a ^R3b , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 deuteralkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( _C1-6 alkyl), _C3-6 cycloalkyl, _4-7 membered heterocyclic, _C6-10 aryl, 5-10 membered heteroaryl, _-C1-6 alkylene- _OC1-6 alkyl, _-OC1-6 alkylene- _OC1-6 alkyl, _-C1-6 alkylene-OH, _-C1-6 alkylene-CN or _-C1-6 alkylene- ^NR3a ^R3b ;

R^3a和R^3b在每次出现时独立地选自H、C_1-6烷基、C_1-6卤代烷基或C_1-6氘代烷基； ^R3a and ^R3b are each independently selected from H, _C1-6 alkyl, _C1-6 haloalkyl, or _C1-6 deuteralkyl when they appear;

R⁴选自氢、氘、卤素、OH、CN、SH、NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、-S(C_1-6烷基)、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_3-10环烷基、3-12元杂环基、-C_1-6亚烷基-C_3-10环烷基或-C_1-6亚烷基-3-12元杂环基；所述C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、-S(C_1-6烷基)、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_3-10环烷基、3-12元杂环基、-C_1-6亚烷基-C_3-10环烷基或-C_1-6亚烷基-3-12元杂环基任选地被1、2、3、4、5、6个或更多个选自氘、卤素、OH、CN、NH₂、SF₅、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、-S(C_1-6烷基)、-S(C_1-6卤代烷基)、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、-S(＝O)(C_1-6烷基)、-S(＝O)₂(C_1-6烷基)、-S(＝O)(C_1-6卤代烷基)、-S(＝O)₂(C_1-6卤代烷基)、-O(C_3-6环烷基)、-O(C_3-6卤代环烷基)、-S(C_3-6环烷基)或-S(C_3-6卤代环烷基)的取代基取代； ^R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -S ( _C1-6 alkyl), -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- _C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, -S ( _C1-6 alkyl), -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl)2, _C3-10 cycloalkyl, 3-12 membered heterocyclic, _-C1-6 alkylene- _C3-10 cycloalkyl, -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene-C3-10 cycloalkyl, -N ( _C1-6 haloalkyl)2, - ... The _3-10 cycloalkyl or _-C1-6 alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, ₅ , 6 or more groups selected from deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 alkyl), -S( _C1-6 haloalkyl), -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -NH( _C1-6 haloalkyl), -N( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

R^g、R^h各自独立地选自氢或氘； ^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键； Indicates a single or double bond;

条件是所述化合物不是 The condition is that the compound is not

本发明中，作为实施方案之一，式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，In this invention, as one embodiment, a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

其中：in:

R¹各自独立地选自氘、C_1-6烷基、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_1-6卤代烷基、C_1-6卤代烷氧基、-NH(C_1-6氘代烷基)、-N(C_1-6氘代烷基)₂、C_1-6氘代烷基、C_1-6氘代烷氧基、C_3-6环烷基或4-7元杂环基； ^R1 is independently selected from deuterium, _C1-6 alkyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterium alkyl), -N ( _C1-6 deuterium alkyl) ₂ , _C1-6 deuterium alkyl, _C1-6 deuterium alkoxy, _C3-6 cycloalkyl or 4-7 membered heterocyclic group;

R^3a和R^3b在每次出现时独立地选自H、C_1-6烷基、C_1-6卤代烷基或C_1-6氘代烷基； ^R3a and ^R3b are independently selected from H, _C1-6 alkyl, _C1-6 haloalkyl, or _C1-6 deuteralkyl each time they appear;

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R²选自氘、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_1-6卤代烷基、C_1-6卤代烷氧基、-NH(C_1-6氘代烷基)、-N(C_1-6氘代烷基)₂、C_1-6氘代烷基、C_1-6氘代烷氧基或4-7元杂环基； ^R2 is selected from deuterium, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, C1-6 haloalkoxy, _{-NH (C1-6 deuterium alkyl), -N (C1-6} _deuterium _alkyl ) ₂ , _C1-6 deuterium alkyl, _C1-6 deuterium alkoxy, or 4-7 membered heterocyclic groups;

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R³选自氘、4-7元杂环基、C_6-10芳基、5-10元杂芳基或-C_1-6亚烷基-CN；R ³ is selected from deuterium, 4-7 membered heterocyclic groups, C _6-10 aryl groups, 5-10 membered heteroaryl groups, or -C _1-6 alkylene-CN groups;

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R^3a和R^3b在每次出现时独立地选自C_1-6卤代烷基或C_1-6氘代烷基； ^R3a and ^R3b are each independently selected from _C1-6 haloalkyl or _C1-6 deuteralkyl when they appear;

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R⁴选自氘或-S(C_1-6烷基)；所述-S(C_1-6烷基)任选地被1、2、3、4、5、6个或更多个选自氘、卤素、OH、CN、NH₂、SF₅、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、-S(C_1-6烷基)、-S(C_1-6卤代烷基)、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、-S(＝O)(C_1-6烷基)、-S(＝O)₂(C_1-6烷基)、-S(＝O)(C_1-6卤代烷基)、-S(＝O)₂(C_1-6卤代烷基)、-O(C_3-6环烷基)、-O(C_3-6卤代环烷基)、-S(C_3-6环烷基)或-S(C_3-6卤代环烷基)的取代基取代； ^R4 is selected from deuterium or -S ( _C1-6 alkyl); said -S ( _C1-6 alkyl) is optionally selected from 1, 2, 3, 4, ₅ , 6 or more of deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S ( _C1-6 alkyl), -S ( _C1-6 haloalkyl), -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R⁴选自氘或-S(C_1-6烷基)，所述-S(C_1-6烷基)任选地被1、2、3、4、5、6个或更多个选自氘、卤素、OH、CN、NH₂、SF₅、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、-S(C_1-6烷基)、-S(C_1-6卤代烷基)、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、-S(＝O)(C_1-6烷基)、-S(＝O)₂(C_1-6烷基)、-S(＝O)(C_1-6卤代烷基)、-S(＝O)₂(C_1-6卤代烷基)、-O(C_3-6环烷基)、-O(C_3-6卤代环烷基)、-S(C_3-6环烷基)或-S(C_3-6卤代环烷基)的取代基取代； ^R4 is selected from deuterium or -S ( _C1-6 alkyl), wherein -S ( _C1-6 alkyl) is optionally composed of 1, 2, 3, 4, ₅ , 6 or more of deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S ( _C1-6 alkyl), -S ( _C1-6 haloalkyl), -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

其中：in:

R¹各自独立地选自卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)或-N(C_1-6烷基)₂； ^R1 is independently selected from halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl) or -N ( _C1-6 alkyl) ₂ ;

R²选自氢、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基或C_3-6环烷基； ^R2 is selected from hydrogen, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), _-N ( _C1-6 alkyl), _C1-6 alkyl, or _C3-6 cycloalkyl;

R³选自氢、卤素、OH、SH、CN、-NR^3aR^3b、C_1-6烷基、C_1-6卤代烷基、C_1-6氘代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、C_1-6氘代烷氧基、-S(C_1-6烷基)、C_3-6环烷基、-C_1-6亚烷基-OC_1-6烷基、-OC_1-6亚烷基-OC_1-6烷基、-C_1-6亚烷基-OH或-C_1-6亚烷基-NR^3aR^3b； ^R3 is selected from hydrogen, halogen, OH, SH, CN, ^-NR3a ^R3b , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 deuterated alkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 deuterated alkoxy, -S ( _C1-6 alkyl), _C3-6 cycloalkyl, -C1-6 alkylene _- _OC1-6 alkyl, -OC1-6 alkylene _-OC1-6 _alkyl , _-C1-6 alkylene-OH, or _-C1-6 alkylene- ^NR3a ^R3b ;

R^3a和R^3b在每次出现时独立地选自H或C_1-6烷基； ^R3a and ^R3b are independently selected from H or _C1-6 alkyl groups each time they appear;

R⁴选自氢、卤素、OH、CN、SH、NH₂、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_3-10环烷基、3-12元杂环基、-C_1-6亚烷基-C_3- ₁₀环烷基或-C_1-6亚烷基-3-12元杂环基；所述C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、C_3-10环烷基、3-12元杂环基、-C_1-6亚烷基-C_3- ₁₀环烷基或-C_1-6亚烷基-3-12元杂环基任选地被1、2、3、4、5、6个或更多个选自氘、卤素、OH、CN、NH₂、SF₅、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基、-S(C_1- ₆烷基)、-S(C_1-6卤代烷基)、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-NH(C_1-6卤代烷基)、-N(C_1-6卤代烷基)₂、-S(＝O)(C_1-6烷基)、-S(＝O)₂(C_1-6烷基)、-S(＝O)(C_1-6卤代烷基)、-S(＝O)₂(C_1-6卤代烷基)、-O(C_3-6环烷基)、-O(C_3-6卤代环烷基)、-S(C_3-6环烷基)或-S(C_3-6卤代环烷基)的取代基取代； ^R4 is selected from hydrogen, halogen, OH, CN, SH, NH2, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 _cycloalkyl , 3-12 membered heterocyclic, _-C1-6 alkylene- _C3-10 cycloalkyl, or -C1-6 alkylene- _3-12 membered heterocyclic; wherein _{the C1-6} _alkyl , _C2-6 alkenyl, _C2-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, _-C1-6 alkylene _- _C3-10 _cycloalkyl , or -C _{The 1-6} alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3 _, 4, ₅ , 6 or more groups selected from deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 alkyl), -S( _C1-6 haloalkyl), -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -NH( _C1-6 haloalkyl), -N( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ _(C1-6 _haloalkyl ), -O(C3-6 cyclo ... Substitution with substituents of _3-6 halocycloalkyl, -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;

表示单键或者双键。 It indicates a single or double bond.

在一些实施方案中，R^g、R^h均为氢。In some implementation schemes, both ^Rg and ^Rh are hydrogen.

在一些实施方案中，本发明所述化合物不是：

In some embodiments, the compound described in this invention is not:

在一些实施方案中，本发明所述式(I)的化合物具有式(I-1)或(I-2)所示结构：
In some embodiments, the compounds of formula (I) of the present invention have the structures shown in formula (I-1) or (I-2):

在一些实施方案中，本发明所述式(I)的化合物具有式(I-3)或(I-4)所示结构：
In some embodiments, the compounds of formula (I) of the present invention have the structures shown in formula (I-3) or (I-4):

在一些实施方案中，n选自0、1或2；优选地，n选自0或1；优选地，n为0。In some implementations, n is selected from 0, 1, or 2; preferably, n is selected from 0 or 1; preferably, n is 0.

在一些实施方案中，本发明所述式(I)的化合物具有式(II-1)-(II-6)之一所示的结构：
In some embodiments, the compound of formula (I) of the present invention has a structure shown in one of formulas (II-1)-(II-6):

在一些实施方案中，本发明所述式(I)的化合物具有式(II-1)所示的结构：
In some embodiments, the compound of formula (I) of the present invention has the structure shown in formula (II-1):

在一些实施方案中，本发明所述式(I)的化合物具有式(II-7)-(II-18)之一所示的结构：
In some embodiments, the compounds of formula (I) of the present invention have the structure shown in one of formulas (II-7)-(II-18):

在一些实施方案中，本发明所述式(I)的化合物具有式(II-7)所示的结构：
In some embodiments, the compounds of formula (I) of the present invention have the structures shown in formulas (II-7):

在一些实施方案中，本发明所述式(I)的化合物具有式(II-19)-(II-30)之一所示的结构：
In some embodiments, the compounds of formula (I) of the present invention have the structure shown in one of formulas (II-19)-(II-30):

在一些实施方案中，本发明所述式(I)的化合物具有式(II-19)所示的结构：
In some embodiments, the compounds of formula (I) of the present invention have the structure shown in formula (II-19):

在一些实施方案中，R¹选自氘、卤素、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、C_1-4烷基、C_1-4烷氧基、-NH(C_1-4卤代烷基)、-N(C_1-4卤代烷基)₂、C_1-4卤代烷基、C_1-4卤代烷氧基、-NH(C_1-4氘代烷基)、-N(C_1-4氘代烷基)₂、C_1-4氘代烷基、C_1-4氘代烷氧基、C_3-6环烷基或4-7元杂环基。In some embodiments, ^R1 is selected from deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C1-4 haloalkyl, _C1-4 haloalkoxy, -NH ( _C1-4 deuterated alkyl), -N ( _C1-4 deuterated alkyl) ₂ , _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.

在一些实施方案中，R¹选自卤素或C_1-4烷基。In some embodiments, ^R1 is selected from halogens or _C1-4 alkyl groups.

在一些实施方案中，R¹选自F、Cl或甲基。In some implementations, ^R1 is selected from F, Cl, or methyl.

在一些实施方案中，R²选自氢、氘、卤素、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、C_1-4烷基、C_1-4烷氧基、-NH(C_1-4卤代烷基)、-N(C_1-4卤代烷基)₂、C_1-4卤代烷基、C_1-4卤代烷氧基、-NH(C_1-4氘代烷基)、-N(C_1-4氘代烷基)₂、C_1-4氘代烷基、C_1-4氘代烷氧基、C_3-6环烷基或4-7元杂环基。In some embodiments, ^R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C1-4 haloalkyl, _C1-4 haloalkoxy, -NH ( _C1-4 deuterated alkyl), -N ( _C1-4 deuterated alkyl) ₂ , _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.

在一些实施方案中，R²选自氢、卤素或C_1-4烷基。In some implementations, ^R2 is selected from hydrogen, halogen, or _C1-4 alkyl.

在一些实施方案中，R²选自氢或卤素。In some implementations, ^R2 is selected from hydrogen or halogen.

在一些实施方案中，R²选自氢、F或Cl。In some implementations, ^R2 is selected from hydrogen, F, or Cl.

在一些实施方案中，R²为氢。In some implementations, ^R2 is hydrogen.

在一些实施方案中，R³选自氢、氘、卤素、OH、SH、CN、-NR^3aR^3b、C_1-4烷基、C_1-4卤代烷基、C_1-4氘代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、C_1-4氘代烷氧基、-S(C_1-4烷基)、C_3-6环烷基、4-7元杂环基、C_6-10芳基、5-6元杂芳基、-C_1-4亚烷基-OC_1-4烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-CN或-C_1-4亚烷基-NR^3aR^3b。In some embodiments, ^R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, ^-NR3a ^R3b , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 deuteralkyl, _C1-4 alkoxy, _C1-4 haloalkoxy, _C1-4 deuteralkyl, -S ( _C1-4 alkyl), C3-6 cycloalkyl, 4-7 heterocyclic, _C6-10 aryl, _5-6 heteroaryl, -C1-4 alkylene- _OC1-4 alkyl, _-OC1-4 alkylene _- _OC1-4 alkyl, _-C1-4 alkylene-OH, _-C1-4 alkylene-CN, or _-C1-4 alkylene- ^NR3a ^R3b .

在一些实施方案中，R^3a和R^3b在每次出现时独立地选自H、C_1-4烷基、C_1-4卤代烷基或C_1-4氘代烷基。In some embodiments, ^R3a and ^R3b are independently selected from H, _C1-4 alkyl, _C1-4 haloalkyl, or _C1-4 deuteralkyl each time they appear.

在一些实施方案中，R³选自卤素、CN、C_1-4烷基、-S(C_1-4烷基)、-NR^3aR^3b、C_1-4烷氧基、C_3-6环烷基、4-7元杂环基或-C_1-4亚烷基-OC_1-4烷基。In some embodiments, ^R3 is selected from halogens, CN, _C1-4 alkyl, -S ( _C1-4 alkyl), ^-NR3a ^R3b , _C1-4 alkoxy, _C3-6 cycloalkyl, 4-7 heterocyclic, or _-C1-4 alkylene- _OC1-4 alkyl.

在一些实施方案中，R^3a和R^3b在每次出现时独立地选自H或C_1-4烷基。In some embodiments, ^R3a and ^R3b are independently selected from H or _C1-4 alkyl groups each time they appear.

在一些实施方案中，R³选自F、Cl、CN、C_1-4烷基、-S(C_1-4烷基)、-NR^3aR^3b、C_1-4烷氧基、C_3-6环烷基、4-7元杂环基或-C_1-4亚烷基-OC_1-4烷基。In some embodiments, ^R3 is selected from F, Cl, CN, _C1-4 alkyl, -S ( _C1-4 alkyl), ^-NR3a ^R3b , _C1-4 alkoxy, _C3-6 cycloalkyl, 4-7 heterocyclic, or _-C1-4 alkylene- _OC1-4 alkyl.

在一些实施方案中，R^3a和R^3b在每次出现时独立地选自H或C_1-4烷基；优选R^3a和R^3b其中一者为H，另一者为C_1-4烷基。In some embodiments, ^R3a and ^R3b are independently selected from H or _C1-4 alkyl groups each time they appear; preferably, one of ^R3a and ^R3b is H and the other is _C1-4 alkyl.

在一些实施方案中，R³选自CN、C_1-4烷基、C_1-4烷氧基、C_3-6环烷基。In some embodiments, ^R3 is selected from CN, _C1-4 alkyl, _C1-4 alkoxy, and _C3-6 cycloalkyl.

在一些实施方案中，R³为C_1-4烷基。In some implementations, ^R3 is a _C1-4 alkyl group.

在一些实施方案中，R³选自CN、C_1-4烷基、-S(C_1-4烷基)、C_1-4烷氧基、C_3-6环烷基或4-7元杂环基。In some embodiments, ^R3 is selected from CN, _C1-4 alkyl, -S ( _C1-4 alkyl), _C1-4 alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups.

在一些实施方案中，R³选自F、Cl、-CN、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-SCH₃、-NHCH₃、-OCH₃、-OCH₂CH₃、-OCH(CH₃)₂、-CH₂OCH₃、环丙基、环丁基、氧杂环丁基(例如)、硫杂环丁基(例如)或氮杂环丁基(例如)。In some embodiments, ^R3 is selected from F, Cl, -CN, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , _-SCH3 , -NHCH3, _-OCH3 , -OCH2CH3 _, -OCH(CH3 ₎ ₂ , _-CH2OCH3 , cyclopropyl, _cyclobutyl , _{oxacyclobutyl} ( _e.g. ) ), thioheterobutyl (e.g.) ) or nitrogen-containing heterocyclic butyl (e.g. ).

在一些实施方案中，R³选自CN、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-SCH₃、环丁基、氧杂环丁基、-OCH₃、环丙基或-OCH₂CH₃。In some implementations, ^R3 is selected from CN, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , _-SCH3 , cyclobutyl _, oxacyclobutyl, _-OCH3 , cyclopropyl or _-OCH2CH3 .

在一些实施方案中，R³选自CN、-CH₃、-CH₂CH₃、-CH(CH₃)₂、-SCH₃、环丁基或氧杂环丁基。In some implementations, ^R3 is selected _from CN, _-CH3 , _-CH2CH3 , -CH( _CH3 ) ₂ , _-SCH3 , cyclobutyl or oxacyclobutyl.

在一些实施方案中，R⁴选自C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4烷氧基、-S(C_1-4烷基)、-NH(C_1-4卤代烷基)、-N(C_1-4卤代烷基)₂、C_3-6环烷基、4-7元杂环基、-C_1-4亚烷基-C_3-6环烷基或-C_1-4亚烷基-4-7元杂环基；所述C_1-4烷基、C_2-4烯基、C_2-4炔基、C_1-4烷氧基、-S(C_1-4烷基)、-NH(C_1-4卤代烷基)、-N(C_1-4卤代烷基)₂、C_3-6环烷基、4-7元杂环基、-C_1-4亚烷基-C_3-6环烷基或-C_1-4亚烷基-4-7元杂环基任选地被1、2、3、4、5或6个选自氘、卤素、OH、CN、NH₂、C_1-4烷基、C_1-4卤代烷基、C_1-4烷氧基、C_1-4卤代烷氧基、-S(C_1-4烷基)、-S(C_1-4卤代烷基)、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、-NH(C_1-4卤代烷基)、-N(C_1-4卤代烷基)₂、-S(＝O)(C_1-4烷基)、-S(＝O)₂(C_1-4烷基)、-S(＝O)(C_1-4卤代烷基)、-S(＝O)₂(C_1-4卤代烷基)、-O(C_3-6环烷基)或-O(C_3-6卤代环烷基)的取代基取代。In some embodiments, ^R4 is selected from _C1-4 alkyl, _C2-4 alkenyl, C2-4 alkynyl, _C1-4 alkoxy, -S ( _C1-4 alkyl), -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl), _C3-6 cycloalkyl, 4-7 membered heterocyclic, _-C1-4 alkylene- _C3-6 cycloalkyl, or -C1-4 alkylene- _4-7 membered heterocyclic; wherein _{the C1-4} _alkyl , _C2-4 _alkenyl , _C2-4 alkoxy, -S ( _C1-4 alkyl), -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl), _C3-6 cycloalkyl, _4-7 membered heterocyclic, _-C1-4 alkylene- _C3-6 _cycloalkyl , or -C _{The 1-4} alkylene-4-7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, ₅ or 6 substituents selected from deuterium, halogen, OH, CN, _NH2 , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, C1-4 haloalkoxy, -S( _C1-4 alkyl), -S( _C1-4 haloalkyl), -NH( _C1-4 _{alkyl), -N(C1-4} _alkyl ) ₂ , -NH( _C1-4 haloalkyl), -N( _C1-4 haloalkyl) ₂ , -S(=O)( _C1-4 alkyl), -S(=O) ₂ ( _C1-4 alkyl), -S(=O)( _C1-4 haloalkyl), -S(=O) ₂ ( _C1-4 haloalkyl), -O(C3-6 cycloalkyl) or -O( _C3-6 halocycloalkyl).

在一些实施方案中，R⁴选自C_1-6烷基、C_3-10环烷基、-C_1-6亚烷基-C_3-10环烷基；所述C_1-6烷基任选地被1、2、3、4、5或6个选自卤素、C_1-6烷氧基、C_1-6卤代烷氧基、-S(C_1-6卤代烷基)、-S(O)(C_1-6卤代烷基)、-S(O)₂(C_1-6卤代烷基)、-O(C_3-6卤代环烷基)的取代基取代；所述C_3-10环烷基、-C_1-6亚烷基-C_3-10环烷基中C_3-10环烷基任选地被1、2、3、4、5或6个选自卤素、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代。In some embodiments, ^R4 is selected from _C1-6 alkyl, _C3-10 cycloalkyl, _-C1-6 alkylene- _C3-10 cycloalkyl; the _C1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 haloalkyl), -S(O)( _C1-6 haloalkyl), -S(O) ₂ ( _C1-6 haloalkyl), -O( _C3-6 halocycloalkyl); the _C3-10 cycloalkyl in the C3-10 cycloalkyl and _-C1-6 alkylene- _C3-10 cycloalkyl is optionally substituted with 1, 2, 3 _, 4, 5 or 6 substituents selected from halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy.

在一些实施方案中，R⁴选自C_1-4烷基、C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基；所述C_1- ₄烷基任选地被1、2、3、4、5或6个选自卤素、C_1-4烷氧基、C_1-4卤代烷氧基、-S(C_1-4卤代烷基)、-S(＝O)(C_1-4卤代烷基)、-S(＝O)₂(C_1-4卤代烷基)或-O(C_3-6卤代环烷基)的取代基取代；所述C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基中C_3-6环烷基任选地被1、2、3、4、5或6个选自卤素、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代。In some embodiments, ^R4 is selected from _C1-4 alkyl, _C3-6 cycloalkyl, or _-C1-4 alkylene- _C3-6 cycloalkyl; _the _C1-4 alkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halogen, _C1-4 alkoxy, _C1-4 haloalkoxy, -S ( _C1-4 haloalkyl), -S(=O) ( _C1-4 haloalkyl), -S(=O) ₂ ( _C1-4 haloalkyl), or -O ( _C3-6 halocycloalkyl); the _C3-6 cycloalkyl in the C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl is optionally substituted with 1, 2, 3 _, 4, 5, or 6 substituents selected from halogen, _C1-4 haloalkyl, or _C1-4 haloalkoxy.

在一些实施方案中，R⁴选自C_1-4烷基；所述C_1-4烷基任选地被1、2、3、4、5或6个选自卤素、C_1-4烷氧基、C_1-4卤代烷氧基、-S(C_1-4卤代烷基)或-O(C_3-6卤代环烷基)的取代基取代。In some embodiments, ^R4 is selected from _C1-4 alkyl; the _C1-4 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, _C1-4 alkoxy, _C1-4 haloalkoxy, -S ( _C1-4 haloalkyl) or -O ( _C3-6 halocycloalkyl).

在一些实施方案中，R⁴选自C_1-4烷基；所述C_1-4烷基任选地被1、2、3、4、5或6个选自卤素、C_1-4烷氧基或C_1-4卤代烷氧基的取代基取代。In some embodiments, ^R4 is selected from _C1-4 alkyl groups; the _C1-4 alkyl group is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogens, _C1-4 alkoxy groups or _C1-4 haloalkoxy groups.

在一些实施方案中，R⁴选自(优选)、(优选)、(优选)、(优选 )、(优选)、 In some implementations, ^R4 is selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

在一些实施方案中，R⁴选自(优选 )、(优选)、 (优选)、(优选)。In some implementations, ^R4 is selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ).

在一些实施方案中，R⁴选自(优选)或(优选)。In some implementations, ^R4 is selected from (Preferred) )or (Preferred) ).

在一些实施方案中，本发明所述化合物具有式(III-1)所示的结构：
In some embodiments, the compounds of the present invention have the structure shown in formula (III-1):

其中：in:

n选自0或1；n is selected from 0 or 1;

p选自0、1、2或3；p is selected from 0, 1, 2, or 3;

Q选自卤素、C_1-6卤代烷基、C_1-6卤代烷氧基、-S(C_1-6卤代烷基)、-S(＝O)(C_1-6卤代烷基)或-S(＝O)₂(C_1-6卤代烷基)；Q is selected from halogens, _C1-6 haloalkyl, _C1-6 haloalkoxy, -S ( _C1-6 haloalkyl), -S(=O) ( _C1-6 haloalkyl), or -S(=O) ₂ ( _C1-6 haloalkyl);

R^a、R^b各自独立地选自H、氘、卤素、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基或C_1-6卤代烷氧基； ^Ra and ^Rb are each independently selected from H, deuterium, halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy or _C1-6 haloalkoxy;

L选自-CR^L1R^L2-、-C_3-6亚环烷基-、-C_3-6卤代亚环烷基-、-O-C_3-6亚环烷基-*、-O-C_3-6卤代亚环烷基-*、-S-C_3-6亚环烷基-*或-S-C_3-6卤代亚环烷基-*，其中以“*”标识的键连接至Q；L is selected from -CR ^L1 R ^L2 -, -C _3-6 cycloalkyl-, -C _3-6 halocycloalkyl-, -OC _3-6 cycloalkyl-*, -OC _3-6 halocycloalkyl-*, -SC _3-6 cycloalkyl-* or -SC _3-6 halocycloalkyl-*, wherein the bond marked with "*" is connected to Q;

R^L1、R^L2各自独立地选自H、氘、卤素、CN、OH、NH₂、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基或C_1-6卤代烷氧基；或者R^L1、R^L2和它们连接的碳原子一起形成C_3-6环烷基、4-7元杂环基； ^RL1 and ^RL2 are each independently selected from H, deuterium, halogen, CN, OH, _NH2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy or _C1-6 haloalkoxy; or ^RL1 , ^RL2 and the carbon atoms they are attached to form _C3-6 cycloalkyl or 4-7 heterocyclic groups;

R¹、R²、R³、R^g、R^h如本前述任一方案所定义。 ^R1 , ^R2 , ^R3 , ^Rg , and ^Rh are as defined in any of the aforementioned schemes.

在一些实施方案中，本发明所述化合物具有式(III-2)或(III-3)所示结构：
In some embodiments, the compounds of the present invention have the structure shown in formula (III-2) or (III-3):

在一些实施方案中，本发明所述化合物具有式(III-4)-(III-7)任一所示结构：
In some embodiments, the compounds of the present invention have a structure shown in any of formulas (III-4)-(III-7):

在一些实施方案中，本发明所述化合物具有式(III-8)-(III-11)任一所示结构：
In some embodiments, the compounds of the present invention have the structures shown in any of formulas (III-8)-(III-11):

在一些实施方案中，n选自0。In some implementations, n is selected from 0.

在一些实施方案中，p选自0、1或2。In some implementations, p is selected from 0, 1, or 2.

在一些实施方案中，p为1。In some implementations, p is 1.

在一些实施方案中，Q选自F、Cl、Br、C_1-3卤代烷基、C_1-3卤代烷氧基、-S(C_1-3卤代烷基)、-S(＝O)(C_1-3卤代烷基)或-S(＝O)₂(C_1-3卤代烷基)。In some embodiments, Q is selected from F, Cl, Br, _C1-3 haloalkyl, _C1-3 haloalkoxy, -S ( _C1-3 haloalkyl), -S(=O) ( _C1-3 haloalkyl), or -S(=O) ₂ ( _C1-3 haloalkyl).

在一些实施方案中，Q选自C_1-3卤代烷基(例如C_1-3氟代烷基)、C_1-3卤代烷氧基(例如C_1-3氟代烷氧基)。In some embodiments, Q is selected from _C1-3 haloalkyl (e.g., _C1-3 fluoroalkyl) and _C1-3 haloalkoxy (e.g., _C1-3 fluoroalkoxy).

在一些实施方案中，Q选自C_1-3卤代烷基(例如C_1-3氟代烷基)。In some embodiments, Q is selected from _C1-3 haloalkyl (e.g., _C1-3 fluoroalkyl).

在一些实施方案中，Q选自F、-OCF₃、-OCF₂H、-CF₃、-CF₂H、-SCF₃、-SCF₂H、-S(＝O)CF₃、-S(＝O)₂CF₃或-OCH₂CF₃。In some implementations, Q is selected from F, -OCF ₃ , -OCF ₂ H, -CF ₃ , -CF ₂ H, -SCF ₃ , -SCF ₂ H, -S(=O)CF ₃ , -S(=O) ₂ CF ₃ or -OCH ₂ CF ₃ .

在一些实施方案中，Q选自-OCF₃或-CF₃。In some implementations, Q is selected from -OCF ₃ or -CF ₃ .

在一些实施方案中，Q为-CF₃。In some implementations, Q is -CF ₃ .

在一些实施方案中，R^a、R^b各自独立地选自H、氘、卤素、C_1-6烷基或C_1-6卤代烷基。In some embodiments, ^Ra and ^Rb are each independently selected from H, deuterium, halogen, _C1-6 alkyl, or _C1-6 haloalkyl.

在一些实施方案中，R^a、R^b各自独立地选自H或C_1-6烷基。In some embodiments, ^Ra and ^Rb are each independently selected from H or _C1-6 alkyl groups.

在一些实施方案中，R^a、R^b各自独立地选自H或C_1-3烷基。In some embodiments, ^Ra and ^Rb are each independently selected from H or _C1-3 alkyl groups.

在一些实施方案中，R^a、R^b均为H，或者R^a、R^b其中一者为H，另一者为C_1-3烷基；更优选地，R^a、R^b均为H。In some embodiments, ^Ra and ^Rb are both H, or one of ^Ra and ^Rb is H and the other is a _C1-3 alkyl group; more preferably, ^Ra and ^Rb are both H.

在一些实施方案中，L选自-CR^L1R^L2-、-C_3-6亚环烷基-或-O-C_3-6卤代亚环烷基-*；其中以“*”标识的键连接至Q。In some embodiments, L is selected from -CR ^L1 R ^L2 -, -C _3-6 cycloalkyl- or -OC _3-6 halocycloalkyl-*; wherein the bond identified by "*" is connected to Q.

在一些实施方案中，L选自-CR^L1R^L2-。In some implementations, L is selected from -CR ^L1 R ^L2 -.

在一些实施方案中，R^L1、R^L2各自独立地选自H、C_1-6烷基或C_1-6烷氧基；或者R^L1、R^L2和它们连接的碳原子一起形成C_3-6环烷基。In some embodiments, ^RL1 and ^RL2 are each independently selected from H, _C1-6 alkyl, or _C1-6 alkoxy; or ^RL1 , ^RL2 , and the carbon atoms to which they are attached together form a _C3-6 cycloalkyl group.

在一些实施方案中，R^L1、R^L2各自独立地选自H、C_1-3烷基或C_1-3烷氧基。In some embodiments, ^RL1 and ^RL2 are each independently selected from H, _C1-3 alkyl, or _C1-3 alkoxy.

在一些实施方案中，R^L1、R^L2均为H，或者R^L1、R^L2其中一者为H，另一者为C_1-3烷基或C_1-3烷氧基。In some embodiments, ^RL1 and ^RL2 are both H, or one of ^RL1 and ^RL2 is H and the other is a _C1-3 alkyl or _C1-3 alkoxy group.

在一些实施方案中，R^L1、R^L2其中一者为H，另一者为C_1-3烷氧基。In some implementations, one of ^RL1 and ^RL2 is H and the other is a _C1-3 alkoxy group.

在一些实施方案中，L选自-CR^L1R^L2-、 In some implementations, L is selected from -CR ^L1 R ^L2 -,

在一些实施方案中，L选自-CH₂-、-CH(CH₃)-、-CH(OCH₃)-、 In some implementations, L is selected from _-CH2- , -CH( _CH3 )-, -CH( _OCH3 )-,

在一些实施方案中，L选自-CH₂-、-CH(CH₃)-或-CH(OCH₃)-。In some implementations, L is selected from _-CH2- , -CH( _CH3 )-, or -CH( _OCH3 )-.

在一些实施方案中，L为-CH(OCH₃)-。In some implementations, L is -CH(OCH ₃ )-.

在一些实施方案中，本发明所述化合物具有式(IV-1)所示的结构：
In some embodiments, the compound of the present invention has the structure shown in formula (IV-1):

其中R¹、R²、R³、R^g、R^h、n、R^a、R^b、R^L1、R^L2如前述任一方案所定义。 ^R1 , ^R2 , ^R3 , ^Rg , ^Rh , n, ^Ra , ^Rb , ^RL1 , and ^RL2 are defined as in any of the aforementioned schemes.

在一些实施方案中，本发明所述化合物具有式(IV-2)所示的结构：
In some embodiments, the compounds of the present invention have the structure shown in formula (IV-2):

在一些实施方案中，本发明所述化合物具有式(IV-3)所示的结构：
In some embodiments, the compounds of the present invention have the structure shown in formula (IV-3):

在一些实施方案中，本发明所述化合物选自：

In some embodiments, the compounds of this invention are selected from:

在一些实施方案中，本发明所述化合物具有式(I-18)所示的结构：
In some embodiments, the compounds of the present invention have the structure shown in formula (I-18):

其中，环D为5-10元桥杂环烷基；Wherein, ring D is a 5-10 member bridged heterocyclic alkyl group;

R⁴选自：R ⁴ is selected from:

H、卤素、OH、SH、CN或N(R^7a)₂，H, halogens, OH, SH, CN, or N(R ^7a ) ₂ ,

各自任选地被1、2、3、4、5、6或更多个独立地选自卤素、OH、SH、NH₂或CN的取代基取代的C_1-6烷基、C_2-6烯基或C_2-6炔基，Each of the following is optionally substituted with one, two, three, four, five, six or more _C1-6 alkyl, _C2-6 alkenyl or _C2-6 ynyl groups independently selected from halogen, OH, SH, NH2 or _CN .

-O-C_1-6烷基、-O-卤代C_1-6烷基、-C_1-6亚烷基-O-C_1-6烷基或-C_1-6亚烷基-O-卤代C_1-6烷基，-OC _1-6 alkyl, -O-halogenated C _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkyl or -C _1-6 alkylene-O-halogenated C _1-6 alkyl,

C_3-10环烃基、-C_1-6亚烷基-C_3-10环烃基、-O-C_1-6亚烷基-C_3-10环烃基或-C(O)-C_3-10环烃基，其中所述C_3-10环烃基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代，以及 _C3-10 cyclic hydrocarbon group, _-C1-6 alkylene- _C3-10 cyclic hydrocarbon group, _-OC1-6 alkylene- _C3-10 cyclic hydrocarbon group, or -C(O) _-C3-10 cyclic hydrocarbon group, wherein the _C3-10 cyclic hydrocarbon group is independently and optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, _or _C1-6 haloalkoxy groups in each occurrence, and

3-10元杂环烷基或-C_1-6亚烷基-3-10元杂环烷基，其中所述3-10元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代；3-10-membered heterocyclic alkyl or _-C1-6 alkylene-3-10-membered heterocyclic alkyl, wherein the 3-10-membered heterocyclic alkyl is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-6 haloalkyl or _C1-6 haloalkoxy in each occurrence;

R^7a各自独立地选自：H、C_1-6烷基、-(CH₂)_q-C_3-10环烃基或-(CH₂)_q-3-10元杂环烷基，q选自0至6的整数，且所述C_1-6烷基、-(CH₂)_q-C_3-10环烃基或-(CH₂)_q-3-10元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代；并且R ^7a are each independently selected from: H, _C1-6 alkyl, -( _CH2 ) _q - _C3-10 cycloalkyl or -( _CH2 ) _q -3-10 heterocyclic alkyl, where q is an integer selected from 0 to 6, and each of the _C1-6 alkyl, -( _CH2 ) _q - _C3-10 cycloalkyl or -( _CH2 ) _q - _3-10 heterocyclic alkyl is optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl or _C1-6 haloalkoxy; and

m为1、2或3；m is 1, 2, or 3;

L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B； ^L1 is selected from: *-CR ^g ^{R h} -NR ^4c -, *-C(O)-NR ^4c -, *-C(S)-NR ^4c -, *-S(O) ₂ -NR ^4c -, *-NR ^4c -C(O)-, *-NR ^4c -S(O) ₂ -, *-NR ^4c -CR ^g R ^h - or *-NR ^4c -C(S)-, wherein the bond indicated by * is connected to the phenyl ring B;

R^g和R^h各自独立地选自H、氘、卤素、OH、SH、CN、C_1-6烷基、C_1-6卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b；或者R^g和R^h与它们二者共同连接的碳原子一起形成C_3-6环烷基或4-7元杂环烷基； ^Rg and ^Rh are each independently selected from H, deuterium, halogen, OH, SH, CN, _C1-6 alkyl, _C1-6 haloalkyl, NR ^5a R ^5b , -C(O)OR ^5a or -C(O)-NR ^5a R ^5b ; or ^Rg and ^Rh together with the carbon atom to which they are connected form a _C3-6 cycloalkyl or a 4-7 membered heterocyclic alkyl.

R^4c选自H、C_1-6烷基或C_1-6卤代烷基；R ^4c is selected from H, _C1-6 alkyl, or _C1-6 haloalkyl;

R³选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-6烷基、C_1-6卤代烷基、C_2-6烯基、C_2-6炔基、-O-C_1-6烷基、-O-C_1-6卤代烷基、-S-C_1-6烷基、-S(O)₂-C_1-6烷基、-C_1-6亚烷基-O-C_1-6烷基、-OC_1-6亚烷基-OC_1-6烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH、-C_1-6亚烷基-NR^6aR^6b、-C_1-6亚烷基-NR^6a-C(O)R^6b、-OC_1-6亚烷基C(O)OR^6a、-OC_1-6亚烷基C(O)NR^6aR^6b、C_3-10环烃基或-OC_1-6亚烷基-C_3-10环烃基，其中所述C_1-6烷基、C_1-6卤代烷基、C_2-6烯基、C_2-6炔基、-O-C_1-6烷基、-O-C_1-6卤代烷基、-S-C_1-6烷基、-S(O)₂-C_1-6烷基、-C_1-6亚烷基-O-C_1-6烷基、-OC_1-6亚烷基-OC_1-6烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH、-C_1-6亚烷基-NR^6aR^6b、-C_1-6亚烷基-NR^6a-C(O)R^6b、-OC_1-6亚烷基C(O)OR^6a、-OC_1-6亚烷基C(O)NR^6aR^6b、C_3-10环烃基或-OC_1-6亚烷基-C_3-10环烃基各自任选地被一个或多个氘(D)取代；R ³ is selected from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 ynyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -SC _1-6 alkyl, -S(O) ₂ -C _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkyl, -OC _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-NR ^6a R ^6b , -C _1-6 alkylene-NR ^6a -C(O)R ^6b , -OC _1-6 alkylene C(O)OR ^6a , -OC _1-6 alkylene C(O)NR ^6a R ^6b , C _3-10 cyclic hydrocarbon group or -OC _1-6 alkylene-C _3-10 cyclic hydrocarbon group, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 ynyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, -SC _1-6 alkyl, -S(O) ₂ -C _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkyl, -OC _1-6 alkylene-OC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH, -C _1-6 alkylene-NR ^6a R ^6b , -C _1-6 alkylene-NR ^6a -C(O)R ^6b , -OC _1-6 alkylene C(O)OR ^6a , -OC _1-6 alkylene C(O)NR ^6a R ^6b , C _The _3-10 cyclic hydrocarbon group or the -OC _1-6 alkylene group is optionally substituted with one or more deuterium (D) groups;

R⁵选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-6烷基、C_1-6卤代烷基、C_2-6烯基、C_2-6炔基、-O-C_1-6烷基、-S-C_1-6烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH或C_3-10环烃基；并且 ^R5 is selected from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , _C1-6 alkyl, _C1-6 haloalkyl, _C2-6 alkenyl, _C2-6 ynyl, _-OC _1-6 alkyl, -SC _1-6 alkyl, -C1-6 alkylene-OH, _-C1-6 alkylene-SH, or _C3-10 cyclic hydrocarbon; and

R^5a、R^5b、R^6a或R^6b在每次出现时独立地选自H或C_1-6烷基； ^R5a , ^R5b , ^R6a , or ^R6b are each independently selected from H or _C1-6 alkyl groups when they appear.

R²或R⁸在每次出现时各自独立地选自：H、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、C_1-6烷基或C_3-10环烃基； ^R2 or ^R8 is independently selected from: H, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl or _C3-10 cyclic hydrocarbon group each time it appears;

在一些实施方案中，R⁴选自：H、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1- ₆烷基)₂、C_1-6烷基、C_1-6卤代烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH、-C_1-6亚烷基-CN、-O-C_1-6烷基、-O-卤代C_1-6烷基、-O-C_1-6烷基-C_3-10环烃基，以及任选地被1个、2个或更多个独立地选自卤素、OH、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代的C_3-10环烃基；并且In some embodiments, ^R4 is selected from: H, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 _{haloalkyl, -C1-6} _alkylene -OH, _-C1-6 alkylene-SH, _-C1-6 alkylene-CN, _-OC1-6 alkyl, -O- _haloC1-6 alkyl, _-OC1-6 alkyl- _{C3-10 cyclic hydrocarbon, and C3-10} cyclic hydrocarbons optionally substituted with one, _two or more substituents independently selected from halogen, OH, SH, _NH2 , CN, _C1-6 alkyl or _C1-6 haloalkyl; and

R^g或R^h各自独立地选自H、卤素、OH、SH、CN、C_1-6烷基、C_1-6卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b；以及 ^Rg or ^Rh are each independently selected from H, halogen, OH, SH, CN, _C1-6 alkyl, _C1-6 ^haloalkyl , ^NR5aR5b , -C(O) ^OR5a or -C(O) ^-NR5aR5b ; ^and

R⁵选自：卤素、OH、SH、CN、-NR^6aR^6b、C_1-6烷基、C_1-6卤代烷基、C_2-6烯基、C_2-6炔基、-O-C_1-6烷基、-S-C_1-6烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH或C_3-10环烃基。 ^R5 is selected from: halogen, OH, SH, CN, -NR ^6a R ^6b , C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 alkynyl, -OC _1-6 alkyl, -SC _1-6 alkyl, -C _1-6 alkylene-OH, -C _1-6 alkylene-SH or C _3-10 cyclic hydrocarbon.

在一些实施方案中，环D为5-8元桥杂环烷基。In some implementations, ring D is a 5-8 membered bridged heterocyclic alkyl group.

在一些实施方案中，环D为其中，$^A为与环A的连接点，$^L1为与L¹的连接点；In some implementations, ring D is Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 ;

在一些实施方案中，R⁴选自：In some implementations, ^R4 is selected from:

-O-C_1-6烷基、-O-卤代C_1-6烷基、-C_1-6亚烷基-O-C_1-6烷基、-C_1-6亚烷基-O-卤代C_1- ₆烷基，-OC _1-6 alkyl, -O-halogenated _C1-6 alkyl, -C _1-6 alkylene _- OC _1-6 alkyl, -C _1-6 alkylene-O-halogenated _C1-6 alkyl,

C_3-6环烷基、-C_1-6亚烷基-C_3-6环烷基、-O-C_1-6亚烷基-C_3-6环烷基或-C(O)-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代，以及 _C3-6 cycloalkyl, _-C1-6 alkylene- _C3-6 cycloalkyl, _-OC1-6 alkylene- _C3-6 cycloalkyl, or -C(O) _-C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is, each time present, independently and optionally substituted by one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , _{CN, oxo, C1-6} _alkyl , _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, or _C1-6 haloalkoxy, and

4-7元杂环烷基或-C_1-6亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代；并且4-7-membered heterocyclic alkyl or _-C1-6 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl group, each time appearing, is independently and optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C1-6 haloalkyl or _C1-6 haloalkoxy; and

R^7a各自独立地选自：H、C_1-6烷基、-(CH₂)_q-C_3-6环烷基或-(CH₂)_q-4-7元杂环烷基，q选自0至4的整数，且所述C_1-6烷基、所述-(CH₂)_q-C_3-6环烷基中的C_3-6环烷基、以及所述-(CH₂)_q-4-7元杂环烷基中的4-7元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代。R ^7a are each independently selected from: H, _C1-6 alkyl, -( _CH2 ) _q - _C3-6 cycloalkyl or -( _CH2 ) _q -4-7 heterocyclic alkyl, where q is an integer selected from 0 to 4, and each of the _C1-6 alkyl, the _C3-6 cycloalkyl in the -( _CH2 ) _q - _C3-6 cycloalkyl, and the 4-7 heterocyclic alkyl in the -( _CH2 ) _q _{-4-7 heterocyclic alkyl is optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, oxo, C1-6} _alkyl _, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl or _C1-6 haloalkoxy.

在一些优选的实施方案中，N(R^7a)₂中的1个R^7a为H。In some preferred embodiments, one of the R ^7a in N(R ^7a ) ₂ is H.

在一些优选的实施方案中，R⁴选自：In some preferred embodiments, ^R4 is selected from:

H、F、Cl、OH、SH、CN或NH₂，H, F, Cl, OH, SH, CN or _NH₂ ,

-NH(C_1-4烷基)、-N(C_1-4烷基)₂、-NH(C_3-6环烃基)或-NH(4-7元杂环烷基)，其中所述-NH(C_1-4烷基)和-N(C_1-4烷基)₂中的C_1-4烷基、所述-NH(C_3-6环烃基)中的C_3-6环烃基以及所述-NH(4-7元杂环烷基)中的4-7元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代，-NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -NH (C _3-6 cyclic hydrocarbon) or -NH (4-7 membered heterocyclic alkyl), wherein the C 1-4 alkyl group in -NH (C _1-4 alkyl) and -N (C _1-4 alkyl) ₂ , the C _3-6 _cyclic hydrocarbon group in -NH (C _3-6 cyclic hydrocarbon) and the 4-7 membered heterocyclic alkyl group in -NH (4-7 membered heterocyclic alkyl) are each optionally and independently substituted by one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH ₂ , CN, C _1-6 alkyl or C _1-6 haloalkyl.

-NH(C_1-4亚烷基)-(C_3-6环烃基)、-NH(C_1-4亚烷基)-CN、C_1-4烷基、C_1-6卤代烷基、-C_1-4亚烷基-OH、-C_1-4卤代烷基-OH、-C_1-4亚烷基-SH、-C_1-4卤代烷基-SH、-C_1-4亚烷基-CN、-C_1-4卤代烷基-CN、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-卤代C_1-4烷基、-C_1-4亚烷基-O-C_1-4烷基或-C_1-4烷基-O-卤代C_1-4烷基，-NH( _C1-4 alkylene)-( _C3-6 cycloalkyl), -NH( _C1-4 alkylene)-CN, _C1-4 alkyl, _C1-6 haloalkyl, -C1-4 alkylene-OH, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-SH, _-C1-4 haloalkyl-SH, _-C1-4 alkylene-CN, _-C1-4 haloalkyl-CN, _C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl, -O- _haloC1-4 alkyl, _-C1-4 alkylene- _OC1-4 alkyl or _-C1-4 alkyl-O _-haloC1-4 _alkyl ,

C_3-6环烷基、-C_1-4亚烷基-C_3-6环烷基、-O-C_1-4亚烷基-C_3-6环烷基或-C(O)-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代，以及 _C3-6 cycloalkyl, _-C1-4 alkylene- _C3-6 cycloalkyl, _-OC1-4 alkylene- _C3-6 cycloalkyl, or -C(O) _-C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is, each time present, independently and optionally substituted by one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl, _C1-4 haloalkyl, or _C1-4 haloalkoxy groups, and

4-7元杂环烷基或-C_1-4亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-4烷基、C_2-6烯基、C_2-6炔基、C_1-4烷氧基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代。4-7-membered heterocyclic alkyl or _-C1-4 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl is, each time present, independently and optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-4 alkoxy, _C1-4 haloalkyl or _C1-4 haloalkoxy.

在一些更优选的实施方案中，R⁴选自：In some preferred embodiments, ^R4 is selected from:

H、OH或SH，H, OH or SH,

-NH(C_1-4烷基)、-NH(C_3-6部分不饱和环烃基)或-NH(4-6元杂环烷基)，所述-NH(C_1-4烷基)中的C_1-4烷基、所述-NH(C_3-6部分不饱和环烃基)中的C_3-6部分不饱和环烃基以及所述-NH(4-6元杂环烷基)中的4-6元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代，-NH (C _1-4 alkyl), -NH (C _3-6 partially unsaturated cycloalkyl), or -NH (4-6 membered heterocyclic alkyl), wherein the C _1-4 alkyl group in -NH (C _1-4 alkyl), the C _3-6 partially unsaturated cycloalkyl group in -NH (C _3-6 partially unsaturated cycloalkyl), and the 4-6 membered heterocyclic alkyl group in -NH (4-6 membered heterocyclic alkyl) are each optionally and independently substituted by one, two, or more substituents independently selected from deuterium, halogen, OH, oxo, SH, _NH₂ , CN, C _1-4 alkyl, or C _1-4 haloalkyl.

-NH(C_1-4亚烷基)-(C_3-6环烷基)、-NH(C_1-4亚烷基)-CN、C_1-4烷基、C_1-6卤代烷基、-C_1-4亚烷基-OH、-C_1-4卤代烷基-OH、-C_1-4亚烷基-CN、C_2-4炔基、-O-C_1-4烷基、-O-卤代C_1-4烷基、-C_1-4亚烷基-O-C_1-4烷基或-C_1-4烷基-O-卤代C_1-4烷基，-NH( _C1-4 alkylene)-( _C3-6 cycloalkyl), -NH( _C1-4 alkylene)-CN, _C1-4 alkyl, C1-6 haloalkyl, _-C1-4 alkylene-OH, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-CN, _C2-4 alkynyl, _-OC1-4 alkyl, -O-halogenated _C1-4 alkyl, _-C1-4 alkylene _- _OC1-4 alkyl or _-C1-4 alkyl-O-halogenated _C1-4 alkyl,

C_3-6环烷基、-C_1-4亚烷基-C_3-6环烷基或-O-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代，以及 _C3-6 cycloalkyl, _-C1-4 alkylene- _C3-6 cycloalkyl, or _-OC1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is, in each occurrence, independently and optionally substituted by one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl, _C1-4 haloalkyl, or _C1-4 haloalkoxy groups, and

4-7元杂环烷基或-C_1-4亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代。4-7-membered heterocyclic alkyl or _-C1-4 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl or _C1-4 haloalkyl each time it appears.

在另一些实施方案中，R⁴选自：H、卤素、OH、SH、CN、N(R^7a)₂、C_1-6烷基、-O-C_1- ₆烷基或-O-C_1-6烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基和C_1-6卤代烷氧基的取代基取代的C_3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代的4-7元杂环烷基。In other embodiments, ^R4 is selected from: H, halogen, OH, SH, CN, N( ^R7a ) ₂ , _C1-6 alkyl, _-OC1-6 alkyl or _-OC1-6 alkyl- _C3-6 cycloalkyl, and optionally substituted with one, two or _more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 _haloalkyl and _C1-6 haloalkoxy, optionally substituted with one, two or _more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl or _C3-6 cycloalkyl. 4-7 membered heterocyclic alkyl groups substituted with _1-6 haloalkoxy groups.

在一些优选的实施方案中，R⁴选自：H、卤素、OH、SH、CN、NH₂、-NH(C_1-6烷基)、-N(C_1-6烷基)₂、-NH(C_3-10环烃基)、C_1-6烷基、C_1-6卤代烷基、-C_1-6亚烷基-OH、-C_1-6亚烷基-SH、-C_1-6亚烷基-CN、-O-C_1-6烷基、-O-卤代C_1-6烷基、-O-C_1-6烷基-C_3-10环烃基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代的C_3-10环烃基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代的3-10元杂环烷基；所述-NH(C_1-6烷基)、-N(C_1-6烷基)₂中的C_1-6烷基，以及所述-NH(C_3-10环烃基)中的C_3-10环烃基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代。In some preferred embodiments, ^R4 is selected from: H, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -NH ( _C3-10 cycloalkyl), _C1-6 alkyl, _C1-6 haloalkyl, _-C1-6 alkylene-OH, _-C1-6 alkylene-SH, _-C1-6 alkylene-CN, _-OC1-6 alkyl, -O- _haloC1-6 alkyl, _-OC1-6 alkyl- _C3-10 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, _SH , _NH2 , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl or _C1-6 haloalkoxy. The _3-10 cyclic hydrocarbon group is optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH₂ , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, or _C1-6 haloalkoxy. The C1-6 alkyl group of -NH( _C1-6 alkyl), -N( _C1-6 alkyl) _₂ , and _the _C3-10 cyclic hydrocarbon group of -NH ₍ _C3-10 cyclic hydrocarbon) are each optionally substituted with one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH₂ , CN, oxo, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, _C1-6 haloalkyl, or _C1-6 haloalkyl. Substituents of _1-6 haloalkoxy groups.

在一些优选的实施方案中，R⁴选自：H、F、Cl、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、-NH(C_3-6环烃基)、-NH(C_1-4亚烷基)-(C_3-6环烃基)、-NH(C_1-4亚烷基)-CN、C_1-4烷基、C_1-4卤代烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-CN、-O-C_1-4烷基、-O-卤代C_1-4烷基、-O-C_1-4烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的C_3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-4烷基、C_2-6烯基、C_2-6炔基、C_1-4烷氧基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代的4-7元杂环烷基；所述-NH(C_1-4烷基)、-N(C_1-4烷基)₂中的C_1-4烷基，以及所述-NH(C_3-6环烃基)中的C_3-6环烃基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代。In some preferred embodiments, ^R4 is selected from: H, F, Cl, OH, SH, _CN , NH2, -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , -NH ( _C3-6 cycloalkyl), -NH (C1-4 alkylene)-( _{C3-6 cycloalkyl), -NH (C1-4} alkylene)-CN, _C1-4 _alkyl , _C1-4 haloalkyl, _-C1-4 alkylene-OH, _-C1-4 alkylene-SH, _-C1-4 alkylene-CN, _-OC1-4 alkyl, -O _- _haloC1-4 alkyl, _-OC1-4 alkyl- _C3-6 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _{NH2, CN, C1-4} _alkyl or _C1-4 haloalkyl. _3-6 cycloalkyl, optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-4 alkoxy, _C1-4 haloalkyl or _C1-4 haloalkoxy; the _C1-4 alkyl in -NH( _C1-4 alkyl) ₂ and the _C3-6 cycloalkyl in -NH( _C3-6 cycloalkyl) ₂ are each optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, _NH2 , CN, _C1-6 alkyl or _C1-6 haloalkyl.

在一些优选的实施方案中，R⁴选自：H、OH、SH、-NH(C_1-4烷基)、-NH(C_3-6部分不饱和环烃基)、-NH(C_1-4亚烷基)-(C_3-6环烷基)、-NH(C_1-4亚烷基)-CN、C_1-4烷基、C_1-4卤代烷基、-O-C_1-4烷基、-O-卤代C_1-4烷基、-O-C_1-4烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的C_3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的4-7元杂环烷基；所述-NH(C_1-4烷基)中的C_1-4烷基，以及所述-NH(C_3-6部分不饱和环烃基)中的C_3-6部分不饱和环烃基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代。In some preferred embodiments, ^R4 is selected from: H, OH, SH, -NH ( _C1-4 alkyl), -NH ( _C3-6 partially unsaturated cycloalkyl), -NH ( _C1-4 alkylene)-( _C3-6 cycloalkyl), -NH ( _C1-4 alkylene)-CN, _C1-4 alkyl, _C1-4 haloalkyl, -OC1-4 alkyl, -O- _haloC1-4 alkyl, _-OC1-4 alkyl- _C3-6 cycloalkyl, and _C3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl _or _C1-4 haloalkyl, optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl or C3-6 haloalkyl. The 4-7 membered heterocyclic alkyl group substituted with a _1-4 haloalkyl group; the _C1-4 alkyl group in the -NH ( _C1-4 alkyl) and the _C3-6 partially unsaturated cyclic alkyl group in the -NH ( _C3-6 partially unsaturated cyclic alkyl) are each optionally and independently substituted with one, two or more substituents independently selected from deuterium, halogen, OH, oxo, _SH , NH2, CN, _C1-4 alkyl or _C1-4 haloalkyl.

在一些更优选的实施方案中，R⁴选自组C所列的基团：In some preferred embodiments, ^R4 is selected from the groups listed in group C:

(组C)H、OH、SH、甲基、乙基、异丙基、-CF₃、-CH₂CF₃、-CH₂CHF₂、-CH₂CN、-OCH₃、-OCH₂CH₃、-OCF₃、-OCH₂CF₃、二氟环丙基、氨基、-NHCH₃、-N(CH₃)_2、-NHCH₂CH₃、-NHCH₂CN、-NHCH₂CF₃、-NH-环丙基、-NHCH₂-环丙基、-NH-环丁烷、或-O-CH₂-环丙基。(Group C)H, OH, SH, methyl, ethyl, isopropyl _, _-CF3 , -CH2CF3, -CH2CHF2, _-CH2CN , _-OCH3 , -OCH2CH3, _-OCF3 , _-OCH2CF3 , _{difluorocyclopropyl} , amino, _-NHCH3 , _-N ( _CH3 ₎ ₂ _, -NHCH2CH3, _-NHCH2CN _, _-NHCH2CF3 , _-NH _- _cyclopropyl , _-NHCH2 _- cyclopropyl -NH-cyclobutane, Or -O-CH ₂ -cyclopropyl.

在一些实施方案中，所述组C进一步包括以下基团：In some embodiments, group C further includes the following groups:

环丙基、 Cyclopropyl

在另一些实施方案中，R⁴选自H、OH、SH、甲基、乙基、异丙基、-CF₃、-CH₂CF₃、-CH₂CHF₂、 -CH₂CN、-OCH₃、-OCH₂CH₃、-OCF₃、-OCH₂CF₃、环丙基、二氟环丙基、氨基、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-NHCH₂CN、-NHCH₂CF₃、-NH-环丙基、-NHCH₂-环丙基、-NH-环丁烷、 -O-CH₂-环丙基或 In other embodiments, ^R4 is selected from H, OH, SH, methyl, ethyl, isopropyl, _-CF3 , _-CH2CF3 , _-CH2CHF2 _, _etc. -CH ₂ CN、 -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , Cyclopropyl, difluorocyclopropyl, Amino, _-NHCH3 , -N( _CH3 ) ₂ , _-NHCH2CH3 , _-NHCH2CN , _-NHCH2CF3 , _-NH _- cyclopropyl, _-NHCH2 -cyclopropyl -NH-cyclobutane, -O-CH ₂ -cyclopropyl or

在一些实施方案中，R⁴选自：H、OH、SH、甲基、乙基、异丙基、-CF₃、-CH₂CF₃、-CH₂CHF₂、 -CH₂CN、-OCH₃、-OCH₂CH₃、-OCF₃、-OCH₂CF₃、环丙基、二氟环丙基、氨基、-NHCH₃、-N(CH₃)_2、-NHCH₂CH₃、-NHCH₂CN、-NHCH₂CF₃、-NH-环丙基、-NHCH₂-环丙基、-NH-环丁烷、 -O-CH₂-环丙基或 In some embodiments, ^R4 is selected from: H, OH, SH, methyl, ethyl, isopropyl, _-CF3 , _-CH2CF3 , _-CH2CHF2 _, _etc. -CH ₂ CN、 -OCH ₃ , -OCH ₂ CH ₃ , -OCF ₃ , -OCH ₂ CF ₃ , Cyclopropyl, difluorocyclopropyl, Amino, _-NHCH3 , -N( _CH3 ) _2, _-NHCH2CH3 , _-NHCH2CN , _-NHCH2CF3 , _-NH _- cyclopropyl, _-NHCH2 -cyclopropyl -NH-cyclobutane, -O-CH ₂ -cyclopropyl or

在另一些实施方案中，R⁴选自：H、F、Cl、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、C_1-4烷基、C_1-4卤代烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-CN、-O-C_1-4烷基、-O-卤代C_1-4烷基、-O-C_1-4烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的C_3-6环烷基。In other embodiments, ^R4 is selected from: H, F, Cl, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 haloalkyl, _-C1-4 alkylene-OH, _-C1-4 alkylene-SH, _-C1-4 alkylene-CN, _-OC1-4 alkyl, -O- _haloC1-4 alkyl, _-OC1-4 alkyl- _C3-6 cycloalkyl, and optionally C3-6 cycloalkyl substituted with one, two _or more substituents independently selected from halogen, OH, SH, _NH2 , CN, _C1-4 alkyl or _C1-4 haloalkyl.

在一些优选的实施方案中，R⁴选自：H、OH、SH、C_1-4烷基、C_1-4卤代烷基、-O-C_1-4烷基、-O-卤代C_1-4烷基、-O-C_1-4烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的C_3-6环烷基。In some preferred embodiments, ^R4 is selected from: H, OH, SH, _C1-4 alkyl, _C1-4 haloalkyl, _-OC1-4 alkyl, -O- _haloC1-4 alkyl, _-OC1-4 alkyl- _C3-6 cycloalkyl, and optionally _C3-6 cycloalkyl substituted with one, two or more substituents independently selected from halogen, OH, SH, _NH2 , CN, _C1-4 alkyl or _C1-4 haloalkyl.

在一些优选的实施方案中，R⁴选自：H、OH、SH、甲基、乙基、异丙基、-CF₃、-CH₂CF₃、-OCH₃、-OCH₂CH₃、-OCF₃、-OCH₂CF₃、二氟环丙基或-O-CH₂-环丙基。In some preferred embodiments, ^R4 is selected from: H, OH, SH, methyl, _ethyl , _{isopropyl, -CF3} _, -CH2CF3, _-OCH3 , _{-OCH2CH3, -OCF3} _, _-OCH2CF3 , difluorocyclopropyl or -O- _CH2 _- _cyclopropyl .

在一些优选的实施方案中，m为1。In some preferred embodiments, m is 1.

在一些更优选的实施方案中，部分为其中，$^A为与环A的连接点，$^L1为与L¹的连接点。In some more preferred embodiments, Part of Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 .

H、F、Cl、OH、SH、CN、NH₂，H, F, Cl, OH, SH, CN, NH ₂ ,

-NH(C_1-4烷基)、-N(C_1-4烷基)₂、-NH(C_3-6环烃基)、-NH(4-7元杂环烷基)，其中所述-NH(C_1-4烷基)和-N(C_1-4烷基)₂中的C_1-4烷基、所述-NH(C_3-6环烃基)中的C_3-6环烃基以及所述-NH(4-7元杂环烷基)中的4-7元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代，-NH (C _1-4 alkyl), -N (C _1-4 alkyl) ₂ , -NH (C _3-6 cyclic hydrocarbon), -NH (4-7 membered heterocyclic alkyl), wherein the C _1-4 alkyl group in -NH (C _1-4 alkyl) and -N (C _1-4 alkyl) ₂ , the C _3-6 cyclic hydrocarbon group in -NH (C _3-6 cyclic hydrocarbon), and the 4-7 membered heterocyclic alkyl group in -NH (4-7 membered heterocyclic alkyl) are each optionally and independently substituted by one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, NH ₂ , CN, C _1-6 alkyl or C _1-6 haloalkyl.

-NH(C_1-4亚烷基)-(C_3-6环烃基)、-NH(C_1-4亚烷基)-CN、C_1-4烷基、C_1-6卤代烷基、-C_1-4亚烷基-OH、-C_1-4卤代烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-CN、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基或-O-卤代C_1-4烷基，-NH( _C1-4 alkylene)-( _C3-6 cycloalkyl), -NH( _C1-4 alkylene)-CN, _C1-4 alkyl, _C1-6 haloalkyl, -C1-4 alkylene _- OH, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-SH, _-C1-4 alkylene-CN, _C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl or -O _-haloC1-4 alkyl,

C_3-6环烷基、-C_1-4亚烷基-C_3-6环烷基或-O-C_1-4烷基-C_3-6环烷基，其中所述C_3- ₆环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代，以及 _C3-6 cycloalkyl, _-C1-4 alkylene- _C3-6 cycloalkyl, or _-OC1-4 alkyl- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl _group is, in each occurrence, independently and optionally substituted by one, two, or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl, _C1-4 haloalkyl, or _C1-4 haloalkoxy groups, and

C_1-4烷基、C_1-6卤代烷基、-C_1-4卤代烷基-OH、-C_1-4亚烷基-CN或C_2-4炔基， _C1-4 alkyl, _C1-6 haloalkyl, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-CN, or _C2-4 ynyl.

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代， _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl, _C1-4 haloalkyl or _C1-4 haloalkoxy groups in each occurrence.

4-7元杂环烷基或-C_1-4亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-4烷基、C_2-6烯基、C_2-6炔基、C_1-4烷氧基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代，以及4-7-membered heterocyclic alkyl or _-C1-4 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl group is, each time appearing, independently and optionally substituted by one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-4 alkoxy, _C1-4 haloalkyl or _C1-4 haloalkoxy, and

-NH(4-7元杂环烷基)，其中所述4-7元杂环烷基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代。-NH (4-7 membered heterocyclic alkyl), wherein each of the 4-7 membered heterocyclic alkyl groups is optionally substituted by one, two or more substituents selected independently from deuterium, halogen, OH, oxo, SH, _NH2 , CN, _C1-6 alkyl or _C1-6 haloalkyl.

C_1-4烷基、C_1-6卤代烷基、-C_1-4卤代烷基-OH、-C_1-4亚烷基-CN、C_2-4炔基或-NH(4-6元杂环烷基)， _C1-4 alkyl, _C1-6 haloalkyl, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-CN, _C2-4 ynyl or -NH (4-6 membered heterocyclic alkyl),

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自卤素、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代，以及 _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from halogens, _C1-4 haloalkyl groups or _C1-4 haloalkoxy groups in each occurrence, and

4-7元杂环烷基或-C_1-4亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、NH₂、CN或C_1-4烷基的取代基取代。4-7-membered heterocyclic alkyl or _-C1-4 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl is optionally and independently substituted with one, two or more substituents independently selected from deuterium, halogen, OH, _NH2 , CN or _C1-4 alkyl each time it appears.

在另一些实施方案中，R⁴选自：H、F、Cl、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、-NH(C_3-6环烃基)、-NH(C_1-4亚烷基)-(C_3-6环烃基)、-NH(C_1-4亚烷基)-CN、C_1- ₄烷基、C_1-4卤代烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-CN、-O-C_1-4烷基、-O-卤代C_1-4烷基、-O-C_1-4烷基-C_3-6环烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代的C_3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-4烷基、C_2-6烯基、C_2-6炔基、C_1-4烷氧基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代的4-7元杂环烷基；所述-NH(C_1-4烷基)、-N(C_1-4烷基)₂中的C_1-4烷基，以及所述-NH(C_3-6环烃基)中的C_3-6环烃基各自独立任选地被1个、2个或更多个独立地选自氘、卤素、OH、氧代、SH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代。In other embodiments, ^R4 is selected from: H, F, Cl, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , -NH (C3-6 cycloalkyl), -NH ( _C1-4 alkylene)-( _C3-6 cycloalkyl), -NH ( _C1-4 alkylene)-CN, _C1-4 _alkyl , _C1-4 haloalkyl, _-C1-4 alkylene-OH, _-C1-4 alkylene-SH, _-C1-4 alkylene-CN, _-OC1-4 alkyl, -O _-haloC1-4 _alkyl , _-OC1-4 alkyl- _C3-6 cycloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _{NH2, CN, C1-4} _alkyl or _C1-4 haloalkyl. _3-6 cycloalkyl, optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-4 alkoxy, _C1-4 haloalkyl or _C1-4 haloalkoxy; the _C1-4 alkyl in -NH( _C1-4 alkyl) ₂ and the _C3-6 cycloalkyl in -NH( _C3-6 cycloalkyl) ₂ are each optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, oxo, SH, _NH2 , CN, _C1-6 alkyl or _C1-6 haloalkyl.

在一些优选的实施方案中，R⁴选自：C_1-4烷基、C_1-4卤代烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、C_1-4烷基和C_1-4卤代烷基的取代基取代的C_3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH₂、CN、氧代、C_1-4烷基、C_2-6烯基、C_2-6炔基、C_1-4烷氧基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代的4-7元杂环烷基。In some preferred embodiments, ^R4 is selected from: _C1-4 alkyl, _C1-4 haloalkyl, and _C3-6 cycloalkyl optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, _C1-4 alkyl and _C1-4 haloalkyl, and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, _NH2 , CN, oxo, _C1-4 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-4 alkoxy, _C1-4 haloalkyl or _C1-4 haloalkoxy alkyl.

在一些优选的实施方案中，环D为5-8元桥杂环烷基，R⁴选自C_1-4烷基、C_1-4卤代烷基，以及任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH2、CN、C1-4烷基或和C1-4卤代烷基的取代基取代的C3-6环烷基，任选地被1个、2个或更多个独立地选自氘、卤素、OH、SH、NH2、CN、C1-4烷基或C1-4卤代烷基的取代基取代的4-7元杂环烷基；更优选地，部分为其中，$^A为与环A的连接点，$^L1为与L¹的连接点。In some preferred embodiments, ring D is a 5-8 membered bridged heterocyclic alkyl group, ^R4 is selected from _C1-4 alkyl groups, _C1-4 haloalkyl groups, and optionally C3-6 cycloalkyl groups substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl groups or C1-4 haloalkyl groups; and optionally 4-7 membered heterocyclic alkyl groups substituted with one, two or more substituents independently selected from deuterium, halogen, OH, SH, NH2, CN, C1-4 alkyl groups or C1-4 haloalkyl groups; more preferably, Part of Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 .

在一些实施方案中，R³在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-C_1-4卤代烷基、-S-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4亚烷基-O-C_1-6烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-NR^6aR^6b、-C_1-4亚烷基-NR^6a-C(O)R^6b、-OC_1-4亚烷基C(O)OR^6a、-OC_1-4亚烷基C(O)NR^6aR^6b、C_3-6环烷基和-OC_1-4亚烷基-C_3-6环烷基，其中所述C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-C_1-4卤代烷基、-S-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4亚烷基-O-C_1-6烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-NR^6aR^6b、-C_1-4亚烷基-NR^6a-C(O)R^6b、-OC_1-4亚烷基C(O)OR^6a、-OC_1-4亚烷基C(O)NR^6aR^6b、C_3-6环烷基或-OC_1-4亚烷基-C_3-6环烷基各自任选地被一个或多个D取代，以及In some embodiments, ^R3 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , _C1-4 alkyl, _C1-4 haloalkyl, _C2-4 alkenyl, C2-4 alkynyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-OC _1-6 alkyl, -OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene _- OH, -C _1-4 alkylene-SH, -C _1-4 alkylene-NR ^6a R ^6b , -C _1-4 alkylene-NR ^6a -C(O)R ^6b , -OC _1-4 alkylene C(O)OR ^6a , -OC _1-4 alkylene C(O)NR ^6a R ^6b _C3-6 cycloalkyl and _-OC1-4 alkylene- _C3-6 cycloalkyl, wherein the _C1-4 alkyl, C1-4 haloalkyl, _C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl, _-OC1-4 haloalkyl, _-SC1-4 alkyl, -S(O) ₂ - _C1-4 alkyl, _-C1-4 alkylene- _OC1-6 alkyl, -OC1-4 alkylene- _OC1-4 alkyl, _{-C1-4 alkylene-OH, -C1-4} _alkylene -SH, _-C1-4 alkylene- ^{NR6a R6b} , _-C1-4 alkylene- ^NR6a -C(O) ^R6b , _-OC1-4 alkylene ^C (O) _OR6a ^, _-OC1-4 alkylene C(O) _NR6a ^R6b ^, C _3-6 cycloalkyl or -OC _1-4 alkylene-C _3-6 cycloalkyl groups are each optionally substituted with one or more D groups, and

R⁵在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-C_1-4卤代烷基、-S-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4亚烷基-O-C_1-6烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-NR^6aR^6b、-C_1-4亚烷基-NR^6a-C(O)R^6b、-OC_1-4亚烷基C(O)OR^6a、-OC_1-4亚烷基C(O)NR^6aR^6b、C_3-6环烷基或-OC_1-4亚烷基-C_3-6环烷基。 ^R5 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 ynyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -SC _1-4 alkyl, -S(O) ₂ -C _1-4 alkyl, -C _1-4 alkylene-OC _1-6 alkyl, -OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-SH, -C _1-4 alkylene-NR ^6a R ^6b , -C _1-4 alkylene-NR ^6a -C(O)R ^6b , -OC _1-4 alkylene C(O)OR ^6a , -OC _1-4 alkylene C(O)NR ^6a R ^6b , C _3-6 cycloalkyl or -OC _1-4 alkylene-C _3-6 cycloalkyl.

在一些优选的实施方案中，R³在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-S-C_1-4烷基或C_3-6环烷基，其中所述C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-S-C_1-4烷基或C_3-6环烷基各自任选地被一个或多个D取代，以及In some preferred embodiments, ^R3 is independently selected each time it appears from: H, halogen, OH, SH, CN, ^-NR6a ^R6b , _C1-4 alkyl, _C1-4 haloalkyl, C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl, _-SC1-4 alkyl, or _C3-6 _cycloalkyl , wherein the _C1-4 alkyl, _C1-4 haloalkyl, _C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl, _-SC1-4 alkyl, or _C3-6 cycloalkyl are each optionally substituted with one or more D atoms, and

R⁵在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-S-C_1-4烷基或C_3-6环烷基。在另一些实施方案中，R³或R⁵在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-C_1-4卤代烷基、-S-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4亚烷基-O-C_1-6烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-NR^6aR^6b、-C_1-4亚烷基-NR^6a-C(O)R^6b、-OC_1-4亚烷基C(O)OR^6a、-OC_1-4亚烷基C(O)NR^6aR^6b、C_3-6环烷基或-OC_1-4亚烷基-C_3-6环烷基。在一些优选的实施方案中，R³或R⁵在每次出现时独立地选自：H、卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-S-C_1-4烷基或C_3-6环烷基。 ^R5 is selected independently each time it appears from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 alkynyl, -OC _1-4 alkyl, -SC _1-4 alkyl or C _3-6 cycloalkyl. In other embodiments, ^R3 or ^R5 is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , _C1-4 alkyl, _C1-4 haloalkyl, C2-4 alkenyl, _{C2-4 ynyl, -OC 1-4} _alkyl , -OC _1-4 haloalkyl, -SC _1-4 alkyl, -S(O) ₂ _-C1-4 alkyl, _{-C1-4 alkylene-OC 1-6} _alkyl , -OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-SH, -C _1-4 alkylene-NR ^6a R ^6b , _{-C 1-4 alkylene-NR 6a -C(O)R 6b, -OC 1-4} _alkylene ^C ⁽ _O )OR ^6a , -OC _1-4 alkylene C(O)NR ^6a R ^6b , C _3-6 cycloalkyl or -OC _1-4 alkylene-C _3-6 cycloalkyl. In some preferred embodiments, R ³ or R ⁵ is independently selected each time it appears from: H, halogen, OH, SH, CN, -NR ^6a R ^6b , C _1-4 alkyl, C _1-4 haloalkyl, C _2-4 alkenyl, C _2-4 ynyl, -OC _1-4 alkyl, -SC _1-4 alkyl or C _3-6 cycloalkyl.

在另一些实施方案中，R³或R⁵在每次出现时独立地选自：卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-O-C_1-4卤代烷基、-S-C_1-4烷基、-S(O)₂-C_1-4烷基、-C_1-4亚烷基-O-C_1-6烷基、-OC_1-4亚烷基-OC_1-4烷基、-C_1-4亚烷基-OH、-C_1-4亚烷基-SH、-C_1-4亚烷基-NR^6aR^6b、-C_1-4亚烷基-NR^6a-C(O)R^6b、-OC_1-4亚烷基C(O)OR^6a、-OC_1-4亚烷基C(O)NR^6aR^6b、C_3-6环烷基或-OC_1-4亚烷基-C_3-6环烷基。在一些优选的实施方案中，R³或R⁵在每次出现时独立地选自：卤素、OH、SH、CN、-NR^6aR^6b、C_1-4烷基、C_1-4卤代烷基、C_2-4烯基、C_2-4炔基、-O-C_1-4烷基、-S-C_1-4烷基或C_3-6环烷基。In other embodiments, ^R3 or ^R5 is independently selected each time it appears from: halogen, OH, SH, CN, -NR ^6a R ^6b , _C1-4 alkyl, _C1-4 haloalkyl, C2-4 alkenyl, _C2-4 ynyl, -OC _1-4 alkyl, -OC _1-4 haloalkyl, -SC _1-4 alkyl, -S(O) ₂ _-C1-4 alkyl, _-C1-4 alkylene-OC _1-6 alkyl, -OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OH, -C _1-4 alkylene-SH, -C _1-4 alkylene-NR _6a ^{R 6b} ^, -C _1-4 alkylene-NR ^6a -C(O)R ^6b , -OC _1-4 alkylene C(O)OR ^6a , -OC _1-4 alkylene C(O)NR ^6a R ^6b , _C3-6 cycloalkyl or -OC1-4 alkylene- _C3-6 _cycloalkyl . In some preferred embodiments, ^R3 or ^R5 is independently selected each time it appears from: halogen, OH, SH, CN, -NR6a, ^R6b , _C1-4 alkyl, _C1-4 haloalkyl, ^C2-4 alkenyl, _C2-4 ynyl, _-OC1-4 alkyl, _-SC1-4 alkyl or _C3-6 _cycloalkyl .

在一些优选的实施方案中，R^6a或R^6b在每次出现时独立地选自H或C_1-4烷基。In some preferred embodiments, R ^6a or R ^6b is independently selected from H or C _1-4 alkyl groups each time it appears.

在一些优选的实施方案中，R³在每次出现时独立地选自：H、F、Cl、OH、SH、CN、-NH₂、-NHCH₃、-NH(CH₃)₂、甲基、乙基、CF₃、乙烯基、乙炔基、-O-CH₃、-O-CD₃、-S-CH₃、-S-CD₃和环丙基，以及R⁵在每次出现时独立地选自：H、F、Cl、OH、SH、CN、-NH₂、-NHCH₃、-NH(CH₃)₂、甲基、乙基、CF₃、乙烯基、乙炔基、-O-CH₃、-S-CH₃或环丙基。在一些更优选的实施方案中，R³为-O-C_1-4烷基、-O-氘代C_1-4烷基、或环丙基，并且R⁵为H或C_1-4烷基。在一些更优选的实施方案中，R³为-O-CH₃、-O-CD₃、或环丙基，和/或R⁵为甲基。In some preferred embodiments, ^R3 is independently selected each time it appears from: H, F, Cl, OH, SH, CN, _-NH2 , _-NHCH3 , -NH( _CH3 ) ₂ , methyl, ethyl, _CF3 , vinyl, ethynyl, -O- _CH3 , -O- _CD3 , -S- _CH3 , -S- _CD3 , and cyclopropyl, and ^R5 is independently selected each time it appears from: H, F, Cl, OH, SH, _CN , -NH2, _-NHCH3 , -NH( _CH3 ) ₂ , methyl, ethyl, _CF3 , vinyl, ethynyl, -O- _CH3 , -S- _CH3 , or cyclopropyl. In some more preferred embodiments, ^R3 is _-OC1-4 alkyl, -O-deuterated _C1-4 alkyl, or cyclopropyl, and ^R5 is H or _C1-4 alkyl. In some preferred embodiments, ^R3 is -O- _CH3 , -O- _CD3 , or cyclopropyl, and/or ^R5 is methyl.

在一些优选的实施方案中，R³和R⁵在每次出现时独立地选自：H、F、Cl、OH、SH、CN、-NH₂、-NHCH₃、-NH(CH₃)₂、甲基、乙基、CF₃、乙烯基、乙炔基、-O-CH₃、-S-CH₃或环丙烷。在另一些实施方案中，R³和R⁵在每次出现时独立地选自：F、Cl、OH、SH、CN、-NH₂、-NHCH₃、-NH(CH₃)₂、甲基、乙基、CF₃、乙烯基、乙炔基、-O-CH₃、-S-CH₃或环丙烷。In some preferred embodiments, ^R3 and ^R5 are independently selected each time they appear from: H, F, Cl, OH, SH, CN, _-NH2 , _-NHCH3 , -NH( _CH3 ) ₂ , methyl, ethyl, _CF3 , vinyl, ethynyl, -O- _CH3 , -S- _CH3 , or cyclopropane. In other embodiments, ^R3 and ^R5 are independently selected each time they appear from: F, Cl, OH, SH, CN, _-NH2 , _-NHCH3 , -NH( _CH3 ) ₂ , methyl, ethyl, _CF3 , vinyl, ethynyl, -O- _CH3 , -S- _CH3 , or cyclopropane.

在另一些实施方案中，R³为-O-CH₃。在一些优选的实施方案中，R⁵为H或甲基。在一些优选的实施方案中，R⁵为甲基。In some embodiments, ^R3 is -O- _CH3 . In some preferred embodiments, ^R5 is H or methyl. In some preferred embodiments, ^R5 is methyl.

在又一些实施方案中，R³为-O-C_1-4烷基，并且R⁵为氢或C_1-4烷基。在一些优选的实施方案中，R³为-O-CH₃，并且R⁵为甲基。In some other embodiments, ^R3 is -OC _1-4 alkyl, and ^R5 is hydrogen or C _1-4 alkyl. In some preferred embodiments, ^R3 is -O-CH ₃ , and ^R5 is methyl.

在一些实施方案中，R²和R⁸在每次出现时各自独立地选自：H、卤素、OH、SH、CN、NH₂、-NH(C_1-4烷基)、-N(C_1-4烷基)₂、C_1-4烷基或C_3-6环烷基。In some embodiments, ^R2 and ^R8 are each independently selected from: H, halogen, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, or _C3-6 cycloalkyl.

在一些优选的实施方案中，R²和R⁸在每次出现时各自独立地选自：H、F、Cl、OH、SH、CN、NH₂、-NH(CH₃)、-N(CH₃)₂、甲基、乙基或环丙基，优选H、F、Cl、甲基、乙基或环丙基。In some preferred embodiments, ^R2 and ^R8 are each independently selected from: H, F, Cl, OH, SH, CN, _NH2 , -NH( _CH3 ), -N( _CH3 ) ₂ , methyl, ethyl or cyclopropyl, preferably H, F, Cl, methyl, ethyl or cyclopropyl.

在一些实施方案中，L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B；并且In some embodiments, ^L1 is selected from: *-CR ^g R ^h -NR ^4c -, *-C(O)-NR ^4c -, *-C(S)-NR ^4c -, *-S(O) ₂ -NR ^4c -, *-NR ^4c -C(O)-, *-NR ^4c -S(O) ₂ -, *-NR ^4c -CR ^g R ^h - or *-NR ^4c -C(S)-, wherein the bond indicated by * is connected to the phenyl ring B; and

R^g和R^h各自独立地选自H、氘、卤素、OH、SH、CN、C_1-6烷基、C_1-6卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b；或者R^g或R^h与它们二者共同连接的碳原子一起形成C_3-4环烷基或4-5元杂环烷基。 ^Rg and ^Rh are each independently selected from H, deuterium, halogen, OH, SH, CN, _C1-6 alkyl, _C1-6 haloalkyl, NR ^5a R ^5b , -C(O)OR ^5a or -C(O)-NR ^5a R ^5b ; or ^Rg or ^Rh together with the carbon atom to which they are connected form a _C3-4 cycloalkyl or a 4-5 membered heterocyclic alkyl.

在一些优选的实施方案中，L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B；并且R^g和R^h各自独立地选自：H、氘、F、Cl、OH、SH、CN、C_1-4烷基、C_1-4卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b，优选H、F、Cl、OH、SH、CN、CH₃、CF₃、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b；或者R^g或R^h与它们二者共同连接的碳原子一起形成C_3-4环烷基或4-5元杂环烷基。In some preferred embodiments, ^L1 is selected from: * ^-CRgRh ^-NR4c- ^, *-C(O) ^-NR4c- , *-C(S)-NR4c-, *-S(O) _2- ^NR4c- , *-NR4c- ^C (O)-, * ^-NR4c -S(O) _2- , * ^-NR4c - ^CRgRh- , or * ^-NR4c -C(S)- ^, wherein the bond indicated by * is connected to the phenyl ring B; and ^Rg ^and ^Rh are each independently selected from: H, deuterium, F, Cl, OH, SH, CN, _C1-4 alkyl, _C1-4 haloalkyl, ^NR5aR5b , -C(O) ^OR5a , or -C(O) ^-NR5aR5b , ^preferably H, F, Cl, OH, SH, CN, _CH3 , _CF3 , ^or ^NR5aR5b ^. -C(O)OR ^5a or -C(O)-NR ^5a R ^5b ; or R ^g or R ^h together with the carbon atom to which they are connected to form a C _3-4 cycloalkyl or a 4-5 heterocyclic alkyl.

在另一些实施方案中，L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B；并且In other embodiments, ^L1 is selected from: *-CR ^g R ^h -NR ^4c -, *-C(O)-NR ^4c -, *-C(S)-NR ^4c -, *-S(O) ₂ -NR ^4c -, *-NR ^4c -C(O)-, *-NR ^4c -S(O) ₂ -, *-NR ^4c -CR ^g R ^h - or *-NR ^4c -C(S)-, wherein the bond indicated by * is connected to the phenyl ring B; and

在一些优选的实施方案中，L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B；并且In some preferred embodiments, ^L1 is selected from: *-CR ^g R ^h -NR ^4c -, *-C(O)-NR ^4c -, *-C(S)-NR ^4c -, *-S(O) ₂ -NR ^4c -, *-NR ^4c -C(O)-, *-NR ^4c -S(O) ₂ -, *-NR ^4c -CR ^g R ^h - or *-NR ^4c -C(S)-, wherein the bond indicated by * is connected to the phenyl ring B; and

R^g或R^h各自独立地选自H、氘、F、Cl、OH、SH、CN、C_1-4烷基、C_1-4卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b；或者R^g或R^h与它们二者共同连接的碳原子一起形成C_3-4环烷基或4-5元杂环烷基。 ^Rg or ^Rh are each independently selected from H, deuterium, F, Cl, OH, SH, CN, _C1-4 alkyl, _C1-4 haloalkyl, ^NR5a ^R5b , -C(O) ^OR5a or -C(O) ^-NR5a ^R5b ; or ^Rg or ^Rh together with the carbon atom to which they are connected form a _C3-4 cycloalkyl or a 4-5 membered heterocyclic alkyl.

在另一些实施方案中，L¹选自：*-CR^gR^h-NR^4c-、*-C(O)-NR^4c-、*-C(S)-NR^4c-、*-S(O)₂-NR^4c-、*-NR^4c-C(O)-、*-NR^4c-S(O)₂-、*-NR^4c-CR^gR^h-或*-NR^4c-C(S)-，其中用*标识的键连接至苯基环B；并且R^g和R^h各自独立地选自：H、F、Cl、OH、SH、CN、C_1-4烷基、C_1-4卤代烷基、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b，优选H、F、Cl、OH、SH、CN、CH₃、CF₃、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b。In other embodiments, ^L1 is selected from: * ^-CRgRh ^-NR4c- ^, *-C(O)-NR4c-, *-C(S) ^-NR4c- , *-S(O) _2- ^NR4c- , *-NR4c-C(O)-, * ^-NR4c -S(O) _2- , * ^-NR4c - ^CRgRh- , or * ^-NR4c ^- ^C (S)-, wherein the bond indicated by * is connected to the phenyl ring B; and ^Rg and ^Rh are each independently selected from: H, F, Cl, OH, SH, CN, _C1-4 alkyl, _C1-4 haloalkyl ^, ^NR5aR5b , -C(O) ^OR5a , or -C(O) ^-NR5aR5b , ^preferably H, F, Cl, OH, SH, CN, _CH3 , ^CF3 , ^NR5aR5b , ^or -C( _O )OR ^5a or -C(O)-NR ^5a R ^5b .

在一些优选的实施方案中，R^5a和R^5b在每次出现时独立地选自H或C_1-4烷基。In some preferred embodiments, ^R5a and ^R5b are independently selected from H or _C1-4 alkyl groups each time they appear.

在一些优选的实施方案中，R^g和R^h各自独立地选自H、氘、F、Cl、OH、SH、CN、CH₃、CF₃、NR^5aR^5b、-C(O)OR^5a或-C(O)-NR^5aR^5b。在一些优选的实施方案中，R^g或R^h各自独立地选自H、氘、F、Cl、OH、SH、CN、-NH₂、-C(O)OH、-C(O)OCH₃、-C(O)-NH₂或-C(O)-NCH₃。在一些优选的实施方案中，R^g或R^h与它们二者共同连接的碳原子一起形成环丙烷基。In some preferred embodiments, ^Rg and ^Rh are each independently selected from H, deuterium, F, Cl, OH, SH, CN, _CH3 , _CF3 , ^NR5aR5b , -C(O) ^OR5a , or ^-C (O) ^-NR5aR5b . In some preferred embodiments, ^Rg or ^Rh are each independently selected from H, deuterium, F, Cl, OH, SH, CN, _-NH2 , -C(O)OH, -C(O) _OCH3 , -C(O) ^-NH2 _, or -C(O) _-NCH3 . In some preferred embodiments, ^Rg or ^Rh, together with the carbon atom to which they are connected, forms a cyclopropane group.

在另一些实施方案中，R^g或R^h各自独立地选自H、F、Cl、OH、SH、CN、-NH₂、-C(O)OH、-C(O)OCH₃、-C(O)-NH₂或-C(O)-NCH₃。In other embodiments, ^Rg or ^Rh is each independently selected from H, F, Cl, OH, SH, CN, -NH ₂ , -C(O)OH, -C(O)OCH ₃ , -C(O)-NH ₂ or -C(O)-NCH ₃ .

在一些优选的实施方案中，R^4c选自H、C_1-4烷基或C_1-4卤代烷基。In some preferred embodiments, ^R4c is selected from H, _C1-4 alkyl, or _C1-4 haloalkyl.

在一些优选的实施方案中，R^4c选自H、甲基、乙基、-CH₂F、-CHF₂或-CF₃。In some preferred embodiments, ^R4c is selected from H, methyl, ethyl, _-CH2F , _-CHF2 or _-CF3 .

在一些优选的实施方案中，L¹选自：*-CH₂-NH-、*-CF₂-NH-、*-CD₂-NH-、*-CH(CF₃)-NH-、*-C(CH₃)₂-NH-、*-CH₂-N(CH₃)-、*-CH₂-N(CH₂CH₃)-、*-CH₂-N(CH₂F)-、*-C(O)-NH-、*-C(S)-NH-、*-S(O)₂-NH-、*-NH-CH₂-、*-NH-CF₂-、*-NH-C(O)-、*-NH-C(S)-、*-NH-S(O)₂-、其中用*标识的键连接至苯基环B。In some preferred embodiments, ^L1 is selected from: * _-CH2 -NH-, *-CF2-NH-, * _-CD2 _- NH-, *-CH( _CF3 )-NH-, *-C( _CH3 ) _2- NH-, * _{-CH2-N(CH3)-, *-CH2} -N( _CH2CH3 )-, * _-CH2 _- N( _CH2F )-, _* -C(O)-NH-, *-C( _S )-NH-, *-S(O) _2- NH-, *-NH- _CH2- , *-NH- _CF2- , *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O) _2- , The bonds marked with * are connected to the phenyl ring B.

在另一些实施方案中，L¹选自：*-CH₂-NH-、*-CF₂-NH-、*-CH(CF₃)-NH-、*-CH₂-N(CH₃)-、*-CH₂-N(CH₂CH₃)-、*-CH₂-N(CH₂F)-、*-C(O)-NH-、*-C(S)-NH-、*-S(O)₂-NH-、*-NH-CH₂-、*-NH-CF₂-、*-NH-C(O)-、*-NH-C(S)-、*-NH-S(O)₂-、更优选*-CH₂-NH-和*-C(O)-NH-，其中用*标识的键连接至苯基环B。In other embodiments, ^L1 is selected from: * _-CH2 -NH-, *-CF2- _NH- , *-CH( _CF3 )-NH-, * _-CH2 -N( _CH3 )-, * _-CH2 -N( _CH2CH3 )-, * _-CH2 -N( _CH2F )-, *-C(O)-NH-, *-C( _S )-NH-, *-S(O) _2- NH-, *-NH- _CH2- , *-NH- _CF2- , *-NH-C(O)-, *-NH-C(S)-, *-NH-S(O) _2- , More preferably, * _-CH2- NH- and *-C(O)-NH-, wherein the bond indicated by * is attached to the phenyl ring B.

在一些更优选的实施方案中，L¹选自：*-CH₂-NH-、*-CD₂-NH-、*-C(CH₃)₂-NH-*-C(O)-NH-或其中用*标识的键连接至苯基环B。In some preferred embodiments, ^L1 is selected from: * _-CH2- NH-, * _-CD2- NH-, *-C( _CH3 ) _2- NH-, *-C(O)-NH-, or The bonds marked with * are connected to the phenyl ring B.

在一些优选的实施方案中，本发明所述化合物具有式(I-19)所示的结构：
In some preferred embodiments, the compound of the present invention has the structure shown in formula (I-19):

在根据所述式(I-19)的化合物的一些实施方案中，L¹选自*-CR^gR^h-NR^4c-和*-C(O)-NR^4c-，其中用*标识的键连接至苯基环B；In some embodiments of the compounds according to formula (I-19), ^L1 is selected from *-CR ^g R ^h -NR ^4c- and *-C(O)-NR ^4c- , wherein the bond indicated by * is linked to the phenyl ring B;

R^g或R^h各自独立地选自H或氘；R ^g or R ^h are each independently selected from H or deuterium;

R^4c为H；R ^4c is H;

R³选自-O-C_1-6烷基或C_3-6环烷基，其中所述-O-C_1-6烷基和C_3-6环烷基各自任选地被1、2、3或更多个D取代；R ³ is selected from -OC _1-6 alkyl or C _3-6 cycloalkyl, wherein the -OC _1-6 alkyl and C _3-6 cycloalkyl are each optionally substituted with 1, 2, 3 or more D atoms;

R⁵选自C_1-6烷基； ^R5 is selected from _C1-6 alkyl groups;

环D为5-8元桥杂环烷基；优选其中$^A为与环A的连接点，$^L1为与L¹的连接点；Ring D is a 5-8 membered bridged heterocyclic alkyl group; preferably Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 ;

R⁴选自：R ⁴ is selected from:

各自任选地被1、2、3、4、5、6或更多个独立地选自卤素、OH、NH₂或CN的取代基取代的C_1-6烷基、C_2-6烯基或C_2-6炔基，Each of the following is optionally substituted with one, two, three, four, five, six or more _C1-6 alkyl, _C2-6 alkenyl or _C2-6 ynyl groups independently selected from halogen, OH, _NH2 or CN.

-C_1-6亚烷基-O-卤代C_1-6烷基，-C _1-6 alkylene-O-halogenated C _1-6 alkyl

C_3-6环烷基或-C_1-6亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自卤素、OH、NH₂、CN、C_1-6烷基、C_1-6卤代烷基或C_1-6卤代烷氧基的取代基取代， _C3-6 cycloalkyl or _-C1-6 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from halogen, OH, _NH2 , CN, _C1-6 alkyl, _C1-6 haloalkyl or _C1-6 haloalkoxy groups each time it appears.

4-7元杂环烷基或-C_1-6亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、NH₂、CN、C_1-6烷基或C_1-6卤代烷基的取代基取代，以及4-7-membered heterocyclic alkyl or _-C1-6 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl group is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, _NH2 , CN, _C1-6 alkyl or _C1-6 haloalkyl in each occurrence, and

-NH(4-7元杂环烷基)；以及-NH (4-7 membered heterocyclic alkyl groups); and

m为1。m is 1.

在一些此类实施方案中，环D优选为其中$^A为与环A的连接点，$^L1为与L¹的连接点。更优选地，部分为其中，$^A为与环A的连接点，$^L1为与L¹的连接点。In some such implementations, ring D is preferred. Where $ ^A$ is the connection point with ring A, and $ ^L1 $ is the connection point with ^L1 . More preferably, Part of Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 .

在一些优选的实施方案中，L¹选自*-CH₂-NH-、*-CD₂-NH-或*-C(O)-NH-，其中用*标识的键连接至苯基环B。In some preferred embodiments, ^L1 is selected from * _-CH2- NH-, * _-CD2- NH-, or *-C(O)-NH-, wherein the bond indicated by * is attached to the phenyl ring B.

在一些优选的实施方案中，R³选自-O-C_1-4烷基或C_3-6环烷基，其中所述-O-C_1-4烷基和C_3-6环烷基各自任选地被1、2、3或更多个D取代。更优选地，R³选自-O-C_1-2烷基或C_3-6环烷基，其中所述-O-C_1-2烷基和C_3-6环烷基各自任选地被1、2、3或更多个D取代。In some preferred embodiments, ^R3 is selected from -OC _1-4 alkyl or C _3-6 cycloalkyl, wherein the -OC _1-4 alkyl and C _3-6 cycloalkyl are each optionally substituted with 1, 2, 3 or more D atoms. More preferably, ^R3 is selected from -OC _1-2 alkyl or C _3-6 cycloalkyl, wherein the -OC _1-2 alkyl and C _3-6 cycloalkyl are each optionally substituted with 1, 2, 3 or more D atoms.

在一些优选的实施方案中，R⁵选自C_1-4烷基，更优选C_1-2烷基。In some preferred embodiments, ^R5 is selected from _C1-4 alkyl, more preferably _C1-2 alkyl.

在一些更优选的实施方案中，R³为-O-CH₃、-O-CD₃、或环丙基，并且R⁵为甲基。In some preferred embodiments, ^R3 is -O- _CH3 , -O- _CD3 , or cyclopropyl, and ^R5 is methyl.

任选地被1、2、3、4、5、6或更多个独立地选自卤素、OH、NH₂或CN的取代基取代的C_1-6烷基、C_2-4烯基或C_2-4炔基，Optionally substituted with 1, 2, 3, 4, 5, 6 or more substituents independently selected from halogen, OH, _NH2 or CN, _C1-6 alkyl, _C2-4 alkenyl or _C2-4 ynyl groups.

-C_1-4亚烷基-O-卤代C_1-4烷基或-NH(4-6元杂环烷基)，-C _1-4 alkylene-O-halogenated C _1-4 alkyl or -NH (4-6 membered heterocyclic alkyl),

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自卤素、OH、NH₂、CN、C_1-4烷基、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代， _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from halogen, OH, _NH2 , CN, _C1-4 alkyl, _C1-4 haloalkyl or _C1-4 haloalkoxy groups each time it appears.

4-7元杂环烷基或-C_1-4亚烷基-4-7元杂环烷基，其中所述4-7元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、OH、NH₂、CN、C_1-4烷基或C_1-4卤代烷基的取代基取代。4-7-membered heterocyclic alkyl or _-C1-4 alkylene-4-7-membered heterocyclic alkyl, wherein the 4-7-membered heterocyclic alkyl is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, OH, _NH2 , CN, _C1-4 alkyl or _C1-4 haloalkyl each time it appears.

各自任选地被1、2、3、4、5、6或更多个独立地选自卤素、OH或CN的取代基取代的C_1-6烷基、C_2-4烯基或C_2-4炔基，Each of the following is optionally substituted with one, two, three, four, five, six or more _C1-6 alkyl, _C2-4 alkenyl or _C2-4 ynyl groups independently selected from halogen, OH or CN.

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自卤素或C_1-4卤代烷基的取代基取代， _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is optionally and independently substituted with one, two or more substituents independently selected from halogens or _C1-4 haloalkyl groups each time it appears.

4-6元杂环烷基或-C_1-4亚烷基-4-6元杂环烷基，其中所述4-6元杂环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自氘、卤素、CN或C_1-4烷基的取代基取代，并且4-6-membered heterocyclic alkyl or _-C1-4 alkylene-4-6-membered heterocyclic alkyl, wherein the 4-6-membered heterocyclic alkyl is independently and optionally substituted with one, two or more substituents independently selected from deuterium, halogen, CN or _C1-4 alkyl in each occurrence, and

其中以上所述卤代或卤素在每次出现时独立地选自F或Cl。The halogens or halogens mentioned above are each independently selected from F or Cl each time they appear.

C_1-4烷基、C_1-6卤代烷基、-C_1-4卤代烷基-OH、-C_1-4亚烷基-CN、C_2-4炔基、-C_1-4亚烷基-O-卤代C_1-4烷基或-NH(4-6元杂环烷基)， _C1-4 alkyl, _C1-6 haloalkyl, _-C1-4 haloalkyl-OH, _-C1-4 alkylene-CN, _C2-4 ynyl, _-C1-4 alkylene-O-haloC1-4 alkyl or -NH ( _4-6 membered heterocyclic alkyl),

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自卤素、C_1-4卤代烷基或C_1-4卤代烷氧基的取代基取代， _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is optionally and independently substituted with one, two or more substituents independently selected from halogens, _C1-4 haloalkyl groups or _C1-4 haloalkoxy groups each time it appears.

C_1-4烷基、C_1-6氟烷基、-C_1-4氟烷基-OH、-C_1-4亚烷基-CN、C_2-4炔基或-NH(具有1个O或S杂原子的4-6元杂环烷基)， _C1-4 alkyl, _C1-6 fluoroalkyl, _-C1-4 fluoroalkyl-OH, _-C1-4 alkylene-CN, _C2-4 alkynyl or -NH (4-6 membered heterocyclic alkyl groups with one O or S heteroatom),

C_3-6环烷基或-C_1-4亚烷基-C_3-6环烷基，其中所述C_3-6环烷基在每次出现时独立地任选地被1个、2个或更多个独立地选自F、C_1-4氟烷基或C_1-4氟烷氧基的取代基取代，以及 _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the _C3-6 cycloalkyl group is independently and optionally substituted with one, two or more substituents independently selected from F, _C1-4 fluoroalkyl or _C1-4 fluoroalkoxy groups in each occurrence, and

4-6元杂环烷基或-C_1-4亚烷基-4-6元杂环烷基，其中所述4-6元杂环烷基在每次出现时独立地为具有1个N杂原子的4-6元杂环烷基并且任选地被1个、2个或更多个独立地选自氘、F、CN或C_1-4烷基的取代基取代。4-6-membered heterocyclic alkyl or -C _1-4 alkylene-4-6-membered heterocyclic alkyl, wherein the 4-6-membered heterocyclic alkyl is independently a 4-6-membered heterocyclic alkyl having one N heteroatom each time it appears and is optionally substituted by one, two or more substituents independently selected from deuterium, F, CN or C _1-4 alkyl.

在一些更优选的实施方案中，R⁴选自甲基、乙基、 In some preferred embodiments, ^R4 is selected from methyl, ethyl,

在一些更优选的实施方案中，所述式(I-19)的化合物具有式(I-20)或(I-21)所示结构：
In some more preferred embodiments, the compound of formula (I-19) has the structure shown in formula (I-20) or (I-21):

优选具有式(I-24)或(I-25)所示结构 Preferably, it has the structure shown in formula (I-24) or (I-25).

更优选具有式(I-24)所示结构 More preferably, it has the structure shown in formula (I-24)

在一些优选的实施方案中，部分为其中$^A为与环A的连接点，$^L1为与L¹的连接点。In some preferred embodiments, Part of Where $ ^A is the connection point with ring A, and $ ^L1 is the connection point with ^L1 .

在一些此类实施方案中，优选地，R³为-O-CH₃或环丙基，并且R⁵为甲基。在一些实施方案中，R⁴选自被1、2、3、4或更多个独立地选自卤素和OH的取代基取代的C_1-4烷基。在一些优选的实施方案中，R⁴选自被1、2、3、4或更多个独立地选自F、Cl和OH的取代基取代的C_1-6烷基。在一些优选的实施方案中，R⁴选自被1、2、3、4或更多个独立地选自F或OH的取代基取代的C_1-6烷基。在一些优选的实施方案中，R⁴选自被1、2、3或更多个F和0或1个OH取代的C_1-6烷基。在一些优选的实施方案中，R⁴选自被1、2、3或更多个F和0或1个OH取代的C_3-6烷基。在一些更优选的实施方案中，R⁴选自
In some such embodiments, preferably, ^R3 is -O- _CH3 or cyclopropyl, and ^R5 is methyl. In some embodiments, ^R4 is selected from _C1-4 alkyl groups substituted with 1, 2, 3, 4 or more substituents independently selected from halogens and OH. In some preferred embodiments, ^R4 is selected from C1-6 alkyl groups substituted with 1, 2, 3, 4 or more substituents independently selected from F, Cl, and OH. In some preferred embodiments, ^R4 is selected from _C1-6 alkyl groups substituted with 1, 2, 3 _, 4 or more substituents independently selected from F or OH. In some preferred embodiments, ^R4 is selected from _C1-6 alkyl groups substituted with 1, 2, 3 or more F and 0 or 1 OH. In some preferred embodiments, ^R4 is selected from _C3-6 alkyl groups substituted with 1, 2, 3 or more F and 0 or 1 OH. In some more preferred embodiments, ^R4 is selected from...

本发明涵盖对各个实施方案进行任意组合所得的化合物。This invention covers compounds obtained by arbitrarily combining various embodiments.

在一些实施方案中，本发明提供所述式(I)的化合物、或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，其中所述化合物选自：

In some embodiments, the present invention provides a compound of formula (I), or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

药物组合物和用途Pharmaceutical Compositions and Uses

在另一方面，本发明提供药物组合物，其包含根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，以及药学上可接受的载体。所述药物组合物优选是固体制剂、液体制剂或半固体制剂。In another aspect, the present invention provides pharmaceutical compositions comprising compounds of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. The pharmaceutical compositions are preferably solid, liquid, or semi-solid dosage forms.

在另一个方面，本发明提供药物组合，其包括根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，和另一种治疗活性剂。In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts thereof, and another therapeutically active agent.

在另一个方面，本发明提供根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐，或者根据本发明的所述药物组合物，或者根据本发明的所述药物组合，其用作药物。In another aspect, the present invention provides compounds of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or their stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, or pharmaceutical compositions according to the present invention, or pharmaceutical compositions according to the present invention, which are used as pharmaceuticals.

在另一个方面，本发明提供调节个体的补体旁路途径活性的方法，其中所述方法包括：向所述个体施用治疗有效量的根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐；或者向所述个体施用治疗有效量的根据本发明的所述药物组合物；或者向所述个体施用治疗有效量的根据本发明的所述药物组合。In another aspect, the present invention provides a method for modulating the activity of the complement bypass pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present invention.

在一些实施方案中，根据本发明的化合物、药物组合物、或者药物组合用于预防或治疗由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症。In some embodiments, the compounds, pharmaceutical compositions, or combinations of pharmaceuticals according to the invention are used to prevent or treat diseases, disorders, or conditions mediated by complement activation, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway.

在另一个方面，本发明提供预防或治疗个体中由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症的方法，其中所述方法包括向所述个体施用治疗有效量的根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐；或者向所述个体施用治疗有效量的根据本发明的所述药物组合物；或者向所述个体施用治疗有效量的根据本发明的所述药物组合。In another aspect, the present invention provides a method for preventing or treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway, wherein the method comprises administering to the individual a therapeutically effective amount of a compound of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or their stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to the present invention; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to the present invention.

在另一个方面，本发明提供根据本发明的所述式(I)的化合物，包括所述式(I-1)至式(I-4)、式(II-1)至式(II-30)、式(III-1)至式(III-11)、式(IV-1)至式(IV-3)的化合物，或者其立体异构体、互变异构体、非对映异构体、外消旋物、顺反异构体、同位素标记化合物(优选氘代物)、N-氧化物、代谢物、酯、前药、晶型、水合物、溶剂合物或药学上可接受的盐、或者根据本发明的所述药物组合物、或者根据本发明的所述药物组合在制备用于治疗个体中由补体激活介导的疾病、障碍或病症，特别是由补体旁路途径的激活介导的疾病、障碍或病症的药物中的用途。In another aspect, the present invention provides the use of compounds of formula (I) according to the present invention, including compounds of formulas (I-1) to (I-4), (II-1) to (II-30), (III-1) to (III-11), (IV-1) to (IV-3), or their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or pharmaceutical compositions according to the present invention, or pharmaceutical compositions according to the present invention, in the preparation of medicaments for treating diseases, disorders or conditions mediated by complement activation in an individual, particularly diseases, disorders or conditions mediated by activation of the complement alternative pathway.

在一些实施方案中所述疾病、障碍或病症选自与年龄相关的黄斑变性、黄斑地图状萎缩、糖尿病视网膜病变、葡萄膜炎、视网膜色素变性、黄斑水肿、白塞氏葡萄膜炎、多灶性脉络膜炎、Vogt-Koyangi-Harada综合征、中间葡萄膜炎、鸟眼视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮，非动脉性缺血性视神经病变、术后炎症、视网膜静脉阻塞、神经系统疾病、多发性硬化、中风、格林-巴利综合征、创伤性脑损伤、帕金森氏病、不适当或不期望的补体激活导致的病症、血液透析并发症、超急性同种异体移植排斥、异种移植排斥、白细胞介素-2(IL-2)治疗期间IL-2诱导的毒性、炎症性疾病、自身免疫性疾病的炎症、克罗恩病、成人呼吸窘迫综合征、心肌炎、缺血后再灌注病症、心肌梗死、球囊血管成形术、心肺转流术或肾转流术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建后肠系膜动脉再灌注、感染性疾病或败血症、免疫复合物病症和自身免疫性疾病、类风湿性关节炎、系统性红斑狼疮(SLE)、SLE肾炎、增生性肾炎、C3肾小球疾病(C3G)、免疫球蛋白A肾病(IgAN)或具有肾小球C3沉积证据的其他肾病(例如膜性肾病(MN)和大肠杆菌诱导的溶血性尿毒症综合征(HUS))、阵发性夜间血红蛋白尿(PNH)、非典型溶血性尿毒症综合征(aHUS)、免疫性血小板减少性紫癜(ITP)、冷凝集素疾病(CAD)、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、哮喘、慢性阻塞性肺病(COPD)、肺气肿、肺栓塞和梗塞、肺炎、纤维原性粉尘病、肺纤维化、过敏、支气管收缩、超敏性肺炎、寄生虫病、肺出血肾炎综合征、肺血管炎、Pauci免疫血管炎、免疫复合物相关炎症、抗磷脂综合征、肾小球肾炎和肥胖症。In some implementations, the diseases, disorders, or conditions described are selected from age-related macular degeneration, geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, multiple sclerosis, stroke, etc. Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, symptoms caused by inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis, renal ischemia. The following conditions are considered: mesenteric artery reperfusion after aortic reconstruction; infectious diseases or sepsis; immune complex disorders and autoimmune diseases; rheumatoid arthritis; systemic lupus erythematosus (SLE); SLE nephritis; proliferative nephritis; C3 glomerular disease (C3G); immunoglobulin A nephropathy (IgAN) or other nephropathy with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and Escherichia coli-induced hemolytic uremic syndrome (HUS)); paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (a HUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, allergies, bronchoconstriction, hypersensitivity pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, and obesity.

在一些实施方案中，所述疾病、障碍或病症选自与年龄相关的黄斑变性(AMD)、黄斑地图状萎缩、糖尿病视网膜病变、葡萄膜炎、视网膜色素变性、黄斑水肿、白塞氏葡萄膜炎、多灶性脉络膜炎、Vogt-Koyangi-Harada综合征、中间葡萄膜炎、鸟眼视网膜脉络膜炎、交感性眼炎、眼瘢痕性类天疱疮、眼天疱疮，非动脉性缺血性视神经病变、术后炎症、视网膜静脉阻塞、神经系统疾病、多发性硬化、中风、格林-巴利综合征、创伤性脑损伤、帕金森氏病、不适当或不期望的补体激活导致的病症、血液透析并发症、超急性同种异体移植排斥、异种移植排斥、白细胞介素-2(IL-2)治疗期间IL-2诱导的毒性、炎症性疾病、自身免疫性疾病的炎症、克罗恩病、成人呼吸窘迫综合征、心肌炎、缺血后再灌注病症、心肌梗死、球囊血管成形术、心肺转流术或肾转流术中的泵后综合征、动脉粥样硬化、血液透析、肾缺血、主动脉重建后肠系膜动脉再灌注、感染性疾病或败血症、免疫复合物病症和自身免疫性疾病、类风湿性关节炎、系统性红斑狼疮(SLE)、狼疮肾炎(LN)、增生性肾炎、C3肾小球疾病(C3G)、免疫球蛋白A肾病(IgAN)或具有肾小球C3沉积证据的其他肾病(例如膜性肾病(MN)和溶血性尿毒症综合征(HUS))、阵发性夜间血红蛋白尿(PNH)、非典型溶血性尿毒症综合征(aHUS)、免疫性血小板减少性紫癜(ITP)、冷凝集素疾病(CAD)、肝纤维化、溶血性贫血、重症肌无力、组织再生、神经再生、呼吸困难、咯血、哮喘、慢性阻塞性肺病(COPD)、肺气肿、肺栓塞和梗塞、肺炎、纤维原性粉尘病、肺纤维化、过敏、支气管收缩、超敏性肺炎、寄生虫病、肺出血肾炎综合征、肺血管炎、Pauci免疫血管炎、免疫复合物相关炎症、抗磷脂综合征、肾小球肾炎或肥胖症。In some embodiments, the disease, disorder, or condition is selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological disorders, and multiple sclerosis. Chemotherapy, stroke, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, symptoms caused by inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis Analysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative nephritis, C3 glomerular disease (C3G), immunoglobulin A nephropathy (IgAN) or other nephropathy with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (a HUS), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity.

本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and/or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.

除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。Unless otherwise stated, as used herein, the term “treatment” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

在另种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。In another embodiment, the pharmaceutical composition of the present invention may also contain one or more additional therapeutic or preventative agents.

Attached Figure Description

图1A、1B显示实验例8A中LNP023和本发明化合物对绵羊抗大鼠FxlA血清诱导的大鼠被动海曼肾炎的治疗作用。Figures 1A and 1B show the therapeutic effects of LNP023 and the compounds of the present invention on passive Hyman nephritis induced by sheep anti-rat FxlA serum in rats in Experiment 8A.

图2A、2B显示实验例8B中LNP023和本发明化合物对绵羊抗大鼠FxlA血清诱导的大鼠被动海曼肾炎的治疗作用。Figures 2A and 2B show the therapeutic effects of LNP023 and the compounds of this invention on passive Hyman nephritis induced by sheep anti-rat FxlA serum in rats in Experiment 8B.

图3A、3B、3C、3D、3E、3F、4A、4B、4C和4D显示实验例8C中LNP023和本发明化合物对绵羊抗大鼠FxlA血清诱导的大鼠被动海曼肾炎的治疗作用。Figures 3A, 3B, 3C, 3D, 3E, 3F, 4A, 4B, 4C, and 4D show the therapeutic effects of LNP023 and the compounds of this invention on passive Heyman nephritis induced by sheep anti-rat FxlA serum in rats in Experimental Example 8C.

图5A、5B显示实验例9A中LNP023和本发明化合物对脂多糖LPS诱导的大鼠补体激活的抑制作用。Figures 5A and 5B show the inhibitory effects of LNP023 and the compounds of this invention on LPS-induced complement activation in rats in Experiment 9A.

图6A、6B、6C、6D、6E和6F显示实验例9B中LNP023和本发明化合物对脂多糖LPS诱导的大鼠补体激活的抑制作用。Figures 6A, 6B, 6C, 6D, 6E and 6F show the inhibitory effects of LNP023 and the compounds of this invention on LPS-induced complement activation in rats in Experimental Example 9B.

图7显示实验例9C中LNP023和本发明化合物对脂多糖LPS诱导的大鼠补体激活的抑制作用。Figure 7 shows the inhibitory effects of LNP023 and the compounds of this invention on LPS-induced complement activation in rats in Experiment 9C.

实施例Example

下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本发明，而不应视为限制本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

NMR是用Bruker Avance III 400核磁仪测定，化学位移(δ)以10^-6(ppm)作为单位给出。溶剂为氘代甲醇(CD₃OD)、氘代氯仿(CDCl₃)或六氘代二甲基亚砜(DMSO-d6)等，内标为四甲基硅烷(TMS)。NMR was determined using a Bruker Avance III 400 NMR spectrometer, and chemical shifts (δ) are given in units of ^10⁻⁶ (ppm). Solvents included deuterated methanol ( _CD₃OD ), deuterated chloroform ( _CDCl₃ ), or hexadeuterated dimethyl sulfoxide (DMSO-d₆), with tetramethylsilane (TMS) as the internal standard.

MS是用Agilent(ESI)质谱仪(Agilent 1260，Agilent 6125B)测定，液质联用仪(LCMS)测定条件：Agilent(agilent 1260infinityⅡ-G6125B)，色谱柱：Waters CORTECS C18+，2.7μm，4.6mm×30mm，流动相：Α：水(0.01％三氟乙酸-10％乙腈)，B：乙腈(0.01％三氟乙酸)，梯度：B％：0-95％梯度流动0-2分钟，流速：2mL/min，紫外检测波段为220和254nm。。MS was performed using an Agilent (ESI) mass spectrometer (Agilent 1260, Agilent 6125B). LC-MS conditions were as follows: Agilent (Agilent 1260 Infinity II-G6125B), column: Waters CORTECS C18+, 2.7 μm, 4.6 mm × 30 mm; mobile phase: A: water (0.01% trifluoroacetic acid - 10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid); gradient: B%: 0-95% gradient flow for 0-2 minutes, flow rate: 2 mL/min; UV detection bands: 220 and 254 nm.

高效液相色谱(HPLC)测定条件一：Agilent高压液相色谱仪(agilent 1260infinityⅡ)，色谱柱：Agilent EC-C18,2.7μm,4.6×100mm，流动相：Α：水(0.01％三氟乙酸-10％乙腈)，B：乙腈(0.01％三氟乙酸)，梯度：B％：5-95％梯度流动10分钟，流速：1.2mL/min，紫外检测波段为220和254nm。High Performance Liquid Chromatography (HPLC) Determination Conditions 1: Agilent high performance liquid chromatograph (Agilent 1260 Infinity II), chromatographic column: Agilent EC-C18, 2.7 μm, 4.6 × 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid - 10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow for 10 minutes, flow rate: 1.2 mL/min, UV detection bands: 220 and 254 nm.

高效液相色谱(HPLC)测定条件二：Agilent高压液相色谱仪(agilent 1260infinityⅡ)，色谱柱：Agilent EC-C18,2.7μm,4.6×100mm，流动相：Α：水(0.01％三氟乙酸-10％乙腈)，B：乙腈(0.01％三氟乙酸)，梯度：B％：5-95％梯度流动5分钟，流速：1.2mL/min，紫外检测波段为220和254nm。High Performance Liquid Chromatography (HPLC) Determination Conditions 2: Agilent high performance liquid chromatograph (Agilent 1260 Infinity II), column: Agilent EC-C18, 2.7 μm, 4.6 × 100 mm, mobile phase: A: water (0.01% trifluoroacetic acid - 10% acetonitrile), B: acetonitrile (0.01% trifluoroacetic acid), gradient: B%: 5-95% gradient flow for 5 min, flow rate: 1.2 mL/min, UV detection bands: 220 and 254 nm.

高效液相色谱(HPLC)测定条件三：Shimadzu高压液相色谱仪(Shimadzu 2020Series with LC-30AD xs pumps and SPD-M20A detector)，色谱柱：Kinetex C18,2.1×50mm,1.7μm，流动相：Α：水(0.075％三氟乙酸)，B：乙腈，梯度：B％：0-30％梯度流动7分钟，流速：1.2mL/min，紫外检测波段为220和254nm。High Performance Liquid Chromatography (HPLC) Determination Conditions 3: Shimadzu HPLC system (Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector), column: Kinetex C18, 2.1×50mm, 1.7μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-30% gradient flow for 7 minutes, flow rate: 1.2mL/min, UV detection bands are 220 and 254nm.

高效液相色谱(HPLC)测定条件四：Shimadzu高压液相色谱仪(Shimadzu 2020Series with LC-30AD xs pumps and SPD-M20A detector)，色谱柱：Kinetex C18,2.1×50mm,1.7μm，流动相：Α：水(0.075％三氟乙酸)，B：乙腈，梯度：B％：0-60％梯度流动7分钟，流速：1.2mL/min，紫外检测波段为220和254nm。High Performance Liquid Chromatography (HPLC) Determination Conditions 4: Shimadzu HPLC system (Shimadzu 2020 Series with LC-30AD xs pumps and SPD-M20A detector), column: Kinetex C18, 2.1×50mm, 1.7μm, mobile phase: A: water (0.075% trifluoroacetic acid), B: acetonitrile, gradient: B%: 0-60% gradient flow for 7 minutes, flow rate: 1.2mL/min, UV detection bands are 220 and 254nm.

反相纯化使用Biotage Isolera快速纯化系统。Reverse-phase purification was performed using the Biotage Isolera rapid purification system.

薄层层析分离纯化是用薄层色谱硅胶板(Meck产的铝板(20cm x 20cmx 1mm)，或烟台产GF 254)。Thin-layer chromatography separation and purification were performed using thin-layer chromatography silica gel plates (Meck aluminum plates (20cm x 20cm x 1mm) or Yantai GF 254).

微波反应使用Biotage Initiator+(400W,RT～300℃)微波反应器。The microwave reaction was performed using a Biotage Initiator+ (400W, RT～300℃) microwave reactor.

反应监测常用TLC或LCMS，常用展开剂体系：二氯甲烷/甲醇，正己烷/乙酸乙酯，石油醚/乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。TLC or LCMS are commonly used for reaction monitoring. Commonly used developing solvent systems include dichloromethane/methanol, n-hexane/ethyl acetate, and petroleum ether/ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine, etc.

柱层析所用硅胶一般是100～200目硅胶。常用洗脱剂体系：二氯甲烷/甲醇，石油醚/乙酸乙酯，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。The silica gel used in column chromatography is generally 100-200 mesh. Commonly used eluent systems include dichloromethane/methanol and petroleum ether/ethyl acetate. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

本发明的试剂和溶剂等购买于Aldrich Chemical Company、安耐吉、百灵威科技、上海毕得医药科技有限公司、药石科技和上海泰坦科技有限公司等。The reagents and solvents used in this invention were purchased from Aldrich Chemical Company, Anaiji, Bailingwei Technology, Shanghai Bide Pharmaceutical Technology Co., Ltd., Yaoshi Technology, and Shanghai Titan Technology Co., Ltd.

在常规的合成法以及本发明的化合物和中间体合成例中，各缩写的意思如以下所示。

In conventional synthesis methods and in the examples of compound and intermediate synthesis of the present invention, the meanings of the abbreviations are as follows.

合成实施例Synthesis Examples

实施例1：化合物1的制备
Example 1: Preparation of Compound 1

步骤1：将化合物1-1(10g,62.26mmol)和4-甲氧基苄氯(10.13mL,74.71mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入碳酸钾(25.81g,186.78mmol)，室温搅拌18个小时，通过LCMS监测反应完成。加入冰水(50mL)淬灭，用二氯甲烷萃取3次(3×60mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：5％-30％乙酸乙酯/石油醚)纯化，得到化合物1-2。MS m/z(ESI)：246.2[M+H]⁺。Step 1: Compound 1-1 (10 g, 62.26 mmol) and 4-methoxybenzyl chloride (10.13 mL, 74.71 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (25.81 g, 186.78 mmol) was added. The mixture was stirred at room temperature for 18 hours, and the reaction was monitored by LCMS. The reaction was quenched with ice water (50 mL), and extracted three times with dichloromethane (3 × 60 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 5%-30% ethyl acetate/petroleum ether) to obtain compound 1-2. MS m/z (ESI): 246.2 [M+H] ⁺ .

步骤2：氮气保护下将化合物1-2(14g,57.06mmol)，对甲基苯磺酰甲基异腈(16.71g,85.60mmol)和叔丁醇(8.13mL,85.60mmol)溶于四氢呋喃(140mL)中，0℃下滴加叔丁醇钾的四氢呋喃溶液(114.1mL,1.0M,114.1mmol)，反应液维持0℃搅拌1小时，然后升至室温继续搅拌24小时，通过LCMS监测反应完成。反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：5％-30％乙酸乙酯/石油醚)纯化，得到化合物1-3。MS m/z(ESI)：257.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.27-7.22(m,2H),6.90-6.84(m,2H),3.73(s,3H),3.32(s,2H),3.10(p,J＝2.9Hz,2H),2.99(tt,J＝11.1,6.9Hz,1H),1.98-1.90(m,2H),1.79-1.69(m,4H),1.60-1.52(m,2H)。Step 2: Under nitrogen protection, compounds 1-2 (14 g, 57.06 mmol), p-methylbenzenesulfonylmethylisocyanate (16.71 g, 85.60 mmol), and tert-butanol (8.13 mL, 85.60 mmol) were dissolved in tetrahydrofuran (140 mL). A tetrahydrofuran solution of potassium tert-butoxide (114.1 mL, 1.0 M, 114.1 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then heated to room temperature and stirred for another 24 hours. The reaction was monitored for completion by LCMS. The reaction mixture was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 5%-30% ethyl acetate/petroleum ether) to obtain compounds 1-3. MS m/z (ESI): 257.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.27-7.22(m,2H),6.90-6.84(m,2H),3.73(s,3H),3.32(s,2H),3.10(p,J＝2.9Hz,2H) ,2.99(tt,J=11.1,6.9Hz,1H),1.98-1.90(m,2H),1.79-1.69(m,4H),1.60-1.52(m,2H).

步骤3：将化合物1-3(4.88g,19.04mmol)、对氟苯甲酸乙酯(5.12mL,38.07mmol)溶于四氢呋喃(50mL)中，置换氮气保护，于0℃下滴加双三甲基硅基胺基锂的四氢呋喃溶液(28.6mL,1.0M,28.6mmoL)，随后体系升至室温搅拌2小时，通过LCMS和TLC监测反应完成。反应液加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：5％-60％乙酸乙酯/石油醚)纯化，得到化合物1-4。MS m/z(ESI)：405.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.05-7.95(m,2H),7.72-7.62(m,2H),7.32-7.25(m,2H),6.92-6.83(m,2H),4.33(q,J＝7.1Hz,2H),3.73(s,3H),3.47(s,2H),3.31(s,2H),2.35-2.27(m,2H),2.16(tt,J＝13.8,6.0Hz,6H),1.32(t,J＝7.1Hz,3H)。Step 3: Compounds 1-3 (4.88 g, 19.04 mmol) and ethyl p-fluorobenzoate (5.12 mL, 38.07 mmol) were dissolved in tetrahydrofuran (50 mL). Under nitrogen protection, a tetrahydrofuran solution of lithium bis(trimethylsilylamino)amine (28.6 mL, 1.0 M, 28.6 mmol) was added dropwise at 0 °C. The system was then heated to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction solution was quenched with saturated ammonium chloride solution and extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 5%-60% ethyl acetate/petroleum ether) to obtain compounds 1-4. MS m/z (ESI): 405.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ8.05-7.95(m,2H),7.72-7.62(m,2H),7.32-7.25(m,2H),6.92-6.83(m,2H),4.33(q,J＝7.1Hz,2H),3.73 (s,3H),3.47(s,2H),3.31(s,2H),2.35-2.27(m,2H),2.16(tt,J＝13.8,6.0Hz,6H),1.32(t,J＝7.1Hz,3H).

步骤4：将化合物1-4(20g,49.44mmol)溶于乙醇(150mL)中，再往其中加入饱和的氢氧化钠溶液(150mL,3042mmol),反应在100℃下反应3天，通过LCMS监测反应完全。将反应液减压浓缩至大部分乙醇旋掉，剩余液体在0℃下加入6N的盐酸调至pH值至3左右，有大量固体析出，滤出固体并真空干燥，得到化合物1-5。MS m/z(ESI)：395.2[M+H]⁺。Step 4: Dissolve compounds 1-4 (20 g, 49.44 mmol) in ethanol (150 mL), then add saturated sodium hydroxide solution (150 mL, 3042 mmol). The reaction was carried out at 100 °C for 3 days, and the reaction was monitored for completeness by LC-MS. The reaction solution was concentrated under reduced pressure until most of the ethanol was removed by rotary evaporation. The remaining liquid was adjusted to pH 3 by adding 6 N hydrochloric acid at 0 °C, resulting in the precipitation of a large amount of solid. The solid was filtered off and dried under vacuum to obtain compounds 1-5. MS m/z (ESI): 395.2 [M+H] ⁺ .

步骤5：将化合物1-5(12.5g,31.69mmol)溶于N,N-二甲基甲酰胺(200mL)中，在0℃下缓慢加入碳酸钾(13.14g,95.06mmol)和碘乙烷(5.07mL,63.38mmol)，反应液在25℃下搅拌16小时。通过LCMS监测反应完成，在反应液中加入水(300mL)淬灭，并用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：20％-40％乙酸乙酯/石油醚)纯化，得到化合物1-6。MS m/z(ESI)：423.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.89-7.83(m,2H),7.50-7.43(m,2H),7.38(s,1H),7.25-7.18(m,2H),6.97(s,1H),6.87-6.81(m,2H),4.30(q,J＝7.1Hz,2H),4.03(q,J＝7.1Hz,5H),3.72(s,3H),3.37(s,2H),3.17(d,J＝5.2Hz,1H),3.12(s,2H),2.94(d,J＝12.9Hz,2H),1.30(t,J＝7.1Hz,3H)。Step 5: Compounds 1-5 (12.5 g, 31.69 mmol) were dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (13.14 g, 95.06 mmol) and iodoethane (5.07 mL, 63.38 mmol) were slowly added at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS until completion. Water (300 mL) was added to quench the reaction mixture, and the mixture was extracted three times with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 20%-40% ethyl acetate/petroleum ether) to obtain compounds 1-6. MS m/z (ESI): 423.2 [M+H] ⁺ . ^1H NMR (400MHz, DMSO-d6) δ7.89-7.83(m,2H),7.50-7.43(m,2H),7.38(s,1H),7.25-7.18(m,2H),6.97(s,1H),6.87-6.81(m,2H),4.30(q,J=7. 1Hz, 2H), 4.03 (q, J = 7.1Hz, 5H), 3.72 (s, 3H), 3.37 (s, 2H), 3.17 (d, J = 5.2Hz, 1H), 3.12 (s, 2H), 2.94 (d, J = 12.9Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

步骤6：将化合物1-6(2.00g,4.73mmol)溶于乙醇(40mL)，加入10％钯碳(0.50g)，甲酸铵(2.98g,47.34mmol)，在80℃下搅拌8小时，通过LCMS监测反应完全。反应液过滤并减压浓缩，得到化合物1-7。MS m/z(ESI)：303.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.88-7.82(m,2H),7.48-7.42(m,2H),7.33(s,1H),6.94(s,1H),4.29(q,J＝7.1Hz,2H),3.39(s,2H),2.93(d,J＝13.0Hz,2H),1.85(t,J＝7.1Hz,2H),1.76(d,J＝13.3Hz,2H),1.53(s,2H),1.30(t,J＝7.1Hz,3H)。Step 6: Compounds 1-6 (2.00 g, 4.73 mmol) were dissolved in ethanol (40 mL), and 10% palladium on carbon (0.50 g) and ammonium formate (2.98 g, 47.34 mmol) were added. The mixture was stirred at 80 °C for 8 hours, and the reaction was monitored for completeness by LCMS. The reaction solution was filtered and concentrated under reduced pressure to obtain compounds 1-7. MS m/z (ESI): 303.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.88-7.82(m,2H),7.48-7.42(m,2H),7.33(s,1H),6.94(s,1H),4.29(q,J＝7.1Hz,2H),3.39(s,2H),2 .93(d,J＝13.0Hz,2H),1.85(t,J＝7.1Hz,2H),1.76(d,J＝13.3Hz,2H),1.53(s,2H),1.30(t,J＝7.1Hz,3H).

步骤7：将化合物1-8(4g,17.46mmol)，硫氰酸钠(2.12g,26.19mmol)溶于N,N-二甲基甲酰胺(60mL)中，升温60℃反应3小时，然后将反应液降至室温，依次加入硫氰酸亚铜(2.80g,23.05mmol)，氟化铯(13.26g,87.31mmol)，(三氟甲基)三甲基硅烷(6.46g,45.40mmol)，室温下继续搅拌过夜，通过LCMS监测反应完成。反应液中加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-20％乙酸乙酯/石油醚)纯化，得到化合物1-9。¹H NMR(400MHz,Chloroform-d)δ8.02-7.96(m,2H),7.54-7.49(m,1H),7.39(dd,J＝8.4,7.1Hz,2H),4.54-4.45(m,2H),3.20(t,J＝6.5Hz,2H)。Step 7: Compounds 1-8 (4 g, 17.46 mmol) and sodium thiocyanate (2.12 g, 26.19 mmol) were dissolved in N,N-dimethylformamide (60 mL). The mixture was heated to 60 °C and reacted for 3 hours. The reaction solution was then cooled to room temperature, and cuprous thiocyanate (2.80 g, 23.05 mmol), cesium fluoride (13.26 g, 87.31 mmol), and (trifluoromethyl)trimethylsilane (6.46 g, 45.40 mmol) were added sequentially. The mixture was stirred overnight at room temperature, and the reaction was monitored for completion by LCMS. The reaction solution was quenched with ice water, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether) to obtain compounds 1-9. ¹ H NMR (400MHz, Chloroform-d) δ 8.02-7.96 (m, 2H), 7.54-7.49 (m, 1H), 7.39 (dd, J = 8.4, 7.1Hz, 2H), 4.54-4.45 (m, 2H), 3.20 (t, J = 6.5Hz, 2H).

步骤8：将化合物1-9(1g,4.00mmol)溶于甲醇(4mL)，THF(4mL)和水(4mL)混合溶液中，加入氢氧化锂(0.50g,11.99mmol)，升温60℃反应3小时，通过LCMS检测反应完成。反应液中加入冰水淬灭，并用二氯甲烷萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并在常温下减压浓缩，得到化合物1-10。¹H NMR(400MHz,Chloroform-d)δ3.81(t,J＝5.7Hz,2H),3.01(t,J＝6.1Hz,2H)。Step 8: Compounds 1-9 (1 g, 4.00 mmol) were dissolved in a mixed solution of methanol (4 mL), THF (4 mL), and water (4 mL). Lithium hydroxide (0.50 g, 11.99 mmol) was added, and the mixture was heated to 60 °C for 3 hours. The reaction was detected by LCMS. The reaction solution was quenched with ice water and extracted three times with dichloromethane (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at room temperature to obtain compounds 1-10. ^1H NMR (400 MHz, Chloroform-d) δ 3.81 (t, J = 5.7 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H).

步骤9：将化合物1-10(600mg,4.11mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.57mL,4.11mmol)，在0℃下加入对甲苯磺酰氯(939.31mg,4.93mmol)，室温下反应过夜，通过LCMS监测反应完成。反应液中加入冰水淬灭，并用二氯甲烷萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-20％乙酸乙酯/石油醚)纯化，得到化合物1-11。¹H NMR(400MHz,DMSO-d6)δ7.85-7.78(m,2H),7.56-7.46(m,2H),4.21(t,J＝6.0Hz,2H),3.29(t,J＝6.0Hz,2H),2.43(s,3H)。Step 9: Compound 1-10 (600 mg, 4.11 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.57 mL, 4.11 mmol) was added, and p-toluenesulfonyl chloride (939.31 mg, 4.93 mmol) was added at 0 °C. The reaction was carried out overnight at room temperature, and the reaction was monitored by LCMS. The reaction solution was quenched with ice water and extracted three times with dichloromethane (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether) to obtain compound 1-11. ¹ H NMR (400MHz, DMSO-d6) δ7.85-7.78 (m, 2H), 7.56-7.46 (m, 2H), 4.21 (t, J = 6.0 Hz, 2H), 3.29 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H).

步骤10：将化合物1-11(360mg,1.20mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入化合物1-7(434.96mg,1.44mmol)，N,N-二异丙基乙胺(309.88mg,2.40mmol)，反应升温85℃搅拌过夜，通过LCMS监测反应完成。反应液冷却至室温后加入冰水淬灭，并用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水(50mL)洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物1-12。MS m/z(ESI)：431.2[M+H]⁺。Step 10: Compound 1-11 (360 mg, 1.20 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 1-7 (434.96 mg, 1.44 mmol) and N,N-diisopropylethylamine (309.88 mg, 2.40 mmol) were added. The reaction was heated to 85 °C and stirred overnight. The reaction was monitored by LCMS until completion. After cooling to room temperature, the reaction solution was quenched with ice water and extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 1-12. MS m/z (ESI): 431.2 [M+H] ⁺ .

步骤11：将化合物1-12(380mg,0.88mmol)溶于乙腈(4mL)和水(2mL)中，加入[双(三氟乙酰氧基)碘]苯(762.77mg,1.77mmol)，在室温下搅拌3个小时，通过LCMS监测反应。在反应液中加入冰水，并用饱和碳酸氢钠溶液调pH大于7，有固体析出，过滤掉固体，滤液使用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物1-13。MS m/z(ESI)：403.1[M+H]⁺。Step 11: Compounds 1-12 (380 mg, 0.88 mmol) were dissolved in acetonitrile (4 mL) and water (2 mL). [bis(trifluoroacetoxy)iodide]benzene (762.77 mg, 1.77 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. Ice water was added to the reaction mixture, and the pH was adjusted to greater than 7 with saturated sodium bicarbonate solution. A solid precipitated; the solid was filtered off, and the filtrate was extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compounds 1-13. MS m/z (ESI): 403.1 [M+H] ⁺ .

步骤12：将化合物1-13(170mg,0.42mmol)溶于乙腈(6mL)中，加入化合物1-14(95.90mg,0.51mmol)，升温60℃搅拌过夜，然后加入氰基硼氢化钠(53.08mg,0.84mmol)，室温继续反应2个小时，通过LCMS监测反应完成。在反应液中加入冰水，并用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水(50mL)洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物1-15。MS m/z(ESI)：676.3[M+H]⁺。Step 12: Compound 1-13 (170 mg, 0.42 mmol) was dissolved in acetonitrile (6 mL), and compound 1-14 (95.90 mg, 0.51 mmol) was added. The mixture was heated to 60 °C and stirred overnight. Then, sodium cyanoborohydride (53.08 mg, 0.84 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction was monitored for completion by LCMS. Ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 1-15. MS m/z (ESI): 676.3 [M+H] ⁺ .

步骤13：将化合物1-15(150mg,0.22mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)混合溶剂中，加入氢氧化锂(372.53mg,8.88mmol)，升温60℃反应1小时，通过LCMS监测反应完成。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值至5-7，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：548.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.93(d,J＝8.0Hz,2H),7.53(d,J＝8.0Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.91(t,J＝2.5Hz,1H),3.61(s,3H),3.41(s,2H),3.26(s,2H),3.14(t,J＝6.5Hz,2H),2.64(t,J＝6.7Hz,2H),2.40(s,3H),2.22(d,J＝10.4Hz,4H),1.97(d,J＝13.5Hz,2H),1.79-1.69(m,2H)。将纯化产物(75mg,0.14mmol)溶于甲醇(5mL)，缓慢滴加1N盐酸甲醇溶液(0.42mL,0.42mmol)，搅拌30min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物1。MS m/z(ESI)：548.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.86(s,1H),10.04(s,1H),8.00(d,J＝7.8Hz,2H),7.62(s,2H),7.24(s,1H),6.67(s,1H),5.92(t,J＝2.5Hz,1H),4.19-4.13(m,2H),4.07-4.03(m,2H),3.66(s,3H),3.51-3.36(m,4H),3.30-3.21(m,2H),2.71-2.54(m,4H),2.42(s,3H),2.11-1.98(m,2H)。Step 13: Compound 1-15 (150 mg, 0.22 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (372.53 mg, 8.88 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 _× 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 548.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.93(d,J＝8.0Hz,2H),7.53(d,J＝8.0H z,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.91(t,J＝2.5Hz,1H),3.61(s,3H ),3.41(s,2H),3.26(s,2H),3.14(t,J＝6.5Hz,2H),2.64(t,J＝6.7Hz,2H),2. 40(s,3H),2.22(d,J＝10.4Hz,4H),1.97(d,J＝13.5Hz,2H),1.79-1.69(m,2H). The purified product (75 mg, 0.14 mmol) was dissolved in methanol (5 mL), and 1 N hydrochloric acid methanol solution (0.42 mL, 0.42 mmol) was slowly added dropwise. After stirring for 30 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 1. MS m/z (ESI): 548.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.86(s,1H),10.04(s,1H),8.00(d,J＝7.8Hz,2H),7.62(s,2H),7.24(s,1H),6.67(s,1H),5.92(t,J＝2.5Hz,1H),4 .19-4.13(m,2H),4.07-4.03(m,2H),3.66(s,3H),3.51-3.36(m,4H), 3.30-3.21(m,2H),2.71-2.54(m,4H),2.42(s,3H),2.11-1.98(m,2H).

实施例2：化合物2的制备
Example 2: Preparation of Compound 2

步骤1：向500mL的单口瓶中加入化合物2-1(4.9g,34.01mmol)溶于二氯甲烷(100mL)中,在0℃下依次加入三乙胺(9.43mL,68.01mmol)和对甲苯磺酰氯(7.78g,40.81mmol)，体系置换氮气，于室温下反应6小时，LCMS监测反应完全后。反应液在室温下缓慢倒入冰水中淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物2-2。MS m/z(ESI):299.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.83-7.76(m,2H),7.52-7.45(m,2H),4.20-4.13(m,2H),4.03(q,J＝9.3Hz,2H),3.81-3.74(m,2H),2.43(s,3H)。Step 1: Compound 2-1 (4.9 g, 34.01 mmol) was dissolved in dichloromethane (100 mL) and added to a 500 mL single-necked flask. Triethylamine (9.43 mL, 68.01 mmol) and p-toluenesulfonyl chloride (7.78 g, 40.81 mmol) were added sequentially at 0 °C. The system was purged with nitrogen and reacted at room temperature for 6 hours. After the reaction was complete, the reaction solution was slowly poured into ice water at room temperature and extracted three times (3 × 50 mL) with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 2-2. MS m/z(ESI):299.0[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.83-7.76(m,2H),7.52-7.45(m,2H),4.20-4.13(m,2H),4.03(q,J=9.3Hz,2H),3.81-3.74(m,2H),2.43(s,3H).

步骤2：向50mL的单口瓶中加入化合物1-7(2g,6.61mmol)溶于N,N-二甲基甲酰胺(40mL)的溶液，0℃下缓慢加入N,N-二异丙基乙胺(5.84mL,33.53mmol)，维持0℃下反应0.5小时，再向反应液中加入化合物2-2(2.03g,6.81mmol),反应液在85℃下继续搅拌16小时，通过TLC监测反应完成。反应液加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-40％乙酸乙酯/石油醚)纯化得到化合物2-3。MS m/z(ESI):429.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.1Hz,2H),7.45(d,J＝8.2Hz,2H),7.37(s,1H),6.96(s,1H),4.29(q,J＝7.1Hz,2H),4.04(q,J＝9.4Hz,2H),3.62(s,2H),3.23(s,2H),2.90(d,J＝13.4Hz,2H),2.45(s,2H),1.78(d,J＝35.6Hz,6H),1.30(t,J＝7.1Hz,3H)。Step 2: Add a solution of compound 1-7 (2 g, 6.61 mmol) dissolved in N,N-dimethylformamide (40 mL) to a 50 mL single-necked flask. Slowly add N,N-diisopropylethylamine (5.84 mL, 33.53 mmol) at 0 °C and maintain the reaction at 0 °C for 0.5 hours. Then add compound 2-2 (2.03 g, 6.81 mmol) to the reaction solution. Continue stirring the reaction solution at 85 °C for 16 hours. Monitor the reaction completion by TLC. Quench the reaction solution with ice water, extract three times with dichloromethane (3 × 50 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (mobile phase gradient: 0%-40% ethyl acetate/petroleum ether) to obtain compound 2-3. MS m/z(ESI):429.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.86(d,J＝8.1Hz,2H),7.45(d,J＝8.2Hz,2H),7.37(s,1H),6.96(s,1H),4.29(q,J＝7.1Hz,2H),4.04(q,J＝9.4Hz, 2H), 3.62 (s, 2H), 3.23 (s, 2H), 2.90 (d, J = 13.4Hz, 2H), 2.45 (s, 2H), 1.78 (d, J = 35.6Hz, 6H), 1.30 (t, J = 7.1Hz, 3H).

步骤3：向250mL的单口瓶中加入化合物2-3(2.3g,5.37mmol)溶于乙腈(30mL)和水15(mL)的混合溶液,然后0℃下缓慢加入[双(三氟乙酰氧基)碘]苯(4.64g,10.74mmol)，恢复室温反应2小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液中淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(50mL×3)，合并的有机相用饱和食盐水溶液洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-60％乙酸乙酯/石油醚)纯化得到化合物2-4。MS m/z(ESI):401.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.90(d,J＝8.1Hz,2H),7.64(s,2H),4.30(q,J＝7.1Hz,2H),3.93(d,J＝165.8Hz,6H),3.32(s,2H),2.04(s,9H),1.31(t,J＝7.1Hz,3H)。Step 3: Add a mixture of compound 2-3 (2.3 g, 5.37 mmol) dissolved in acetonitrile (30 mL) and water (15 mL) to a 250 mL single-necked flask. Then, slowly add [bis(trifluoroacetoxy)iodo]benzene (4.64 g, 10.74 mmol) at 0 °C. Allow the mixture to return to room temperature for 2 hours. Monitor the reaction completion by LCMS. Quench the reaction solution slowly in a saturated sodium bicarbonate solution at room temperature. Filter off the precipitated solid. Extract the mother liquor three times (50 mL × 3) with dichloromethane. Wash the combined organic phases with saturated saline solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-60% ethyl acetate/petroleum ether) to obtain compound 2-4. MS m/z(ESI):401.2[M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d ₆ )δ7.90(d,J＝8.1Hz,2H),7.64(s,2H),4.30(q,J＝7.1Hz,2H),3.93(d,J＝165.8Hz,6H),3.32(s,2H),2.04(s,9H),1.31(t,J＝7.1Hz,3H).

步骤4：将化合物2-4(300mg,0.75mmol)溶于乙腈(8mL)中，加入化合物1-14(216.76mg,0.75mmol)和5滴醋酸，室温下搅拌过夜。然后在0℃下加入硼氢化钠(85.02mg,2.25mmol)和甲醇(2mL)，室温继续反应1个小时，通过LCMS监测反应完成。反应液缓慢加入冰水中淬灭，用乙酸乙酯萃取3次(30mL×3)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-30乙酸乙酯/石油醚)纯化得到化合物2-5。MS m/z(ESI):674.4[M+H]⁺.¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.2Hz,2H),7.59–7.52(m,3H),6.77(s,1H),6.18(d,J＝3.8Hz,1H),4.33(q,J＝7.1Hz,2H),4.13–4.04(m,2H),3.67(s,4H),3.36(s,3H),3.31(s,2H)，2.75-2.5(m,2H),2.48(s,3H),2.12(m,6H),1.79(s,2H),1.57(s,9H),1.34(t,J＝7.1Hz,3H)。Step 4: Compound 2-4 (300 mg, 0.75 mmol) was dissolved in acetonitrile (8 mL), compound 1-14 (216.76 mg, 0.75 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (85.02 mg, 2.25 mmol) and methanol (2 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was quenched slowly with ice water, extracted three times with ethyl acetate (30 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-30 ethyl acetate/petroleum ether) to obtain compound 2-5. MS m/z(ESI):674.4[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.95(d,J＝8.2Hz,2H),7.59–7.52(m,3H),6.77(s,1H),6.18(d,J＝3.8Hz,1H),4.33(q,J＝7.1Hz,2H),4.13–4.04(m,2H),3.67 (s,4H),3.36(s,3H),3.31(s,2H),2.75-2.5(m,2H),2.48(s,3H),2.12(m,6H),1.79(s,2H),1.57(s,9H),1.34(t,J＝7.1Hz,3H).

步骤5：将化合物2-5(330mg,0.49mmol)溶于甲醇(5mL)，水(5mL)和四氢呋喃(5mL)混合溶剂中，加入氢氧化锂(822.05mg,19.59mmol)，升温60℃反应2小时，通过LCMS监测反应完成。然后冷却至室温，在反应液中缓慢滴加稀HCl(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:CAN；梯度：B％：0％-95％)]纯化，得到纯化产物。¹H NMR(400MHz,Methanol-d₄)δ7.90(d,J＝8.0Hz,2H),7.38(d,J＝8.1Hz,2H),7.10(d,J＝3.1Hz,1H),6.65(s,1H),5.89(d,J＝3.1Hz,1H),4.17–3.99(m,6H),3.72(s,3H),3.55(s,2H),3.30(s,2H),2.78(d,J＝8.9Hz,2H),2.67–2.49(m,4H),2.43(s,3H),2.12(d,J＝10.1Hz,2H)。将纯化产物(135mg,0.25mmol)溶于甲醇(3mL)中，室温搅拌下缓慢滴加4N的盐酸-甲醇溶液(0.20mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物2。MS m/z(ESI):546.3[M+H]⁺.¹H NMR(400MHz,DMSO-d6)δ10.85(s,1H),9.61(s,1H),7.99(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),7.22(d,J＝2.9Hz,1H),6.66(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),4.17(q,J＝9.4Hz,2H),4.03(d,J＝31.5Hz,4H),3.64(s,3H),3.23(d,J＝5.5Hz,2H),2.61(dd,J＝20.8,12.0Hz,4H),2.45(s,1H),2.41(s,3H),2.01(d,J＝22.5Hz,3H)。Step 5: Compounds 2-5 (330 mg, 0.49 mmol) were dissolved in a mixed solvent of methanol (5 mL), water (5 mL), and tetrahydrofuran (5 mL). Lithium hydroxide (822.05 mg, 19.59 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The mixture was then cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to the reaction solution to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm column; mobile phase: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: CAN; gradient: B%: 0%-95%). The purified product was obtained. ¹ H NMR (400MHz, Methanol-d ₄ )δ7.90(d,J＝8.0Hz,2H),7.38(d,J＝8.1Hz,2H),7.10(d,J＝3.1Hz,1H),6.65(s,1H),5.89(d,J＝3.1Hz,1H),4.17–3.99(m,6 H), 3.72 (s, 3H), 3.55 (s, 2H), 3.30 (s, 2H), 2.78 (d, J = 8.9Hz, 2H), 2.67–2.49 (m, 4H), 2.43 (s, 3H), 2.12 (d, J = 10.1Hz, 2H). The purified product (135 mg, 0.25 mmol) was dissolved in methanol (3 mL), and 0.20 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring at room temperature. After stirring for 5 min, the methanol was evaporated to dryness at room temperature, and then 5 mL of deionized water was added. The mixture was sonicated and then lyophilized to obtain compound 2. MS m/z (ESI): 546.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.85(s,1H),9.61(s,1H),7.99(d,J＝8.1Hz,2H),7.61(d ,J＝8.1Hz,2H),7.22(d,J＝2.9Hz,1H),6.66(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),4 .17(q,J＝9.4Hz,2H),4.03(d,J＝31.5Hz,4H),3.64(s,3H),3.23(d,J＝5.5Hz,2H), 2.61(dd,J=20.8,12.0Hz,4H),2.45(s,1H),2.41(s,3H),2.01(d,J=22.5Hz,3H).

实施例3：化合物3的制备
Example 3: Preparation of Compound 3

步骤1：将化合物3-1(500g,2992.22mmol)溶于DMF(6L)中，然后依次加入碳酸钾(496.3g,3590.66mmol),溴化苄(511.7g,2992.22mmol),室温条件下反应4个小时，通过TLC监测反应完成。反应结束后，将反应液倒入水中，析出大量固体，过滤得到滤饼，然后真空干燥后得到化合物3-2。MS m/z(ESI):258.2[M+H]⁺。Step 1: Compound 3-1 (500 g, 2992.22 mmol) was dissolved in DMF (6 L), followed by the sequential addition of potassium carbonate (496.3 g, 3590.66 mmol) and benzyl bromide (511.7 g, 2992.22 mmol). The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC until completion. After the reaction was complete, the reaction solution was poured into water, and a large amount of solid precipitated. The solid was filtered to obtain a filter cake, which was then dried under vacuum to obtain compound 3-2. MS m/z (ESI): 258.2 [M+H] ⁺ .

步骤2：将化合物3-2(277g,1076.61mmol)溶于DMF(2L)中，然后加入依次DMF-DMA(384.87g,3229.83mmol)和四氢吡咯(382.84g,5383.05mmol)，反应液在90℃下搅拌过夜，通过TLC监测反应完成。在反应液中加入水(5L)，用乙酸乙酯萃取3次(3×1L)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，得到化合物3-3。MS m/z(ESI)：339.2[M+H]⁺。Step 2: Compound 3-2 (277 g, 1076.61 mmol) was dissolved in DMF (2 L), followed by the addition of DMF-DMA (384.87 g, 3229.83 mmol) and tetrahydropyrrole (382.84 g, 5383.05 mmol) sequentially. The reaction mixture was stirred overnight at 90 °C, and the reaction was monitored by TLC until completion. Water (5 L) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (3 × 1 L). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 3-3. MS m/z (ESI): 339.2 [M+H] ⁺ .

步骤3：将化合物3-3(160g,472.8mmol)溶于乙酸乙酯(1.5L)中，加入雷尼镍(15mL在水中)，置换氢气后，于室温下反应过夜，通过LCMS和TLC监测反应完成。反应液过滤除掉雷尼镍，滤液浓缩得到化合物3-4。MS m/z(ESI)：238.2[M+H]⁺。Step 3: Compound 3-3 (160 g, 472.8 mmol) was dissolved in ethyl acetate (1.5 L), Raney nickel (15 mL in water) was added, and hydrogen gas was substituted. The reaction was carried out overnight at room temperature, and the reaction was monitored by LCMS and TLC. The reaction solution was filtered to remove Raney nickel, and the filtrate was concentrated to obtain compound 3-4. MS m/z (ESI): 238.2 [M+H] ⁺ .

步骤4：将化合物3-4(100g,421.41mmol)溶于乙腈(1L)中，加入二碳酸二叔丁酯(183.94g,842.82mmol)和4-二甲氨基吡啶(51.48g,421.41mmol)，室温下搅拌过夜，通过LCMS和TLC监测反应完成。反应液加入水中(500mL)，用乙酸乙酯萃取3次(3×300mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯)纯化得到化合物3-5。MS m/z(ESI)：338.2[M+H]⁺。¹H NMR(400MHz,Chloroform-d)δ7.50–7.43(m,3H),7.41–7.36(m,2H),7.34–7.29(m,1H),6.91(d,J＝2.5Hz,1H),6.82(d,J＝2.5Hz,1H),6.44(d,J＝3.8Hz,1H),5.09(s,2H),2.61(s,3H),1.62(s,9H)。Step 4: Compound 3-4 (100 g, 421.41 mmol) was dissolved in acetonitrile (1 L), and di-tert-butyl dicarbonate (183.94 g, 842.82 mmol) and 4-dimethylaminopyridine (51.48 g, 421.41 mmol) were added. The mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS and TLC. The reaction solution was added to water (500 mL), and extracted three times with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate) to obtain compound 3-5. MS m/z (ESI): 338.2 [M+H] ⁺ . ¹ H NMR(400MHz,Chloroform-d)δ7.50–7.43(m,3H),7.41–7.36(m,2H),7.34–7.29(m,1H),6.91(d,J =2.5Hz, 1H), 6.82 (d, J = 2.5Hz, 1H), 6.44 (d, J = 3.8Hz, 1H), 5.09 (s, 2H), 2.61 (s, 3H), 1.62 (s, 9H).

步骤5：将化合物3-5(115g,340.82mmol)溶于乙醇(1.2L)中，依次加入10％钯碳(10g)和甲酸铵(21.49g，340.82mmol)，升温50℃搅拌过夜，通过LCMS监测反应完成。反应液过滤掉钯碳，减压浓缩除去多余乙醇，用二氯甲烷/石油醚(v/v＝1/1)打浆，过滤得到化合物3-6。MS m/z(ESI)：248.0[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ9.08(s,1H),7.52(d,J＝3.7Hz,1H),6.74(d,J＝2.4Hz,1H),6.56(d,J＝2.4Hz,1H),6.49(d,J＝3.7Hz,1H),2.45(s,3H),1.57(s,9H)。Step 5: Compound 3-5 (115 g, 340.82 mmol) was dissolved in ethanol (1.2 L), and 10% palladium on carbon (10 g) and ammonium formate (21.49 g, 340.82 mmol) were added sequentially. The mixture was heated to 50 °C and stirred overnight. The reaction was monitored by LCMS to indicate completion. The palladium on carbon was filtered off from the reaction solution, and excess ethanol was removed by concentration under reduced pressure. The solution was then slurried with dichloromethane/petroleum ether (v/v = 1/1) and filtered to obtain compound 3-6. MS m/z (ESI): 248.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ9.08 (s, 1H), 7.52 (d, J = 3.7Hz, 1H), 6.74 (d, J = 2.4Hz ,1H),6.56(d,J＝2.4Hz,1H),6.49(d,J＝3.7Hz,1H),2.45(s,3H),1.57(s,9H).

步骤6：将多聚甲醛(19.60g,647.01mmol)和三乙胺(71.75mL,517.61mmol)溶于四氢呋喃(500mL)中，在室温下加入氯化镁(46.20g,485.26mmol)，搅拌0.5小时，然后加入化合物3-6(40g,161.75mmol)，升至70℃反应过夜，通过LCMS监测反应完全。过滤掉多余固体，滤液中加入水(500mL)，用乙酸乙酯萃取3次(3×300mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得固体粗品使用乙酸乙酯/石油醚(v/v＝1/5)打浆，过滤得到化合物3-7。MS m/z(ESI)：276.0[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.66(s,1H),10.48(s,1H),7.75(d,J＝3.6Hz,1H),7.27(d,J＝3.6Hz,1H),6.75(s,1H),2.53(s,3H),1.59(s,9H)。Step 6: Paraformaldehyde (19.60 g, 647.01 mmol) and triethylamine (71.75 mL, 517.61 mmol) were dissolved in tetrahydrofuran (500 mL). Magnesium chloride (46.20 g, 485.26 mmol) was added at room temperature, and the mixture was stirred for 0.5 hours. Then, compounds 3-6 (40 g, 161.75 mmol) were added, and the mixture was heated to 70 °C and reacted overnight. The reaction was monitored by LCMS until complete. Excess solid was filtered off, and water (500 mL) was added to the filtrate. The mixture was extracted three times with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude solid was slurried with ethyl acetate/petroleum ether (v/v = 1/5) and filtered to obtain compounds 3-7. MS m/z (ESI): 276.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ 10.66 (s, 1H), 10.48 (s, 1H), 7.75 (d, J = 3.6Hz, 1H), 7.27 (d, J = 3.6Hz, 1H), 6.75 (s, 1H), 2.53 (s, 3H), 1.59 (s, 9H).

步骤7：将化合物3-7(33g,119.87mmol)和三乙胺(49.85mL,359.61mmol)溶于二氯甲烷(350mL)中，加入三氟甲磺酸酐(29.84mL,179.80mmol)，室温下反应过夜，通过LCMS和TLC监测反应完全。向反应液中加入水(300mL)，用二氯甲烷(3×300mL)萃取，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯)纯化得到化合物3-8。MS m/z(ESI)：408.2[M+H]⁺。¹H NMR(400MHz,Chloroform-d)δ10.49(s,1H),7.77(d,J＝3.7Hz,1H),7.51(d,J＝3.7Hz,1H),7.09(s,1H),2.73(s,3H),1.65(s,9H)。Step 7: Compound 3-7 (33 g, 119.87 mmol) and triethylamine (49.85 mL, 359.61 mmol) were dissolved in dichloromethane (350 mL), and trifluoromethanesulfonic anhydride (29.84 mL, 179.80 mmol) was added. The reaction was carried out overnight at room temperature, and the reaction was monitored for completeness by LCMS and TLC. Water (300 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (3 × 300 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate) to obtain compound 3-8. MS m/z (ESI): 408.2 [M+H] ⁺ . ¹ H NMR (400MHz, Chloroform-d) δ 10.49 (s, 1H), 7.77 (d, J = 3.7Hz, 1H), 7.51 (d, J = 3.7Hz, 1H), 7.09 (s, 1H), 2.73 (s, 3H), 1.65 (s, 9H).

步骤8：将化合物3-8(8g,19.64mmol)溶于1,4-二氧六环(50mL)，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.44g,1.96mmol)，碳酸钾(5.43g,39.28mmol)，甲基硼酸(11.76g,196.39mmol)，氮气保护升温100℃反应过夜，通过LCMS监测反应完成。向反应液中加入冰水淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～100％乙酸乙酯)纯化，得到化合物3-9。MS m/z(ESI)：274.2[M+H]⁺。Step 8: Compound 3-8 (8 g, 19.64 mmol) was dissolved in 1,4-dioxane (50 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.44 g, 1.96 mmol), potassium carbonate (5.43 g, 39.28 mmol), and methylboronic acid (11.76 g, 196.39 mmol) were added. The mixture was heated to 100 °C overnight under nitrogen protection, and the reaction was monitored by LCMS. The reaction solution was quenched with ice water, extracted three times with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–100% ethyl acetate) to obtain compound 3-9. MS m/z (ESI): 274.2 [M+H] ⁺ .

步骤9：将化合物3-10(2g,18.50mmol)溶于乙腈(20mL)中，加入溴乙酸叔丁酯(7.22g,37.01mmol)，氢氧化钾(3.11g,55.51mmol)，升温60℃反应过夜，TLC监测反应完全。将反应液过滤，滤液减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物3-11。¹H NMR(400MHz,DMSO-d6)δ4.12-4.01(m,1H),3.96(s,2H),2.93-2.80(m,2H),2.61-2.51(m,2H),1.42(s,9H)。Step 9: Compound 3-10 (2 g, 18.50 mmol) was dissolved in acetonitrile (20 mL), and tert-butyl bromoacetate (7.22 g, 37.01 mmol) and potassium hydroxide (3.11 g, 55.51 mmol) were added. The mixture was heated to 60 °C and reacted overnight. The reaction was monitored by TLC until complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 3-11. ¹ H NMR (400 MHz, DMSO-d6) δ 4.12-4.01 (m, 1H), 3.96 (s, 2H), 2.93-2.80 (m, 2H), 2.61-2.51 (m, 2H), 1.42 (s, 9H).

步骤10：将化合物3-11(4g,18.00mmol)溶于四氢呋喃(50mL)中，在0℃分批加入氢化铝锂(1.02g,27.00mmol)，反应液在0℃搅拌半小时，然后升至室温反应过夜，通过TLC检测反应完全。反应液使用1.0M稀HCl淬灭，用二氯甲烷萃取3次(3×50mL)，合并有机相并用饱和食盐水(50mL)洗涤，再用无水硫酸钠干燥，并在室温下减压浓缩得到化合物3-12。¹H NMR(400MHz,DMSO-d₆)δ4.64(t,J＝5.5Hz,1H),4.04-3.94(m,1H),3.51-3.47(m,2H),3.37-3.35(m,2H),2.93-2.80(m,2H),2.50-2.40(m,2H)。Step 10: Compound 3-11 (4 g, 18.00 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (1.02 g, 27.00 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for half an hour, then allowed to rise to room temperature and reacted overnight. The reaction was confirmed to be complete by TLC. The reaction mixture was quenched with 1.0 M dilute HCl, extracted three times with dichloromethane (3 × 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure at room temperature to obtain compound 3-12. ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.64 (t, J = 5.5 Hz, 1H), 4.04-3.94 (m, 1H), 3.51-3.47 (m, 2H), 3.37-3.35 (m, 2H), 2.93-2.80 (m, 2H), 2.50-2.40 (m, 2H).

步骤11：将化合物3-12(2.5g,16.43mmol)溶于二氯甲烷(40mL)中，加入三乙胺(4.56mL,32.86mmol)，在0℃下分批加入对甲苯磺酰氯(3.76g,19.72mmol)，室温下反应过夜，通过LCMS监测反应完全。反应液直接减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物3-13。MS m/z(ESI)：307.0[M+H]⁺。¹H NMR(400MHz,Chloroform-d)δ7.77-7.71(m,2H),7.33-7.25(m,2H),4.13-4.05(m,2H),3.89-3.77(m,1H),3.53-3.44(m,2H),2.79-2.62(m,2H),2.43-2.29(m,5H)。Step 11: Compound 3-12 (2.5 g, 16.43 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (4.56 mL, 32.86 mmol) was added. Then, p-toluenesulfonyl chloride (3.76 g, 19.72 mmol) was added in portions at 0 °C, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored for completeness by LC-MS. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 3-13. MS m/z (ESI): 307.0 [M+H] ⁺ . ^1H NMR(400MHz,Chloroform-d)δ7.77-7.71(m,2H),7.33-7.25(m,2H),4.13-4.05(m ,2H),3.89-3.77(m,1H),3.53-3.44(m,2H),2.79-2.62(m,2H),2.43-2.29(m,5H).

步骤12：将化合物3-13(1.5g,4.90mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入化合物1-7(1.48g,4.90mmol)，N,N-二异丙基乙胺(1.90g,14.69mmol)，在85℃下反应过夜,通过LCMS监测反应完全。反应液中加入水(50mL)，用乙酸乙酯萃取3次(3×50mL)，合并的有机相使用饱和食盐水洗涤，然后减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化得到化合物3-14。MS m/z(ESI)：437.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.87(d,J＝8.4Hz,2H),7.46(d,J＝8.3Hz,2H),4.32-4.27(m,2H),4.01-3.94(m,1H),3.58-3.36(m,4H),2.95(d,J＝13.6Hz,2H),2.89-2.79(m,2H),2.67-2.53(m,2H),2.49-2.40(m,2H),2.04-1.74(m,6H),1.30(t,J＝7.1Hz,3H)。Step 12: Compound 3-13 (1.5 g, 4.90 mmol) was dissolved in N,N-dimethylformamide (20 mL), and compound 1-7 (1.48 g, 4.90 mmol) and N,N-diisopropylethylamine (1.90 g, 14.69 mmol) were added. The reaction was carried out overnight at 85 °C, and the reaction was monitored to be complete by LCMS. Water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 3-14. MS m/z (ESI): 437.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ7.87(d,J＝8.4Hz,2H),7.46(d,J＝8.3Hz,2H),4.32-4.27(m,2H),4.01-3.94(m,1H),3.58-3.36(m,4H ), 2.95 (d, J = 13.6Hz, 2H), 2.89-2.79 (m, 2H), 2.67-2.53 (m, 2H), 2.49-2.40 (m, 2H), 2.04-1.74 (m, 6H), 1.30 (t, J = 7.1Hz, 3H).

步骤13：在0℃条件下向100mL的单口瓶中加入化合物3-14(1.30g,2.98mmol)溶于乙腈(30mL)和水(15mL)的混合溶液,然后缓慢加入[双(三氟乙酰氧基)碘]苯(2.57g,5.96mmol)，于室温下反应16小时，通过LCMS监测反应完全。反应液在室温下缓慢加入饱和碳酸氢钠水溶液淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×40mL)，合并的有机相并用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-60％乙酸乙酯/石油醚)纯化得到化合物3-15。MS m/z(ESI)：409.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝8.4Hz,2H),7.56(d,J＝8.2Hz,2H),4.29(d,J＝7.1Hz,2H),4.05–3.99(m,1H),3.48(d,J＝6.1Hz,2H),3.28(s,2H),2.90–2.83(m,2H),2.56–2.51(m,2H),2.48–2.41(m,2H),2.33–2.24(m,2H),1.91–1.78(m,4H),1.73–1.64(m,2H),1.31(t,J＝7.1Hz,3H)。Step 13: Compound 3-14 (1.30 g, 2.98 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 100 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodide]benzene (2.57 g, 5.96 mmol) was slowly added. The reaction was allowed to proceed at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate aqueous solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-60% ethyl acetate/petroleum ether) to obtain compound 3-15. MS m/z (ESI): 409.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.87(d,J＝8.4Hz,2H),7.56(d,J＝8.2Hz,2H),4.29(d,J＝7.1Hz,2H),4.05–3.99(m,1H),3.48(d,J＝6.1Hz,2H),3.28(s,2H),2.90– 2.83(m,2H),2.56–2.51(m,2H),2.48–2.41(m,2H),2.33–2.24(m,2H),1.91–1.78(m,4H),1.73–1.64(m,2H),1.31(t,J＝7.1Hz,3H).

步骤14：将化合物3-15(300mg,0.73mmol)溶于乙腈(5mL)中，加入化合物3-9(201mg,0.73mmol)和5滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(83mg,2.19mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完成。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物3-16。MS m/z(ESI)：666.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.00-3.95(m,1H),3.42(t,J＝6.1Hz,2H),3.39(s,2H),2.89-2.80(m,2H),2.55(t,J＝6.2Hz,2H),2.50-2.39(m,7H),2.32-2.19(m,4H),2.06-1.99(m,5H),1.87-1.80(m,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H)。Step 14: Compound 3-15 (300 mg, 0.73 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (201 mg, 0.73 mmol) and 5 drops of acetic acid were added, and the reaction mixture was stirred at room temperature for 16 hours. Then sodium borohydride (83 mg, 2.19 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 3-16. MS m/z (ESI): 666.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6) )δ7.95(d,J＝8.4Hz,2H),7.55(d,J＝8.4Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H), 5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.00-3.95(m,1H),3.42(t,J＝6.1Hz,2H ),3.39(s,2H),2.89-2.80(m,2H),2.55(t,J＝6.2Hz,2H),2.50-2.39(m,7H),2.32-2. 19(m,4H),2.06-1.99(m,5H),1.87-1.80(m,2H),1.56(s,9H),1.34(t,J=7.1Hz,3H).

步骤15：将化合物3-16(250mg,0.38mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)混合溶剂中，加入氢氧化锂(630.20mg,15.02mmol)，升温60℃反应1小时，通过LCMS监测反应完成。反应液冷却至室温，缓慢滴加稀HCl溶液(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相:(A:10mM NH₄HCO₃/H₂O；B:CAN)；梯度：(B％:0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：538.3[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.90(d,J＝8.1Hz,2H),7.50(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.68-5.62(m,1H),4.03-3.94(m,1H),3.49-3.41(m,4H),2.85(ddt,J＝12.8,11.0,7.0Hz,2H),2.54(d,J＝7.3Hz,2H),2.45(d,J＝5.0Hz,2H),2.34(s,3H),2.27(d,J＝13.5Hz,4H),2.05(s,5H),1.84(s,2H)。将纯化产物(77.8mg,0.14mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.10mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物3。MS m/z(ESI)：538.3[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ10.87(s,1H),9.73(s,1H),7.99(d,J＝8.3Hz,2H),7.60(d,J＝8.1Hz,2H),7.13(t,J＝2.9Hz,1H),6.63(s,1H),5.72-5.66(m,1H),4.16-3.99(m,4H),3.75(t,J＝4.9Hz,2H),3.47(s,2H),3.20(d,J＝5.4Hz,2H),2.89(ddd,J＝14.8,12.4,7.4Hz,2H),2.67(t,J＝14.5Hz,2H),2.57(dd,J＝14.3,5.1Hz,4H),2.35(s,3H),2.12(s,2H),2.05(s,3H),1.83(s,1H)。Step 15: Compound 3-16 (250 mg, 0.38 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (630.20 mg, 15.02 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl solution (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 _× 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: CAN); gradient: (B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 538.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.80(s,1H),7.90(d,J＝8.1Hz,2H),7.50(d,J＝8.2Hz,2 H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.68-5.62(m,1H),4.03-3.94(m,1H),3.4 9-3.41(m,4H),2.85(ddt,J＝12.8,11.0,7.0Hz,2H),2.54(d,J＝7.3Hz,2H),2.45 (d, J = 5.0Hz, 2H), 2.34 (s, 3H), 2.27 (d, J = 13.5Hz, 4H), 2.05 (s, 5H), 1.84 (s, 2H). The purified product (77.8 mg, 0.14 mmol) was dissolved in methanol (3 mL), and 0.10 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 3. MS m/z (ESI): 538.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6) )δ10.87(s,1H),9.73(s,1H),7.99(d,J＝8.3Hz,2H),7.60(d,J＝8.1Hz,2H),7.13(t,J＝2 .9Hz,1H),6.63(s,1H),5.72-5.66(m,1H),4.16-3.99(m,4H),3.75(t,J＝4.9Hz,2H),3.4 7(s,2H),3.20(d,J＝5.4Hz,2H),2.89(ddd,J＝14.8,12.4,7.4Hz,2H),2.67(t,J＝14.5Hz ,2H),2.57(dd,J＝14.3,5.1Hz,4H),2.35(s,3H),2.12(s,2H),2.05(s,3H),1.83(s,1H).

实施例4：化合物4的制备
Example 4: Preparation of Compound 4

步骤1：将化合物1-3(10.5g,40.96mmol)和化合物4-1(8.95g,53.25mmol)溶于四氢呋喃(200mL)中，在0℃下缓慢滴入双三甲基硅基胺基锂溶液(1.0N,81.92mL,81.92mmol)，于室温下反应16小时，通过LCMS监测反应完全。在反应液中加入冰水淬灭，并用乙酸乙酯萃取3次(3×100mL),合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯队：10％-30％乙酸乙酯/石油醚)纯化，得到化合物4-2。MS m/z(ESI)：405.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.86–7.76(m,2H),7.66(d,J＝8.3Hz,1H),7.26(d,J＝8.3Hz,2H),6.92–6.83(m,2H),3.85(s,3H),3.73(s,3H),3.43(s,2H),3.35(s,2H),2.70(s,3H),2.36–2.26(m,4H),2.18(q,J＝6.8,4.5Hz,4H)。Step 1: Compounds 1-3 (10.5 g, 40.96 mmol) and 4-1 (8.95 g, 53.25 mmol) were dissolved in tetrahydrofuran (200 mL). A solution of bis(trimethylsilylamino)lithium (1.0 N, 81.92 mL, 81.92 mmol) was slowly added dropwise at 0 °C. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with ice water and extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase: 10%-30% ethyl acetate/petroleum ether) to obtain compound 4-2. MS m/z (ESI): 405.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.86–7.76(m,2H),7.66(d,J＝8.3Hz,1H),7.26(d,J＝8.3Hz,2H),6.92–6.83(m,2H),3.85(s,3H), 3.73(s,3H),3.43(s,2H),3.35(s,2H),2.70(s,3H),2.36–2.26(m,4H),2.18(q,J=6.8,4.5Hz,4H).

步骤2：将化合物4-2(9.7g,23.98mmol)和饱和氢氧化钠溶液(70mL,1420mmol)溶于乙醇(200mL)中，于100℃下反应3天，通过LCMS监测反应完全。反应液在0℃下滴加6N的盐酸调pH值到3左右，有大量固体析出，滤出固体并真空干燥，得到化合物4-3。MS m/z(ESI)：409.2[M+H]⁺。Step 2: Compound 4-2 (9.7 g, 23.98 mmol) and saturated sodium hydroxide solution (70 mL, 1420 mmol) were dissolved in ethanol (200 mL) and reacted at 100 °C for 3 days. The reaction was monitored for completeness by LCMS. The pH of the reaction solution was adjusted to approximately 3 by adding 6 N hydrochloric acid dropwise at 0 °C, resulting in the precipitation of a large amount of solid. The solid was filtered off and dried under vacuum to obtain compound 4-3. MS m/z (ESI): 409.2 [M+H] ⁺ .

步骤3：将化合物4-3(1.5g,3.67mmol)溶于N,N-二甲基甲酰胺(200mL)中，在0℃下缓慢加入碳酸钾(1.52g,11.02mmol)和碘乙烷(0.88mL,11.02mmol)，反应在室温下搅拌16小时，通过LCMS监测反应完全。反应液中加入冰水淬灭，并用乙酸乙酯萃取(3×50mL)，合并的有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：10％-30％乙酸乙酯/石油醚)纯化，得到化合物4-4。MS m/z(ESI)：437.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.74–7.61(m,2H),7.50(d,J＝8.4Hz,1H),7.28–6.97(m,4H),6.84(d,J＝8.2Hz,2H),4.29(q,J＝7.1Hz,2H),3.72(s,3H),3.34(s,2H),3.15(s,2H),2.87(d,J＝13.4Hz,2H),2.54(s,2H),2.06(d,J＝13.5Hz,2H),1.85(s,3H),1.30(t,J＝7.1Hz,3H)。Step 3: Compound 4-3 (1.5 g, 3.67 mmol) was dissolved in N,N-dimethylformamide (200 mL). Potassium carbonate (1.52 g, 11.02 mmol) and iodoethane (0.88 mL, 11.02 mmol) were slowly added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with ice water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 10%–30% ethyl acetate/petroleum ether) to obtain compound 4-4. MS m/z (ESI): 437.2 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ7.74–7.61(m,2H),7.50(d,J＝8.4Hz,1H),7.28–6.97(m,4H),6.84(d,J＝8.2Hz,2H),4.29(q,J＝7.1Hz,2H),3.72(s,3H), 3.34(s,2H),3.15(s,2H),2.87(d,J＝13.4Hz,2H),2.54(s,2H),2.06(d,J＝13.5Hz,2H),1.85(s,3H),1.30(t,J＝7.1Hz,3H).

步骤4：将化合物4-4(200mg,0.46mmol)溶于二氧六环(5mL)中，在氮气保护下加入10％钯碳(50mg)和甲酸铵(433.35mg,6.87mmol)，在100℃下反应32小时，通过LCMS监测反应完全。反应液冷却至室温后过滤，滤液旋干后得到化合物4-5。MS m/z(ESI)：317.2[M+H]⁺。Step 4: Compound 4-4 (200 mg, 0.46 mmol) was dissolved in dioxane (5 mL). Under nitrogen protection, 10% palladium on carbon (50 mg) and ammonium formate (433.35 mg, 6.87 mmol) were added. The reaction was carried out at 100 °C for 32 hours, and the reaction was monitored for completeness by LCMS. After cooling the reaction solution to room temperature, it was filtered, and the filtrate was evaporated to dryness to obtain compound 4-5. MS m/z (ESI): 317.2 [M+H] ⁺ .

步骤5：将化合物4-6(50g,384.41mmol)溶于二氯甲烷(500mL)中，在0℃下依次加入三乙胺(106.6mL,768.82mmol)和对甲基苯磺酰氯(87.94g,461.29mmol)，加料完毕后反应液在室温下搅拌16小时，通过LCMS监测反应完全。反应液中加入水(500mL)，用二氯甲烷萃取3次(3×400mL)，合并有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯/石油醚)纯化得到化合物4-7。MS m/z(ESI)：285.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.81(d,J＝8.3Hz,2H),7.50(d,J＝8.2Hz,2H),4.29–4.23(m,4H),2.43(s,3H)。Step 5: Compound 4-6 (50 g, 384.41 mmol) was dissolved in dichloromethane (500 mL). Triethylamine (106.6 mL, 768.82 mmol) and p-toluenesulfonyl chloride (87.94 g, 461.29 mmol) were added sequentially at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 16 hours, and the reaction was monitored for completeness by LC-MS. Water (500 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (3 × 400 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 4-7. MS m/z (ESI): 285.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.81 (d, J = 8.3 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 4.29–4.23 (m, 4H), 2.43 (s, 3H).

步骤6：将化合物4-5(1.89g,5.98mmol)和化合物4-7(1.7g,5.98mmol)溶于N,N-二甲基甲酰胺(30mL)中，在0℃下缓慢加入N,N-二异丙基乙胺(5.21mL,29.90mmol)，反应在室温下反应32小时，通过LCMS监测反应完全。在反应液中加入水(50mL)淬灭，并用乙酸乙酯萃取3次(3×50mL),合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：10％-30％乙酸乙酯/石油醚)纯化得到化合物4-8。MS m/z(ESI)：429.2[M+H]⁺。Step 6: Compounds 4-5 (1.89 g, 5.98 mmol) and 4-7 (1.7 g, 5.98 mmol) were dissolved in N,N-dimethylformamide (30 mL). N,N-diisopropylethylamine (5.21 mL, 29.90 mmol) was slowly added at 0 °C. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with water (50 mL) and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 10%-30% ethyl acetate/petroleum ether) to obtain compound 4-8. MS m/z (ESI): 429.2 [M+H] ⁺ .

步骤7：将化合物4-8(1.4g,3.03mmol,crude)溶于乙腈(10mL)和水(5mL)中，加入[双(三氟乙酰氧基)碘]苯(2.62g,6.07mmol)，室温下反应3小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液，调pH值>7，并用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物4-9。MS m/z(ESI)：401.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.77(d,J＝8.9Hz,1H),7.67(dd,J＝5.9,2.1Hz,2H),4.30-4.23(m,2H),4.10(t,J＝5.6Hz,2H),2.71(s,3H),2.58(t,J＝5.6Hz,2H),2.34-2.30(m,2H),2.22-2.17(m,2H),1.86–1.81(m,4H),1.40–1.35(m,2H),1.30(t,J＝7.1Hz,3H)。Step 7: Compounds 4-8 (1.4 g, 3.03 mmol, crude) were dissolved in acetonitrile (10 mL) and water (5 mL), and [bis(trifluoroacetoxy)iodo]benzene (2.62 g, 6.07 mmol) was added. The reaction was carried out at room temperature for 3 hours, and the reaction was monitored to be complete by LCMS. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to >7, and the mixture was extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compounds 4-9. MS m/z (ESI): 401.2 [M+H] ⁺ . ^1H NMR (400MHz, DMSO-d6) δ7.77(d,J＝8.9Hz,1H),7.67(dd,J＝5.9,2.1Hz,2H),4.30-4.23(m,2H),4.10(t,J＝5.6Hz,2H),2.71(s, 3H),2.58(t,J＝5.6Hz,2H),2.34-2.30(m,2H),2.22-2.17(m,2H),1.86–1.81(m,4H),1.40–1.35(m,2H),1.30(t,J＝7.1Hz,3H).

步骤8：将化合物4-9(180mg,0.45mmol)溶于乙腈(5mL)中，加入化合物1-14(156.07mg,0.54mmol)，升温60℃反应过夜。室温下加入氰基硼氢化钠(56.56mg,0.90mmol)，然后室温继续反应2小时，通过LCMS监测反应完全。反应液加入冰水(40mL),用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-60％乙酸乙酯/石油醚)纯化，得到化合物4-10。MS m/z(ESI)：674.4[M+H]⁺。Step 8: Compound 4-9 (180 mg, 0.45 mmol) was dissolved in acetonitrile (5 mL), and compound 1-14 (156.07 mg, 0.54 mmol) was added. The mixture was heated to 60 °C and reacted overnight. Sodium cyanoborohydride (56.56 mg, 0.90 mmol) was added at room temperature, and the reaction was continued at room temperature for 2 hours. The reaction was monitored for completeness by LCMS. The reaction solution was added to ice water (40 mL), and extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-60% ethyl acetate/petroleum ether) to obtain compound 4-10. MS m/z (ESI): 674.4 [M+H] ⁺ .

步骤9：将化合物4-10(260mg,0.39mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)混合溶剂中，加入氢氧化锂(654.58mg,15.60mmol)，于60℃下反应1小时，通过LCMS监测反应完全。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值小于5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％:0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：546.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ12.70(s,1H),10.85(d,J＝2.4Hz,1H),7.75-7.67(m,2H),7.59(d,J＝8.3Hz,1H),7.26(t,J＝2.8Hz,1H),6.68(s,1H),6.13(dd,J＝3.1,1.9Hz,1H),4.09(t,J＝5.7Hz,2H),3.70(s,3H),3.48(s,2H),2.62(s,3H),2.59(t,J＝5.8Hz,2H),2.43(s,3H),2.21(d,J＝3.1Hz,4H),2.19-1.96(m,3H),1.94-1.69(m,3H)。将纯化产物(49mg,0.09mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.07mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物4。MS m/z(ESI)：546.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ12.86(s,1H),10.87(d,J＝2.5Hz,1H),10.17(s,1H),7.83-7.76(m,2H),7.49(d,J＝8.3Hz,1H),7.24(t,J＝2.8Hz,1H),6.66(s,1H),6.06(dd,J＝3.1,1.9Hz,1H),4.56(t,J＝5.1Hz,2H),4.08(s,2H),3.66(s,3H),3.42-3.33(m,2H),2.81(d,J＝14.5Hz,2H),2.59(s,3H),2.58(s,5H),2.41(s,3H),2.13(s,1H),2.00(s,2H)。Step 9: Compound 4-10 (260 mg, 0.39 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (654.58 mg, 15.60 mmol) was added, and the mixture was reacted at 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 _× 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 546.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d6) δ12.70 (s, 1H), 10.85 (d, J = 2.4Hz, 1H), 7.75-7.67 (m, 2H), 7.59(d,J＝8.3Hz,1H),7.26(t,J＝2.8Hz,1H),6.68(s,1H),6.13(dd,J＝3.1,1.9Hz, 1H),4.09(t,J＝5.7Hz,2H),3.70(s,3H),3.48(s,2H),2.62(s,3H),2.59(t,J＝5.8 Hz, 2H), 2.43 (s, 3H), 2.21 (d, J = 3.1Hz, 4H), 2.19-1.96 (m, 3H), 1.94-1.69 (m, 3H). The purified product (49 mg, 0.09 mmol) was dissolved in methanol (3 mL), and 0.07 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 4. MS m/z (ESI): 546.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 10.87 (d, J = 2.5 Hz, 1H), 10.17 (s, 1H), 7.83–7.76 (m, 2H), 7.49 (d, J = 8.3 Hz, 1H), 7.24 (t, J = 2.8 Hz, 1H), 6.66 (s, 1H), 6.06 (dd, J = 3.1 Hz). ,1.9Hz,1H),4.56(t,J＝5.1Hz,2H),4.08(s,2H),3.66(s,3H),3.42-3.33(m,2H),2.8 1(d,J＝14.5Hz,2H),2.59(s,3H),2.58(s,5H),2.41(s,3H),2.13(s,1H),2.00(s,2H).

实施例5：化合物5的制备
Example 5: Preparation of Compound 5

步骤1：向1000mL的单口瓶中加入化合物4-7(66g,232.19mmol)和化合物1-7(14.04g,46.44mmol)溶于N,N-二甲基甲酰胺(300mL)的溶液，然后缓慢加入N,N-二异丙基乙胺(38.48mL,232.19mmol)，于室温下反应40小时，通过LCMS监测反应完全。反应液在室温下缓慢加入冰水中(400mL)淬灭，用乙酸乙酯萃取3次(3×300mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-80％乙酸乙酯/石油醚)纯化得到化合物5-1。MS m/z(ESI)：415.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.4Hz,2H),7.48–7.42(m,2H),4.29(q,J＝7.1Hz,2H),3.25(s,2H),2.89(s,4H),2.73(s,2H),2.55(s,2H),1.79(m,6H),1.30(t,J＝7.1Hz,3H)。Step 1: Compound 4-7 (66 g, 232.19 mmol) and compound 1-7 (14.04 g, 46.44 mmol) dissolved in N,N-dimethylformamide (300 mL) were added to a 1000 mL single-necked flask. Then, N,N-diisopropylethylamine (38.48 mL, 232.19 mmol) was slowly added, and the reaction was carried out at room temperature for 40 hours. The reaction was monitored for completeness by LCMS. The reaction solution was quenched by slowly adding ice water (400 mL) at room temperature. The mixture was extracted three times with ethyl acetate (3 × 300 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-80% ethyl acetate/petroleum ether) to obtain compound 5-1. MS m/z (ESI): 415.2 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ7.86(d,J＝8.4Hz,2H),7.48–7.42(m,2H),4.29(q,J＝7.1Hz,2H),3.25(s,2H ), 2.89 (s, 4H), 2.73 (s, 2H), 2.55 (s, 2H), 1.79 (m, 6H), 1.30 (t, J = 7.1Hz, 3H).

步骤2：向250mL的单口瓶中加入化合物5-1(9g,21.72mmol)溶于乙腈(60mL)和水(30mL)的混合溶液,然后缓慢加入[双(三氟乙酰氧基)碘]苯(18.77g,43.43mmol)，室温下反应16小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-50％乙酸乙酯/石油醚梯度)得到化合物5-2。MS m/z(ESI)：387.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.89–7.84(m,2H),7.54(d,J＝8.5Hz,2H),4.29(q,J＝7.1Hz,2H),4.10(t,J＝5.9Hz,2H),3.26(t,J＝3.8Hz,2H),2.63(t,J＝5.9Hz,2H),2.27(d,J＝7.1Hz,2H),2.06(dd,J＝13.7,3.8Hz,2H),1.87–1.75(m,4H),1.72–1.65(m,2H),1.31(t,J＝7.1Hz,3H)。Step 2: Compound 5-1 (9 g, 21.72 mmol) dissolved in a mixture of acetonitrile (60 mL) and water (30 mL) was added to a 250 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (18.77 g, 43.43 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether gradient) to obtain compound 5-2. MS m/z (ESI): 387.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.89–7.84(m,2H),7.54(d,J＝8.5Hz,2H),4.29(q,J＝7.1Hz,2H),4.10(t,J＝5.9Hz,2H),3.26(t,J＝3.8Hz,2H),2.63(t,J＝5 .9Hz,2H),2.27(d,J＝7.1Hz,2H),2.06(dd,J＝13.7,3.8Hz,2H),1.87–1.75(m,4H),1.72–1.65(m,2H),1.31(t,J＝7.1Hz,3H).

步骤3：将化合物3-9(3.4g,12.07mmol)溶于四氢呋喃(10mL)，甲醇(10mL)和水(10mL)混合溶液中，加入氢氧化锂(5.07g,120.73mmol)，反应液升温到60℃搅拌3小时，通过LCMS监测反应完成。反应液降至室温，加入冰水淬灭，用乙酸乙酯萃取3次(3×30mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物5-3。MS m/z(ESI)：174.0[M+H]⁺。¹H NMR(400MHz,Chloroform-d)δ10.63(s,1H),7.32-7.25(m,2H),6.80(s,1H),2.69(s,3H),2.46(s,3H)。Step 3: Compound 3-9 (3.4 g, 12.07 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (5.07 g, 120.73 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction was monitored by LCMS to indicate completion. The reaction mixture was cooled to room temperature, quenched with ice water, and extracted three times with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 5-3. MS m/z (ESI): 174.0 [M+H] ⁺ . ¹ H NMR (400MHz, Chloroform-d) δ 10.63 (s, 1H), 7.32-7.25 (m, 2H), 6.80 (s, 1H), 2.69 (s, 3H), 2.46 (s, 3H).

步骤4：将化合物5-2(4.5g,11.65mmol)溶于乙腈(5mL)中，加入化合物5-3(2.02g,11.65mmol)和醋酸(1mL)，室温搅拌反应过夜。然后加入硼氢化钠(1.3g,34.95mmol)和甲醇(2mL)，室温下继续搅拌0.5小时，通过LCMS监测反应完全。反应液缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-20％乙酸乙酯/石油醚)纯化得到化合物5-4。MS m/z(ESI)：544.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.80(s,1H),7.95(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.66(t,J＝2.5Hz,1H),4.34(q,J＝7.1Hz,2H),4.08(t,J＝5.7Hz,2H),3.43(s,2H),2.68–2.59(m,2H),2.36–2.22(m,7H),2.01(d,J＝19.2Hz,5H),1.91(s,3H),1.87–1.77(m,2H),1.34(t,J＝7.1Hz,3H)。Step 4: Compound 5-2 (4.5 g, 11.65 mmol) was dissolved in acetonitrile (5 mL), and compound 5-3 (2.02 g, 11.65 mmol) and acetic acid (1 mL) were added. The mixture was stirred overnight at room temperature. Then, sodium borohydride (1.3 g, 34.95 mmol) and methanol (2 mL) were added, and the mixture was stirred for another 0.5 hours at room temperature. The reaction was monitored for completeness by LCMS. The reaction solution was quenched slowly with ice water, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether) to obtain compound 5-4. MS m/z (ESI): 544.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.80(s,1H),7.95(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.10(t,J＝2 .8Hz,1H),6.60(s,1H),5.66(t,J＝2.5Hz,1H),4.34(q,J＝7.1Hz,2H),4.08 (t,J＝5.7Hz,2H),3.43(s,2H),2.68–2.59(m,2H),2.36–2.22(m,7H),2.01 (d,J＝19.2Hz,5H),1.91(s,3H),1.87–1.77(m,2H),1.34(t,J＝7.1Hz,3H).

步骤5：将化合物5-4(2.7g,4.97mmol)溶于四氢呋喃(15mL)、甲醇(15mL)和水(15mL)混合溶剂中，加入氢氧化锂(4.17g,99.33mmol)，室温反应3小时，通过LCMS监测反应完全。在反应液中缓慢滴加稀HCl(1.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体先用纯水打浆，然后真空干燥得到纯化产物。MS m/z(ESI)：516.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.83(s,1H),10.80(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.4Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.68–5.62(m,1H),4.08(t,J＝5.7Hz,2H),3.44(s,2H),3.30(s,2H),2.62(s,2H),2.34(s,3H),2.27(t,J＝10.5Hz,4H),2.04(s,5H),1.81(s,2H)。将纯化产物(2.3g，4.46mmol)溶于甲醇(30mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(3.35mL)，搅拌15min后室温下将甲醇旋干，然后加入20mL的去离子水，超声均匀后冻干得到化合物5。MS m/z(ESI)：516.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.98(s,1H),10.86(s,1H),9.78(s,1H),7.99(d,J＝8.2Hz,2H),7.60(d,J＝8.2Hz,2H),7.13(t,J＝2.8Hz,1H),6.63(s,1H),5.70(t,J＝2.5Hz,1H),4.54(s,2H),4.12(s,2H),3.46(s,2H),3.40(d,J＝5.6Hz,2H),2.71(t,J＝15.5Hz,2H),2.58(d,J＝8.1Hz,2H),2.45(s,1H),2.35(s,3H),2.13(s,2H),2.05(s,3H),1.85(s,1H)。Step 5: Compound 5-4 (2.7 g, 4.97 mmol) was dissolved in a mixed solvent of tetrahydrofuran (15 mL), methanol (15 mL), and water (15 mL). Lithium hydroxide (4.17 g, 99.33 mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction was monitored for completeness by LCMS. Dilute HCl (1.0 M) was slowly added dropwise to the reaction solution to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The obtained solid was filtered, slurried with pure water, and then vacuum dried to obtain the purified product. MS m/z (ESI): 516.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.83(s,1H),10.80(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.4Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.68–5.62(m,1 H), 4.08 (t, J = 5.7Hz, 2H), 3.44 (s, 2H), 3.30 (s, 2H), 2.62 (s, 2H), 2.34 (s, 3H), 2.27 (t, J = 10.5Hz, 4H), 2.04 (s, 5H), 1.81 (s, 2H). The purified product (2.3 g, 4.46 mmol) was dissolved in methanol (30 mL), and a 4 N hydrochloric acid-methanol solution (3.35 mL) was slowly added dropwise with stirring. After stirring for 15 min, the methanol was evaporated to dryness at room temperature. Then, 20 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 5. MS m/z (ESI): 516.2 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ12.98(s,1H),10.86(s,1H),9.78(s,1H),7.99(d,J＝8.2Hz,2H),7.60(d,J＝8. 2Hz,2H),7.13(t,J＝2.8Hz,1H),6.63(s,1H),5.70(t,J＝2.5Hz,1H),4.54(s,2H), 4.12(s,2H),3.46(s,2H),3.40(d,J＝5.6Hz,2H),2.71(t,J＝15.5Hz,2H),2.58(d ,J＝8.1Hz,2H),2.45(s,1H),2.35(s,3H),2.13(s,2H),2.05(s,3H),1.85(s,1H).

实施例6：化合物6的制备
Example 6: Preparation of Compound 6

步骤1：将化合物3-9(800mg,2.93mmol)溶于甲醇(10mL)中，在0℃下加入硼氢化钠(221mg,5.85mmol)，反应液在室温下搅拌1小时，通过LCMS监测反应完全。反应液中加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物6-1。¹H NMR(400MHz,DMSO-d₆)δ7.57(d,J＝3.8Hz,1H),6.90(s,1H),6.78(d,J＝3.8Hz,1H),4.84(s,1H),4.66(s,2H),2.47(s,3H),2.36(s,3H),1.59(s,9H)。Step 1: Compound 3-9 (800 mg, 2.93 mmol) was dissolved in methanol (10 mL), and sodium borohydride (221 mg, 5.85 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored for completeness by LCMS. The reaction mixture was quenched with ice water, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 6-1. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.57(d,J＝3.8Hz,1H),6.90(s,1H),6.78(d,J＝3.8Hz,1H),4.84(s,1H),4.66(s,2H),2.47(s,3H),2.36(s,3H),1.59(s,9H).

步骤2：将化合物6-1(690mg,2.51mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入N-氯代丁二酰亚胺(1g,7.52mmol)，反应液在40℃下搅拌16小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得到粗品，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化得到化合物6-2。¹H NMR(400MHz,DMSO-d₆)δ7.76(s,1H),7.03(s,1H),4.94(s,2H),4.91(s,1H),2.43(s,3H),2.41(s,3H),1.59(s,9H)。Step 2: Compound 6-1 (690 mg, 2.51 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-chlorosuccinimide (1 g, 7.52 mmol) was added. The reaction mixture was stirred at 40 °C for 16 hours, and the reaction was monitored to be complete by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 6-2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.76 (s, 1H), 7.03 (s, 1H), 4.94 (s, 2H), 4.91 (s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.59 (s, 9H).

步骤3：将化合物6-2(490mg,1.58mmol)溶于1,2-二氯乙烷(30mL)中，加入活性MnO₂(3.44g,39.50mmol)，反应液在50℃下搅拌16小时，通过LCMS监测反应完全。将反应液进行过滤，滤液经无水硫酸钠干燥后减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯/石油醚)纯化得到化合物6-3。MS m/z(ESI)：308.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.16(s,1H),8.05(s,1H),7.19(s,1H),2.54(s,3H),2.53(s,3H),1.61(s,9H)。Step 3: Compound 6-2 (490 mg, 1.58 mmol) was dissolved in 1,2-dichloroethane (30 mL), and active _MnO2 (3.44 g, 39.50 mmol) was added. The reaction solution was stirred at 50 °C for 16 hours, and the reaction was monitored to be complete by LCMS. The reaction solution was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 6-3. MS m/z (ESI): 308.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.16 (s, 1H), 8.05 (s, 1H), 7.19 (s, 1H), 2.54 (s, 3H), 2.53 (s, 3H), 1.61 (s, 9H).

步骤4：将化合物6-3(260mg,0.84mmol)和化合物5-2(415mg,1.10mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时，通过LCMS监测反应，有大量亚胺生成。然后加入硼氢化钠(95mg,2.52mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物6-4。MS m/z(ESI)：678.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.91(d,J＝8.5Hz,2H),7.68(s,1H),7.55(d,J＝8.5Hz,2H),6.96(s,1H),4.31(q,J＝7.1Hz,2H),4.08-4.01(m,2H),3.63(d,J＝6.9Hz,2H),3.25(s,2H),2.56(t,J＝5.8Hz,2H),2.40-2.35(m,3H),2.31(d,J＝14.3Hz,2H),2.14(d,J＝11.2Hz,5H),2.07-2.00(m,2H),1.74-1.61(m,3H),1.56(s,9H),1.32(d,J＝7.0Hz,3H)。Step 4: Compound 6-3 (260 mg, 0.84 mmol) and compound 5-2 (415 mg, 1.10 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (95 mg, 2.52 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. LCMS monitoring showed the reaction was complete. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 6-4. MS m/z (ESI): 678.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.91(d,J＝8.5Hz,2H),7.68(s,1H),7.55(d,J＝8.5Hz,2H),6.96(s,1H),4.31 (q,J＝7.1Hz,2H),4.08-4.01(m,2H),3.63(d,J＝6.9Hz,2H),3.25(s,2H),2.56( t,J＝5.8Hz,2H),2.40-2.35(m,3H),2.31(d,J＝14.3Hz,2H),2.14(d,J＝11.2Hz, 5H), 2.07-2.00 (m, 2H), 1.74-1.61 (m, 3H), 1.56 (s, 9H), 1.32 (d, J = 7.0Hz, 3H).

步骤5：将化合物6-4(200mg,0.29mmol)溶于四氢呋喃(4mL)，甲醇(4mL)和水(4mL)中,加入氢氧化锂一水合物(495mg,11.80mmol)，反应液在60℃搅拌2小时，通过LCMS监测反应完全。待反应液降至室温后，使用2M稀盐酸调pH至5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％:0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：550.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.13(s,1H),7.86(d,J＝7.7Hz,2H),7.48(s,2H),7.32(d,J＝2.7Hz,1H),6.71(s,1H),4.05(t,J＝5.8Hz,2H),3.60(s,2H),3.25(s,2H),2.56(t,J＝5.8Hz,2H),2.33(s,3H),2.29(s,2H),2.16(d,J＝7.1Hz,2H),2.10(s,3H),2.05(d,J＝12.6Hz,2H),1.68(s,2H),1.48(s,1H)。将纯化产物(110mg,0.20mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.15mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物6。MS m/z(ESI)：550.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ11.21(s,1H),10.07(s,1H),7.96(d,J＝8.3Hz,2H),7.59(d,J＝8.1Hz,2H),7.35(d,J＝2.8Hz,1H),6.73(s,1H),4.54(t,J＝5.2Hz,2H),4.10(s,2H),3.69(s,2H),3.36(q,J＝5.3Hz,2H),2.75(d,J＝14.9Hz,2H),2.60-2.51(m,6H),2.34(s,3H),2.05(s,3H)。Step 5: Compound 6-4 (200 mg, 0.29 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (495 mg, 11.80 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored for completeness by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 550.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ11.13(s,1H),7.86(d,J＝7.7Hz,2H),7.48(s,2H),7.32(d,J＝2.7Hz,1H),6.71(s,1H),4.05(t,J＝5.8Hz,2H),3.60(s,2H),3.25(s,2H) ,2.56(t,J＝5.8Hz,2H),2.33(s,3H),2.29(s,2H),2.16(d,J＝7.1Hz,2H),2.10(s,3H),2.05(d,J＝12.6Hz,2H),1.68(s,2H),1.48(s,1H). The purified product (110 mg, 0.20 mmol) was dissolved in methanol (3 mL), and 0.15 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 6. MS m/z (ESI): 550.2 [M+H] ⁺ . ^1H NMR (400MHz, DMSO-d6) δ11.21(s,1H),10.07(s,1H),7.96(d,J＝8.3Hz,2H),7.59(d,J＝8.1Hz,2H),7.35(d,J＝2.8Hz,1H),6.73(s,1H),4.5 4(t,J＝5.2Hz,2H),4.10(s,2H),3.69(s,2H),3.36(q,J＝5.3Hz,2H),2.75(d,J＝14.9Hz,2H),2.60-2.51(m,6H),2.34(s,3H),2.05(s,3H).

实施例7：化合物7的制备
Example 7: Preparation of Compound 7

步骤1：向100mL的单口瓶中加入化合物3-8(2g,4.91mmol)溶于1,4-二氧六环(10mL)和水(2mL)中，在氮气保护下依次加入乙烯三氟硼酸钾(1.97g,14.73mmol)，1,1-双(二苯基膦)二荗铁二氯化钯(0.37g,0.49mmol)和碳酸钾(1.36g,9.82mmol)，于90℃下反应16小时，通过LCMS检测反应完成。反应液降至室温后加入水(50mL)，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物7-1。MS m/z(ESI)：286.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.60(s,1H),7.85(d,J＝3.7Hz,1H),7.64(dd,J＝17.3,11.0Hz,1H),7.43(s,1H),7.39(d,J＝3.7Hz,1H),5.81(dd,J＝17.3,1.3Hz,1H),5.53(dd,J＝11.0,1.3Hz,1H),2.62(s,3H),1.61(s,9H)。Step 1: Compound 3-8 (2 g, 4.91 mmol) dissolved in 1,4-dioxane (10 mL) and water (2 mL) was added to a 100 mL single-necked flask. Under nitrogen protection, potassium trifluoroborate (1.97 g, 14.73 mmol), 1,1-bis(diphenylphosphine)diberberine palladium dichloride (0.37 g, 0.49 mmol), and potassium carbonate (1.36 g, 9.82 mmol) were added sequentially. The reaction was carried out at 90 °C for 16 hours, and the reaction was detected by LCMS. After the reaction solution cooled to room temperature, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 7-1. MS m/z (ESI): 286.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.60(s,1H),7.85(d,J＝3.7Hz,1H),7.64(dd,J＝17.3,11.0Hz,1H),7.43(s,1H),7.39(d,J＝3 .7Hz, 1H), 5.81 (dd, J＝17.3, 1.3Hz, 1H), 5.53 (dd, J＝11.0, 1.3Hz, 1H), 2.62 (s, 3H), 1.61 (s, 9H).

步骤2：向100mL的单口瓶中加入化合物7-1(1g,3.50mmol)溶于四氢呋喃(10mL)和甲醇(10mL)的溶液，然后加入PtO₂(0.80g,3.50mmol)，置换氢气保护，于室温下反应1小时，通过LCMS检测反应完全。反应液过滤，滤液减压浓缩得到化合物7-2。MS m/z(ESI)：288.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.57(s,1H),7.81(d,J＝3.7Hz,1H),7.38(d,J＝3.7Hz,1H),7.11(s,1H),3.08(q,J＝7.5Hz,2H),2.58(s,3H),1.23(t,J＝7.5Hz,3H),1.60(s,9H)。Step 2: Add a solution of compound 7-1 (1 g, 3.50 mmol) dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) to a 100 mL single-necked flask, then add _PtO₂ (0.80 g, 3.50 mmol), displace the solution with hydrogen gas, and react at room temperature for 1 hour. The reaction was monitored for completeness by LCMS. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain compound 7-2. MS m/z (ESI): 288.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.57(s,1H),7.81(d,J＝3.7Hz,1H),7.38(d,J＝3.7Hz,1H),7.11(s,1H ), 3.08 (q, J = 7.5Hz, 2H), 2.58 (s, 3H), 1.23 (t, J = 7.5Hz, 3H), 1.60 (s, 9H).

步骤3：将化合物7-2(100mg,0.35mmol)溶于乙腈(5mL)中，加入化合物5-2(134.47mg,0.35mmol)和3滴醋酸，反应液搅拌反应1h后，加入三乙酰氧基硼氢化钠(221.26mg,1.04mmol)，室温下继续搅拌过夜，通过LCMS监测反应完全。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物7-3。MS m/z(ESI)：658.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝7.9Hz,2H),7.56(d,J＝8.1Hz,2H),7.42(d,J＝3.8Hz,1H),6.84(s,1H),5.78(d,J＝3.8Hz,1H),4.35(t,J＝7.1Hz,2H),4.07(s,2H),3.43(d,J＝5.8Hz,2H),3.29(s,2H),2.60(s,2H),2.42(s,3H),2.32(d,J＝7.4Hz,4H),2.21(d,J＝7.4Hz,2H),1.99(t,J＝7.0Hz,2H),1.83(s,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H),0.97(t,J＝7.5Hz,3H)。Step 3: Compound 7-2 (100 mg, 0.35 mmol) was dissolved in acetonitrile (5 mL), and compound 5-2 (134.47 mg, 0.35 mmol) and 3 drops of acetic acid were added. The reaction mixture was stirred for 1 h, and then sodium triacetoxyborohydride (221.26 mg, 1.04 mmol) was added. The mixture was stirred overnight at room temperature, and the reaction was monitored for completeness by LCMS. The reaction mixture was quenched slowly with ice water at room temperature, and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 7-3. MS m/z (ESI): 658.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.95(d,J＝7.9Hz,2H),7.56(d,J＝8.1Hz,2H),7.42(d,J＝3.8Hz,1H),6.84(s,1H),5. 78(d,J＝3.8Hz,1H),4.35(t,J＝7.1Hz,2H),4.07(s,2H),3.43(d,J＝5.8Hz,2H),3.29(s ,2H),2.60(s,2H),2.42(s,3H),2.32(d,J＝7.4Hz,4H),2.21(d,J＝7.4Hz,2H),1.99(t, J＝7.0Hz,2H),1.83(s,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H),0.97(t,J＝7.5Hz,3H).

步骤4：将化合物7-3(50mg,0.08mmol)溶于四氢呋喃(2mL)，甲醇(2mL)和水(2mL)混合溶剂中，加入氢氧化锂(127.58mg,3.04mmol)，升温60℃反应1小时，通过LCMS监测反应完全。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：530.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.92(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.08(t,J＝2.8Hz,1H),6.62(s,1H),5.58(dd,J＝3.1,1.9Hz,1H),4.07(t,J＝5.8Hz,2H),3.47(s,2H),3.32(s,3H),2.61(t,J＝5.7Hz,2H),2.37–2.22(m,9H),2.00(d,J＝11.8Hz,2H),1.82(s,2H),0.98(t,J＝7.5Hz,3H)。将纯化产物(50mg,0.09mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.09mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物7。MS m/z(ESI)：530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.86(s,1H),7.99(dd,J＝8.4,2.5Hz,2H),7.59(d,J＝8.1Hz,2H),7.12(t,J＝2.8Hz,1H),6.65(s,1H),5.62(s,1H),4.58(d,J＝18.2Hz,2H),4.12(s,2H),3.50(s,2H),3.41(d,J＝5.5Hz,2H),2.74(d,J＝15.5Hz,2H),2.59(d,J＝8.4Hz,3H),2.36(s,3H),2.33(t,J＝7.6Hz,2H),2.15(d,J＝7.7Hz,2H),1.78(s,1H),0.98(t,J＝7.5Hz,3H)。Step 4: Compound 7-3 (50 mg, 0.08 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (127.58 mg, 3.04 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 530.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),7.92(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.08(t,J＝2.8Hz,1H),6.62(s,1H),5.58(dd,J＝3.1,1.9Hz,1H),4.07(t,J＝5 .8Hz,2H),3.47(s,2H),3.32(s,3H),2.61(t,J＝5.7Hz,2H),2.37–2.22(m,9H),2.00(d,J＝11.8Hz,2H),1.82(s,2H),0.98(t,J＝7.5Hz,3H). The purified product (50 mg, 0.09 mmol) was dissolved in methanol (3 mL), and 0.09 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 7. MS m/z (ESI): 530.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 7.99 (dd, J = 8.4, 2.5 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.12 (t, J = 2.8 Hz, 1H), 6.65 (s, 1H), 5.62 (s, 1H), 4.58 (d, J = 18.2 Hz, 2H), 4.12 (s, 2H). 3.50(s,2H),3.41(d,J＝5.5Hz,2H),2.74(d,J＝15.5Hz,2H),2.59(d,J＝8.4Hz,3H),2.36( s, 3H), 2.33 (t, J = 7.6Hz, 2H), 2.15 (d, J = 7.7Hz, 2H), 1.78 (s, 1H), 0.98 (t, J = 7.5Hz, 3H).

实施例8：化合物8的制备
Example 8: Preparation of Compound 8

步骤1：向20mL的微波管中加入化合物3-8(1.0g,2.45mmol)溶于1,4-二氧六环(10mL)和水(2mL)的溶液,在氮气保护下依次加入异丙烯基硼酸频哪醇酯(1.24g,7.36mmol)，1,1-双(二苯基膦)二荗铁二氯化钯(0.18g,0.25mmol)和碳酸钾(1.02g,7.36mmol)，于100℃下微波反应2小时，通过LCMS监测反应完全。反应液降至室温，加入水(40mL)，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物8-1。MS m/z(ESI)：300.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.22(s,1H),7.86(d,J＝3.7Hz,1H),7.38(d,J＝3.7Hz,1H),7.20(s,1H),5.47(q,J＝1.6Hz,1H),4.89(q,J＝2.1,1.0Hz,1H),2.61(s,3H),2.19(d,J＝1.2Hz,3H),1.61(s,9H)。Step 1: Add a solution of compound 3-8 (1.0 g, 2.45 mmol) dissolved in 1,4-dioxane (10 mL) and water (2 mL) to a 20 mL microwave tube. Under nitrogen protection, add isopropenylboronic acid pinacol ester (1.24 g, 7.36 mmol), 1,1-bis(diphenylphosphine)dimerferropalladium dichloride (0.18 g, 0.25 mmol), and potassium carbonate (1.02 g, 7.36 mmol) sequentially. Microwave the mixture at 100 °C for 2 hours, and monitor the reaction until complete by LCMS. Cool the reaction solution to room temperature, add water (40 mL), and extract three times with ethyl acetate (3 × 40 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 8-1. MS m/z(ESI): 300.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.22(s,1H),7.86(d,J＝3.7Hz,1H),7.38(d,J＝3.7Hz,1H),7.20(s,1H),5.47(q,J＝1 .6Hz, 1H), 4.89 (q, J = 2.1, 1.0Hz, 1H), 2.61 (s, 3H), 2.19 (d, J = 1.2Hz, 3H), 1.61 (s, 9H).

步骤2：向100mL的单口瓶中加入化合物8-1(650mg,2.17mmol)溶于四氢呋喃(10mL)和甲醇(10mL)的溶液，然后加入二氧化铂(100mg)，置换氢气保护，于室温下反应1小时，通过LCMS检测反应完成。将反应液过滤，滤液减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-30％乙酸乙酯/石油醚)纯化得到化合物8-2。MS m/z(ESI)：302.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.67(s,1H),7.81(d,J＝3.7Hz,1H),7.37(d,J＝3.7Hz,1H),7.26(s,1H),4.07–3.97(m,1H),2.60(s,3H),1.60(s,9H),1.31(s,3H),1.29(s,3H)。Step 2: Add a solution of compound 8-1 (650 mg, 2.17 mmol) dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) to a 100 mL single-necked flask, then add platinum dioxide (100 mg), displace the solution with hydrogen for protection, and react at room temperature for 1 hour. The reaction was monitored by LCMS to confirm completion. Filter the reaction solution, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-30% ethyl acetate/petroleum ether) to obtain compound 8-2. MS m/z (ESI): 302.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.67(s,1H),7.81(d,J＝3.7Hz,1H),7.37(d,J＝3.7Hz,1H),7.26(s,1H ),4.07–3.97(m,1H),2.60(s,3H),1.60(s,9H),1.31(s,3H),1.29(s,3H).

步骤3：将化合物8-2(120mg,0.40mmol)溶于乙腈(5mL)中，加入化合物5-2(185mg,0.48mmol)和5滴醋酸，室温下搅拌过夜，通过LCMS监测反应，有大量亚胺生成。然后在0℃下加入硼氢化钠(38mg,1.00mmol)和甲醇(3mL)，室温条件下继续反应1小时，通过LCMS监测反应完全。反应液加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-40％乙酸乙酯/石油醚)纯化得到化合物8-3。MS m/z(ESI)：672.4[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.96(d,J＝8.2Hz,2H),7.56(d,J＝8.5Hz,2H),7.41(d,J＝3.8Hz,1H),6.94(s,1H),5.77(s,1H),5.71(d,J＝3.8Hz,1H),4.36(q,J＝7.1Hz,2H),4.08(t,J＝5.8Hz,2H),3.45(d,J＝5.3Hz,2H),3.30(s,2H),3.18(d,J＝5.2Hz,1H),2.62(t,J＝5.9Hz,2H),2.45(s,3H),2.33-2.21(m,4H),2.00(t,J＝7.5Hz,2H),1.88-1.81(m,2H),1.56(s,9H),1.35(s,3H),1.04(d,J＝6.8Hz,6H)。Step 3: Compound 8-2 (120 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and compound 5-2 (185 mg, 0.48 mmol) and 5 drops of acetic acid were added. The mixture was stirred overnight at room temperature. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (38 mg, 1.00 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued for 1 hour at room temperature. LCMS monitoring showed the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-40% ethyl acetate/petroleum ether) to obtain compound 8-3. MS m/z (ESI): 672.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ7.96(d,J＝8.2Hz,2H),7.56(d,J＝8.5Hz,2H),7.41(d,J＝3.8Hz,1H),6.94 (s,1H),5.77(s,1H),5.71(d,J＝3.8Hz,1H),4.36(q,J＝7.1Hz,2H),4.08(t,J＝5.8Hz,2H),3.45(d, J＝5.3Hz,2H),3.30(s,2H),3.18(d,J＝5.2Hz,1H),2.62(t,J＝5.9Hz,2H),2.45(s,3H),2.33-2.21( m, 4H), 2.00 (t, J = 7.5Hz, 2H), 1.88-1.81 (m, 2H), 1.56 (s, 9H), 1.35 (s, 3H), 1.04 (d, J = 6.8Hz, 6H).

步骤4：将化合物8-3(110mg,0.16mmol)溶于甲醇(4mL)，水(4mL)和四氢呋喃(4mL)混合溶剂中，加入一水合氢氧化锂(275mg,6.55mmol)，于60℃反应2小时，通过LCMS监测反应完全。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调pH值至5～7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：544.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.78(s,1H),10.78(s,1H),7.94(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.07(t,J＝2.8Hz,1H),6.72(s,1H),5.55-5.50(m,1H),4.08(t,J＝5.7Hz,2H),3.49(s,2H),3.28(s,2H),2.83-2.74(m,1H),2.63(d,J＝5.8Hz,2H),2.36(s,3H),2.32-2.22(m,4H),2.01(d,J＝12.7Hz,2H),1.84(s,2H),1.14(s,1H),1.03(d,J＝6.8Hz,6H)。将纯化产物(35mg,0.06mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入1N的盐酸-甲醇溶液(0.18mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物8。MS m/z(ESI)：544.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.84(s,1H),9.95(s,1H),8.00(d,J＝8.3Hz,2H),7.58(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.75(s,1H),5.51(t,J＝2.4Hz,1H),4.55(t,J＝5.2Hz,2H),4.13(s,2H),3.53(d,J＝4.8Hz,2H),3.41(d,J＝5.3Hz,2H),2.75(d,J＝15.3Hz,2H),2.61(d,J＝8.5Hz,2H),2.47(s,2H),2.37(s,3H),2.18(s,2H),1.72(s,1H),1.05(d,J＝6.8Hz,6H)。Step 4: Compound 8-3 (110 mg, 0.16 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide monohydrate (275 mg, 6.55 mmol) was added, and the reaction was carried out at 60 °C for 2 hours. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5–7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [Model: Waters-Xbridge-C18-10 μm-19 × 250 mm; Mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; Gradient: B%: 0%–95%)] to obtain the purified product. MS m/z (ESI): 544.3 [M+H] ^⁺ . ^¹H NMR (400 MHz, DMSO- _d⁻¹) )δ12.78(s,1H),10.78(s,1H),7.94(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),7.07 (t,J＝2.8Hz,1H),6.72(s,1H),5.55-5.50(m,1H),4.08(t,J＝5.7Hz,2H),3.49(s,2 3.28 (s, 2H), 2.83–2.74 (m, 1H), 2.63 (d, J = 5.8 Hz, 2H), 2.36 (s, 3H), 2.32–2.22 (m, 4H), 2.01 (d, J = 12.7 Hz, 2H), 1.84 (s, 2H), 1.14 (s, 1H), 1.03 (d, J = 6.8 Hz, 6H). The purified product (35 mg, 0.06 mmol) was dissolved in methanol (5 mL), and 0.18 mL of 1 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 8. MS m/z (ESI): 544.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.84(s,1H),9.95(s,1H),8.00(d,J＝8.3Hz,2H),7.58(d,J＝8.2Hz,2H),7.10(t, J＝2.8Hz,1H),6.75(s,1H),5.51(t,J＝2.4Hz,1H),4.55(t,J＝5.2Hz,2H),4.13(s,2H) ,3.53(d,J＝4.8Hz,2H),3.41(d,J＝5.3Hz,2H),2.75(d,J＝15.3Hz,2H),2.61(d,J＝8. 5Hz,2H),2.47(s,2H),2.37(s,3H),2.18(s,2H),1.72(s,1H),1.05(d,J＝6.8Hz,6H).

实施例9：化合物9的制备
Example 9: Preparation of Compound 9

步骤1：向10mL的单口瓶中加入化合物3-8(500mg,1.2mmol)溶于甲苯(30mL)和水(6mL)的溶液，然后依次加入环丁基硼酸(1.17g,4656mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(89.0mg,0.1mmol)和碳酸铯(1.170mg,3.6mmol)，置换氮气，于100℃下反应16小时，通过LCMS监测反应完全。反应液加入水中淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-40％乙酸乙酯/石油醚)纯化，得到化合物9-1。MS m/z(ESI)：314.1[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.51(s,1H),7.81(d,J＝3.7Hz,1H),7.35(d,J＝3.7Hz,1H),7.18(s,1H),4.33(p,J＝8.9Hz,1H),2.62(s,3H),2.36(ddq,J＝10.5,4.9,2.7,2.2Hz,2H),2.26(ddt,J＝11.2,9.6,4.3Hz,2H),1.93–1.83(m,2H),1.60(s,9H)。Step 1: A solution of compound 3-8 (500 mg, 1.2 mmol) dissolved in toluene (30 mL) and water (6 mL) was added to a 10 mL single-necked flask. Cyclobutylboronic acid (1.17 g, 4656 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (89.0 mg, 0.1 mmol), and cesium carbonate (1.170 mg, 3.6 mmol) were added sequentially. Nitrogen gas was then introduced, and the mixture was reacted at 100 °C for 16 hours. The reaction was monitored for completeness by LC-MS. The reaction solution was quenched in water and extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-40% ethyl acetate/petroleum ether) to obtain compound 9-1. MS m/z (ESI): 314.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.51(s,1H),7.81(d,J＝3.7Hz,1H),7.35(d,J＝3.7Hz,1H),7.18(s,1H),4.33(p,J＝8.9Hz,1H),2.62(s,3H) ,2.36(ddq,J＝10.5,4.9,2.7,2.2Hz,2H),2.26(ddt,J＝11.2,9.6,4.3Hz,2H),1.93–1.83(m,2H),1.60(s,9H).

步骤2：将化合物5-2(200mg,0.52mmol)，化合物9-1(162.21mg,0.52mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(59mg,1.56mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物9-2。MS m/z(ESI)：684.4[M+H]⁺。Step 2: Compound 5-2 (200 mg, 0.52 mmol) and compound 9-1 (162.21 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completeness by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 9-2. MS m/z (ESI): 684.4 [M+H] ⁺ .

步骤3：将化合物9-2(200mg,0.33mmol)溶于四氢呋喃(4mL)、甲醇(4mL)和水(4mL)混合溶剂中，加入氢氧化锂一水合物(490.90mg,11.70mmol)，反应液在60℃搅拌1小时，通过LCMS监测反应完全。待反应液降至室温后,使用2N稀盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mMNH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：556.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.78(s,1H),10.81(s,1H),7.97(d,J＝8.3Hz,2H),7.54(d,J＝8.3Hz,2H),7.15(t,J＝2.8Hz,1H),6.84(s,1H),5.86(dd,J＝3.1,1.9Hz,1H),4.08(t,J＝5.7Hz,2H),3.44(s,2H),3.30(s,2H),3.11-3.07(m,1H),2.62(t,J＝5.8Hz,2H),2.39(s,3H),2.35-2.26(m,4H),2.04-1.81(m,8H),1.64(q,J＝8.4Hz,2H)。将纯化产物(75mg,0.13mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.10mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物9。MS m/z(ESI)：556.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),10.87(s,1H),9.73(s,1H),8.03(d,J＝8.0Hz,2H),7.61(d,J＝8.2Hz,2H),7.18(t,J＝2.8Hz,1H),6.86(s,1H),5.89(t,J＝2.6Hz,1H),4.54(d,J＝5.1Hz,2H),4.14(s,2H),3.44(dd,J＝20.4,5.4Hz,4H),3.07(q,J＝8.9Hz,1H),2.77(d,J＝14.8Hz,2H),2.67-2.58(m,2H),2.45(s,1H),2.40(s,3H),2.17(s,2H),1.91(dt,J＝19.3,9.2Hz,4H),1.74-1.56(m,3H)。Step 3: Compound 9-2 (200 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (490.90 mg, 11.70 mmol) was added. The reaction solution was stirred at 60 °C for 1 hour, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 with 2N dilute hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250mm; mobile phase: (A: ₁₀ mM _NH4HCO3 / _H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 556.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.78(s,1H),10.81(s,1H),7.97(d,J＝8.3Hz,2H),7.54(d,J＝8.3Hz,2H), 7.15(t,J＝2.8Hz,1H),6.84(s,1H),5.86(dd,J＝3.1,1.9Hz,1H),4.08(t,J＝5 .7Hz,2H),3.44(s,2H),3.30(s,2H),3.11-3.07(m,1H),2.62(t,J＝5.8Hz,2H ), 2.39 (s, 3H), 2.35-2.26 (m, 4H), 2.04-1.81 (m, 8H), 1.64 (q, J = 8.4Hz, 2H). The purified product (75 mg, 0.13 mmol) was dissolved in methanol (5 mL), and 0.10 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 9. MS m/z (ESI): 556.3 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ12.95(s,1H),10.87(s,1H),9.73(s,1H),8.03(d,J＝8.0Hz,2H),7.61(d,J＝8.2Hz,2H),7. 18(t,J＝2.8Hz,1H),6.86(s,1H),5.89(t,J＝2.6Hz,1H),4.54(d,J＝5.1Hz,2H),4.14(s,2H), 3.44(dd,J＝20.4,5.4Hz,4H),3.07(q,J＝8.9Hz,1H),2.77(d,J＝14.8Hz,2H),2.67-2.58(m,2 H), 2.45 (s, 1H), 2.40 (s, 3H), 2.17 (s, 2H), 1.91 (dt, J = 19.3, 9.2Hz, 4H), 1.74-1.56 (m, 3H).

实施例10：化合物10的制备
Example 10: Preparation of Compound 10

步骤1：将化合物3-8(27g,66.28mmol)加入甲苯(810mL)和水(135mL)混合溶剂中，再依次加入环丙基硼酸(17.08g,198.84mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(9.70g,13.26mmol)和碳酸钾(18.32g,132.56mmol)，置换氮气后，于110℃反应过夜，通过LCMS监测反应完成。反应液中加入水中淬灭，用乙酸乙酯萃取3次(3×300mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯/石油醚)纯化，得到化合物10-1。MS m/z(ESI)：300.0[M+H]⁺。¹H NMR(400MHz,Chloroform-d)δ10.98(s,1H),7.64(d,J＝3.7Hz,1H),7.47(d,J＝3.7Hz,1H),6.93(s,1H),2.64(d,J＝0.8Hz,3H),2.48(td,J＝8.5,4.3Hz,1H),1.63(s,9H),1.11–1.04(m,2H),0.85–0.80(m,2H)。Step 1: Compound 3-8 (27 g, 66.28 mmol) was added to a mixed solvent of toluene (810 mL) and water (135 mL), followed by the sequential addition of cyclopropylboronic acid (17.08 g, 198.84 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (9.70 g, 13.26 mmol), and potassium carbonate (18.32 g, 132.56 mmol). After purging with nitrogen, the reaction was carried out overnight at 110 °C, and the reaction was monitored by LCMS. The reaction solution was quenched with water, extracted three times with ethyl acetate (3 × 300 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 10-1. MS m/z (ESI): 300.0 [M+H] ⁺ . ¹ H NMR(400MHz,Chloroform-d)δ10.98(s,1H),7.64(d,J＝3.7Hz,1H),7.47(d,J＝3.7Hz,1H),6.93(s,1H), 2.64(d,J＝0.8Hz,3H),2.48(td,J＝8.5,4.3Hz,1H),1.63(s,9H),1.11–1.04(m,2H),0.85–0.80(m,2H).

步骤2：将化合物5-2(200mg,0.52mmol)，化合物10-1(155mg,0.52mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(59mg,1.56mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物10-2。MS m/z(ESI)：670.4[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.93(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.47(d,J＝3.8Hz,1H),6.56(s,1H),5.98(d,J＝3.8Hz,1H),4.33(q,J＝7.1Hz,2H),4.06(t,J＝5.8Hz,2H),3.57(d,J＝5.6Hz,2H),3.30-3.25(m,2H),2.60(t,J＝5.7Hz,2H),2.40(s,3H),2.30(d,J＝13.7Hz,2H),2.20(d,J＝7.2Hz,2H),2.02-1.95(m,2H),1.80(s,2H),1.56(s,9H),1.33(t,J＝7.1Hz,3H),1.26-1.22(m,2H),0.60-0.53(m,2H),0.53-0.46(m,2H)。Step 2: Compound 5-2 (200 mg, 0.52 mmol) and compound 10-1 (155 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completeness by LCMS. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 10-2. MS m/z (ESI): 670.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.93(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.47(d,J＝3.8Hz,1H),6.56(s,1H),5.98(d,J＝3.8Hz ,1H),4.33(q,J＝7.1Hz,2H),4.06(t,J＝5.8Hz,2H),3.57(d,J＝5.6Hz,2H),3.30-3.25(m,2H),2.60(t ,J＝5.7Hz,2H),2.40(s,3H),2.30(d,J＝13.7Hz,2H),2.20(d,J＝7.2Hz,2H),2.02-1.95(m,2H),1.80( s,2H),1.56(s,9H),1.33(t,J＝7.1Hz,3H),1.26-1.22(m,2H),0.60-0.53(m,2H),0.53-0.46(m,2H).

步骤3：将化合物10-2(220mg,0.33mmol)溶于四氢呋喃(4mL)，甲醇(4mL)和水(4mL)混合溶剂中，加入氢氧化锂一水合物(551mg,13.14mmol),反应液在60℃下搅拌2小时，通过LCMS监测反应完全。待反应液降至室温后，使用2M盐酸调pH至5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mMNH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：542.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.81(s,1H),10.80(s,1H),7.91(d,J＝8.4Hz,2H),7.53(d,J＝8.2Hz,2H),7.13(t,J＝2.8Hz,1H),6.38(s,1H),5.80(t,J＝2.6Hz,1H),4.07(t,J＝5.7Hz,2H),3.62(s,2H),3.29(s,2H),2.61(t,J＝5.9Hz,2H),2.33(s,3H),2.30-2.23(m,3H),2.01(d,J＝12.5Hz,2H),1.80(s,2H),1.56-1.50(m,1H),1.28(s,1H),0.58-0.51(m,2H),0.44-0.38(m,2H)。将纯化产物(75mg,0.14mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.12mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物10。MS m/z(ESI)：542.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.91(s,1H),10.87(s,1H),10.11(s,1H),7.97(d,J＝8.1Hz,2H),7.60(d,J＝8.2Hz,2H),7.17(t,J＝2.8Hz,1H),6.41(s,1H),5.83(t,1H),4.56(s,2H),4.12(s,2H),3.69-3.61(m,2H),3.40(s,2H),2.75(d,J＝14.7Hz,2H),2.59(d,J＝8.6Hz,2H),2.53(s,2H),2.34(s,3H),2.11(s,2H),1.60-1.50(m,1H),0.58-0.51(m,2H),0.46-0.39(m,2H)。Step 3: Compound 10-2 (220 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (551 mg, 13.14 mmol) was added. The reaction solution was stirred at 60 °C for 2 hours, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250mm; mobile phase: (A: ₁₀ mM _NH4HCO3 / _H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 542.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.81(s,1H),10.80(s,1H),7.91(d,J＝8.4Hz,2H),7.53(d,J＝8.2Hz,2H),7.13(t,J ＝2.8Hz,1H),6.38(s,1H),5.80(t,J＝2.6Hz,1H),4.07(t,J＝5.7Hz,2H),3.62(s,2H),3. 29 (s, 2H), 2.61 (t, J = 5.9 Hz, 2H), 2.33 (s, 3H), 2.30–2.23 (m, 3H), 2.01 (d, J = 12.5 Hz, 2H), 1.80 (s, 2H), 1.56–1.50 (m, 1H), 1.28 (s, 1H), 0.58–0.51 (m, 2H), 0.44–0.38 (m, 2H). The purified product (75 mg, 0.14 mmol) was dissolved in methanol (5 mL), and 0.12 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 10. MS m/z (ESI): 542.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.91(s,1H),10.87(s,1H),10.11(s,1H),7.97(d,J＝8.1Hz,2H),7.60(d,J＝8.2Hz ,2H),7.17(t,J＝2.8Hz,1H),6.41(s,1H),5.83(t,1H),4.56(s,2H),4.12(s,2H),3.69 -3.61(m,2H),3.40(s,2H),2.75(d,J＝14.7Hz,2H),2.59(d,J＝8.6Hz,2H),2.53(s,2H ),2.34(s,3H),2.11(s,2H),1.60-1.50(m,1H),0.58-0.51(m,2H),0.46-0.39(m,2H).

实施例11：化合物11的制备
Example 11: Preparation of Compound 11

步骤1：向10mL的单口瓶中加入化合物3-7(600mg,1.2mmol)的DMF(10mL)溶液，依次加入碳酸钾(602.4mg,4.36mmol)，碘乙烷(679.85mg,4.36mmol)，室温反应16小时，通过LCMS检测反应完成。反应液中加入水中淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～30％乙酸乙酯/石油醚)纯化，得到化合物11-1。LC-MS:m/z:304.2[M+H]⁺。Step 1: Add a 10 mL DMF (10 mL) solution of compound 3-7 (600 mg, 1.2 mmol) to a 10 mL single-necked flask, followed by the addition of potassium carbonate (602.4 mg, 4.36 mmol) and iodoethane (679.85 mg, 4.36 mmol). Incubate at room temperature for 16 hours. Detect the reaction as complete by LC-MS. Quench the reaction solution with water, extract three times with ethyl acetate (3 × 40 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%–30% ethyl acetate/petroleum ether) to obtain compound 11-1. LC-MS: m/z: 304.2 [M+H] ⁺ .

步骤2：将化合物5-2(200mg,0.52mmol)、化合物11-1(157.01mg,0.52mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时，通过LCMS监测反应，可以看到有大量亚胺生成。然后加入硼氢化钠(59mg,1.56mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物11-2。MS m/z(ESI)：674.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.93(d,J＝8.4Hz,2H),7.59–7.51(m,3H),6.75(s,1H),6.17(dd,J＝3.8,1.7Hz,1H),4.32(q,J＝7.2Hz,2H),4.06(q,J＝5.9Hz,2H),3.92(q,J＝6.9Hz,2H),3.37(s,2H),3.26(s,2H),2.46(d,J＝2.8Hz,3H),2.20(dd,J＝23.1,11.1Hz,4H),2.05-2.00(m,1H),1.98(s,1H),1.90(s,3H),1.74(s,2H),1.56(d,J＝4.0Hz,9H),1.36-1.30(m,3H),1.25-1.18(m,3H)。Step 2: Compound 5-2 (200 mg, 0.52 mmol) and compound 11-1 (157.01 mg, 0.52 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (59 mg, 1.56 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. LCMS monitoring showed the reaction was complete. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 11-2. MS m/z (ESI): 674.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.93(d,J＝8.4Hz,2H),7.59–7.51(m,3H),6.75(s,1H),6.17(dd,J＝3.8,1.7Hz,1H),4. 32(q,J＝7.2Hz,2H),4.06(q,J＝5.9Hz,2H),3.92(q,J＝6.9Hz,2H),3.37(s,2H),3.26(s,2 H),2.46(d,J＝2.8Hz,3H),2.20(dd,J＝23.1,11.1Hz,4H),2.05-2.00(m,1H),1.98(s,1H) ,1.90(s,3H),1.74(s,2H),1.56(d,J＝4.0Hz,9H),1.36-1.30(m,3H),1.25-1.18(m,3H).

步骤3：将化合物11-2(220mg,0.33mmol)溶于四氢呋喃(4mL)、甲醇(4mL)和水(4mL)混合溶剂中，加入氢氧化锂一水合物(548mg,13.06mmol)，反应液在60℃搅拌1小时，通过LCMS监测反应完全。待反应液降至室温后，使用2M稀盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mMNH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：546.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.87(s,1H),10.80(s,1H),7.90(d,J＝8.1Hz,2H),7.49(d,J＝8.1Hz,2H),7.19(t,J＝2.8Hz,1H),6.61(s,1H),5.92(t,J＝2.4Hz,1H),4.07(t,J＝5.8Hz,2H),3.84(q,J＝7.0Hz,2H),3.42(s,2H),3.26(s,3H),2.60(t,J＝5.7Hz,2H),2.38(s,3H),2.26-2.17(m,4H),2.05-1.97(m,2H),1.75(s,2H),1.18(t,J＝6.9Hz,3H)。将纯化产物(85mg,0.16mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.12mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物11。MS m/z(ESI)：546.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ12.87(s,1H),10.80(s,1H),9.93(s,1H),7.99(d,J＝8.0Hz,2H),7.61(d,J＝8.0Hz,2H),7.21(t,J＝4.0Hz,1H),6.63(s,1H),5.91(t,J＝4.0Hz,1H),4.55(s,2H),4.10(s,2H),3.89-3.84(m,2H),3.55(s,2H),3.45-3.38(m,3H),2.69-2.59(m,4H),2.49-2.46(m,1H),2.39(s,3H),2.05-1.98(m,2H),1.19(t,J＝6.9Hz,3H)。Step 3: Compound 11-2 (220 mg, 0.33 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (548 mg, 13.06 mmol) was added. The reaction solution was stirred at 60 °C for 1 hour, and the reaction was monitored for completeness by LCMS. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250mm; mobile phase: (A: ₁₀ mM _NH4HCO3 / _H2O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 546.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.87(s,1H),10.80(s,1H),7.90(d,J＝8.1Hz,2H),7.49(d,J＝8.1Hz,2H),7. 19(t,J＝2.8Hz,1H),6.61(s,1H),5.92(t,J＝2.4Hz,1H),4.07(t,J＝5.8Hz,2H), 3.84(q,J＝7.0Hz,2H),3.42(s,2H),3.26(s,3H),2.60(t,J＝5.7Hz,2H),2.38(s ,3H),2.26-2.17(m,4H),2.05-1.97(m,2H),1.75(s,2H),1.18(t,J＝6.9Hz,3H). The purified product (85 mg, 0.16 mmol) was dissolved in methanol (5 mL), and 0.12 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 11. MS m/z (ESI): 546.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.87(s,1H),10.80(s,1H),9.93(s,1H),7.99(d,J＝8.0Hz,2H),7.61(d,J＝8 .0Hz,2H),7.21(t,J＝4.0Hz,1H),6.63(s,1H),5.91(t,J＝4.0Hz,1H),4.55(s,2H ),4.10(s,2H),3.89-3.84(m,2H),3.55(s,2H),3.45-3.38(m,3H),2.69-2.59(m ,4H),2.49-2.46(m,1H),2.39(s,3H),2.05-1.98(m,2H),1.19(t,J＝6.9Hz,3H).

实施例12：化合物12的制备
Example 12: Preparation of Compound 12

步骤1：将化合物3-8(1.0g,2.45mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入四(三苯基膦)钯(1.42g,1.23mmol)和氰化锌(865mg,7.36mmol)，置换氮气后，反应液在100℃下搅拌2小时，通过LCMS监测反应完全。待反应液降至室温后，加入水(40mL)淬灭，用乙酸乙酯萃取3次(3×40mL),合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM FA/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到化合物12-1。MS m/z(ESI)：＝185.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.22(s,1H),10.49(s,1H),7.83(d,J＝3.1Hz,1H),7.53(s,1H),7.25(d,J＝3.1Hz,1H),2.62(s,3H)。Step 1: Compound 3-8 (1.0 g, 2.45 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) and zinc cyanide (865 mg, 7.36 mmol) were added. After purging with nitrogen, the reaction mixture was stirred at 100 °C for 2 hours, and the reaction was monitored to be complete by LCMS. After the reaction mixture cooled to room temperature, it was quenched with water (40 mL), extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10 μm-19 × 250 mm; mobile phase: (A: 10 mM FA/ _H₂O ; B: ACN; gradient: B%: 0%-95%)] to obtain compound 12-1. MS m/z(ESI): =185.0[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.22 (s, 1H), 10.49 (s, 1H), 7.83 (d, J = 3.1 Hz, 1H), 7.53 (s, 1H), 7.25 (d, J = 3.1 Hz, 1H), 2.62 (s, 3H).

步骤2：将化合物12-1(120mg,0.65mmol)，化合物5-2(250mg,0.65mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时，通过LCMS监测反应，可以看到有大量亚胺生成。然后加入硼氢化钠(246mg,6.50mmol)和甲醇(3mL)，反应液在室温下继续搅拌3小时，通过LCMS监测反应完全。反应液中加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～35％乙酸乙酯/石油醚)纯化，得到化合物12-2。MS m/z(ESI)：555.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.58(s,1H),7.95(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,2H),7.43(t,J＝2.9Hz,1H),7.14(s,1H),6.03(s,1H),4.33(q,J＝7.2Hz,2H),4.06(s,2H),3.57(d,J＝6.6Hz,2H),3.25(s,2H),2.58(s,2H),2.44(s,3H),2.29-2.14(m,4H),2.01(d,J＝15.1Hz,2H),1.72(s,2H),1.34(t,J＝7.0Hz,3H)。Step 2: Compound 12-1 (120 mg, 0.65 mmol) and compound 5-2 (250 mg, 0.65 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. LCMS monitoring showed the formation of a large amount of imine. Then, sodium borohydride (246 mg, 6.50 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another 3 hours. LCMS monitoring showed the reaction was complete. The reaction mixture was quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–35% ethyl acetate/petroleum ether) to obtain compound 12-2. MS m/z (ESI): 555.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ11.58(s,1H),7.95(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,2H),7.43(t,J＝2.9Hz,1H),7.14(s,1H),6.03(s,1H),4.33(q,J＝7.2Hz,2H),4.06(s,2 H),3.57(d,J＝6.6Hz,2H),3.25(s,2H),2.58(s,2H),2.44(s,3H),2.29- 2.14(m,4H),2.01(d,J＝15.1Hz,2H),1.72(s,2H),1.34(t,J＝7.0Hz,3H).

步骤3：将化合物12-2(100mg,0.18mmol)溶于四氢呋喃(2mL)，甲醇(2mL)，水(2mL)混合溶剂中，加入氢氧化锂(37.83mg,0.90mmol)，室温反应2小时，通过LCMS监测反应完成。在反应液中缓慢滴加稀HCl(2.0M)，调节pH值5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：527.5[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.58(s,1H),7.93(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.42(t,J＝2.8Hz,1H),7.14(s,1H),5.98(d,J＝2.8Hz,1H),4.06(t,J＝5.8Hz,2H),3.58(s,2H),3.25(s,2H),2.59(t,J＝5.8Hz,2H),2.44(s,3H),2.22(dd,J＝19.8,10.6Hz,4H),2.01(d,J＝13.3Hz,2H),1.72(s,2H)。将纯化产物(30mg,0.06mmol)溶于甲醇(3mL)，加入4M盐酸甲醇溶液(0.05mL)，搅拌3小时后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物12。MS m/z(ESI)：527.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.00(s,1H),11.70(s,1H),9.94(s,1H),8.75(s,1H),7.94-7.85(m,3H),7.67-7.59(m,3H),6.70(s,1H),5.59(s,1H),5.46(s,1H),5.29(s,1H),4.77(s,2H),4.29(s,2H),3.52(d,J＝5.3Hz,2H),3.12(s,4H),2.60(s,4H),2.21(s,3H)。Step 3: Compound 12-2 (100 mg, 0.18 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (37.83 mg, 0.90 mmol) was added, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS to indicate completion. Dilute HCl (2.0 M) was slowly added dropwise to the reaction solution to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19×250 mm mobile phase (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 527.5 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ11.58(s,1H),7.93(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.42(t,J＝2.8Hz,1H),7.14(s,1H),5.98(d,J＝2.8Hz,1H),4.06(t,J＝5.8H z,2H),3.58(s,2H),3.25(s,2H),2.59(t,J＝5.8Hz,2H),2.44(s,3H),2.22(dd,J＝19.8,10.6Hz,4H),2.01(d,J＝13.3Hz,2H),1.72(s,2H). The purified product (30 mg, 0.06 mmol) was dissolved in methanol (3 mL), and 0.05 mL of 4 M hydrochloric acid-methanol solution was added. After stirring for 3 hours, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 12. MS m/z (ESI): 527.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.00(s,1H),11.70(s,1H),9.94(s,1H),8.75(s,1H),7.94-7.85(m,3H),7.67-7.59(m,3H),6.70(s,1H),5.59(s,1 H), 5.46 (s, 1H), 5.29 (s, 1H), 4.77 (s, 2H), 4.29 (s, 2H), 3.52 (d, J = 5.3Hz, 2H), 3.12 (s, 4H), 2.60 (s, 4H), 2.21 (s, 3H).

实施例13：化合物13的制备
Example 13: Preparation of Compound 13

步骤1：向500mL的单口瓶中加入化合物4-6(4g,18.5mmol)的乙腈(40mL)溶液，在70℃下依次加入CuI(0.7g,3.70mmol)，2-氟磺酰基二氟乙酸(6.59g,36.99mmol)和无水硫酸钠(1g,33.00mmol)，然后维持70℃下搅拌1.5小时，通过LCMS检测反应完全。待反应液降至室温后，缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[流动相梯度：0％～20％乙酸乙酯/石油醚]纯化，得到化合物13-1。MS m/z(ESI)：284.0[M+18]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.81(d,J＝8Hz,2H),7.36(q,J＝8Hz,2H),6.15(t,J＝76Hz,1H),4.23-4.20(m,2H),4.04-4.01(m,2H),2.46(s,3H)。Step 1: Add a 40 mL solution of acetonitrile (4 g, 18.5 mmol) of compound 4-6 to a 500 mL single-necked flask. Then, sequentially add CuI (0.7 g, 3.70 mmol), 2-fluorosulfonyl difluoroacetic acid (6.59 g, 36.99 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C. Maintain the mixture at 70 °C and stir for 1.5 hours. Detect the reaction as complete by LC-MS. After the reaction mixture cools to room temperature, quench it slowly with ice water. Extract three times with ethyl acetate (3 × 40 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product using a silica gel column [mobile phase gradient: 0%–20% ethyl acetate/petroleum ether] to obtain compound 13-1. MS m/z (ESI): 284.0 [M+18] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.81 (d, J = 8Hz, 2H), 7.36 (q, J = 8Hz, 2H), 6.15 (t, J = 76Hz, 1H), 4.23-4.20 (m, 2H), 4.04-4.01 (m, 2H), 2.46 (s, 3H).

步骤2：在0℃条件下向100mL的单口瓶中加入化合物13-1(1690.71mg,6.35mmol)和化合物1-7(1600mg,5.29mmol)溶于N,N-二甲基甲酰胺(20mL)的溶液，然后缓慢加入N,N-二异丙基乙胺(4.62mL,26.46mmol)，于60℃下搅拌10小时，通过LCMS检测反应完成。反应液在室温下缓慢加入水中淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[流动相梯度：0％-40％乙酸乙酯/石油醚]纯化得到化合物13-2。MS m/z(ESI)：397.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.90–7.81(m,2H),7.50–7.43(m,2H),7.38(s,1H),6.97(s,1H),6.64(m,1H),4.29(q,J＝7.1Hz,2H),3.83(t,J＝6.0Hz,2H),3.32(s,2H),3.02–2.83(m,2H),2.48(d,J＝5.4Hz,2H),1.97–1.67(m,6H),1.30(t,J＝7.1Hz,3H)。Step 2: Compound 13-1 (1690.71 mg, 6.35 mmol) and compound 1-7 (1600 mg, 5.29 mmol) dissolved in N,N-dimethylformamide (20 mL) were added to a 100 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (4.62 mL, 26.46 mmol) was slowly added, and the mixture was stirred at 60 °C for 10 hours. The reaction was monitored by LC-MS to confirm completion. The reaction solution was quenched slowly with water at room temperature, extracted three times with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0%-40% ethyl acetate/petroleum ether] to obtain compound 13-2. MS m/z (ESI): 397.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.90–7.81(m,2H),7.50–7.43(m,2H),7.38(s,1H),6.97(s,1H),6.64(m,1H),4.29(q,J＝7.1Hz,2H),3.83(t, J＝6.0Hz,2H),3.32(s,2H),3.02–2.83(m,2H),2.48(d,J＝5.4Hz,2H),1.97–1.67(m,6H),1.30(t,J＝7.1Hz,3H).

步骤3：在0℃条件下向100mL的单口瓶中加入化合物13-2(400mg,1.01mmol)溶于乙腈(10mL)和水(10mL)的混合溶液,然后再缓慢加入[双(三氟乙酰氧基)碘]苯(871.90mg,2.02mmol)，于室温下反应16小时，通过LCMS检测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，将母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-60％乙酸乙酯/石油醚)纯化得到化合物13-3。MS m/z(ESI)：369.1[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.92–7.83(m,2H),7.56(d,J＝8.1Hz,2H),6.69(m,1H),4.29(q,J＝7.1Hz,2H),3.91(d,J＝7.6Hz,2H),3.31(s,2H),2.59(s,2H),2.27(s,2H),2.09(d,J＝12.8Hz,2H),1.77(m,4H),1.31(t,J＝7.1Hz,3H)。Step 3: Compound 13-2 (400 mg, 1.01 mmol) dissolved in a mixture of acetonitrile (10 mL) and water (10 mL) was added to a 100 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (871.90 mg, 2.02 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LC-MS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-60% ethyl acetate/petroleum ether) to obtain compound 13-3. MS m/z (ESI): 369.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.92–7.83(m,2H),7.56(d,J＝8.1Hz,2H),6.69(m,1H),4.29(q,J＝7.1Hz,2H),3.91(d,J＝7.6Hz,2H ), 3.31 (s, 2H), 2.59 (s, 2H), 2.27 (s, 2H), 2.09 (d, J = 12.8Hz, 2H), 1.77 (m, 4H), 1.31 (t, J = 7.1Hz, 3H).

步骤4：将化合物13-3(170mg,0.46mmol)溶于甲醇(5mL)中，依次加入化合物1-14(200mg,0.69mmol)和3滴醋酸，搅拌0.5h后加入氰基硼氢化钠(86.99mg,1.38mmol)，室温下搅拌过夜，通过LCMS监测反应完全。反应液缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[流动相梯度：0％-20％乙酸乙酯/石油醚梯度]纯化得到化合物13-4。MS m/z(ESI)：642.2[M+H]⁺。Step 4: Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), followed by the addition of compound 1-14 (200 mg, 0.69 mmol) and 3 drops of acetic acid. After stirring for 0.5 h, sodium cyanoborohydride (86.99 mg, 1.38 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. The reaction solution was quenched slowly with ice water, and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0%-20% ethyl acetate/petroleum ether gradient] to obtain compound 13-4. MS m/z (ESI): 642.2 [M+H] ⁺ .

步骤5：将化合物13-4(200mg,0.31mmol)溶于甲醇(7mL)，水(2mL)的混合溶剂中，加入氢氧化锂(523.06mg,12.47mmol)，升温60℃反应1小时，通过LCMS监测反应完全。反应液冷却至室温，然后缓慢滴加稀HCl(1.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：514.1[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.51(brs,1H),10.81(s,1H),7.93(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.21(t,J＝2.8Hz,1H),6.85-6.47(m,2H),5.91(dd,J＝3.1,1.9Hz,1H),3.86(t,J＝6.0Hz,2H),3.61(s,3H),3.41(s,2H),3.32(s,2H),2.56(d,J＝6.0Hz,2H),2.40(s,3H),2.30-2.11(m,4H),2.02(d,J＝12.9Hz,2H),1.77(brs,2H),1.52(brs,1H)。将纯化产物(50mg,0.10mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.18mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物13。MS m/z(ESI)：514.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.86(brs,1H),9.80(brs,1H),8.00(d,J＝7.8Hz,2H),7.61(d,J＝7.9Hz,2H),7.23(s,1H),6.96-6.56(m,2H),5.98-5.87(m,1H),4.19-4.36(m,3H),4.09(s,2H),3.37-3.48(m,2H),3.25-3.34(m,2H),2.75-2.54(m,7H),2.41(s,3H),1.94-2.11(m,2H)。Step 5: Compound 13-4 (200 mg, 0.31 mmol) was dissolved in a mixed solvent of methanol (7 mL) and water (2 mL). Lithium hydroxide (523.06 mg, 12.47 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and then dilute HCl ( _1.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 514.1 [M+H] ^⁺ . ^¹H NMR (400 MHz, DMSO-d₆ ₎ )δ12.51(brs,1H),10.81(s,1H),7.93(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7 .21(t,J＝2.8Hz,1H),6.85-6.47(m,2H),5.91(dd,J＝3.1,1.9Hz,1H),3.86(t,J＝ 6.0Hz,2H),3.61(s,3H),3.41(s,2H),3.32(s,2H),2.56(d,J＝6.0Hz,2H),2.40( s,3H),2.30-2.11(m,4H),2.02(d,J=12.9Hz,2H),1.77(brs,2H),1.52(brs,1H). The purified product (50 mg, 0.10 mmol) was dissolved in methanol (3 mL), and 0.18 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 13. MS m/z (ESI): 514.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.86(brs,1H),9.80(brs,1H),8.00(d,J＝7.8Hz,2H),7.61(d,J＝7.9Hz,2H),7.23(s,1H),6.96-6.56(m,2H),5.98-5.87(m, 1H),4.19-4.36(m,3H),4.09(s,2H),3.37-3.48(m,2H),3.25-3.34(m,2H),2.75-2.54(m,7H),2.41(s,3H),1.94-2.11(m,2H).

实施例14：化合物14的制备
Example 14: Preparation of Compound 14

步骤1：将化合物13-3(170mg,0.46mmol)溶于甲醇(5mL)中，依次加入化合物3-9(189.18mg,0.69mmol)和3滴醋酸，搅拌0.5h后加入氰基硼氢化钠(86.99mg,1.38mmol)，室温下搅拌过夜，通过LCMS监测反应完全。反应液缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[流动相梯度：0％-20％乙酸乙酯/石油醚梯度]纯化得到化合物14-1。MS m/z(ESI)：626.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(s,2H),7.57(d,J＝7.9Hz,2H),7.44(d,J＝3.7Hz,1H),6.83(s,1H),5.86(s,1H),4.34(q,J＝7.1Hz,2H),3.84(s,2H),3.40(s,2H),3.28(d,J＝10.0Hz,2H),2.41(s,3H),2.23(d,J＝24.2Hz,4H),2.03(s,3H),1.96(s,2H),1.81(s,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H)。Step 1: Compound 13-3 (170 mg, 0.46 mmol) was dissolved in methanol (5 mL), followed by the addition of compound 3-9 (189.18 mg, 0.69 mmol) and 3 drops of acetic acid. After stirring for 0.5 h, sodium cyanoborohydride (86.99 mg, 1.38 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction was monitored for completeness by LCMS. The reaction solution was quenched slowly with ice water, and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0%-20% ethyl acetate/petroleum ether gradient] to obtain compound 14-1. MS m/z (ESI): 626.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.95(s,2H),7.57(d,J＝7.9Hz,2H),7.44(d,J＝3.7Hz,1H),6.83(s,1H),5.86(s,1H),4.34(q,J＝7.1Hz,2H),3.84(s,2H),3.40(s,2H), 3.28(d,J＝10.0Hz,2H),2.41(s,3H),2.23(d,J＝24.2Hz,4H),2.03(s,3H),1.96(s,2H),1.81(s,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H).

步骤2：将化合物14-1(180mg,0.29mmol)溶于四氢呋喃(3mL)、甲醇(3mL)和水(3mL)的混合溶剂中，加入氢氧化锂(482.79mg,11.51mmol)，升温60℃反应1小时，通过LCMS监测反应完全。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值至5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号:Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：498.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.79(d,J＝2.7Hz,1H),7.88(d,J＝8.2Hz,2H),7.43(d,J＝8.4Hz,2H),7.10(t,J＝2.8Hz,1H),6.65(s,3H),6.60(s,1H),5.66(dd,J＝3.1,1.9Hz,1H),3.85(t,J＝6.0Hz,2H),3.44(s,2H),2.55(t,J＝6.0Hz,2H),2.34(s,3H),2.28-2.19(m,4H),2.08-1.97(m,5H),1.84-1.77(m,2H),1.16(s,1H)。将纯化产物(51mg,0.10mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.18mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物14。MS m/z(ESI)：498.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),10.86(s,1H),9.87(s,1H),7.99(d,J＝8.3Hz,2H),7.59(d,J＝8.4Hz,2H),7.31-7.05(m,2H),6.53(s,1H),5.71(dd,J＝3.1,1.9Hz,1H),4.27(t,J＝5.1Hz,2H),4.11(s,2H),3.46(d,J＝4.9Hz,2H),3.31(d,J＝5.4Hz,2H),2.71(d,J＝14.7Hz,2H),2.58(d,J＝8.3Hz,2H),2.46(s,1H),2.35(s,3H),2.20–1.98(m,5H),1.85(s,1H)。Step 2: Compound 14-1 (180 mg, 0.29 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (482.79 mg, 11.51 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 _× 250 mm column; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 498.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(d,J＝2.7Hz,1H),7.88(d,J＝8.2Hz,2H),7.43(d,J＝8.4Hz,2H),7.10(t,J＝2.8Hz,1H),6.65(s,3H),6.60(s,1H),5.66(dd,J＝3.1,1.9Hz,1 H),3.85(t,J＝6.0Hz,2H),3.44(s,2H),2.55(t,J＝6.0Hz,2H),2.34(s,3H ),2.28-2.19(m,4H),2.08-1.97(m,5H),1.84-1.77(m,2H),1.16(s,1H). The purified product (51 mg, 0.10 mmol) was dissolved in methanol (3 mL), and 0.18 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature, and then 5 mL of deionized water was added. After sonication and homogenization, the mixture was lyophilized to obtain compound 14. MS m/z (ESI): 498.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.95 (s, 1H), 10.86 (s, 1H), 9.87 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.31–7.05 (m, 2H), 6.53 (s, 1H), 5.71 (dd, J = 3.1, 1.9 Hz, 1H), 4.27 (t, J = 5.1 Hz, 2H),4.11(s,2H),3.46(d,J＝4.9Hz,2H),3.31(d,J＝5.4Hz,2H),2.71(d,J＝14.7Hz,2 H), 2.58 (d, J = 8.3Hz, 2H), 2.46 (s, 1H), 2.35 (s, 3H), 2.20–1.98 (m, 5H), 1.85 (s, 1H).

实施例15：化合物15的制备
Example 15: Preparation of Compound 15

步骤1：向500mL的单口瓶中加入化合物15-1(8.5g,111.71mmol)的DCM(200mL)溶液，在0℃下再依次加入对甲苯磺酰氯(21.30g,111.71mmol)和三乙胺(30.97mL,223.42mmol)，室温下反应16小时，通过LCMS检测反应完成。反应液中加入饱和碳酸氢钠溶液淬灭，用DCM萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物15-2。MS m/z(ESI)：231.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.79(d,J＝8.4Hz,2H),7.48(d,J＝8.2Hz,2H),4.99(s,1H),3.86-3.73(m,3H),2.43(s,3H),0.99(d,J＝6.1Hz,3H)。Step 1: Add a 200 mL solution of DCM containing 8.5 g (111.71 mmol) of compound 15-1 to a 500 mL single-necked flask. Then, add p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (30.97 mL, 223.42 mmol) sequentially at 0 °C. React at room temperature for 16 hours, and the reaction is monitored by LCMS to confirm completion. Quench the reaction mixture with saturated sodium bicarbonate solution. Extract three times with DCM (3 × 200 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product using a silica gel column (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 15-2. MS m/z (ESI): 231.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.99 (s, 1H), 3.86-3.73 (m, 3H), 2.43 (s, 3H), 0.99 (d, J = 6.1 Hz, 3H).

步骤2：向500mL的单口瓶中加入化合物15-2(14g,60.80mmol)的乙腈(140mL)溶液，在70℃下依次加入CuI(2.32g,12.16mmol)，2-氟磺酰基二氟乙酸(21.65g,121.59mmol)和无水硫酸钠(1g,33.00mmol)，然后继续在70℃下搅拌1.5小时，通过LCMS检测反应完成。待反应液降至室温后，缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物15-3。MS m/z(ESI)：281.1[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.80(d,J＝8.4Hz,2H),7.49(d,J＝7.8Hz,2H),6.65(t,J＝72Hz,1H),4.46-4.39(m,1H),4.12-4.07(m,1H),4.03-3.97(m,1H),2.43(s,3H),1.15(d,J＝6.5Hz,3H)。Step 2: Add a 140 mL solution of acetonitrile (14 g, 60.80 mmol) of compound 15-2 to a 500 mL single-necked flask. Then, sequentially add CuI (2.32 g, 12.16 mmol), 2-fluorosulfonyl difluoroacetic acid (21.65 g, 121.59 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) at 70 °C. Continue stirring at 70 °C for 1.5 hours. Detect the reaction as complete by LCMS. After the reaction solution cools to room temperature, quench with ice water. Extract three times with ethyl acetate (3 × 200 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 15-3. MS m/z (ESI): 281.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.80(d,J＝8.4Hz,2H),7.49(d,J＝7.8Hz,2H),6.65(t,J＝72Hz,1H),4.46-4.39( m,1H),4.12-4.07(m,1H),4.03-3.97(m,1H),2.43(s,3H),1.15(d,J=6.5Hz,3H).

步骤3：在室温下向500mL的单口瓶中加入化合物1-7(5.24g,17.34mmol)和化合物15-3(4.63g,16.52mmol)溶于N,N-二甲基甲酰胺(200mL)的溶液，然后缓慢加入N,N-二异丙基乙胺(14.43mL,82.59mmol)，于80℃下反应16小时，通过LCMS检测反应完成。待反应液降至室温后，缓慢加入水中淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物15-4。MS m/z(ESI)：411.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.5Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.97(s,1H),6.90-6.50(s,1H),4.29(q,J＝7.1Hz,2H),4.21-4.13(m,1H),3.34(s,2H),2.93(d,J＝13.4Hz,2H),2.42-2.35(m,1H),2.32-2.25(m,1H),1.90-1.66(m,6H),1.30(t,J＝7.1Hz,3H),1.17(d,J＝6.3Hz,3H)。Step 3: At room temperature, add a solution of compound 1-7 (5.24 g, 17.34 mmol) and compound 15-3 (4.63 g, 16.52 mmol) dissolved in N,N-dimethylformamide (200 mL) to a 500 mL single-necked flask. Then, slowly add N,N-diisopropylethylamine (14.43 mL, 82.59 mmol) and react at 80 °C for 16 hours. The reaction was monitored by LCMS to confirm completion. After the reaction solution cooled to room temperature, it was quenched slowly with water. The mixture was extracted three times with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 15-4. MS m/z (ESI): 411.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.86(d,J＝8.5Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.97(s,1H),6.90-6.50(s,1H),4.29(q,J＝7.1Hz,2H),4.21-4.13(m,1H),3. 34(s,2H),2.93(d,J＝13.4Hz,2H),2.42-2.35(m,1H),2.32-2.25(m,1H),1.90-1.66(m,6H),1.30(t,J＝7.1Hz,3H),1.17(d,J＝6.3Hz,3H).

步骤4：在室温下向100mL的单口瓶中加入化合物15-4(3g,7.31mmol)溶于乙腈(80mL)和水(40mL)的混合溶液，然后缓慢加入[双(三氟乙酰氧基)碘]苯(6.32g,14.62mmol)，于室温下反应2小时，通过LCMS检测反应完成。向反应液加入饱和碳酸氢钠溶液进行淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物15-5。MS m/z(ESI)：383.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.87(d,J＝8.6Hz,2H),7.54(d,J＝8.5Hz,2H),6.97-6.50(s,1H),4.29(d,J＝7.1Hz,2H),4.24-4.18(m,1H),3.22(d,J＝8.2Hz,2H),2.49-2.44(m,1H),2.40-2.35(m,1H),2.24(t,J＝6.5Hz,2H),2.08(d,J＝6.4Hz,2H),1.79(d,J＝6.5Hz,4H),1.71-1.63(m,2H),1.31(s,3H),1.23(d,J＝6.2Hz,3H)。Step 4: At room temperature, a mixture of compound 15-4 (3 g, 7.31 mmol) dissolved in acetonitrile (80 mL) and water (40 mL) was added to a 100 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (6.32 g, 14.62 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The reaction was detected by LCMS. The reaction solution was quenched with saturated sodium bicarbonate solution, and the precipitated solid was filtered off. The mother liquor was extracted three times with dichloromethane (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 15-5. MS m/z (ESI): 383.2 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ7.87(d,J＝8.6Hz,2H),7.54(d,J＝8.5Hz,2H),6.97-6.50(s,1H),4.29( d,J＝7.1Hz,2H),4.24-4.18(m,1H),3.22(d,J＝8.2Hz,2H),2.49-2.44(m, 1H),2.40-2.35(m,1H),2.24(t,J＝6.5Hz,2H),2.08(d,J＝6.4Hz,2H),1.7 9(d,J＝6.5Hz,4H),1.71-1.63(m,2H),1.31(s,3H),1.23(d,J＝6.2Hz,3H).

步骤5：将化合物15-5(300mg,0.75mmol)溶于乙腈(5mL)中，加入化合物3-9(204mg,0.75mmol)和5滴醋酸，室温下搅拌过夜。然后在0℃下加入硼氢化钠(85mg,2.24mmol)和甲醇(3mL)，室温继续反应1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入水中淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％石油醚/乙酸乙酯)纯化，得到化合物15-6。MS m/z(ESI)：640.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.5Hz,2H),7.56(d,J＝8.5Hz,2H),7.43(d,J＝3.8Hz,1H),6.97-6.50(s,1H),6.82(s,1H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.18(s,1H),3.39(d,J＝5.6Hz,2H),3.24(s,2H),2.41(s,3H),2.24(dd,J＝33.6,11.0Hz,5H),2.02(s,3H),1.99(s,3H),1.79(s,2H),1.56(s,9H),1.44(d,J＝7.4Hz,1H),1.34(t,J＝7.1Hz,3H),1.18(d,J＝4.7Hz,3H)。Step 5: Compound 15-5 (300 mg, 0.75 mmol) was dissolved in acetonitrile (5 mL), compound 3-9 (204 mg, 0.75 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (85 mg, 2.24 mmol) and methanol (3 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was quenched slowly with water at room temperature, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% petroleum ether/ethyl acetate) to give compound 15-6. MS m/z (ESI): 640.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6) )δ7.95(d,J＝8.5Hz,2H),7.56(d,J＝8.5Hz,2H),7.43(d,J＝3.8Hz,1H),6.97-6.50(s,1H), 6.82(s,1H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.18(s,1H),3.39(d,J＝5.6Hz,2 H),3.24(s,2H),2.41(s,3H),2.24(dd,J＝33.6,11.0Hz,5H),2.02(s,3H),1.99(s,3H),1.7 9 (s, 2H), 1.56 (s, 9H), 1.44 (d, J = 7.4Hz, 1H), 1.34 (t, J = 7.1Hz, 3H), 1.18 (d, J = 4.7Hz, 3H).

步骤6：将化合物15-6(300mg,0.47mmol)溶于四氢呋喃(4mL)、甲醇(4mL)和水(4mL)的混合溶剂中，加入一水合氢氧化锂(787mg,18.76mmol)，升温至60℃反应2小时，通过LCMS监测反应完成。待反应液降至室温后，使用2M稀盐酸调pH在5-7之间，大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：512.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.75(s,1H),10.80(t,J＝2.2Hz,1H),7.93(d,J＝8.4Hz,2H),7.52(d,J＝8.3Hz,2H),7.10(t,J＝2.8Hz,1H),6.91-6.51(m,2H),5.67-5.61(m,1H),4.19(q,J＝6.2Hz,1H),3.44(s,2H),3.26(s,2H),2.48-2.42(m,1H),2.37(d,J＝5.0Hz,1H),2.34(s,3H),2.31-2.21(m,4H),2.04(s,3H),2.03-1.97(m,2H),1.80(d,J＝8.6Hz,2H),1.18(d,J＝6.2Hz,3H)。将纯化产物(120mg,0.23mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.17mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物15。MS m/z(ESI)：512.3[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.59(s,1H),7.99(d,J＝8.3Hz,2H),7.59(d,J＝8.1Hz,2H),7.13(t,J＝2.8Hz,1H),6.83(dd,J＝77.2,73.6Hz,1H),6.63(s,1H),5.68(dd,J＝3.1,1.9Hz,1H),4.83(s,1H),4.10(d,J＝11.0Hz,2H),3.46(s,2H),3.21(d,J＝5.0Hz,2H),2.72(t,J＝12.3Hz,2H),2.57(t,J＝14.0Hz,3H),2.44(d,J＝14.8Hz,1H),2.35(s,3H),2.13(dt,J＝21.2,10.0Hz,2H),2.04(s,3H),1.81(s,1H),1.28(d,J＝6.2Hz,3H)。Step 6: Compound 15-6 (300 mg, 0.47 mmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (787 mg, 18.76 mmol) was added, and the mixture was heated to 60 °C and reacted for 2 hours. The reaction was monitored by LCMS to ensure completion. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M dilute hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 512.3 [M+H] ^⁺ . ^¹H NMR (400 MHz, DMSO- _d⁻¹) )δ12.75(s,1H),10.80(t,J＝2.2Hz,1H),7.93(d,J＝8.4Hz,2H),7.52(d,J＝8.3Hz,2H), 7.10(t,J＝2.8Hz,1H),6.91-6.51(m,2H),5.67-5.61(m,1H),4.19(q,J＝6.2Hz,1H),3.4 4(s,2H), 3.26(s,2H), 2.48-2.42(m,1H), 2.37(d,J＝5.0Hz,1H), 2.34(s,3H), 2.31-2.21(m,4H), 2.04(s,3H), 2.03-1.97(m,2H), 1.80(d,J＝8.6Hz,2H), 1.18(d,J＝6.2Hz,3H). The purified product (120 mg, 0.23 mmol) was dissolved in methanol (3 mL), and 0.17 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 15. MS m/z (ESI): 512.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.59(s,1H),7.99(d,J＝8.3Hz,2H),7.59(d,J＝8.1Hz,2H),7.13(t,J＝ 2.8Hz,1H),6.83(dd,J＝77.2,73.6Hz,1H),6.63(s,1H),5.68(dd,J＝3.1,1.9Hz,1H),4.83(s,1H),4.10(d,J ＝11.0Hz,2H),3.46(s,2H),3.21(d,J＝5.0Hz,2H),2.72(t,J＝12.3Hz,2H),2.57(t,J＝14.0Hz,3H),2.44(d,J ＝14.8Hz,1H),2.35(s,3H),2.13(dt,J＝21.2,10.0Hz,2H),2.04(s,3H),1.81(s,1H),1.28(d,J＝6.2Hz,3H).

实施例16：化合物16的制备
Example 16: Preparation of Compound 16

步骤1：向500mL的单口瓶中加入化合物16-1(8.5g,111.71mmol)的二氯甲烷(200mL)溶液，在0℃的条件下再依次加入对甲苯磺酰氯(21.30g,111.71mmol)和三乙胺(15.48mL,111.71mmol)，反应在室温下反应16小时，通过LCMS检测反应完成。反应液中加入饱和碳酸氢钠溶液淬灭，用DCM萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物16-2。MS m/z(ESI)：231.0[M+H]⁺。¹HNMR(400MHz,DMSO-d6)δ7.83-7.76(m,2H),7.48(d,J＝8.0Hz,2H),4.98(d,J＝4.3Hz,1H),3.84-3.73(m,3H),2.42(s,3H),0.98(d,J＝5.7Hz,3H)。Step 1: Add a solution of compound 16-1 (8.5 g, 111.71 mmol) in dichloromethane (200 mL) to a 500 mL single-necked flask. Then, add p-toluenesulfonyl chloride (21.30 g, 111.71 mmol) and triethylamine (15.48 mL, 111.71 mmol) sequentially at 0 °C. The reaction was allowed to proceed for 16 hours at room temperature, and the reaction was monitored by LC-MS. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted three times with DCM (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 16-2. MS m/z (ESI): 231.0 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d6) δ7.83-7.76 (m, 2H), 7.48 (d, J = 8.0Hz, 2H), 4.98 (d, J = 4.3Hz, 1H), 3.84-3.73 (m, 3H), 2.42 (s, 3H), 0.98 (d, J = 5.7Hz, 3H).

步骤2：向25mL的单口瓶中加入化合物16-2(10g,33.00mmol)的乙腈(200mL)溶液，在70℃下依次加入碘化亚铜(1.26g,6.60mmol)，2-氟磺酰基二氟乙酸(11.75g,66.01mmol)和无水硫酸钠(1g,33.00mmol)，然后继续在70℃下搅拌1.5小时，通过LCMS检测反应完成。待反应液降至室温后，缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％乙酸乙酯/石油醚)纯化，得到化合物16-3。MS m/z(ESI)：281.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.83-7.76(m,2H),7.49(d,J＝8.1Hz,2H),6.85-6.44(m,1H),4.42(pd,J＝6.5,2.9Hz,1H),4.09(dd,J＝10.9,3.0Hz,1H),4.03-3.98(m,1H),2.43(s,3H),1.15(d,J＝6.4Hz,3H)。Step 2: Add a 200 mL solution of acetonitrile (10 g, 33.00 mmol) of compound 16-2 to a 25 mL single-necked flask. At 70 °C, add cuprous iodide (1.26 g, 6.60 mmol), 2-fluorosulfonyl difluoroacetic acid (11.75 g, 66.01 mmol), and anhydrous sodium sulfate (1 g, 33.00 mmol) sequentially. Stir at 70 °C for 1.5 hours. Detect the reaction as complete by LCMS. After the reaction solution cools to room temperature, quench with ice water slowly. Extract three times with ethyl acetate (3 × 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 16-3. MS m/z (ESI): 281.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ7.83-7.76(m,2H),7.49(d,J＝8.1Hz,2H),6.85-6.44(m,1H),4.42(pd,J＝6. 5, 2.9Hz, 1H), 4.09 (dd, J = 10.9, 3.0Hz, 1H), 4.03-3.98 (m, 1H), 2.43 (s, 3H), 1.15 (d, J = 6.4Hz, 3H).

步骤3：在0℃条件下向250mL的单口瓶中加入化合物1-7(6.47g,21.41mmol)和化合物16-3(6g,21.41mmol)溶于N,N-二甲基甲酰胺(140mL)的溶液，然后缓慢加入N,N-二异丙基乙胺(18.69mL,107.03mmol)，于100℃下反应3小时，通过LCMS检测反应完成。待反应液降至室温后，缓慢加入水中淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物16-4。MS m/z(ESI)：411.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.90-7.84(m,2H),7.48-7.43(m,2H),7.39(s,1H),6.99(s,1H),6.71(dd,J＝79.0,75.3Hz,1H),4.29(q,J＝7.1Hz,2H),4.15(p,J＝6.3Hz,1H),3.22(s,2H),2.93(d,J＝13.5Hz,2H),2.38(dd,J＝13.3,6.9Hz,1H),2.28(dd,J＝13.3,5.0Hz,1H),1.90-1.78(m,4H),1.77-1.66(m,2H),1.30(t,J＝7.1Hz,3H),1.16(d,J＝6.2Hz,3H)。Step 3: Compound 1-7 (6.47 g, 21.41 mmol) and compound 16-3 (6 g, 21.41 mmol) dissolved in N,N-dimethylformamide (140 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (18.69 mL, 107.03 mmol) was slowly added, and the reaction was carried out at 100 °C for 3 hours. The reaction was monitored by LC-MS to confirm completion. After the reaction solution cooled to room temperature, it was quenched slowly with water. The mixture was extracted three times with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 16-4. MS m/z (ESI): 411.2 [M+H] ⁺ . ¹ H NMR(400MHz,DMSO-d6)δ7.90-7.84(m,2H),7.48-7.43(m,2H),7.39(s,1H),6.99(s,1H ),6.71(dd,J＝79.0,75.3Hz,1H),4.29(q,J＝7.1Hz,2H),4.15(p,J＝6.3Hz,1H),3.22(s ,2H),2.93(d,J＝13.5Hz,2H),2.38(dd,J＝13.3,6.9Hz,1H),2.28(dd,J＝13.3,5.0Hz,1 H), 1.90-1.78 (m, 4H), 1.77-1.66 (m, 2H), 1.30 (t, J = 7.1Hz, 3H), 1.16 (d, J = 6.2Hz, 3H).

步骤4：在0℃环境下向250mL的单口瓶中加入化合物16-4(2.7g,6.58mmol)溶于乙腈(30mL)和水(15mL)的混合溶液,然后缓慢加入[双(三氟乙酰氧基)碘]苯(5.68g,13.16mmol)，于室温下反应1.5小时，通过LCMS检测反应完成。向反应液加入饱和碳酸氢钠溶液进行淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物16-5。MS m/z(ESI)：383.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.91-7.85(m,2H),7.61-7.53(m,2H),6.77(dd,J＝78.7,75.2Hz,1H),4.29(q,J＝7.1Hz,3H),3.32(s,2H),2.44(s,2H),2.25(d,J＝8.2Hz,2H),2.13(dd,J＝14.0,4.0Hz,2H),1.90-1.67(m,4H),1.31(t,J＝7.1Hz,3H),1.22(d,J＝6.3Hz,3H)。Step 4: Compound 16-4 (2.7 g, 6.58 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (5.68 g, 13.16 mmol) was slowly added. The reaction was carried out at room temperature for 1.5 hours, and the reaction was monitored by LCMS to confirm completion. The reaction solution was quenched with saturated sodium bicarbonate solution, and the precipitated solid was filtered off. The mother liquor was extracted three times with dichloromethane (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 16-5. MS m/z (ESI): 383.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.91-7.85(m,2H),7.61-7.53(m,2H),6.77(dd,J＝78.7,75.2Hz,1H),4.29(q,J＝7.1Hz,3H),3.32(s,2H),2.44(s,2H ), 2.25 (d, J = 8.2Hz, 2H), 2.13 (dd, J = 14.0, 4.0Hz, 2H), 1.90-1.67 (m, 4H), 1.31 (t, J = 7.1Hz, 3H), 1.22 (d, J = 6.3Hz, 3H).

步骤5：将化合物16-5(300mg,0.78mmol)溶于乙腈(10mL)中，加入化合物3-9(214.40mg,0.78mmol)和5滴醋酸，室温下搅拌过夜。在0℃下加入硼氢化钠(89.02mg,2.35mmol)，室温继续反应1个小时，通过LCMS监测反应完全。反应液在室温下缓慢加入水中淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％石油醚/乙酸乙酯)纯化，得到化合物16-6。MS m/z(ESI)：640.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.44(d,J＝3.8Hz,1H),6.82(s,1H),6.92-6.49(m,2H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.17(d,J＝6.6Hz,1H),3.39(d,J＝5.8Hz,2H),3.24(s,2H),2.41(s,3H),2.28(d,J＝15.8Hz,4H),2.19(d,J＝7.5Hz,2H),2.02(s,5H),1.79(s,2H),1.56(s,9H),1.34(t,J＝7.1Hz,3H),1.18(d,J＝6.3Hz,3H)。Step 5: Compound 16-5 (300 mg, 0.78 mmol) was dissolved in acetonitrile (10 mL), compound 3-9 (214.40 mg, 0.78 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Sodium borohydride (89.02 mg, 2.35 mmol) was added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completeness by LCMS. The reaction solution was quenched by slow addition of water at room temperature, and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% petroleum ether/ethyl acetate) to give compound 16-6. MS m/z (ESI): 640.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.95(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.44(d,J＝3.8Hz,1H),6.82(s,1H),6.9 2-6.49(m,2H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),4.17(d,J＝6.6Hz,1H),3.39 (d,J＝5.8Hz,2H),3.24(s,2H),2.41(s,3H),2.28(d,J＝15.8Hz,4H),2.19(d,J＝7.5Hz,2 H), 2.02 (s, 5H), 1.79 (s, 2H), 1.56 (s, 9H), 1.34 (t, J = 7.1Hz, 3H), 1.18 (d, J = 6.3Hz, 3H).

步骤6：将化合物16-6(220mg,0.34mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)的混合溶剂中，加入氢氧化锂(577.15mg,13.75mmol)，升温60℃反应2小时，通过LCMS监测反应完成。反应液冷却至室温，在反应液中缓慢滴加稀HCl(2.0M)，调节pH值至到5-7左右，大量固体析出，过滤得到白色固体，粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：512.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.92(d,J＝8.0Hz,2H),7.52(d,J＝8.1Hz,2H),7.09(d,J＝2.9Hz,1H),6.71(m,1H),6.60(s,1H),5.63(s,1H),4.18(q,J＝6.1Hz,1H),3.43(s,2H),3.25(s,2H),2.44(d,J＝6.8Hz,1H),2.36-2.33(m,4H),2.38-2.22(m,4H),2.04-1.98(m,5H),1.80-1.79(s,2H),1.18(d,J＝6.3Hz,3H)。将纯化产物(100mg,0.20mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.15mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物16。MS m/z(ESI)：512.3[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ10.86(s,1H),9.67(s,1H),7.99(d,J＝8.3Hz,2H),7.59(d,J＝8.2Hz,2H),7.13(t,J＝2.8Hz,1H),6.83(dd,J＝77.3,73.6Hz,1H),6.63(s,1H),5.68(dd,J＝3.1,1.9Hz,1H),4.85(s,1H),4.10(d,J＝17.2Hz,2H),3.46(s,2H),3.21(d,J＝5.3Hz,2H),2.71(t,J＝11.4Hz,2H),2.57(t,J＝13.7Hz,3H),2.44(s,1H),2.35(s,3H),2.13(dt,J＝19.7,9.7Hz,2H),2.04(s,3H),1.81(s,1H),1.28(d,J＝6.3Hz,3H)。Step 6: Compound 16-6 (220 mg, 0.34 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (577.15 mg, 13.75 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated out. The solid was filtered to obtain a white solid. The crude product was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm column; mobile phase: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 512.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),7.92(d,J＝8.0Hz,2H),7.52(d,J＝8.1Hz,2H),7.09(d,J＝ 2.9Hz,1H),6.71(m,1H),6.60(s,1H),5.63(s,1H),4.18(q,J＝6.1Hz,1H), 3.43(s,2H),3.25(s,2H),2.44(d,J＝6.8Hz,1H),2.36-2.33(m,4H),2.38- 2.22(m,4H),2.04-1.98(m,5H),1.80-1.79(s,2H),1.18(d,J＝6.3Hz,3H). The purified product (100 mg, 0.20 mmol) was dissolved in methanol (3 mL), and 0.15 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 16. MS m/z (ESI): 512.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.86(s,1H),9.67(s,1H),7.99(d,J＝8.3Hz,2H),7.59(d,J＝8.2Hz,2H),7.13(t,J＝2.8Hz,1H),6 .83(dd,J＝77.3,73.6Hz,1H),6.63(s,1H),5.68(dd,J＝3.1,1.9Hz,1H),4.85(s,1H),4.10(d,J＝17. 2Hz,2H),3.46(s,2H),3.21(d,J＝5.3Hz,2H),2.71(t,J＝11.4Hz,2H),2.57(t,J＝13.7Hz,3H),2.44( s,1H),2.35(s,3H),2.13(dt,J＝19.7,9.7Hz,2H),2.04(s,3H),1.81(s,1H),1.28(d,J＝6.3Hz,3H).

实施例17：化合物17的制备
Example 17: Preparation of Compound 17

步骤1：向500mL的单口瓶中加入化合物17-1(30.7g,259.88mmol)的二氯甲烷(300mL)溶液，在0℃下依次加入2,2,2-三氯乙酰胺苄酯(72.19g,285.87mmol)和三氟甲磺酸(2.3mL,25.99mmol)，于室温下反应2小时，通过LCMS监测反应完全。反应液在室温下缓慢加入碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚梯度)纯化得到化合物17-2。MS m/z(ESI)：209.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.35-7.26(m,5H),4.46(s,2H),3.60(s,3H),3.58-3.54(m,1H),3.51-3.46(m,1H),2.80-2.69(m,1H),1.08(d,J＝7.1Hz,3H)。Step 1: A solution of compound 17-1 (30.7 g, 259.88 mmol) in dichloromethane (300 mL) was added to a 500 mL single-necked flask. 2,2,2-Trichloroacetamide benzyl ester (72.19 g, 285.87 mmol) and trifluoromethanesulfonic acid (2.3 mL, 25.99 mmol) were added sequentially at 0 °C. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched by slow addition of sodium bicarbonate solution at room temperature. The mixture was extracted three times with dichloromethane (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether gradient) to obtain compound 17-2. MS m/z (ESI): 209.2 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ7.35-7.26(m,5H),4.46(s,2H),3.60(s,3H),3.58-3.54(m,1H),3.51-3.46(m,1H),2.80-2.69(m,1H),1.08(d,J＝7.1Hz,3H).

步骤2：向500mL的三口瓶中加入化合物17-2(30g,144.05mmol)的四氢呋喃(300mL)溶液，在0℃下缓慢加入氢化铝锂(6.56g,172.86mmol)，维持0℃下反应1小时，通过LCMS检测反应完成。反应液在冰水浴下缓慢加入稀盐酸(1M)淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-30％乙酸乙酯/石油醚)纯化，得到化合物17-3。MS m/z(ESI)：181.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.39-7.19(m,5H),4.44(s,2H),4.42(t,J＝5.3Hz,1H),3.43-3.35(m,2H),3.31-3.22(m,2H),1.86-1.75(m,1H),0.87(d,J＝6.8Hz,3H)。Step 2: A tetrahydrofuran (300 mL) solution of compound 17-2 (30 g, 144.05 mmol) was added to a 500 mL three-necked flask. Lithium aluminum hydride (6.56 g, 172.86 mmol) was slowly added at 0 °C, and the reaction was maintained at 0 °C for 1 hour. The reaction was detected as complete by LCMS. The reaction solution was quenched by slow addition of dilute hydrochloric acid (1 M) in an ice-water bath. The mixture was extracted three times with ethyl acetate (3 × 200 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-30% ethyl acetate/petroleum ether) to obtain compound 17-3. MS m/z (ESI): 181.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.39-7.19(m,5H),4.44(s,2H),4.42(t,J＝5.3Hz,1H),3.43-3.35(m,2H),3.31-3.22(m,2H),1.86-1.75(m,1H),0.87(d,J＝6.8Hz,3H).

步骤3：向500mL的单口瓶中加入化合物17-3(21.3g,100.44mmol)的二氯甲烷(250mL)溶液，在0℃下缓慢加入戴斯-马丁氧化剂(55.38g,130.58mmol)，恢复室温反应2小时，通过TLC监测反应完全。反应液缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚梯度)纯化得到化合物17-4。¹HNMR(400MHz,DMSO-d₆)δ9.64(d,J＝1.4Hz,1H),7.37-7.28(m,5H),4.48(s,2H),3.70-3.63(m,2H),2.71-2.62(m,1H),1.02(d,J＝7.1Hz,3H)。Step 3: Add a 250 mL solution of dichloromethane containing 21.3 g (100.44 mmol) of compound 17-3 to a 500 mL single-necked flask. Slowly add Dys-Martin oxidant (55.38 g, 130.58 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture slowly with saturated sodium bicarbonate solution. Extract three times with ethyl acetate (3 × 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether gradient) to obtain compound 17-4. ¹ HNMR (400MHz, DMSO-d ₆ ) δ 9.64 (d, J = 1.4 Hz, 1H), 7.37-7.28 (m, 5H), 4.48 (s, 2H), 3.70-3.63 (m, 2H), 2.71-2.62 (m, 1H), 1.02 (d, J = 7.1 Hz, 3H).

步骤4：向500mL的单口瓶中加入化合物17-4(15g,84.16mmol)的二氯甲烷(150mL)溶液，在0℃下缓慢加入二乙胺基三氟化硫(27.13g,168.32mmol)，恢复室温反应2小时，通过TLC监测反应完全。反应液在冰水浴下缓慢加入碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和碳酸氢钠溶液洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物17-5。¹H NMR(400MHz,DMSO-d₆)δ7.40-7.24(m,5H),6.02(td,J＝56.7,3.9Hz,1H),4.49(s,2H),3.49-3.37(m,2H),2.31-2.17(m,1H),0.96(d,J＝7.0Hz,3H)。Step 4: Add a solution of compound 17-4 (15 g, 84.16 mmol) in dichloromethane (150 mL) to a 500 mL single-necked flask. Slowly add diethylaminosulfur trifluoride (27.13 g, 168.32 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture with sodium bicarbonate solution slowly in an ice-water bath. Extract three times with dichloromethane (3 × 100 mL). Wash the combined organic phases with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 17-5. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.40-7.24(m,5H),6.02(td,J＝56.7,3.9Hz,1H),4.49(s,2H),3.49-3.37(m,2H),2.31-2.17(m,1H),0.96(d,J＝7.0Hz,3H).

步骤5：向500mL的单口瓶中加入化合物17-5(4.5g,22.47mmol)的四氢呋喃(80mL)溶液，加入10％钯碳(1g)，置换氢气保护，于室温下反应16小时，通过TLC监测反应完全。反应液直接过滤并干燥，含化合物17-6的滤液直接用于下一步反应。Step 5: Add a tetrahydrofuran (80 mL) solution of compound 17-5 (4.5 g, 22.47 mmol) to a 500 mL single-necked flask, add 10% palladium on carbon (1 g), displace the hydrogen atmosphere, and react at room temperature for 16 hours. Monitor the reaction for completeness by TLC. Filter the reaction solution directly and dry it. The filtrate containing compound 17-6 is used directly for the next step of the reaction.

步骤6：向500mL的单口瓶中加入上一步含化合物17-6的四氢呋喃溶液，在0℃下缓慢加入对甲苯磺酰氯(5.19g,27.25mmol)和三乙胺(4.60g,45.41mmol)，恢复室温反应16小时，通过LCMS监测反应完全。反应液加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物17-7。MS m/z(ESI)：265.0[M+H]⁺。Step 6: Add the tetrahydrofuran solution containing compound 17-6 from the previous step to a 500 mL single-necked flask. Slowly add p-toluenesulfonyl chloride (5.19 g, 27.25 mmol) and triethylamine (4.60 g, 45.41 mmol) at 0 °C. Allow the mixture to return to room temperature and react for 16 hours. Monitor the reaction for completeness using LC-MS. Quench the reaction mixture with ice water, extract three times with dichloromethane (3 × 50 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product using a silica gel column (mobile phase gradient: 0%–10% ethyl acetate/petroleum ether) to obtain compound 17-7. MS m/z (ESI): 265.0 [M+H] ⁺ .

步骤7：在0℃条件下向250mL的单口瓶中加入化合物17-7(1.3g,4.92mmol)和化合物1-7(1.49g,4.92mmol)溶于N,N-二甲基甲酰胺(50mL)的溶液,然后缓慢加入N,N-二异丙基乙胺(0.64g,4.92mmol)，于室温下反应32小时后，通过LCMS检测反应完成。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[流动相梯度：0％-50％乙酸乙酯/石油醚]纯化得到化合物17-8。MS m/z(ESI)：395.2[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.96(s,1H),6.02(td,J＝57.1,2.8Hz,1H),4.29(q,J＝7.1Hz,2H),3.17(d,J＝17.1Hz,2H),2.93(d,J＝13.4Hz,2H),2.33-2.25(m,1H),2.22-2.14(m,1H),2.11-1.95(m,1H),1.90-1.69(m,6H),1.30(t,J＝7.1Hz,3H),0.90(d,J＝6.8Hz,3H)。Step 7: Compound 17-7 (1.3 g, 4.92 mmol) and compound 1-7 (1.49 g, 4.92 mmol) dissolved in N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (0.64 g, 4.92 mmol) was slowly added. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was confirmed by LC-MS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [mobile phase gradient: 0%-50% ethyl acetate/petroleum ether] to obtain compound 17-8. MS m/z (ESI): 395.2 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ7.86(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.96(s,1H), 6.02(td,J＝57.1,2.8Hz,1H),4.29(q,J＝7.1Hz,2H),3.17(d,J＝17.1Hz,2H ),2.93(d,J＝13.4Hz,2H),2.33-2.25(m,1H),2.22-2.14(m,1H),2.11-1.9 5(m,1H),1.90-1.69(m,6H),1.30(t,J＝7.1Hz,3H),0.90(d,J＝6.8Hz,3H).

步骤8：在0℃条件下向250mL的单口瓶中加入化合物17-8(1.4g,3.55mmol)溶于乙腈(30mL)和水(15mL)的混合溶液，然后缓慢加入[双(三氟乙酰氧基)碘]苯(3.07g,7.10mmol)，于室温下反应16小时，通过LCMS检测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，将母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-60％乙酸乙酯/石油醚)纯化得到化合物17-9。MS m/z(ESI)：367.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝8.6Hz,2H),7.56(d,J＝8.6Hz,2H),6.12(td,J＝57.1,2.9Hz,1H),4.29(q,J＝7.1Hz,2H),3.19(d,J＝22.7Hz,2H),2.40-2.33(m,1H),2.29-2.21(m,3H),2.11-2.02(m,3H),1.86-1.74(m,4H),1.68(d,J＝14.2Hz,2H),1.30(t,J＝7.1Hz,3H),0.96(d,J＝6.8Hz,3H)。Step 8: Compound 17-8 (1.4 g, 3.55 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodide]benzene (3.07 g, 7.10 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LC-MS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-60% ethyl acetate/petroleum ether) to obtain compound 17-9. MS m/z (ESI): 367.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.87(d,J＝8.6Hz,2H),7.56(d,J＝8.6Hz,2H),6.12(td,J＝57.1,2.9Hz,1H),4.29(q,J＝7.1Hz,2H),3.19(d,J＝22.7Hz,2H),2.40-2.33 (m,1H),2.29-2.21(m,3H),2.11-2.02(m,3H),1.86-1.74(m,4H),1.68(d,J＝14.2Hz,2H),1.30(t,J＝7.1Hz,3H),0.96(d,J＝6.8Hz,3H).

步骤9：将化合物17-9(250mg,0.68mmol)溶于乙腈(8mL)中，加入化合物3-9(187mg,0.68mmol)和5滴醋酸，室温下搅拌过夜。在0℃下加入硼氢化钠(77mg,2.05mmol)和甲醇(4mL)，室温继续反应1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％-20％乙酸乙酯/石油醚梯度)得到化合物17-10。MS m/z(ESI)：624.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.94(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.43(d,J＝3.7Hz,1H),6.82(s,1H),6.02(t,J＝57.1Hz,1H),5.84(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.39(d,J＝5.9Hz,2H),3.20(d,J＝19.1Hz,2H),2.41(s,3H),2.39-2.16(m,6H),2.02(s,3H),2.01-1.94(m,2H),1.81(s,2H),1.56(s,9H),1.43(s,1H),1.34(t,J＝7.1Hz,3H),0.91(d,J＝6.8Hz,3H)。Step 9: Compound 17-9 (250 mg, 0.68 mmol) was dissolved in acetonitrile (8 mL), compound 3-9 (187 mg, 0.68 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Sodium borohydride (77 mg, 2.05 mmol) and methanol (4 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 × 50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was passed through a silica gel column (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether gradient) to give compound 17-10. MS m/z (ESI): 624.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6) )δ7.94(d,J＝8.1Hz,2H),7.56(d,J＝8.2Hz,2H),7.43(d,J＝3.7Hz,1H),6.82(s,1H),6.0 2(t,J＝57.1Hz,1H),5.84(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.39(d,J＝5.9Hz,2H) ,3.20(d,J＝19.1Hz,2H),2.41(s,3H),2.39-2.16(m,6H),2.02(s,3H),2.01-1.94(m,2H ), 1.81 (s, 2H), 1.56 (s, 9H), 1.43 (s, 1H), 1.34 (t, J = 7.1Hz, 3H), 0.91 (d, J = 6.8Hz, 3H).

步骤10：将化合物17-10(200mg,0.32mmol)溶于甲醇(4mL)、水(4mL)和四氢呋喃(4mL)的混合溶剂中，加入一水合氢氧化锂(538mg,12.82mmol)，升温60℃反应2小时，通过LCMS监测反应完成。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：496.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.93(s,1H),10.79(s,1H),7.91(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),6.03(t,J＝56.4Hz,1H),5.67-5.60(m,1H),3.44(s,2H),3.20(d,J＝18.9Hz,2H),2.38-2.31(m,4H),2.30-2.19(m,5H),2.10-1.95(m,6H),1.81(s,2H),1.24(s,1H),0.91(d,J＝6.8Hz,3H)。将纯化产物(95mg,0.19mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.16mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物17。MS m/z(ESI)：496.3[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ12.94(s,1H),10.87(s,1H),9.58(s,1H),7.99(d,J＝8.2Hz,2H),7.59(d,J＝8.5Hz,2H),7.42–7.03(m,1H),6.63(s,1H),6.21(t,J＝56.0Hz,1H),5.70(dd,J＝3.1,1.9Hz,1H),4.09(d,J＝13.6Hz,2H),3.45(s,2H),3.16–3.08(m,1H),2.96–2.87(m,1H),2.73–2.51(m,6H),2.35(s,3H),2.12(d,J＝8.4Hz,2H),2.05(s,3H),1.85(s,1H),1.10(d,J＝6.9Hz,3H)。Step 10: Compound 17-10 (200 mg, 0.32 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide monohydrate (538 mg, 12.82 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O B: _ACN ; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 496.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.93(s,1H),10.79(s,1H),7.91(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,2H ),7.10(t,J＝2.8Hz,1H),6.60(s,1H),6.03(t,J＝56.4Hz,1H),5.67-5.60(m ,1H),3.44(s,2H),3.20(d,J＝18.9Hz,2H),2.38-2.31(m,4H),2.30-2.19( m,5H),2.10-1.95(m,6H),1.81(s,2H),1.24(s,1H),0.91(d,J＝6.8Hz,3H). The purified product (95 mg, 0.19 mmol) was dissolved in methanol (3 mL), and 0.16 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 17. MS m/z (ESI): 496.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.94(s,1H),10.87(s,1H),9.58(s,1H),7.99(d,J＝8.2Hz,2H),7.59(d,J＝8.5Hz,2H) ,7.42–7.03(m,1H),6.63(s,1H),6.21(t,J＝56.0Hz,1H),5.70(dd,J＝3.1,1.9Hz,1H),4. 09(d,J＝13.6Hz,2H),3.45(s,2H),3.16–3.08(m,1H),2.96–2.87(m,1H),2.73–2.51(m,6 H), 2.35 (s, 3H), 2.12 (d, J = 8.4Hz, 2H), 2.05 (s, 3H), 1.85 (s, 1H), 1.10 (d, J = 6.9Hz, 3H).

实施例18：化合物18的制备
Example 18: Preparation of Compound 18

步骤1：向100mL的单口瓶中加入化合物18-1(5g,42.33mmol)的二氯甲烷(100mL)溶液，在0℃下依次加入2,2,2-三氯乙酰胺苄酯(11.76g,46.56mmol)和三氟甲磺酸(0.37mL,4.23mmol)，恢复室温反应2小时，通过LCMS监测反应完全。反应液在室温下缓慢加入碳酸氢钠水溶液淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物18-2。MS m/z(ESI)：209.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.38–7.26(m,5H),4.46(s,2H),3.60(s,3H),3.56(dd,J＝9.2,7.1Hz,1H),3.48(dd,J＝9.2,5.5Hz,1H),2.75(pd,J＝7.1,5.5Hz,1H),1.08(d,J＝7.1Hz,3H)。Step 1: Add a 100 mL solution of compound 18-1 (5 g, 42.33 mmol) in dichloromethane (100 mL) to a 100 mL single-necked flask. Add 2,2,2-trichloroacetamide benzyl ester (11.76 g, 46.56 mmol) and trifluoromethanesulfonic acid (0.37 mL, 4.23 mmol) sequentially at 0 °C. Allow the mixture to return to room temperature for 2 hours, monitoring the reaction until complete via LC-MS. Quench the reaction solution slowly with sodium bicarbonate solution at room temperature. Extract three times with dichloromethane (3 × 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product using a silica gel column (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 18-2. MS m/z (ESI): 209.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.38–7.26(m,5H),4.46(s,2H),3.60(s,3H),3.56(dd,J＝9.2,7.1Hz,1H),3 .48(dd,J＝9.2,5.5Hz,1H), 2.75(pd,J＝7.1,5.5Hz,1H), 1.08(d,J＝7.1Hz,3H).

步骤2：向100mL的单口瓶中加入化合物18-2(15g,72.03mmol)的四氢呋喃(150mL)溶液，在0℃下缓慢加入1N的氢化铝锂溶液(86.43mL,86.43mmol)，维持0℃下反应1小时，通TLC监测反应完全。反应液在冰水浴下缓慢加入稀盐酸(1M)淬灭，用乙酸乙酯萃取3次(3×200mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-30％乙酸乙酯/石油醚)纯化,得到化合物18-3。MS m/z(ESI)：181.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.40-7.22(m,5H),4.44(s,2H),4.42(t,J＝5.3Hz,1H),3.43-3.34(m,2H),3.27(ddd,J＝13.5,10.0,6.0Hz,2H),1.81(dq,J＝12.8,6.4Hz,1H),0.87(d,J＝6.8Hz,3H)。Step 2: Add a tetrahydrofuran (150 mL) solution of compound 18-2 (15 g, 72.03 mmol) to a 100 mL single-necked flask. Slowly add a 1 N lithium aluminum hydride solution (86.43 mL, 86.43 mmol) at 0 °C, and maintain the reaction at 0 °C for 1 hour. Monitor the reaction for completeness by TLC. Quench the reaction solution with dilute hydrochloric acid (1 M) slowly in an ice-water bath. Extract three times with ethyl acetate (3 × 200 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-30% ethyl acetate/petroleum ether) to obtain compound 18-3. MS m/z (ESI): 181.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.40-7.22(m,5H),4.44(s,2H),4.42(t,J＝5.3Hz,1H),3.43-3.34(m,2H),3.27( ddd,J＝13.5,10.0,6.0Hz,2H), 1.81(dq,J＝12.8,6.4Hz,1H), 0.87(d,J＝6.8Hz,3H).

步骤3：向500mL的单口瓶中加入化合物18-3(10g,55.48mmol)的二氯甲烷(200mL)溶液，在0℃下缓慢加入戴斯-马丁氧化剂(30.59g,72.12mmol)，恢复室温反应2小时，通过TLC监测反应完全。反应液缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚梯度)纯化得到化合物18-4。¹H NMR(400MHz,DMSO-d₆)δ9.64(d,J＝1.4Hz,1H),7.39-7.28(m,5H),4.48(s,2H),3.67(qd,J＝9.5,5.5Hz,2H),2.73-2.62(m,1H),1.02(d,J＝7.1Hz,3H)。Step 3: Add a 200 mL solution of dichloromethane containing 10 g (55.48 mmol) of compound 18-3 to a 500 mL single-necked flask. Slowly add Dys-Martin oxidant (30.59 g, 72.12 mmol) at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture slowly with saturated sodium bicarbonate solution. Extract three times with ethyl acetate (3 × 100 mL). Wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether gradient) to obtain compound 18-4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.64(d,J＝1.4Hz,1H),7.39-7.28(m,5H),4.48(s,2H),3.67(qd,J＝9.5,5.5Hz,2H),2.73-2.62(m,1H),1.02(d,J＝7.1Hz,3H).

步骤4：向500mL的单口瓶中加入化合物18-4(6.9g,38.71mmol)的二氯甲烷(150mL)溶液，在0℃下缓慢加入二乙胺基三氟化硫(12.48g,77.43mmol)，恢复室温反应2小时，通过TLC监测反应完全。反应液在冰水浴下缓慢加入碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和碳酸氢钠溶液洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物18-5。¹H NMR(400MHz,DMSO-d₆)δ7.39-7.27(m,5H),6.03(td,J＝56.7,3.9Hz,1H),4.49(s,2H),3.49-3.38(m,2H),2.24(ddtt,J＝20.4,10.5,6.6,3.3Hz,1H),0.96(d,J＝6.9Hz,3H)。Step 4: Add a 150 mL solution of dichloromethane containing 6.9 g (38.71 mmol) of compound 18-4 to a 500 mL single-necked flask. Slowly add 12.48 g (77.43 mmol) of diethylaminotrifluoride at 0 °C, and allow the mixture to return to room temperature for 2 hours. Monitor the reaction for completeness by TLC. Quench the reaction mixture with sodium bicarbonate solution slowly in an ice-water bath. Extract three times with dichloromethane (3 × 100 mL). Wash the combined organic phases with saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 18-5. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.39-7.27(m,5H),6.03(td,J＝56.7,3.9Hz,1H),4.49(s,2H),3.49-3.3 8(m,2H),2.24(ddtt,J＝20.4,10.5,6.6,3.3Hz,1H),0.96(d,J＝6.9Hz,3H).

步骤5：向500mL的单口瓶中加入化合物18-5(4.5g,22.47mmol)的四氢呋喃(80mL)溶液，再加入10％钯碳(2.39g)，置换氢气保护，于室温下反应16小时，通过TLC监测反应完全，反应液直接过滤并干燥，含化合物18-6的滤液直接用于下一步反应。Step 5: Add a tetrahydrofuran (80 mL) solution of compound 18-5 (4.5 g, 22.47 mmol) to a 500 mL single-necked flask, then add 10% palladium on carbon (2.39 g), replace with hydrogen for protection, and react at room temperature for 16 hours. Monitor the reaction by TLC until it is complete. Filter the reaction solution directly and dry it. Use the filtrate containing compound 18-6 directly for the next step of the reaction.

步骤6：向500mL的单口瓶中加入上一步含化合物18-6的四氢呋喃溶液，在0℃下缓慢加入对甲苯磺酰氯(6.23g,32.70mmol)和三乙胺(7.55mL,54.50mmol)，于室温下反应16小时，通过LCMS监测反应完全。反应液加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化得到化合物18-7。MS m/z(ESI)：265.1[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.84-7.78(m,2H),7.50(d,J＝8.1Hz,2H),5.98(td,J＝56.0,3.9Hz,1H),4.02(td,J＝6.4,5.7,2.4Hz,3H),2.43(s,3H),0.91(d,J＝7.0Hz,3H)。Step 6: Add the tetrahydrofuran solution containing compound 18-6 from the previous step to a 500 mL single-necked flask. Slowly add p-toluenesulfonyl chloride (6.23 g, 32.70 mmol) and triethylamine (7.55 mL, 54.50 mmol) at 0 °C. React at room temperature for 16 hours, and monitor the reaction for completeness by LCMS. Quench the reaction solution with ice water, extract three times with dichloromethane (3 × 50 mL), wash the combined organic phases with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 18-7. MS m/z (ESI): 265.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.84-7.78(m,2H),7.50(d,J＝8.1Hz,2H),5.98(td,J＝56.0,3.9Hz,1H),4.02(td,J＝6.4,5.7,2.4Hz,3H),2.43(s,3H),0.91(d,J＝7.0Hz,3H).

步骤7：在0℃条件下向250mL的单口瓶中加入化合物18-7(1.75g,6.61mmol)和化合物1-7(2g,6.61mmol)溶于N,N-二甲基甲酰胺(50mL)的溶液，然后缓慢滴入N,N-二异丙基乙胺(5.76mL,33.07mmol)，于室温下反应32小时后，通过LCMS检测反应完成。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-50％乙酸乙酯/石油醚)纯化，得到化合物18-8。MS m/z(ESI)：395.2[M+H]⁺。Step 7: Compound 18-7 (1.75 g, 6.61 mmol) and compound 1-7 (2 g, 6.61 mmol) dissolved in N,N-dimethylformamide (50 mL) were added to a 250 mL single-necked flask at 0 °C. Then, N,N-diisopropylethylamine (5.76 mL, 33.07 mmol) was slowly added dropwise. The reaction was allowed to proceed for 32 hours at room temperature, and the reaction was confirmed by LC-MS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to obtain compound 18-8. MS m/z (ESI): 395.2 [M+H] ⁺ .

步骤8：在0℃条件下向250mL的单口瓶中加入化合物18-8(3.4g,8.62mmol)溶于乙腈(30mL)和水(15mL)的混合溶液,然后缓慢加入[双(三氟乙酰氧基)碘]苯(7.45g,17.24mmol)，于室温下反应16小时，通过LCMS检测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，将母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化得到化合物18-9。MS m/z(ESI)：367.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.89-7.84(m,2H),7.58-7.53(m,2H),6.11(td,J＝57.2,2.9Hz,1H),4.29(q,J＝7.1Hz,2H),3.19(d,J＝22.8Hz,2H),2.37(dd,J＝12.6,7.8Hz,1H),2.25(d,J＝7.2Hz,2H),2.07(dt,J＝13.6,4.7Hz,3H),1.81(s,3H),1.68(d,J＝13.4Hz,2H),1.30(t,J＝7.1Hz,3H),0.95(d,J＝6.8Hz,3H)。Step 8: Compound 18-8 (3.4 g, 8.62 mmol) dissolved in a mixture of acetonitrile (30 mL) and water (15 mL) was added to a 250 mL single-necked flask at 0 °C. Then, [bis(trifluoroacetoxy)iodo]benzene (7.45 g, 17.24 mmol) was slowly added. The reaction was carried out at room temperature for 16 hours, and the reaction was monitored by LCMS to confirm completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 18-9. MS m/z (ESI): 367.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.89-7.84(m,2H),7.58-7.53(m,2H),6.11(td,J＝57.2,2.9Hz,1H),4.29(q,J＝7.1Hz,2H),3.19(d,J＝22.8Hz,2H),2.37(dd,J＝12.6,7.8Hz ,1H),2.25(d,J＝7.2Hz,2H),2.07(dt,J＝13.6,4.7Hz,3H),1.81(s,3H),1.68(d,J＝13.4Hz,2H),1.30(t,J＝7.1Hz,3H),0.95(d,J＝6.8Hz,3H).

步骤9：将化合物18-9(300mg,0.82mmol)溶于乙腈(8mL)中，加入化合物3-9(223.77mg,0.82mmol)和5滴醋酸，室温下搅拌过夜。在0℃下加入硼氢化钠(77mg,2.05mmol)和甲醇(4mL)，室温继续反应1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％乙酸乙酯/石油醚)纯化，得到化合物18-10。MS m/z(ESI)：624.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.94(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.43(d,J＝3.7Hz,1H),6.82(s,1H),6.02(td,J＝57.1,2.8Hz,1H),5.84(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.40(d,J＝6.0Hz,2H),3.20(d,J＝18.8Hz,2H),2.41(s,3H),2.34-2.17(m,6H),2.01(d,J＝9.7Hz,6H),1.81(s,2H),1.56(s,9H),1.44(t,J＝6.0Hz,1H),1.34(t,J＝7.1Hz,3H),0.91(d,J＝6.8Hz,3H)。Step 9: Compound 18-9 (300 mg, 0.82 mmol) was dissolved in acetonitrile (8 mL), compound 3-9 (223.77 mg, 0.82 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Sodium borohydride (77 mg, 2.05 mmol) and methanol (4 mL) were added at 0 °C, and the reaction was continued at room temperature for 1 hour. The reaction was monitored for completion by LCMS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with ethyl acetate (3 × 50 mL), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-10% ethyl acetate/petroleum ether) to obtain compound 18-10. MS m/z (ESI): 624.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.94(d,J＝8.4Hz,2H),7.56(d,J＝8.4Hz,2H),7.43(d,J＝3.7Hz,1H),6.82(s,1H),6.02 (td,J＝57.1,2.8Hz,1H),5.84(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.40(d,J＝6.0Hz, 2H),3.20(d,J＝18.8Hz,2H),2.41(s,3H),2.34-2.17(m,6H),2.01(d,J＝9.7Hz,6H),1.81 (s, 2H), 1.56 (s, 9H), 1.44 (t, J = 6.0Hz, 1H), 1.34 (t, J = 7.1Hz, 3H), 0.91 (d, J = 6.8Hz, 3H).

步骤10：将化合物18-10(220mg,0.35mmol)溶于甲醇(4mL)、水(4mL)和四氢呋喃(4mL)混合溶剂中，加入氢氧化锂(591.94mg,14.11mmol)，升温60℃反应2小时，通过LCMS监测反应完成。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：496.5[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ12.84(s,1H),10.79(s,1H),7.92(d,J＝8.4Hz,2H),7.52(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),6.19-5.88(m,1H),5.64(dd,J＝3.2,1.9Hz,1H),3.44(s,2H),3.21(d,J＝19.0Hz,2H),2.34(s,3H),2.38-2.20(m,6H),2.04(s,3H),2.01(d,J＝13.1Hz,2H),1.81(s,2H),1.23(s,1H),0.91(d,J＝6.8Hz,3H)。将纯化产物(130mg,0.26mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.20mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物18。MS m/z(ESI)：496.3[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.30(s,1H),8.00(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H),7.13(t,J＝2.8Hz,1H),6.63(s,1H),6.19(td,J＝56.0,2.8Hz,1H),5.69(dd,J＝3.1,1.9Hz,1H),4.08(s,2H),3.49(s,2H),3.17-3.09(m,1H),2.97-2.89(m,1H),2.71(d,J＝15.0Hz,2H),2.58-2.56(m,4H),2.35(s,3H),2.12(d,J＝8.8Hz,2H),2.05(s,3H),1.85(s,1H),1.09(d,J＝6.9Hz,3H)。Step 10: Compound 18-10 (220 mg, 0.35 mmol) was dissolved in a mixed solvent of methanol (4 mL), water (4 mL), and tetrahydrofuran (4 mL). Lithium hydroxide (591.94 mg, 14.11 mmol) was added, and the mixture was heated to 60 °C for 2 hours. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 _× 250 mm mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O B: ACN; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 496.5 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d6) δ12.84(s,1H),10.79(s,1H),7.92(d,J=8.4Hz,2H),7.52(d, J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),6.19-5.88(m,1H),5.64(dd,J＝3.2 ,1.9Hz,1H),3.44(s,2H),3.21(d,J＝19.0Hz,2H),2.34(s,3H),2.38-2.20(m,6H),2.04(s,3H),2.01(d,J＝13.1Hz,2H),1.81(s,2H),1.23(s,1H),0.91(d,J＝6.8Hz,3H). The purified product (130mg,0.26mmol) was dissolved in methanol (3mL), and 0.20mL of 4N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5min, the methanol was evaporated to dryness at room temperature, and then 5mL of deionized water was added. After sonication and homogenization, the mixture was lyophilized to obtain compound 18. MS m/z (ESI): 496.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.86(s,1H),9.30(s,1H),8.00(d,J＝8.4Hz,2H),7.60(d,J＝8.4Hz,2H) ,7.13(t,J＝2.8Hz,1H),6.63(s,1H),6.19(td,J＝56.0,2.8Hz,1H),5.69(dd,J＝3.1,1.9Hz,1H), 4.08(s,2H),3.49(s,2H),3.17-3.09(m,1H),2.97-2.89(m,1H),2.71(d,J＝15.0Hz,2H),2.58-2 .56(m,4H),2.35(s,3H),2.12(d,J＝8.8Hz,2H),2.05(s,3H),1.85(s,1H),1.09(d,J＝6.9Hz,3H).

实施例19：化合物19的制备
Example 19: Preparation of Compound 19

步骤1：将化合物18-9(200mg,0.55mmol)溶于乙腈(8mL)中，加入化合物7-2(156.83mg,0.55mmol)，室温搅拌过夜。在0℃下加入硼氢化钠(62.42mg,1.65mmol)和甲醇(4mL)，恢复室温继续反应2个小时，通过LCMS监测反应完成。反应液在室温下缓慢加入冰水淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物19-1。MS m/z(ESI)：638.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.5Hz,2H),7.56(d,J＝8.3Hz,2H),7.42(d,J＝3.7Hz,1H),6.84(s,1H),6.18-5.87(m,1H),5.78(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.43(d,J＝5.8Hz,2H),3.21(d,J＝18.9Hz,2H),2.42(s,3H),2.36-2.17(m,8H),1.99(t,J＝6.8Hz,2H),1.82(s,2H),1.56(s,9H),1.40(s,1H),1.34(t,J＝7.1Hz,3H),0.97(t,J＝7.5Hz,3H),0.91(d,J＝6.8Hz,3H)。Step 1: Compound 18-9 (200 mg, 0.55 mmol) was dissolved in acetonitrile (8 mL), and compound 7-2 (156.83 mg, 0.55 mmol) was added. The mixture was stirred overnight at room temperature. Sodium borohydride (62.42 mg, 1.65 mmol) and methanol (4 mL) were added at 0 °C, and the reaction was continued for 2 hours at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched slowly with ice water at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 19-1. MS m/z (ESI): 638.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.95(d,J＝8.5Hz,2H),7.56(d,J＝8.3Hz,2H),7.42(d,J＝3.7Hz,1H),6.84(s,1H),6.18 -5.87(m,1H),5.78(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.43(d,J＝5.8Hz,2H),3.21(d ,J＝18.9Hz,2H),2.42(s,3H),2.36-2.17(m,8H),1.99(t,J＝6.8Hz,2H),1.82(s,2H),1.56 (s, 9H), 1.40 (s, 1H), 1.34 (t, J = 7.1Hz, 3H), 0.97 (t, J = 7.5Hz, 3H), 0.91 (d, J = 6.8Hz, 3H).

步骤2：将化合物19-1(156mg,0.24mmol)溶于四氢呋喃(3mL)、甲醇(3mL)和水(3mL)混合溶剂中，加入氢氧化锂(410.51mg,9.78mmol)，升到60℃反应1小时，通过LCMS监测反应完成。反应液冷却至室温，缓慢滴加稀HCl(2.0M)，调节pH值到5-7左右，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：510.5[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.93(d,J＝8.3Hz,2H),7.52(d,J＝8.1Hz,2H),7.08(t,J＝2.8Hz,1H),6.62(s,1H),6.03(t,J＝57.5Hz,3H),5.59(t,J＝2.4Hz,1H),3.47(s,2H),3.22(d,J＝18.7Hz,3H),2.37-2.20(m,9H),2.01(d,J＝13.9Hz,2H),1.83(s,2H),0.97(t,J＝7.5Hz,3H),0.91(d,J＝6.8Hz,3H)。将纯化产物(50mg,0.10mmol)溶于甲醇(3mL)，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.29mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物19。MS m/z(ESI)：510.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.93(s,1H),10.87(s,1H),9.72(s,1H),8.00(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,2H),7.12(t,J＝2.8Hz,1H),6.65(s,1H),6.23(td,J＝56.1,2.8Hz,1H),5.61(t,J＝2.5Hz,1H),4.10(d,J＝12.0Hz,2H),3.49(s,2H),3.13(dt,J＝13.5,5.6Hz,1H),2.92(dt,J＝13.1,5.9Hz,1H),2.77-2.53(m,7H),2.35(d,J＝10.8Hz,5H),2.20-2.09(m,2H),1.10(d,J＝6.9Hz,3H),0.98(t,J＝7.5Hz,3H)。Step 2: Compound 19-1 (156 mg, 0.24 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (410.51 mg, 9.78 mmol) was added, and the mixture was heated to 60 °C and reacted for 1 hour. The reaction was monitored by LCMS to ensure completion. The reaction solution was cooled to room temperature, and dilute HCl (2.0 M) was slowly added dropwise to adjust the pH to approximately 5-7. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O B: _ACN ; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 510.5 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d6) δ10.79(s,1H),7.93(d,J＝8.3Hz,2H),7.52(d,J＝8.1 Hz,2H),7.08(t,J＝2.8Hz,1H),6.62(s,1H),6.03(t,J＝57.5Hz,3H),5.59(t, J＝2.4Hz,1H),3.47(s,2H),3.22(d,J＝18.7Hz,3H),2.37-2.20(m,9H),2.01( d, J＝13.9Hz, 2H), 1.83 (s, 2H), 0.97 (t, J＝7.5Hz, 3H), 0.91 (d, J＝6.8Hz, 3H). The purified product (50 mg, 0.10 mmol) was dissolved in methanol (3 mL), and 0.29 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 19. MS m/z (ESI): 510.3 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO- _d6) )δ12.93(s,1H),10.87(s,1H),9.72(s,1H),8.00(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,2H),7.12( t,J＝2.8Hz,1H),6.65(s,1H),6.23(td,J＝56.1,2.8Hz,1H),5.61(t,J＝2.5Hz,1H),4.10(d,J＝12 .0Hz,2H),3.49(s,2H),3.13(dt,J＝13.5,5.6Hz,1H),2.92(dt,J＝13.1,5.9Hz,1H),2.77-2.53( m,7H),2.35(d,J＝10.8Hz,5H),2.20-2.09(m,2H),1.10(d,J＝6.9Hz,3H),0.98(t,J＝7.5Hz,3H).

实施例20：化合物20的制备
Example 20: Preparation of Compound 20

步骤1：在室温下向100mL的单口瓶中加入化合物1-7(2g,6.61mmol)和(S)-(-)-3,3,3-三氟-1,2-环氧丙烷(2.22g,19.84mmol)溶于N,N-二甲基甲酰胺(30mL)的溶液，然后缓慢加入N,N-二异丙基乙胺(4.27g,33.07mmol)，于室温下反应16小时，通过LCMS检测反应完成。反应液在室温下缓慢加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物20-1。MS m/z(ESI)：415.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.86(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.97(s,1H),6.00(s,1H),4.29(q,J＝7.1Hz,2H),3.98(s,1H),3.31(s,1H),3.25(s,1H),2.93(s,1H),2.90(s,1H),2.50–2.46(m,1H),2.43–2.34(m,1H),1.94–1.66(m,6H),1.30(t,J＝7.1Hz,3H)。Step 1: Compound 1-7 (2 g, 6.61 mmol) and (S)-(-)-3,3,3-trifluoro-1,2-epoxypropane (2.22 g, 19.84 mmol) dissolved in N,N-dimethylformamide (30 mL) were added to a 100 mL single-necked flask at room temperature. Then, N,N-diisopropylethylamine (4.27 g, 33.07 mmol) was slowly added, and the reaction was carried out at room temperature for 16 hours. The reaction was detected by LCMS. The reaction solution was quenched with ice water at room temperature and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to give compound 20-1. MS m/z (ESI): 415.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.86(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.38(s,1H),6.97(s,1H),6.00(s,1H),4.29(q,J＝7.1Hz,2H),3.98(s,1H),3.31 (s,1H),3.25(s,1H),2.93(s,1H),2.90(s,1H),2.50–2.46(m,1H),2.43–2.34(m,1H),1.94–1.66(m,6H),1.30(t,J=7.1Hz,3H).

步骤2：将化合物20-1(1.3g,3.14mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入Cs₂CO₃(2.04g,6.27mmol)，反应液在室温下搅拌1小时，然后加入碘甲烷(0.33mL,4.08mmol)，室温下继续搅拌16小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物20-2。MS m/z(ESI)：429.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.89–7.84(m,2H),7.49–7.43(m,2H),7.39(s,1H),6.98(s,1H),4.29(q,J＝7.1Hz,2H),3.97–3.86(m,1H),3.49(s,3H),3.29(s,2H),2.99–2.91(m,2H),2.49–2.38(m,2H),1.91–1.69(m,6H),1.30(t,J＝7.1Hz,3H)。Step 2: Compound 20-1 (1.3 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (20 mL), _and _Cs₂CO₃ (2.04 g, 6.27 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and then iodomethane (0.33 mL, 4.08 mmol) was added. The mixture was stirred at room temperature for another 16 hours, and the reaction was monitored by LCMS to indicate completion. The reaction mixture was quenched by slow addition of saturated ammonium chloride solution at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 20-2. MS m/z (ESI): 429.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.89–7.84(m,2H),7.49–7.43(m,2H),7.39(s,1H),6.98(s,1H),4.29(q,J＝7.1Hz,2H),3.97–3.86(m,1H) ,3.49(s,3H),3.29(s,2H),2.99–2.91(m,2H),2.49–2.38(m,2H),1.91–1.69(m,6H),1.30(t,J＝7.1Hz,3H).

步骤3：在室温下向100mL的单口瓶中加入化合物20-2(850mg,1.98mmol)溶于乙腈(16mL)和水(8mL)的混合溶液,然后缓慢加入[双(三氟乙酰氧基)碘]苯(1.71g,3.97mmol)，于室温下反应2小时，通过LCMS检测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，将母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～10％二氯甲烷/甲醇)纯化，得到化合物20-3。MS m/z(ESI)：401.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝8.5Hz,2H),7.54(d,J＝8.5Hz,2H),4.28(q,2H),4.01–3.89(m,1H),3.56(s,3H),3.30(s,2H),2.31–2.23(m,2H),2.14–2.04(m,2H),1.92–1.63(m,6H),1.31(t,J＝7.1Hz,3H)。Step 3: At room temperature, a mixture of compound 20-2 (850 mg, 1.98 mmol) dissolved in acetonitrile (16 mL) and water (8 mL) was added to a 100 mL single-necked flask. Then, [bis(trifluoroacetoxy)iodo]benzene (1.71 g, 3.97 mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours. The reaction was detected as complete by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–10% dichloromethane/methanol) to obtain compound 20-3. MS m/z (ESI): 401.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.87(d,J＝8.5Hz,2H),7.54(d,J＝8.5Hz,2H),4.28(q,2H),4.01–3.89(m,1H),3.56(s,3H), 3.30(s,2H),2.31–2.23(m,2H),2.14–2.04(m,2H),1.92–1.63(m,6H),1.31(t,J=7.1Hz,3H).

步骤4：将化合物20-3(300mg,0.60mmol)，化合物3-9(164mg,0.60mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(68mg,1.80mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物20-4。MS m/z(ESI)：658.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.2Hz,2H),7.56(d,J＝8.4Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H),5.84(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.95–3.88(m,1H),3.49(s,3H),3.39(d,J＝5.8Hz,2H),3.30(d,J＝4.6Hz,2H),2.58–2.52(m,1H),2.49–2.44(m,1H),2.41(s,3H),2.30(d,J＝13.6Hz,2H),2.21(d,J＝7.4Hz,2H),2.03(s,3H),2.00(s,1H),1.97(d,J＝4.1Hz,1H),1.84–1.74(m,2H),1.56(s,9H),1.49–1.43(m,1H),1.34(t,J＝7.1Hz,3H)。Step 4: Compound 20-3 (300 mg, 0.60 mmol) and compound 3-9 (164 mg, 0.60 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (68 mg, 1.80 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 20-4. MS m/z (ESI): 658.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.95(d,J＝8.2Hz,2H),7.56(d,J＝8.4Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H),5.84(d,J＝3.8Hz,1H), 4.34(q,J＝7.1Hz,2H),3.95–3.88(m,1H),3.49(s,3H),3.39(d,J＝5.8Hz,2H),3.30(d,J＝4.6Hz,2H),2.58–2 .52(m,1H),2.49–2.44(m,1H),2.41(s,3H),2.30(d,J＝13.6Hz,2H),2.21(d,J＝7.4Hz,2H),2.03(s,3H),2. 00(s,1H),1.97(d,J＝4.1Hz,1H),1.84–1.74(m,2H),1.56(s,9H),1.49–1.43(m,1H),1.34(t,J＝7.1Hz,3H).

步骤5：将化合物20-4(200mg,0.30mmol)溶于四氢呋喃(4mL)、甲醇(4mL)和水(4mL)中，加入氢氧化锂一水合物(510mg,12.16mmol)，反应液在60℃下搅拌2小时，通过LCMS监测反应完成。待反应液降至室温后，使用2M盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mMNH₄HCO₃/H₂O B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.76(s,1H),10.80(s,1H),7.93(d,J＝8.1Hz,2H),7.53(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.64(t,J＝2.5Hz,1H),3.92(s,1H),3.50(s,3H),3.44(s,2H),3.29(s,2H),2.56(d,J＝13.8Hz,2H),2.35–2.23(m,7H),2.04(s,3H),1.99(s,2H),1.81(s,2H)。将纯化产物(115mg,0.22mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.15mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物20。MS m/z(ESI)：530.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.87(s,1H),10.44(s,1H),7.99(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.14(t,J＝2.8Hz,1H),6.63(s,1H),5.70(t,J＝2.5Hz,1H),4.89(t,J＝7.8Hz,1H),4.17(s,2H),3.61(s,3H),3.47(d,J＝8.8Hz,2H),3.37(s,1H),3.23–3.16(m,1H),2.75–2.52(m,6H),2.35(s,3H),2.22–2.09(m,2H),2.05(s,3H)。Step 5: Compound 20-4 (200 mg, 0.30 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide monohydrate (510 mg, 12.16 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored for completion by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase gradient: (A: ₁₀ mM _NH₄HCO₃ / _H₂O B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 530.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.76(s,1H),10.80(s,1H),7.93(d,J＝8.1Hz,2H),7.53(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.64(t,J＝2.5Hz,1H), 3.92(s,1H),3.50(s,3H),3.44(s,2H),3.29(s,2H),2.56(d,J＝13.8Hz,2H),2.35–2.23(m,7H),2.04(s,3H),1.99(s,2H),1.81(s,2H). The purified product (115 mg, 0.22 mmol) was dissolved in methanol (5 mL), and 0.15 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 20. MS m/z (ESI): 530.3 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ10.87(s,1H),10.44(s,1H),7.99(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H) ,7.14(t,J＝2.8Hz,1H),6.63(s,1H),5.70(t,J＝2.5Hz,1H),4.89(t,J＝7.8Hz ,1H),4.17(s,2H),3.61(s,3H),3.47(d,J＝8.8Hz,2H),3.37(s,1H),3.23–3 .16(m,1H),2.75–2.52(m,6H),2.35(s,3H),2.22–2.09(m,2H),2.05(s,3H).

实施例21：化合物21的制备
Example 21: Preparation of compound 21

步骤1：室温下，将化合物1-7(1.00g,3.31mmol)溶于乙醇(20mL)中，加入R-(+)-2-三氟甲基环氧乙烷(1.11g,9.92mmol)和N,N-二异丙基乙胺(2.14g,16.54mmol)，于室温下反应16小时，通过LCMS检测反应完成。反应液在室温下缓慢加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％二氯甲烷/甲醇)纯化，得到化合物21-1。MS m/z(ESI)：415.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.92-7.82(m,2H),7.53-7.43(m,2H),6.97(s,1H),6.00(s,1H),4.29(q,J＝7.1Hz,2H),4.18-3.85(m,2H),3.25(s,2H),2.97-2.90(m,2H),2.48-2.46(m,1H),2.38(dd,J＝13.3,7.9Hz,1H),1.99-1.65(m,6H),1.30(t,J＝7.1Hz,3H)。Step 1: At room temperature, compound 1-7 (1.00 g, 3.31 mmol) was dissolved in ethanol (20 mL), and R-(+)-2-trifluoromethyl ethylene oxide (1.11 g, 9.92 mmol) and N,N-diisopropylethylamine (2.14 g, 16.54 mmol) were added. The reaction was carried out at room temperature for 16 hours, and the reaction was detected by LCMS. The reaction solution was quenched slowly with ice water at room temperature, extracted three times with dichloromethane (3 × 50 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-10% dichloromethane/methanol) to obtain compound 21-1. MS m/z (ESI): 415.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.92-7.82(m,2H),7.53-7.43(m,2H),6.97(s,1H),6.00(s,1H),4.29(q,J＝7.1Hz,2H),4.18-3.85(m,2H),3.25(s ,2H),2.97-2.90(m,2H),2.48-2.46(m,1H),2.38(dd,J＝13.3,7.9Hz,1H),1.99-1.65(m,6H),1.30(t,J＝7.1Hz,3H).

步骤2：室温条件下，将化合物21-1(1000mg,2.41mmol)溶于DMF(20mL)中，在搅拌下依次加入碳酸铯(1179.28mg,3.62mmol)和碘甲烷(0.39mL,4.83mmol)，然后继续搅拌过夜，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和氯化铵溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-10％二氯甲烷/甲醇)纯化，得到化合物21-2。MS m/z(ESI)：429.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.40(s,1H),6.98(s,1H),4.29(q,J＝7.1Hz,2H),3.92(td,J＝7.6,3.4Hz,1H),3.49(s,3H),3.33(s,3H),3.00-2.90(m,2H),2.43(dd,J＝13.5,7.9Hz,1H),1.93-1.67(m,6H),1.30(t,J＝7.1Hz,3H)。Step 2: At room temperature, compound 21-1 (1000 mg, 2.41 mmol) was dissolved in DMF (20 mL). Cesium carbonate (1179.28 mg, 3.62 mmol) and methyl iodide (0.39 mL, 4.83 mmol) were added sequentially with stirring, and the mixture was stirred overnight. The reaction was monitored by LCMS to ensure completion. The reaction solution was quenched by slow addition of saturated ammonium chloride solution at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-10% dichloromethane/methanol) to obtain compound 21-2. MS m/z (ESI): 429.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.87(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),7.40(s,1H),6.98(s,1H),4.29(q,J＝7.1Hz,2H),3.92(td,J＝7.6,3.4Hz, 1H), 3.49 (s, 3H), 3.33 (s, 3H), 3.00-2.90 (m, 2H), 2.43 (dd, J = 13.5, 7.9Hz, 1H), 1.93-1.67 (m, 6H), 1.30 (t, J = 7.1Hz, 3H).

步骤3：室温下，将化合物21-2(500mg,1.16mmol)溶于乙腈(5mL)和水(5mL)混合溶剂中，然后加入[双(三氟乙酰氧基)碘]苯(1.0g,5.79mmol)，于室温下反应18小时，通过LCMS检测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，将母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-50％乙酸乙酯/石油醚)纯化，得到化合物21-3。MS m/z(ESI)：401.2[M+H]⁺。Step 3: At room temperature, compound 21-2 (500 mg, 1.16 mmol) was dissolved in a mixed solvent of acetonitrile (5 mL) and water (5 mL), and then [bis(trifluoroacetoxy)iodo]benzene (1.0 g, 5.79 mmol) was added. The reaction was carried out at room temperature for 18 hours, and the reaction was detected by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to obtain compound 21-3. MS m/z (ESI): 401.2 [M+H] ⁺ .

步骤4：室温下，将化合物21-3(300mg,0.75mmol)溶于乙腈(3mL)中，依次加入化合物3-9(204.77mg,0.75mmol)和3滴醋酸，反应搅拌过夜。然后加入硼氢化钠(85.12mg,2.25mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯/石油醚)纯化，得到化合物21-4。MS m/z(ESI)：658.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.95(d,J＝8.3Hz,2H),7.56(d,J＝8.2Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H),5.85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.97–3.84(m,1H),3.49(s,3H),3.40(d,J＝5.6Hz,2H),3.29(s,2H),2.5(s,3H),2.41(s,3H),2.30(d,J＝14.4Hz,3H),2.21(d,J＝7.5Hz,2H),2.03(s,3H),1.81(s,2H),1.56(s,9H),1.47(s,1H),1.34(t,J＝7.1Hz,3H)。Step 4: At room temperature, compound 21-3 (300 mg, 0.75 mmol) was dissolved in acetonitrile (3 mL), followed by the addition of compound 3-9 (204.77 mg, 0.75 mmol) and 3 drops of acetic acid. The reaction mixture was stirred overnight. Then, sodium borohydride (85.12 mg, 2.25 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred for another hour at room temperature. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. Extraction was performed three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate/petroleum ether) to obtain compound 21-4. MS m/z (ESI): 658.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.95(d,J＝8.3Hz,2H),7.56(d,J＝8.2Hz,2H),7.44(d,J＝3.7Hz,1H),6.82(s,1H),5. 85(d,J＝3.8Hz,1H),4.34(q,J＝7.1Hz,2H),3.97–3.84(m,1H),3.49(s,3H),3.40(d,J＝ 5.6Hz,2H),3.29(s,2H),2.5(s,3H),2.41(s,3H),2.30(d,J＝14.4Hz,3H),2.21(d,J＝7 .5Hz,2H),2.03(s,3H),1.81(s,2H),1.56(s,9H),1.47(s,1H),1.34(t,J＝7.1Hz,3H).

步骤5：将化合物21-4(250mg,0.38mmol)溶于四氢呋喃(3mL)、甲醇(3mL)和水(3mL)的混合溶剂中，加入氢氧化锂(638mg,15.2mmol)，升温60℃反应1小时，通过LCMS监测反应完成。待反应液降至室温后,使用2M盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：530.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.79(s,1H),10.80(s,1H),7.93(d,J＝8.2Hz,2H),7.53(d,J＝8.1Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.73-5.57(m,1H),3.92(s,1H),3.49(s,3H),3.44(s,2H),3.30(s,1H),2.54(s,2H),2.45(s,1H),2.34(s,3H),2.30-2.22(m,3H),2.04(s,2H),1.99(s,2H),1.81(s,2H)。将纯化产物(100mg,0.19mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.14mL)，搅拌5min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物21。MS m/z(ESI)：530.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.87(s,1H),7.99(d,J＝8.0Hz,2H),7.60(d,J＝8.1Hz,2H),7.14(t,J＝2.8Hz,1H),6.63(s,1H),5.70(d,J＝2.8Hz,1H),5.06-4.76(m,1H),4.17(s,2H),3.61(s,3H),3.51-3.41(m,2H),3.35(d,J＝14.0Hz,1H),3.20(s,1H),2.71(d,J＝14.0Hz,3H),2.65-2.53(m,3H),2.35(s,3H),2.16(d,J＝35.2Hz,2H),2.05(s,3H),1.85(s,1H)。Step 5: Compound 21-4 (250 mg, 0.38 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (638 mg, 15.2 mmol) was added, and the mixture was heated to 60 °C for 1 hour. The reaction was monitored by LCMS to ensure completion. After the reaction solution cooled to room temperature, the pH was adjusted to between 5 and 7 using 2 M hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography using a Waters-Xbridge-C18-10 μm-19 × 250 mm mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%). The purified product was obtained. MS m/z (ESI): 530.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.79(s,1H),10.80(s,1H),7.93(d,J＝8.2Hz,2H),7.53(d,J＝8.1Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.73-5.57(m,1H),3.92(s,1 H),3.49(s,3H),3.44(s,2H),3.30(s,1H),2.54(s,2H),2.45(s,1H),2 .34(s,3H),2.30-2.22(m,3H),2.04(s,2H),1.99(s,2H),1.81(s,2H). The purified product (100 mg, 0.19 mmol) was dissolved in methanol (3 mL), and 0.14 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 5 min, the methanol was evaporated to dryness at room temperature, and then 5 mL of deionized water was added. After sonication and homogenization, the mixture was lyophilized to obtain compound 21. MS m/z (ESI): 530.3 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.87 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.14 (t, J = 2.8 Hz, 1H), 6.63 (s, 1H), 5.70 (d, J = 2.8 Hz, 1H), 5.06–4.76 (m, 1H), 4.17 (s, 2H), 3.61 (s, 3H) ),3.51-3.41(m,2H),3.35(d,J＝14.0Hz,1H),3.20(s,1H),2.71(d,J＝14.0Hz,3H), 2.65-2.53(m,3H),2.35(s,3H),2.16(d,J＝35.2Hz,2H),2.05(s,3H),1.85(s,1H).

实施例22：化合物22的制备
Example 22: Preparation of compound 22

步骤1：将化合物20-3(200mg,0.50mmol)和化合物1-14(145mg,0.50mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(57mg,1.50mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～15％乙酸乙酯/石油醚)纯化，得到化合物22-1。MS m/z(ESI)：674.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.94(d,J＝8.2Hz,2H),7.56(d,J＝4.4Hz,2H),7.54(s,1H),6.76(s,1H),6.18(d,J＝3.9Hz,1H),4.33(q,J＝7.1Hz,2H),3.96-3.88(m,1H),3.67(s,3H),3.50(s,3H),3.36(d,J＝6.5Hz,2H),3.29(s,2H),2.57-2.52(m,1H),2.48(s,3H),2.26-2.13(m,4H),2.03-1.95(m,2H),1.77-1.66(m,3H),1.57(s,9H),1.33(t,J＝7.1Hz,3H)。Step 1: Compound 20-3 (200 mg, 0.50 mmol) and compound 1-14 (145 mg, 0.50 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (57 mg, 1.50 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–15% ethyl acetate/petroleum ether) to give compound 22-1. MS m/z (ESI): 674.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.94(d,J＝8.2Hz,2H),7.56(d,J＝4.4Hz,2H),7.54(s,1H),6.76(s,1H),6.18(d ,J＝3.9Hz,1H),4.33(q,J＝7.1Hz,2H),3.96-3.88(m,1H),3.67(s,3H),3.50(s,3H ),3.36(d,J＝6.5Hz,2H),3.29(s,2H),2.57-2.52(m,1H),2.48(s,3H),2.26-2.13 (m,4H),2.03-1.95(m,2H),1.77-1.66(m,3H),1.57(s,9H),1.33(t,J=7.1Hz,3H).

步骤2：将化合物22-1(180mg,0.27mmol)溶于四氢呋喃(4mL)，甲醇(4mL)和水(4mL)中，加入氢氧化锂(256mg,10.69mmol)，反应液在60℃搅拌3小时，通过LCMS监测反应完成。待反应液降至室温后，使用2M盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：546.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.78(s,1H),10.81(s,1H),7.93(d,J＝8.5Hz,2H),7.54(d,J＝8.5Hz,2H),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.91(dd,J＝3.1,1.9Hz,1H),3.93(s,1H),3.61(s,3H),3.51(s,3H),3.41(s,2H),3.29(s,2H),2.59-2.51(m,2H),2.40(s,3H),2.27-2.19(m,4H),2.05-1.98(m,2H),1.80-1.72(m,2H)。将纯化产物(91.7mg,0.17mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.13mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物22。MS m/z(ESI)：546.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.94(s,1H),10.86(s,1H),10.26(s,1H),7.99(d,J＝8.2Hz,2H),7.62(d,J＝8.3Hz,2H),7.23(t,J＝2.8Hz,1H),6.66(s,1H),5.91(dd,J＝3.1,1.9Hz,1H),4.86(s,1H),4.15(s,2H),3.64(s,3H),3.61(s,3H),3.42(d,J＝9.2Hz,2H),2.71-2.52(m,6H),2.41(s,3H),2.21-1.92(m,4H)。Step 2: Compound 22-1 (180 mg, 0.27 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). Lithium hydroxide (256 mg, 10.69 mmol) was added. The reaction mixture was stirred at 60 °C for 3 hours, and the reaction was monitored for completion by LCMS. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with 2 M hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 546.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.78(s,1H),10.81(s,1H),7.93(d,J＝8.5Hz,2H),7.54(d,J＝8.5Hz,2H ),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.91(dd,J＝3.1,1.9Hz,1H),3.93(s ,1H),3.61(s,3H),3.51(s,3H),3.41(s,2H),3.29(s,2H),2.59-2.51(m,2 H),2.40(s,3H),2.27-2.19(m,4H),2.05-1.98(m,2H),1.80-1.72(m,2H). The purified product (91.7 mg, 0.17 mmol) was dissolved in methanol (5 mL), and 0.13 mL of 4 N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 22. MS m/z (ESI): 546.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ12.94(s,1H),10.86(s,1H),10.26(s,1H),7.99(d,J＝8.2Hz,2H),7.62(d,J＝8.3Hz,2H),7.23(t,J＝2.8Hz,1H),6.66(s,1H),5.91(dd,J＝3. 1,1.9Hz,1H),4.86(s,1H),4.15(s,2H),3.64(s,3H),3.61(s,3H),3.4 2(d,J＝9.2Hz,2H),2.71-2.52(m,6H),2.41(s,3H),2.21-1.92(m,4H).

实施例23：化合物23的制备
Example 23: Preparation of compound 23

步骤1：将化合物20-3(130mg,0.32mmol)和化合物10-1(98mg,0.32mmol)溶于乙腈(5mL)中，加入4滴醋酸，反应液在室温下搅拌16小时。然后加入硼氢化钠(37mg,0.97mmol)和甲醇(3mL)，反应液在室温下继续搅拌1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～15％乙酸乙酯/石油醚)纯化，得到化合物23-1。MS m/z(ESI)：684.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.93(d,J＝8.2Hz,2H),7.56(d,J＝8.2Hz,2H),7.47(d,J＝3.7Hz,1H),6.56(s,1H),5.99(d,J＝3.8Hz,1H),4.33(q,J＝7.1Hz,2H),3.96-3.88(m,1H),3.58(d,J＝5.8Hz,2H),3.49(s,3H),3.29(s,2H),2.40(s,3H),2.33(d,J＝13.5Hz,2H),2.21(d,J＝7.5Hz,2H),2.00(d,J＝13.2Hz,2H),1.80(s,2H),1.56(s,9H),1.49(t,J＝5.5Hz,2H),1.33(t,J＝7.1Hz,3H),1.27-1.21(m,1H),0.61-0.54(m,2H),0.51-0.45(m,2H)。Step 1: Compound 20-3 (130 mg, 0.32 mmol) and compound 10-1 (98 mg, 0.32 mmol) were dissolved in acetonitrile (5 mL), and 4 drops of acetic acid were added. The reaction mixture was stirred at room temperature for 16 hours. Then, sodium borohydride (37 mg, 0.97 mmol) and methanol (3 mL) were added, and the reaction mixture was stirred at room temperature for another hour. The reaction was monitored for completion by LCMS. The reaction mixture was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The mixture was extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–15% ethyl acetate/petroleum ether) to obtain compound 23-1. MS m/z (ESI): 684.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ7.93(d,J＝8.2Hz,2H),7.56(d,J＝8.2Hz,2H),7.47(d,J＝3.7Hz,1H),6.56(s,1H),5.99(d,J＝3.8Hz, 1H),4.33(q,J＝7.1Hz,2H),3.96-3.88(m,1H),3.58(d,J＝5.8Hz,2H),3.49(s,3H),3.29(s,2H),2.40(s ,3H),2.33(d,J＝13.5Hz,2H),2.21(d,J＝7.5Hz,2H),2.00(d,J＝13.2Hz,2H),1.80(s,2H),1.56(s,9H), 1.49(t,J＝5.5Hz,2H), 1.33(t,J＝7.1Hz,3H), 1.27-1.21(m,1H), 0.61-0.54(m,2H), 0.51-0.45(m,2H).

步骤2：将化合物23-1(130mg,0.19mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)中，加入氢氧化锂(182mg,7.60mmol)，反应液在60℃搅拌2小时，通过LCMS监测反应完成。待反应液降至室温后，使用2M盐酸调pH在5-7之间，有大量固体析出，过滤所得固体粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：556.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.76(s,1H),10.81(s,1H),7.91(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.14(t,J＝2.8Hz,1H),6.38(s,1H),5.80(dd,J＝3.1,1.9Hz,1H),3.96-3.88(m,1H),3.62(s,2H),3.49(s,3H),3.28(s,2H),2.59-2.52(m,2H),2.36-2.31(m,5H),2.26(d,J＝7.4Hz,2H),2.02(d,J＝13.7Hz,2H),1.80(s,2H),1.57-.49(m,1H),0.58-0.52(m,2H),0.44-0.39(m,2H)。将纯化产物(47.1mg,0.08mmol)溶于甲醇(5mL)中，在搅拌下缓慢滴入4N的盐酸-甲醇溶液(0.06mL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物23。MS m/z(ESI)：556.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.88(s,1H),10.33(s,1H),7.98(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.17(t,J＝2.8Hz,1H),6.41(s,1H),5.85(t,J＝2.5Hz,1H),4.91-4.83(m,1H),4.18(d,J＝6.9Hz,2H),3.61(s,5H),3.38-3.31(m,1H),3.25-3.15(m,1H),2.79-2.56(m,5H),2.34(s,3H),2.14(d,J＝25.0Hz,2H),1.87(s,1H),1.59-1.50(m,1H),0.61-0.52(m,2H),0.49-0.38(m,2H)。Step 2: Compound 23-1 (130 mg, 0.19 mmol) was dissolved in tetrahydrofuran (3 mL), methanol (3 mL), and water (3 mL). Lithium hydroxide (182 mg, 7.60 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours, and the reaction was monitored by LCMS to ensure completion. After the reaction mixture cooled to room temperature, the pH was adjusted to between 5 and 7 with ₂ M hydrochloric acid. A large amount of solid precipitated. The crude solid obtained by filtration was purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase gradient: ₍ A: 10 mM _NH₄HCO₃ /H₂O; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 556.3 [M+H] ^⁺ . ^¹H NMR (400 MHz, DMSO-d₆ ₎ )δ12.76(s,1H),10.81(s,1H),7.91(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.14(t,J＝2 .8Hz,1H),6.38(s,1H),5.80(dd,J＝3.1,1.9Hz,1H),3.96-3.88(m,1H),3.62(s,2H),3.4 9(s,3H), 3.28(s,2H), 2.59-2.52(m,2H), 2.36-2.31(m,5H), 2.26(d,J＝7.4Hz,2H), 2.02(d,J＝13.7Hz,2H), 1.80(s,2H), 1.57-0.49(m,1H), 0.58-0.52(m,2H), 0.44-0.39(m,2H). The purified product (47.1 mg, 0.08 mmol) was dissolved in methanol (5 mL), and 0.06 mL of 4N hydrochloric acid-methanol solution was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 23. MS m/z (ESI): 556.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.88(s,1H),10.33(s,1H),7.98(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.17(t,J＝2 .8Hz,1H),6.41(s,1H),5.85(t,J＝2.5Hz,1H),4.91-4.83(m,1H),4.18(d,J＝6.9Hz,2H), 3.61(s,5H),3.38-3.31(m,1H),3.25-3.15(m,1H),2.79-2.56(m,5H),2.34(s,3H),2.14 (d,J＝25.0Hz,2H),1.87(s,1H),1.59-1.50(m,1H),0.61-0.52(m,2H),0.49-0.38(m,2H).

实施例24：化合物24的制备
Example 24: Preparation of compound 24

步骤1：将三氟甲烷磺酸银(106.94g,416.20mmol)、氟化钾(32.24g,554.94mmol)和1-氯甲基-4-氟-1,4-二叠氮双环[2.2.2]辛烷双四氟硼酸盐(73.72g,208.10mmol)溶于乙酸乙酯(400mL)中，在氮气保护下加入化合物24-1(25g,138.73mmol)，搅拌10分钟后继续加入2-氟吡啶(35.82mL,416.20mmol)和(三氟甲基)三甲基硅烷(61.52mL,416.20mmol)，反应液在室温避光条件下搅拌过夜，通过TLC监测反应完成。将反应液过滤，滤液减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-3％乙酸乙酯/石油醚)纯化，得到化合物24-2。¹H NMR(400MHz,Chloroform-d)δ7.37-7.22(m,5H),5.15(s,2H),4.64-4.69(m,1H),1.50(d,J＝6.9Hz,3H)。Step 1: Silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol), and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octanebistetrafluoroborate (73.72 g, 208.10 mmol) were dissolved in ethyl acetate (400 mL). Compound 24-1 (25 g, 138.73 mmol) was added under nitrogen protection. After stirring for 10 minutes, 2-fluoropyridine (35.82 mL, 416.20 mmol) and (trifluoromethyl)trimethylsilane (61.52 mL, 416.20 mmol) were added. The reaction mixture was stirred overnight at room temperature in the dark. The reaction was monitored by TLC to indicate completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-3% ethyl acetate/petroleum ether) to give compound 24-2. ^¹H NMR (400MHz, Chloroform-d) δ 7.37-7.22 (m, 5H), 5.15 (s, 2H), 4.64-4.69 (m, 1H), 1.50 (d, J = 6.9Hz, 3H).

步骤2：将化合物24-2(9.0g,36.26mmol)溶于四氢呋喃(150mL)中，在0℃分批加入氢化铝锂(2.06g,54.39mmol)，反应液先在0℃搅拌0.5小时，恢复室温反应过夜，通过TLC检测反应完成。反应液在冰水浴下，缓慢加入稀HCl(1M)进行淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得到化合物24-3。Step 2: Compound 24-2 (9.0 g, 36.26 mmol) was dissolved in tetrahydrofuran (150 mL). Lithium aluminum hydride (2.06 g, 54.39 mmol) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 hours, then allowed to return to room temperature overnight. The reaction was monitored by TLC to confirm its completion. The reaction mixture was quenched by slow addition of dilute HCl (1 M) in an ice-water bath. The mixture was extracted three times with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-3.

步骤3：将化合物24-3(5g)溶于二氯甲烷(60mL)中，加入三乙胺(7.02g,69.40mmol)，在0℃下加入三氟甲磺酸酐(9.79g,34.70mmol)，恢复室温反应过夜。通过TLC监测反应完成，反应液加入冰水淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得到化合物24-4。Step 3: Compound 24-3 (5 g) was dissolved in dichloromethane (60 mL), triethylamine (7.02 g, 69.40 mmol) was added, and trifluoromethanesulfonic anhydride (9.79 g, 34.70 mmol) was added at 0 °C. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until it was complete. The reaction solution was quenched with ice water, extracted three times with dichloromethane (3 × 100 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 24-4.

步骤4：将化合物24-4(9g)溶于N,N-二甲基甲酰胺(30mL)中，加入化合物1-7(990mg,3.26mmol)，N,N-二异丙基乙胺(2.93mL,16.30mmol)，反应液在室温下搅拌过夜，通过LCMS监测反应完成。反应液在室温下加水淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱[型号：Boston ODS120g Flash；流动相梯度：Water(NH₄HCO₃(0.1％))/CAN＝27％～57％]纯化，得到化合物24-5。MS m/z(ESI)：＝429.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ7.89(d,J＝7.8Hz,2H),7.48(d,J＝8.5Hz,2H),4.32-4.27(m,2H),3.49-3.47(m,1H),3.24-3.19(m,2H),2.22-1.71(m,6H),1.70-1.48(m,2H),1.33-1.27(m,5H),1.18-1.13(m,3H)。Step 4: Compound 24-4 (9 g) was dissolved in N,N-dimethylformamide (30 mL), and compound 1-7 (990 mg, 3.26 mmol) and N,N-diisopropylethylamine (2.93 mL, 16.30 mmol) were added. The reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction mixture was quenched with water at room temperature and extracted three times with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography [model: Boston ODS120g Flash; mobile phase gradient: Water ( _NH4HCO3 ( _0.1 %))/CAN = 27%–57%] to obtain compound 24-5. MS m/z (ESI): = 429.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ7.89(d,J＝7.8Hz,2H),7.48(d,J＝8.5Hz,2H),4.32-4.27(m,2H),3.49-3.47(m ,1H),3.24-3.19(m,2H),2.22-1.71(m,6H),1.70-1.48(m,2H),1.33-1.27(m,5H),1.18-1.13(m,3H).

步骤5：将化合物24-5(130mg,0.30mmol)溶于乙腈(2mL)和水(1mL)混合溶剂中，加入化合物[双(三氟乙酰氧基)碘]苯(262.19mg,0.61mmol)，在室温下搅拌反应2小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物24-6。MS m/z(ESI)：401.2[M+H]⁺。Step 5: Compound 24-5 (130 mg, 0.30 mmol) was dissolved in a mixed solvent of acetonitrile (2 mL) and water (1 mL). Compound [bis(trifluoroacetoxy)iodide]benzene (262.19 mg, 0.61 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 24-6. MS m/z (ESI): 401.2 [M+H] ⁺ .

步骤6：将化合物24-6(200mg,0.50mmol)溶于乙腈(5mL)，加入化合物5-3(86.51mg,0.50mmol)和5滴醋酸，在室温下搅拌反应过夜。然后再加入硼氢化钠(15.13mg,0.40mmol)和甲醇(1mL)，室温继续搅拌1小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～100％乙酸乙酯/石油醚)纯化，得到化合物24-7。MS m/z(ESI)：558.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.81(s,1H),10.79(s,1H),7.92(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.63(dd,J＝3.1,1.9Hz,1H),4.43(q,J＝6.1Hz,2H),3.44-3.42(m,3H),3.23(s,2H),2.41(dd,J＝13.6,5.2Hz,2H),2.34(s,3H),2.26(t,J＝12.6Hz,4H),2.04(s,3H),1.99(d,J＝13.3Hz,2H),1.79(s,2H),1.28(d,J＝6.2Hz,3H)。Step 6: Compound 24-6 (200 mg, 0.50 mmol) was dissolved in acetonitrile (5 mL), compound 5-3 (86.51 mg, 0.50 mmol) and 5 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the mixture was stirred for another hour at room temperature. The reaction was monitored for completion by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature, and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–100% ethyl acetate/petroleum ether) to obtain compound 24-7. MS m/z (ESI): 558.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6) )δ12.81(s,1H),10.79(s,1H),7.92(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.10(t ,J＝2.8Hz,1H),6.60(s,1H),5.63(dd,J＝3.1,1.9Hz,1H),4.43(q,J＝6.1Hz,2H),3.4 4-3.42(m,3H),3.23(s,2H),2.41(dd,J＝13.6,5.2Hz,2H),2.34(s,3H),2.26(t,J＝1 2.6Hz, 4H), 2.04 (s, 3H), 1.99 (d, J = 13.3Hz, 2H), 1.79 (s, 2H), 1.28 (d, J = 6.2Hz, 3H).

步骤7：将化合物24-7(190mg,0.34mmol)溶于四氢呋喃(2mL)、甲醇(2mL)和水(2mL)混合溶液中，加入氢氧化锂(71.5mg,1.7mmol)，反应液室温搅拌过夜，通过LCMS监测反应完成。反应液直接通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mMNH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到纯化产物。MS m/z(ESI)：530.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.81(s,1H),10.79(s,1H),7.92(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.10(t,J＝2.8Hz,1H),6.60(s,1H),5.63(dd,J＝3.1,1.9Hz,1H),4.43(q,J＝6.1Hz,1H),3.44(s,2H),3.23(s,2H),2.41(dd,J＝13.6,5.2Hz,2H),2.34(s,3H),2.26(t,J＝12.6Hz,4H),2.04(s,3H),1.99(d,J＝13.3Hz,2H),1.79(s,2H),1.28(d,J＝6.2Hz,3H)。将纯化产物(70mg,0.132mmol)溶于甲醇(5mL)中，加入4N盐酸甲醇溶液(99.1μL)，搅拌10min后室温下将甲醇旋干，然后加入5mL去离子水，超声均匀后冻干得到化合物24。MS m/z(ESI)：530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.86(s,1H),9.47(s,1H),8.00(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.13(t,J＝4.0Hz,1H),6.63(s,1H),5.68-5.67(m,1H),5.13(s,1H),4.10(d,J＝8.0Hz,2H),3.44(s,2H),2.75-2.51(m,4H),2.40(s,5H),2.35-2.04(m,3H),2.01(s,3H),1.82(s,1H),1.38(d,J＝6.2Hz,3H)。Step 7: Compound 24-7 (190 mg, 0.34 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (71.5 mg, 1.7 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction solution was directly purified by reversed-phase chromatography [Model: Waters-Xbridge-C18-10 μm-19×250 mm; mobile phase gradient: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%)] to obtain the purified product. MS m/z (ESI): 530.3 [M+H] ^⁺ . ^¹H NMR (400 MHz, DMSO-d₆ ₎ )δ12.81(s,1H),10.79(s,1H),7.92(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.10( t,J＝2.8Hz,1H),6.60(s,1H),5.63(dd,J＝3.1,1.9Hz,1H),4.43(q,J＝6.1Hz,1H),3 .44(s,2H), 3.23(s,2H), 2.41(dd,J＝13.6,5.2Hz,2H), 2.34(s,3H), 2.26(t,J＝12.6Hz,4H), 2.04(s,3H), 1.99(d,J＝13.3Hz,2H), 1.79(s,2H), 1.28(d,J＝6.2Hz,3H). The purified product (70 mg, 0.132 mmol) was dissolved in methanol (5 mL), and 99.1 μL of 4N hydrochloric acid in methanol solution was added. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 24. MS m/z (ESI): 530.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.86(s,1H),9.47(s,1H),8.00(d,J＝8.0Hz,2H),7.59(d,J＝8.0Hz,2H),7.13(t,J＝4.0Hz,1H),6.63(s,1H),5.68-5.67(m,1H),5.13(s,1 H),4.10(d,J＝8.0Hz,2H),3.44(s,2H),2.75-2.51(m,4H),2.40(s,5H),2.35-2.04(m,3H),2.01(s,3H),1.82(s,1H),1.38(d,J＝6.2Hz,3H).

实施例25：化合物25的制备
Example 25: Preparation of compound 25

步骤1：将三氟甲烷磺酸银(106.94g,416.20mmol)、氟化钾(32.24g,554.94mmol)和1-氯甲基-4-氟-1,4-二叠氮双环[2.2.2]辛烷双四氟硼酸盐(73.72g,208.10mmol)溶于乙酸乙酯(400mL)中，在氮气保护下加入化合物25-1(25g,138.73mmol)，搅拌10分钟后依次加入2-氟吡啶(40.41g,416.20mmol)和(三氟甲基)三甲基硅烷(59.18g,416.20mmol)，随后反应在室温避光下搅拌过夜，通过TLC监测反应完成。将反应液过滤，滤液减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-3％乙酸乙酯/石油醚)纯化，得到化合物25-2。¹H NMR(400MHz,DMSO-d₆)δ7.42-7.34(m,5H),5.23(s,2H),5.18(q,J＝6.8Hz,1H),1.50(d,J＝6.8Hz,3H)。Step 1: Silver trifluoromethanesulfonate (106.94 g, 416.20 mmol), potassium fluoride (32.24 g, 554.94 mmol), and 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octanebistetrafluoroborate (73.72 g, 208.10 mmol) were dissolved in ethyl acetate (400 mL). Compound 25-1 (25 g, 138.73 mmol) was added under nitrogen protection. After stirring for 10 minutes, 2-fluoropyridine (40.41 g, 416.20 mmol) and (trifluoromethyl)trimethylsilane (59.18 g, 416.20 mmol) were added sequentially. The reaction was then stirred overnight at room temperature in the dark. The reaction was monitored by TLC to indicate completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-3% ethyl acetate/petroleum ether) to give compound 25-2. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 7.42-7.34 (m, 5H), 5.23 (s, 2H), 5.18 (q, J = 6.8Hz, 1H), 1.50 (d, J = 6.8Hz, 3H).

步骤2：将化合物25-2(19.2g,77.36mmol)溶于四氢呋喃(200mL)中，在0℃加入氢化铝锂(4.40g,116.04mmol)，反应液在0℃搅拌半小时，升至室温反应过夜，通过TLC检测反应完成。反应液在冰水浴下，缓慢加入稀HCl(1M)进行淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得到化合物25-3。¹H NMR(400MHz,DMSO-d₆)δ4.34-4.30(m,1H),3.56-3.54(m,2H),1.26(d,J＝4.0Hz,3H)。Step 2: Compound 25-2 (19.2 g, 77.36 mmol) was dissolved in tetrahydrofuran (200 mL), and lithium aluminum hydride (4.40 g, 116.04 mmol) was added at 0 °C. The reaction solution was stirred at 0 °C for half an hour, then allowed to rise to room temperature and reacted overnight. The reaction was detected by TLC. The reaction solution was quenched by slowly adding dilute HCl (1 M) in an ice-water bath. The mixture was extracted three times with dichloromethane (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25-3. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 4.34–4.30 (m, 1H), 3.56–3.54 (m, 2H), 1.26 (d, J = 4.0 Hz, 3H).

步骤3：将化合物25-3(9g)溶于二氯甲烷(100mL)中，加入三乙胺(12.64g,124.92mmol)，在0℃下加入三氟甲磺酸酐(17.62g,62.46mmol)，恢复室温反应过夜，通过TLC监测反应完成。反应液加入冰水淬灭，用二氯甲烷萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩得到化合物25-4。Step 3: Compound 25-3 (9 g) was dissolved in dichloromethane (100 mL), triethylamine (12.64 g, 124.92 mmol) was added, and trifluoromethanesulfonic anhydride (17.62 g, 62.46 mmol) was added at 0 °C. The reaction was allowed to proceed overnight at room temperature, and the reaction was monitored by TLC until completion. The reaction solution was quenched with ice water, extracted three times with dichloromethane (3 × 100 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25-4.

步骤4：将化合物25-4(17g)溶于N,N-二甲基甲酰胺(40mL)中，然后依次加入化合物1-7(1.24g,4.10mmol)和N,N-二异丙基乙胺(2.65g,20.52mmol)，反应在室温下搅拌过夜，通过LCMS监测反应完成。反应液在室温下加入冰水淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过反相制备[型号：Boston ODS120g Flash；流动相梯度：Water(NH₄HCO₃(0.1％))/CAN＝27％～57％]，得到化合物25-5。MS m/z(ESI):429.2[M+H]⁺。Step 4: Compound 25-4 (17 g) was dissolved in N,N-dimethylformamide (40 mL), followed by the sequential addition of compound 1-7 (1.24 g, 4.10 mmol) and N,N-diisopropylethylamine (2.65 g, 20.52 mmol). The reaction was stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction solution was quenched with ice water at room temperature and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was prepared by reverse-phase chromatography [model: Boston ODS120g Flash; mobile phase gradient: Water ( _NH₄HCO₃ ( _0.1 %))/CAN = 27%–57%] to obtain compound 25-5. MS m/z (ESI): 429.2 [M+H] ^⁺ .

步骤5：将化合物25-5(550mg,1.28mmol)溶于乙腈(10mL)和水(5mL)的混合溶剂中，然后加入化合物[双(三氟乙酰氧基)碘]苯(1109.27mg,2.57mmol)，室温下反应2小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物25-6。MS m/z(ESI):401.2[M+H]⁺。Step 5: Compound 25-5 (550 mg, 1.28 mmol) was dissolved in a mixed solvent of acetonitrile (10 mL) and water (5 mL), and then compound [bis(trifluoroacetoxy)iodo]benzene (1109.27 mg, 2.57 mmol) was added. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 25-6. MS m/z (ESI): 401.2 [M+H] ⁺ .

步骤6：将化合物25-6(120mg,0.30mmol)溶于乙腈(3mL)，加入化合物5-3(51.91mg,0.30mmol)和2滴醋酸，在室温下搅拌反应过夜。然后加入硼氢化钠(34.05mg,0.90mmol)和甲醇(1mL)，继续反应2小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～100％乙酸乙酯/石油醚)纯化，得到化合物25-7。MS m/z(ESI):558.4[M+H]⁺。Step 6: Compound 25-6 (120 mg, 0.30 mmol) was dissolved in acetonitrile (3 mL), compound 5-3 (51.91 mg, 0.30 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (34.05 mg, 0.90 mmol) and methanol (1 mL) were added, and the reaction was continued for 2 hours. The reaction was monitored for completion by LCMS. The reaction solution was quenched by slow addition of saturated sodium bicarbonate solution at room temperature, and extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–100% ethyl acetate/petroleum ether) to obtain compound 25-7. MS m/z (ESI): 558.4 [M+H] ⁺ .

步骤7：将化合物25-7(30mg,0.05mmol)溶于四氢呋喃(1mL)、甲醇(1mL)和水(1mL)混合溶液中，加入氢氧化锂(11.29mg,0.27mmol)，反应液室温搅拌过夜，通过LCMS监测反应完成。反应液直接通过反相制备[型号：Boston ODS120g Flash；流动相梯度：Water(NH₄HCO₃(0.1％))/CAN＝27％～57％]纯化，得到纯化产物。MS m/z(ESI):530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.86(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.09(t,J＝2.8Hz,1H),6.60(s,1H),5.70-5.63(m,1H),4.45-4.41(m,1H),3.44(s,2H),3.23(s,2H),2.43-2.38(m,2H),2.34(s,3H),2.25-2.23(m,4H),2.06(s,3H),2.04-1.97(m,2H),1.81-1.76(m,2H),1.28(d,J＝6.2Hz,3H)。将纯化产物(15mg,0.03mmol)溶于甲醇(2mL)中，加入4N盐酸甲醇溶液(21μL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物25。MS m/z(ESI)：530.3[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ10.80(s,1H),7.88(d,J＝7.8Hz,2H),7.40(d,J＝8.1Hz,2H),7.09(d,J＝3.6Hz,1H),6.60(s,1H),5.67(s,1H),4.44-4.42(m,1H),3.44(s,2H),3.23(s,2H),2.43-2.39(m,2H),2.34(s,3H),2.25-2.23(m,4H),2.06(s,3H),2.02-1.99(m,2H),1.79-1.77(m,2H),1.28(d,J＝6.2Hz,3H)。Step 7: Compound 25-7 (30 mg, 0.05 mmol) was dissolved in a mixed solution of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (11.29 mg, 0.27 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction mixture was directly purified by reverse-phase chromatography [Boston ODS120g Flash; mobile phase gradient: Water ( _NH₄HCO₃ ( _0.1 %))/CAN = 27%–57%] to obtain the purified product. MS m/z (ESI): 530.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),7.86(d,J＝8.0Hz,2H),7.38(d,J＝8.0Hz,2H),7.09(t,J ＝2.8Hz,1H),6.60(s,1H),5.70-5.63(m,1H),4.45-4.41(m,1H),3.44(s ,2H),3.23(s,2H),2.43-2.38(m,2H),2.34(s,3H),2.25-2.23(m,4H),2 .06(s,3H),2.04-1.97(m,2H),1.81-1.76(m,2H),1.28(d,J＝6.2Hz,3H). The purified product (15 mg, 0.03 mmol) was dissolved in methanol (2 mL), and 21 μL of 4N hydrochloric acid methanol solution was added. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 25. MS m/z (ESI): 530.3 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ10.80(s,1H),7.88(d,J＝7.8Hz,2H),7.40(d,J＝8.1Hz,2H),7.09(d,J＝3.6Hz,1H),6.60(s,1H),5.67(s,1H),4.44-4.42(m,1H),3.44(s,2H ),3.23(s,2H),2.43-2.39(m,2H),2.34(s,3H),2.25-2.23(m,4H),2.0 6(s,3H),2.02-1.99(m,2H),1.79-1.77(m,2H),1.28(d,J=6.2Hz,3H).

实施例50：化合物50的制备
Example 50: Preparation of Compound 50

步骤1：将化合物1-14(5g,17.28mmol)溶于四氢呋喃(10mL)，甲醇(10mL)和水(10mL)的混合溶剂中，加入氢氧化锂(14.5g,345.6mmol)，反应液升温到60℃搅拌3小时，通过LCMS监测反应完成。反应液中加入水中淬灭，用乙酸乙酯萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～100％乙酸乙酯/石油醚)纯化，得到化合物50-2。MS m/z(ESI)：190.0[M+H]⁺。Step 1: Compound 1-14 (5 g, 17.28 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (14.5 g, 345.6 mmol) was added, and the reaction mixture was heated to 60 °C and stirred for 3 hours. The reaction was monitored by LCMS to indicate completion. The reaction mixture was quenched in water and extracted three times with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–100% ethyl acetate/petroleum ether) to obtain compound 50-2. MS m/z (ESI): 190.0 [M+H] ⁺ .

步骤2：将化合物24-6(80mg,0.20mmol)溶于乙腈(3mL)，加入化合物50-2(115.42mg,0.61mmol)和2滴醋酸，于室温下搅拌过夜。然后再加入硼氢化钠(15.13mg,0.40mmol)和甲醇(1mL)，继续搅拌反应2小时，通过LCMS监测反应完成。反应液中加入饱和碳酸氢钠溶液淬灭，用二氯甲烷萃取3次(3×40mL),合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～100％乙酸乙酯/石油醚)纯化，得到化合物50-3。MS m/z(ESI)：574.3[M+H]⁺。Step 2: Compound 24-6 (80 mg, 0.20 mmol) was dissolved in acetonitrile (3 mL), compound 50-2 (115.42 mg, 0.61 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Then, sodium borohydride (15.13 mg, 0.40 mmol) and methanol (1 mL) were added, and the reaction was stirred for another 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted three times with dichloromethane (3 × 40 mL), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–100% ethyl acetate/petroleum ether) to obtain compound 50-3. MS m/z (ESI): 574.3 [M+H] ⁺ .

步骤3：将化合物50-3(65mg,0.11mmol)溶于四氢呋喃(2mL)、甲醇(2mL)和水(2mL)的混合溶剂中，加入氢氧化锂(13.57mg,0.57mmol)，反应液室温搅拌过夜，通过LCMS监测反应完成。反应液通过反相制备[型号：Boston ODS120g Flash；流动相梯度：Water(NH₄HCO₃(0.1％))/CAN＝27％～57％]纯化，得到纯化产物。MS m/z(ESI)：546.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.90(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.19(d,J＝2.8Hz,1H),6.63(s,1H),5.90(s,1H),4.47-4.39(m,1H),3.61(s,3H),3.41(s,2H),3.25-3.21(m,2H),2.42-2.39(m,5H),2.21-2.18(m,4H),2.01-1.98(m,2H),1.77-1.71(m,2H),1.29(d,J＝6.2Hz,3H)。将纯化产物(19mg,0.03mmol)溶于甲醇(2mL)中，加入盐酸甲醇溶液(26.1μL)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物50。MS m/z(ESI)：546.2[M+H]⁺。¹H NMR(400MHz,DMSO-d6)δ12.87(s,1H),10.86(s,1H),8.00(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.22(t,J＝2.8Hz,1H),6.65(s,1H),5.93-5.85(m,1H),5.25-5.06(m,1H),4.15-4.02(m,2H),3.63(s,3H),3.45-3.38(m,2H),2.76-2.52(m,6H),2.41(s,3H),2.17-1.87(m,4H),1.38(d,J＝6.1Hz,3H)。Step 3: Compound 50-3 (65 mg, 0.11 mmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL). Lithium hydroxide (13.57 mg, 0.57 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction was monitored by LCMS to indicate completion. The reaction mixture was purified by reverse-phase preparation [model: Boston ODS120g Flash; mobile phase gradient: Water ( _NH₄HCO₃ ( _0.1 %))/CAN = 27%–57%] to obtain the purified product. MS m/z (ESI): 546.3 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.81(s,1H),7.90(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.19(d,J＝2.8Hz,1H),6.63(s,1H),5.90(s,1H),4.47-4.39(m,1H),3.61(s ,3H),3.41(s,2H),3.25-3.21(m,2H),2.42-2.39(m,5H),2.21-2.18(m,4H),2.01-1.98(m,2H),1.77-1.71(m,2H),1.29(d,J＝6.2Hz,3H). The purified product (19 mg, 0.03 mmol) was dissolved in methanol (2 mL), and hydrochloric acid methanol solution (26.1 μL) was added. After stirring for 10 min, the methanol was evaporated to dryness at room temperature. Then, 5 mL of deionized water was added, and the mixture was sonicated and lyophilized to obtain compound 50. MS m/z (ESI): 546.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d6) δ12.87(s,1H),10.86(s,1H),8.00(d,J＝8.1Hz,2H),7.60(d,J＝8.1Hz,2H),7.22(t,J＝2.8Hz,1H),6.65(s,1H),5.93-5.85(m, 1H),5.25-5.06(m,1H),4.15-4.02(m,2H),3.63(s,3H),3.45-3.38(m,2H) ,2.76-2.52(m,6H),2.41(s,3H),2.17-1.87(m,4H),1.38(d,J＝6.1Hz,3H).

实施例51：化合物51的制备
Example 51: Preparation of compound 51

步骤1：将化合物1-14(10g,34.56mmol)，磷酸二氢钠(20.04g,167.02mmol)加入乙腈(50mL)和水(50mL)混合溶剂中，0℃下缓慢加入过氧化氢(16.76mL,167.02mmol,30％)，搅拌15分钟，然后维持0℃下继续加入亚氯酸钠(9.67g,106.89mmol)，加完物料后升至室温反应3小时，通过LCMS监测反应完成。反应液体加入水淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％～20％乙酸乙酯)纯化，得到白色固体化合物51-1(6g,19.65mmol,56.86％)。MS m/z(ESI)：306.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.62(s,1H),7.68(d,J＝3.6Hz,2H),6.95(s,1H),6.79(d,J＝3.6Hz,2H),3.85(s,3H),2.5(s,3H),1.59(s,9H).Step 1: Compound 1-14 (10 g, 34.56 mmol) and sodium dihydrogen phosphate (20.04 g, 167.02 mmol) were added to a mixed solvent of acetonitrile (50 mL) and water (50 mL). Hydrogen peroxide (16.76 mL, 167.02 mmol, 30%) was slowly added at 0 °C and stirred for 15 minutes. Then, sodium chlorite (9.67 g, 106.89 mmol) was added while maintaining 0 °C. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 3 hours. The reaction was monitored by LCMS to indicate completion. The reaction liquid was quenched with water and extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%–20% ethyl acetate) to give a white solid compound 51-1 (6 g, 19.65 mmol, 56.86%). MS m/z(ESI): 306.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.62(s,1H),7.68(d,J＝3.6Hz,2H),6.95(s,1H),6.79(d,J＝3.6Hz,2H),3.85(s,3H),2.5(s,3H),1.59(s,9H).

步骤2：室温条件下，将化合物51-1(5.00g,16.38mmol)和碳酸钾(6.79g,49.13mmol)溶于N,N-二甲基甲酰胺(80mL)中，滴加碘甲烷(4.65g,32.75mmol)，搅拌3小时，通过LCMS和TLC监测反应完成。加入冰水(100mL)淬灭，用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-20％乙酸乙酯/石油醚)纯化，得到化合物51-2。MS m/z(ESI)：320.2[M+H]⁺。Step 2: At room temperature, compound 51-1 (5.00 g, 16.38 mmol) and potassium carbonate (6.79 g, 49.13 mmol) were dissolved in N,N-dimethylformamide (80 mL), and iodomethane (4.65 g, 32.75 mmol) was added dropwise. The mixture was stirred for 3 hours, and the reaction was monitored by LCMS and TLC. The reaction was quenched with ice water (100 mL), and extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-20% ethyl acetate/petroleum ether) to obtain compound 51-2. MS m/z (ESI): 320.2 [M+H] ⁺ .

步骤3：将化合物51-2(5.20g,16.28mmol)溶于甲醇(120mL)中，0℃下缓慢加入硼氘化钠(1.37g,32.57mmol)，升至20℃搅拌4小时，通过LCMS和TLC监测反应完成。在0℃下加入十水合硫酸钠，搅拌2小时，过滤干燥并减压浓缩。粗品通过硅胶色谱柱(流动相梯度：0％-50％乙酸乙酯/石油醚)纯化，得到化合物51-3。MS m/z(ESI)：194.2[M+H]⁺。Step 3: Compound 51-2 (5.20 g, 16.28 mmol) was dissolved in methanol (120 mL). Sodium borodeuteride (1.37 g, 32.57 mmol) was slowly added at 0 °C, and the mixture was stirred at 20 °C for 4 hours. The reaction was monitored by LC-MS and TLC. Sodium sulfate decahydrate was added at 0 °C, and the mixture was stirred for 2 hours. The mixture was filtered, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to give compound 51-3. MS m/z (ESI): 194.2 [M+H] ⁺ .

步骤4：室温下，将化合物51-3(3.00g,15.52mmol)溶于二氯甲烷(120mL)中，加入二氧化锰(1.48g,17.08mmol)，升至50℃搅拌24小时，通过LCMS和TLC监测反应完成。过滤干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-50％乙酸乙酯/石油醚)纯化，得到化合物51-4。MS m/z(ESI)：191.2[M+H]⁺。Step 4: At room temperature, compound 51-3 (3.00 g, 15.52 mmol) was dissolved in dichloromethane (120 mL), and manganese dioxide (1.48 g, 17.08 mmol) was added. The mixture was heated to 50 °C and stirred for 24 hours. The reaction was monitored by LCMS and TLC. The product was filtered, dried, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-50% ethyl acetate/petroleum ether) to obtain compound 51-4. MS m/z (ESI): 191.2 [M+H] ⁺ .

步骤5：将化合物129-6(224mg,0.60mmol)、化合物51-4(115mg,0.60mmol)和乙酸(40mg,0.60mmol)溶于甲醇(8mL)溶液中，在25℃下搅拌16小时后，在0℃下缓慢加入氘代硼氢化钠(127mg,3.02mmol)，在25℃下继续搅拌2小时，通过LCMS监测反应完成。反应液倒入饱和氯化铵溶液中，用乙酸乙酯萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度:0％-40％乙酸乙酯/石油醚)纯化，得到化合物51-5。MS m/z(ESI)：546.4[M+H]⁺。Step 5: Compound 129-6 (224 mg, 0.60 mmol), compound 51-4 (115 mg, 0.60 mmol), and acetic acid (40 mg, 0.60 mmol) were dissolved in methanol (8 mL). After stirring at 25 °C for 16 hours, sodium deuterated borohydride (127 mg, 3.02 mmol) was slowly added at 0 °C, and stirring was continued at 25 °C for 2 hours. The reaction was monitored by LCMS to indicate completion. The reaction solution was poured into a saturated ammonium chloride solution and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-40% ethyl acetate/petroleum ether) to obtain compound 51-5. MS m/z (ESI): 546.4 [M+H] ⁺ .

步骤6：将化合物51-5(270mg,0.49mmol)溶于甲醇(15mL)和水(3mL)中，加入氢氧化锂(104mg，2.47mmol)，加热至60℃搅拌反应18小时，通过LCMS监测反应完成。反应液用稀HCl(2N)调pH值至中性，然后减压浓缩，所得粗品直接通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，冻干得到化合物51。MS m/z(ESI)：518.7[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.94(d,J＝8.6Hz,2H),7.53(d,J＝8.5Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.61(s,3H),3.53–3.39(m,2H),3.18–3.07(m,1H),2.40(s,3H),2.33–2.17(m,4H),2.06–1.95(m,2H),1.85–1.69(m,1H),1.66–1.52(m,1H),1.13(d,J＝6.8Hz,3H)。Step 6: Compound 51-5 (270 mg, 0.49 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (104 mg, 2.47 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS to indicate completion. The pH of the reaction solution was adjusted to neutral with dilute HCl (2N), and then concentrated under reduced pressure. The crude product was directly purified by reversed-phase chromatography [model: Waters-Xbridge-C18-10μm-19×250 mm; mobile phase gradient: (A: 10 mM _NH₄HCO₃ / _H₂O ; B: _ACN ; gradient: B%: 0%-95%)] and lyophilized to obtain compound 51. MS m/z (ESI): 518.7 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.81(s,1H),7.94(d,J＝8.6Hz,2H),7.53(d,J＝8.5Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.61(s,3H),3.53 –3.39(m,2H),3.18–3.07(m,1H),2.40(s,3H),2.33–2.17(m,4H),2.06–1 .95(m,2H),1.85–1.69(m,1H),1.66–1.52(m,1H),1.13(d,J=6.8Hz,3H).

实施例52：化合物52的制备
Example 52: Preparation of compound 52

步骤1：将化合物1-7(500mg,1.65mmol)和2,2-二氟丙基对甲苯磺酸(477mg,4.96mmol)溶于二甲基亚砜(5mL)中，分别加入N,N-二异丙基乙胺(641mg,4.96mmol)和碘化钠(25mg,0.17mmol)，在130℃氮气氛围下搅拌18小时，通过LCMS监测反应完成。在反应液中加入冰水(50mL)，并用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水(300mL)洗涤，再用无水硫酸钠干燥并减压浓缩。粗品通过硅胶色谱柱(流动相梯度：2％-30％乙酸乙酯/石油醚)纯化，得到化合物52-1。MS m/z(ESI)：381.2[M+H]⁺。Step 1: Compounds 1-7 (500 mg, 1.65 mmol) and 2,2-difluoropropyltoluenesulfonic acid (477 mg, 4.96 mmol) were dissolved in dimethyl sulfoxide (5 mL). N,N-diisopropylethylamine (641 mg, 4.96 mmol) and sodium iodide (25 mg, 0.17 mmol) were added separately. The mixture was stirred at 130 °C under a nitrogen atmosphere for 18 hours, and the reaction was monitored by LCMS. Ice water (50 mL) was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 2%–30% ethyl acetate/petroleum ether) to give compound 52-1. MS m/z (ESI): 381.2 [M+H] ⁺ .

步骤2：将化合物52-1(230mg,0.60mmol)溶于乙腈(5mL)和水(5mL)中，0℃下加入(双(三氟乙酰基氧)碘)苯(260mg,0.60mmol)，在室温氮气氛围下搅拌18小时，通过LCMS监测反应完成。反应液在室温下缓慢加入饱和碳酸氢钠溶液淬灭，过滤掉析出的固体，母液用二氯甲烷萃取3次(3×50mL)，合并的有机相用饱和食盐水洗涤，再用无水硫酸钠干燥并减压浓缩，所得粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mMNH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到化合物52-2。MS m/z(ESI)：353.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.90–7.85(m,2H),7.58–7.52(m,2H),4.29(q,J＝7.1Hz,2H),3.24(s,2H),2.67(t,J＝13.9Hz,2H),2.31–2.22(m,2H),2.09(dd,J＝13.7,3.9Hz,2H),1.85–1.59(m,7H),1.31(t,J＝7.1Hz,3H)。Step 2: Compound 52-1 (230 mg, 0.60 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL). (bis(trifluoroacetyloxy)iodide)benzene (260 mg, 0.60 mmol) was added at 0 °C. The mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere, and the reaction was monitored by LCMS. The reaction solution was quenched by slowly adding saturated sodium bicarbonate solution at room temperature. The precipitated solid was filtered off, and the mother liquor was extracted three times with dichloromethane (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography [Model: Waters-Xbridge-C18-10 μm-19 × 250 mm; mobile phase gradient: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%)] to obtain compound 52-2. MS m/z(ESI): 353.0[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.90–7.85(m,2H),7.58–7.52(m,2H),4.29(q,J＝7.1Hz,2H),3.24(s,2H),2.67(t,J＝13.9Hz, 2H),2.31–2.22(m,2H),2.09(dd,J＝13.7,3.9Hz,2H),1.85–1.59(m,7H),1.31(t,J＝7.1Hz,3H).

步骤3：将化合物52-2(130mg,0.37mmol)和化合物1-14(75mg,0.26mmol)溶于N,N-二甲基甲酰胺(2mL)中，加入氰基硼氢化钠(70mg,1.11mmol)和1滴醋酸，在60℃氮气氛围下搅拌18小时，通过LCMS监测反应完成。在反应液中加入冰水，并用乙酸乙酯萃取3次(3×100mL)，合并的有机相用饱和食盐水洗涤，用无水硫酸钠干燥并减压浓缩。粗品通过硅胶色谱柱(流动相梯度：2％-30％乙酸乙酯/石油醚)纯化，得到化合物52-3。MS m/z(ESI)：626.0[M+H]⁺。Step 3: Compound 52-2 (130 mg, 0.37 mmol) and compound 1-14 (75 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (2 mL), sodium cyanoborohydride (70 mg, 1.11 mmol) and 1 drop of acetic acid were added, and the mixture was stirred at 60 °C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. Ice water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 2%-30% ethyl acetate/petroleum ether) to give compound 52-3. MS m/z (ESI): 626.0 [M+H] ⁺ .

步骤4：将化合物52-3(70mg,0.11mmol)溶于四氢呋喃(1mL)、甲醇(1mL)和水(1mL)中，加入氢氧化锂(34mg,0.56mmol)，加热至50℃搅拌4小时，通过LCMS监测反应完成。反应液使用稀盐酸(1N)调pH值至中性，过滤并浓缩滤液，所得粗品通过反相色谱柱[型号：Waters-Xbridge-C18-10μm-19×250mm；流动相梯度：(A:10mM NH₄HCO₃/H₂O；B:ACN；梯度：B％：0％-95％)]纯化，得到化合物52。MS m/z(ESI)：498.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.94(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,2H),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.96–5.89(m,1H),3.61(s,3H),3.41(s,2H),3.25(s,2H),2.70–2.59(m,2H),2.40(s,3H),2.27–2.19(m,4H),2.07–1.99(m,2H),1.79–1.71(m,2H),1.61(t,J＝19.0Hz,3H)。Step 4: Compound 52-3 (70 mg, 0.11 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). Lithium hydroxide (34 mg, 0.56 mmol) was added, and the mixture was heated to 50 °C and stirred for 4 hours. The reaction was monitored by LCMS to ensure completion. The pH of the reaction solution was adjusted to neutral using dilute hydrochloric acid (1 N). The solution was filtered and the filtrate was concentrated. The crude product was purified by reversed-phase chromatography [Model: Waters-Xbridge-C18-10 μm-19 × 250 mm; mobile phase gradient: (A: ₁₀ mM _NH₄HCO₃ / _H₂O ; B: ACN; gradient: B%: 0%-95%)] to obtain compound 52. MS m/z (ESI): 498.2 [M+H] ^⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(s,1H),7.94(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,2H),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.96–5.89(m,1H),3.61(s,3H),3.41 (s,2H),3.25(s,2H),2.70–2.59(m,2H),2.40(s,3H),2.27–2.19(m,4H),2.07–1.99(m,2H),1.79–1.71(m,2H),1.61(t,J＝19.0Hz,3H).

实施例53：化合物53的制备
Example 53: Preparation of compound 53

步骤1：将化合物25-6(150mg,0.37mmol)溶于乙腈(5mL)，加入化合物50-2(107mg,0.57mmol)和2滴醋酸，在室温下搅拌反应过夜。反应液中加入硼氢化钠(43mg,1.14mmol)和甲醇(1mL)，搅拌下继续反应0.5小时，通过LCMS监测反应完成。反应液中加入冰水中淬灭，用二氯甲烷萃取3次(3×40mL)，合并的有机相用饱和食盐水洗涤3次，再用无水硫酸钠干燥并减压浓缩，所得粗品通过硅胶色谱柱(流动相梯度：0％-100％乙酸乙酯/石油醚)纯化，得到化合物53-1。MS m/z(ESI)：574.2[M+H]+。Step 1: Compound 25-6 (150 mg, 0.37 mmol) was dissolved in acetonitrile (5 mL), compound 50-2 (107 mg, 0.57 mmol) and 2 drops of acetic acid were added, and the mixture was stirred overnight at room temperature. Sodium borohydride (43 mg, 1.14 mmol) and methanol (1 mL) were added to the reaction solution, and the reaction was continued for 0.5 hours with stirring. The reaction was monitored by LCMS to indicate completion. The reaction solution was quenched in ice water, extracted three times with dichloromethane (3 × 40 mL), and the combined organic phases were washed three times with saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (mobile phase gradient: 0%-100% ethyl acetate/petroleum ether) to obtain compound 53-1. MS m/z (ESI): 574.2 [M+H]+.

步骤2：将化合物53-1(105mg,0.18mmol)溶于四氢呋喃(2mL)，甲醇(2mL)和水(2mL)的混合溶液中，然后加入氢氧化锂(21.6mg,0.9mmol)，反应液室温搅拌过夜，通过LCMS监测反应完成。反应液通过反相制备[型号：Boston ODS120g Flash；流动相梯度：Water(NH₄HCO₃(0.1％))/CAN＝27％～57％]纯化，得到纯化产物。将纯化产物(40mg,0.073mmol)溶于甲醇(3mL)中，在搅拌下缓慢滴加盐酸甲醇溶液(21μL,1M)，搅拌10min后室温下将甲醇旋干，然后加入5mL的去离子水，超声均匀后冻干得到化合物53。MS m/z(ESI)：546.2[M+H]+。¹H NMR(400MHz,DMSO-d6)δ12.95(s,1H),10.86(s,1H),9.56(s,1H),8.00(d,J＝8.0Hz,2H),7.61(d,J＝8.2Hz,2H),7.22(s,1H),6.66(s,1H),5.89-5.86(m,1H),5.21-5.11(m,1H),4.16-4.06(m,2H),3.64(s,3H),3.30-3.23(m,2H),2.67-2.55(m,4H),2.49-2.44(m,2H),2.41(s,3H),2.16-1.94(m,4H),1.38(d,J＝6.2Hz,3H).Step 2: Compound 53-1 (105 mg, 0.18 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and then lithium hydroxide (21.6 mg, 0.9 mmol) was added. The reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS. The reaction mixture was purified by reverse-phase preparation [model: Boston ODS120g Flash; mobile phase gradient: water ( _NH4HCO3 ( _0.1 %))/CAN = 27%–57%] to obtain the purified product. The purified product (40 mg, 0.073 mmol) was dissolved in methanol (3 mL), and hydrochloric acid methanol solution (21 μL, 1 M) was slowly added dropwise with stirring. After stirring for 10 min, the methanol was evaporated to dryness at room temperature, and then 5 mL of deionized water was added. After sonication and homogenization, the mixture was lyophilized to obtain compound 53. MS m/z (ESI): 546.2 [M+H]+. ^1H NMR (400MHz, DMSO-d6) δ12.95(s,1H),10.86(s,1H),9.56(s,1H),8.00(d,J＝8.0 Hz,2H),7.61(d,J＝8.2Hz,2H),7.22(s,1H),6.66(s,1H),5.89-5.86(m,1H),5.2 1-5.11(m,1H),4.16-4.06(m,2H),3.64(s,3H),3.30-3.23(m,2H),2.67-2.55(m ,4H),2.49-2.44(m,2H),2.41(s,3H),2.16-1.94(m,4H),1.38(d,J＝6.2Hz,3H).

实施例103：化合物103的制备
Example 103: Preparation of compound 103

步骤1：将化合物34-0(10g，62.26mmol)和4-甲氧基苄氯(10.13mL，74.71mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入碳酸钾(25.81g，186.78mmol)，25℃搅拌18个小时。通过LCMS监测反应。加入水(50mL)淬灭，用二氯甲烷(3×60mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-30％乙酸乙酯/石油醚梯度纯化，得到化合物34-1。MS m/z(ESI)：＝246.2[M+H]⁺。Step 1: Compound 34-0 (10 g, 62.26 mmol) and 4-methoxybenzyl chloride (10.13 mL, 74.71 mmol) were dissolved in N,N-dimethylformamide (100 mL), and potassium carbonate (25.81 g, 186.78 mmol) was added. The mixture was stirred at 25 °C for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL), extracted with dichloromethane (3 × 60 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–30% ethyl acetate/petroleum ether to give compound 34-1. MS m/z (ESI): = 246.2 [M+H] ⁺ .

步骤2：氮气氛围下将化合物34-1(14g)、对甲基苯磺酰甲基异腈(16.71g，85.60mmol)和叔丁醇(8.13mL，85.60mmol)溶于乙二醇二甲醚(140mL)中，0℃滴加叔丁醇钾的四氢呋喃溶液(114.1mL，1.0M，114.1mmol)，1小时后体系升至室温继续搅拌24小时。通过LCMS监测反应。加入饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯(3×200mL)萃取，合并的有机相用饱和食盐水(200mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-30％乙酸乙酯/石油醚梯度纯化，得到化合物34-2。MS m/z(ESI)：＝257.2[M+H]⁺。Step 2: Compound 34-1 (14 g), p-toluenesulfonylmethylisocyanate (16.71 g, 85.60 mmol), and tert-butanol (8.13 mL, 85.60 mmol) were dissolved in ethylene glycol dimethyl ether (140 mL) under a nitrogen atmosphere. A tetrahydrofuran solution of potassium tert-butoxide (114.1 mL, 1.0 M, 114.1 mmol) was added dropwise at 0 °C. After 1 hour, the system was brought to room temperature and stirred for another 24 hours. The reaction was monitored by LC-MS. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 200 mL), and the combined organic phases were washed with saturated brine (200 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–30% ethyl acetate/petroleum ether to give compound 34-2. MS m/z (ESI): = 257.2 [M+H] ⁺ .

步骤3：将化合物34-2(4.88g，19.04mmol)、对氟苯甲酸乙酯(5.12mL，38.07mmol)溶于四氢呋喃(50mL)中，氮气保护于0℃滴加双三甲基硅基胺基锂的四氢呋喃溶液(28.6mL，1.0M，28.6mmoL)，随后体系移至室温搅拌2小时。通过LCMS和TLC监测反应。加入饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-60％乙酸乙酯/石油醚梯度纯化，得到化合物34-3。MS m/z(ESI)：＝405.2[M+H]⁺。Step 3: Compound 34-2 (4.88 g, 19.04 mmol) and ethyl p-fluorobenzoate (5.12 mL, 38.07 mmol) were dissolved in tetrahydrofuran (50 mL). Under nitrogen protection at 0 °C, a tetrahydrofuran solution of bis(trimethylsilylamino)lithium (28.6 mL, 1.0 M, 28.6 mmol) was added dropwise. The system was then transferred to room temperature and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–60% ethyl acetate/petroleum ether to give compound 34-3. MS m/z (ESI): 405.2 [M+H] ⁺ .

步骤4：将化合物34-3(1.00g，2.47mmol)和碳酸钾(0.68g，4.94mmol)溶于二甲基亚砜(10mL)中，0℃滴加30％的双氧水(1mL)，随后升至室温搅拌16小时。通过LCMS和TLC监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×20mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：1％-5％甲醇/二氯甲烷梯度纯化，得到化合物34-4。MS m/z(ESI)：＝423.2[M+H]⁺。Step 4: Compound 34-3 (1.00 g, 2.47 mmol) and potassium carbonate (0.68 g, 4.94 mmol) were dissolved in dimethyl sulfoxide (10 mL), and 30% hydrogen peroxide (1 mL) was added dropwise at 0 °C. The mixture was then heated to room temperature and stirred for 16 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 1%–5% methanol/dichloromethane gradient to give compound 34-4. MS m/z (ESI): = 423.2 [M+H] ⁺ .

步骤5：将化合物34-4(2.00g,4.73mmol)溶于乙醇(40mL)，加入钯碳(0.50g,10％)，甲酸铵(2.98g,47.34mmol)，在80℃下搅拌8小时。通过LCMS监测反应。过滤，浓缩，得到化合物103-1。MS m/z(ESI)：＝303.4[M+H]⁺。Step 5: Compound 34-4 (2.00 g, 4.73 mmol) was dissolved in ethanol (40 mL), and palladium on carbon (0.50 g, 10%) and ammonium formate (2.98 g, 47.34 mmol) were added. The mixture was stirred at 80 °C for 8 hours. The reaction was monitored by LCMS. The solution was filtered and concentrated to give compound 103-1. MS m/z (ESI): = 303.4 [M+H] ⁺ .

步骤6：将化合物103-1(500mg,1.65mmol)溶于甲醇(10mL)，加入甲醛的水溶液(1.4mL)和三乙酰氧基硼氢化钠(710.9mg,3.31mmol)，常温搅拌5小时。通过LCMS监测反应。加入饱和碳酸钠溶液(15mL)淬灭，用二氯甲烷(3×15mL)萃取，合并的有机相用饱和食盐水(18mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：1％-10％甲醇/二氯甲烷梯度纯化，得到化合物103-2。MS m/z(ESI)：＝317.2[M+H]⁺。Step 6: Compound 103-1 (500 mg, 1.65 mmol) was dissolved in methanol (10 mL), and an aqueous solution of formaldehyde (1.4 mL) and sodium triacetoxyborohydride (710.9 mg, 3.31 mmol) were added. The mixture was stirred at room temperature for 5 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (15 mL), extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine (18 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 1%–10% methanol/dichloromethane gradient to give compound 103-2. MS m/z (ESI): = 317.2 [M+H] ⁺ .

步骤7：将化合物103-2(500mg,1.58mmol)溶于乙腈(7mL)和水(7mL)，加入[双(三氟乙酰氧基)碘]苯(747.5mg,1.74mmol)，常温搅拌3小时。通过LCMS监测反应。加入饱和碳酸钠溶液(15mL)淬灭，用二氯甲烷(3×15mL)萃取，合并的有机相用饱和食盐水(18mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：1％-10％甲醇/二氯甲烷梯度纯化，得到化合物103-3。MS m/z(ESI)：＝289.2[M+H]⁺。Step 7: Compound 103-2 (500 mg, 1.58 mmol) was dissolved in acetonitrile (7 mL) and water (7 mL), and [bis(trifluoroacetoxy)iodo]benzene (747.5 mg, 1.74 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (15 mL), extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine (18 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 1%–10% methanol/dichloromethane gradient to give compound 103-3. MS m/z (ESI): = 289.2 [M+H] ⁺ .

步骤8：将化合物103-3(415mg,1.44mmol)溶于乙腈(10mL)，加入化合物1-14(379.5mg,1.31mmol)和三乙酰氧基硼氢化钠(553.3mg,2.62mmol)，70℃搅拌16小时。通过LCMS监测反应。加入饱和碳酸钠溶液(15mL)淬灭，用二氯甲烷(3×15mL)萃取，合并的有机相用饱和食盐水(18mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：1％-10％甲醇/二氯甲烷梯度纯化，得到化合物103-4。MS m/z(ESI)：＝562.2[M+H]⁺。Step 8: Compound 103-3 (415 mg, 1.44 mmol) was dissolved in acetonitrile (10 mL), and compound 1-14 (379.5 mg, 1.31 mmol) and sodium triacetoxyborohydride (553.3 mg, 2.62 mmol) were added. The mixture was stirred at 70 °C for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (15 mL), extracted with dichloromethane (3 × 15 mL), and the combined organic phases were washed with saturated brine (18 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 1%–10% methanol/dichloromethane gradient to give compound 103-4. MS m/z (ESI): = 562.2 [M+H] ⁺ .

步骤9：将化合物103-4(675mg,1.20mmol)溶于甲醇(10mL)和水(2mL)，加入一水合氢氧化锂(151.3mg,3.60mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩。粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物103。MS m/z(ESI)：＝434.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.86(s,1H),7.99(d,J＝8.1Hz,2H),7.60(d,J＝8.2Hz,2H),7.23(t,J＝2.8Hz,1H),6.66(s,1H),5.95-5.86(m,1H),3.95-3.84(m,2H),3.65(s,3H),3.46-3.40(m,2H),2.66(s,3H),2.63-2.53(m,4H),2.42(s,3H),2.37-2.29(m,2H),2.10-2.01(m,2H),2.01-1.95(m,1H)。Step 9: Compound 103-4 (675 mg, 1.20 mmol) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide monohydrate (151.3 mg, 3.60 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LC-MS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 103. MS m/z (ESI): = 434.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.86(s,1H),7.99(d,J＝8.1Hz,2H),7.60(d,J＝8.2Hz,2H),7.23(t,J＝2.8Hz,1H),6.66(s,1H),5.95-5.86(m,1H),3.95-3.84(m,2H) ,3.65(s,3H),3.46-3.40(m,2H),2.66(s,3H),2.63-2.53(m,4H),2.42(s,3H),2.37-2.29(m,2H),2.10-2.01(m,2H),2.01-1.95(m,1H).

实施例110：化合物110的制备
Example 110: Preparation of compound 110

步骤1：将化合物109-1(6.84g,63.87mmol)和醋酸钠(28.57g,348.47mmol)溶于水(200mL)中，在0℃、氮气氛围下依次加入1,3-丙酮二羧酸(8.28mL,72.57mmol)和盐酸(72.57mL,1N)，搅拌1小时后，加入丁二醛水溶液(9.43mL,58.08mmol,40％)的四氢呋喃(200ml)溶液，升至40℃搅拌18个小时。通过LCMS监测反应。用乙酸乙酯(2×200mL)萃取，合并的有机相用饱和食盐水(250mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-50％乙酸乙酯/石油醚梯度纯化，得到化合物109-2。¹H NMR(400MHz,DMSO-d₆)δ3.44(tt,J＝4.2,2.2Hz,2H),3.19(hd,J＝7.2,3.8Hz,1H),2.86-2.71(m,2H),2.60(dd,J＝16.2,4.4Hz,2H),2.51-2.35(m,2H),2.11-2.07(m,1H),2.06-2.03(m,1H),1.99-1.87(m,2H),1.56-1.42(m,2H)。Step 1: Compound 109-1 (6.84 g, 63.87 mmol) and sodium acetate (28.57 g, 348.47 mmol) were dissolved in water (200 mL). Under a nitrogen atmosphere at 0 °C, 1,3-propanone dicarboxylic acid (8.28 mL, 72.57 mmol) and hydrochloric acid (72.57 mL, 1N) were added sequentially. After stirring for 1 hour, a tetrahydrofuran solution (9.43 mL, 58.08 mmol, 40%) containing succinaldehyde was added, and the mixture was stirred at 40 °C for 18 hours. The reaction was monitored by LC-MS. The mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were washed with saturated brine (250 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 5%–50% ethyl acetate/petroleum ether gradient to give compound 109-2. ¹ H NMR (400MHz, DMSO-d ₆ )δ3.44(tt,J＝4.2,2.2Hz,2H),3.19(hd,J＝7.2,3.8Hz,1H),2.86-2.71(m,2H),2.60(dd,J＝16.2,4.4H z,2H),2.51-2.35(m,2H),2.11-2.07(m,1H),2.06-2.03(m,1H),1.99-1.87(m,2H),1.56-1.42(m,2H).

步骤2：将化合物109-2(6.30g,29.27mmol)、叔丁醇(6.36mL,43.90mmol)和对甲基苯磺酰甲基异腈(8.57g,43.90mmol)溶于乙二醇二甲醚(70mL)中，在0℃、氮气氛围下滴加叔丁醇钾的四氢呋喃溶液(58.54mL,58.54mmol,1M)，升至25℃搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(200mL)中淬灭，用乙酸乙酯(2×200mL)萃取，合并的有机相用饱和食盐水(300mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-35％乙酸乙酯/石油醚梯度纯化，得到化合物109-3。¹H NMR(400MHz,Chloroform-d)δ3.18-3.09(m,2H),3.06-2.94(m,1H),2.94-2.80(m,1H),2.76-2.62(m,2H),2.38-2.20(m,2H),1.91-1.80(m,2H),1.78-1.68(m,4H),1.64-1.46(m,2H)。Step 2: Compound 109-2 (6.30 g, 29.27 mmol), tert-butanol (6.36 mL, 43.90 mmol), and p-toluenesulfonylmethylisocyanate (8.57 g, 43.90 mmol) were dissolved in ethylene glycol dimethyl ether (70 mL). A tetrahydrofuran solution of potassium tert-butoxide (58.54 mL, 58.54 mmol, 1 M) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was then heated to 25 °C and stirred for 18 hours. The reaction was monitored by LC-MS. The reaction mixture was quenched in saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were washed with saturated brine (300 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–35% ethyl acetate/petroleum ether to obtain compound 109-3. ^1H NMR(400MHz,Chloroform-d)δ3.18-3.09(m,2H),3.06-2.94(m,1H),2.94-2.80(m,1H),2.7 6-2.62(m,2H),2.38-2.20(m,2H),1.91-1.80(m,2H),1.78-1.68(m,4H),1.64-1.46(m,2H).

步骤3：将化合物109-3(2.85g,12.60mmol)和对氟苯甲酸乙酯(3.39g,20.15mmol)溶于四氢呋喃(60mL)中，在0℃、氮气氛围下滴加双三甲基硅基胺基锂的四氢呋喃溶液(25.19mL,25.19mmol,1M)，升至25℃搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(100mL)中淬灭，用乙酸乙酯(2x100 mL)萃取，合并的有机相用饱和食盐水(150mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-30％乙酸乙酯/石油醚梯度纯化，得到化合物109-4。MS m/z(ESI)：＝375.2[M+H]⁺。Step 3: Compound 109-3 (2.85 g, 12.60 mmol) and ethyl p-fluorobenzoate (3.39 g, 20.15 mmol) were dissolved in tetrahydrofuran (60 mL). A tetrahydrofuran solution of bis(trimethylsilylamino)lithium (25.19 mL, 25.19 mmol, 1 M) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was then heated to 25 °C and stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was quenched in saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (2 x 100 mL), and the combined organic phases were washed with saturated brine (150 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–30% ethyl acetate/petroleum ether to give compound 109-4. MS m/z (ESI): = 375.2 [M+H] ⁺ .

步骤4：将化合物109-4(1.50g,4.01mmol)溶于二甲基亚砜(30mL)中，加入碳酸钾(1.11g,8.01mmol)和双氧水(2.67mL,16.02mmol,30％)中，在30℃下搅拌72小时。通过LCMS监测反应。缓慢加入水(150mL)，过滤，固体用乙酸乙酯/石油醚(30mL,1/5)打浆，搅拌1小时后过滤，得到化合物109-5。MS m/z(ESI)：＝393.2[M+H]⁺。Step 4: Compound 109-4 (1.50 g, 4.01 mmol) was dissolved in dimethyl sulfoxide (30 mL), and potassium carbonate (1.11 g, 8.01 mmol) and hydrogen peroxide (2.67 mL, 16.02 mmol, 30%) were added. The mixture was stirred at 30 °C for 72 hours. The reaction was monitored by LCMS. Water (150 mL) was slowly added, and the mixture was filtered. The solid was slurried with ethyl acetate/petroleum ether (30 mL, 1/5), stirred for 1 hour, and then filtered to obtain compound 109-5. MS m/z (ESI): = 393.2 [M+H] ⁺ .

步骤5：25℃下，将化合物109-5(380mg,0.97mmol)溶于乙腈(4mL)和水(4mL)中，加入[双(三氟乙酰氧基)碘]苯(833mg,1.94mmol)，搅拌2小时。通过LCMS监测反应。反应液倒入饱和碳酸氢钠溶液(30mL)中淬灭，用乙酸乙酯(2×40mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-40％乙酸乙酯/石油醚梯度纯化，得到化合物109-6。MS m/z(ESI)：＝365.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ7.88(d,J＝8.5Hz,2H),7.56(d,J＝8.5Hz,2H),4.30(q,J＝7.1Hz,2H),3.19(s,2H),2.96-2.87(m,1H),2.77-2.66(m,2H),2.40-2.23(m,4H),2.05(dd,J＝13.6,3.8Hz,2H),1.88-1.64(m,6H),1.31(t,J＝7.1Hz,3H)。Step 5: At 25°C, compound 109-5 (380 mg, 0.97 mmol) was dissolved in acetonitrile (4 mL) and water (4 mL), and [bis(trifluoroacetoxy)iodo]benzene (833 mg, 1.94 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction solution was quenched in saturated sodium bicarbonate solution (30 mL), extracted with ethyl acetate (2 × 40 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–40% ethyl acetate/petroleum ether to give compound 109-6. MS m/z (ESI): = 365.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ7.88(d,J＝8.5Hz,2H),7.56(d,J＝8.5Hz,2H),4.30(q,J＝7.1Hz,2H),3.19(s,2H),2.96-2.87(m,1H),2.7 7-2.66(m,2H),2.40-2.23(m,4H),2.05(dd,J＝13.6,3.8Hz,2H),1.88-1.64(m,6H),1.31(t,J＝7.1Hz,3H).

步骤6：25℃下，将化合物109-6(252mg,0.69mmol)、化合物1-14(200mg,0.69mmol)和乙酸(42mg,0.69mmol)溶于乙腈(4mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(293mg,1.38mmol)，继续搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(50mL)中淬灭，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-40％乙酸乙酯/石油醚梯度纯化，得到化合物110-1。MS m/z(ESI)：＝638.2[M+H]⁺。Step 6: At 25°C, compound 109-6 (252 mg, 0.69 mmol), compound 1-14 (200 mg, 0.69 mmol), and acetic acid (42 mg, 0.69 mmol) were dissolved in acetonitrile (4 mL). After stirring for 1 hour, sodium triacetoxyborohydride (293 mg, 1.38 mmol) was added, and stirring was continued for 18 hours. The reaction was monitored by LCMS. The reaction solution was quenched in saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-40% ethyl acetate/petroleum ether to give compound 110-1. MS m/z (ESI): = 638.2 [M+H] ⁺ .

步骤7：将化合物110-1(410mg,0.64mmol)溶于甲醇(15mL)和水(4mL)中，加入氢氧化锂(135mg，3.21mmol)，加热至50℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩。粗品通过反相色谱柱：32％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物110。MS m/z(ESI)：＝510.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.92(t,J＝2.4Hz,1H),3.61(s,3H),3.43-3.39(m,2H),3.22-3.17(m,2H),2.98-2.85(m,1H),2.76-2.63(m,2H),2.40(s,3H),2.35-2.17(m,6H),2.00(dd,J＝14.1,3.4Hz,2H),1.82-1.73(m,2H),1.65-1.42(m,1H)。Step 7: Compound 110-1 (410 mg, 0.64 mmol) was dissolved in methanol (15 mL) and water (4 mL), and lithium hydroxide (135 mg, 3.21 mmol) was added. The mixture was heated to 50 °C and stirred for 18 hours. The reaction was monitored by LC-MS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase column using a gradient of 32%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 110. MS m/z (ESI): = 510.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.20(t,J＝2.8H z,1H),6.63(s,1H),5.92(t,J＝2.4Hz,1H),3.61(s,3H),3.43-3.39(m,2H),3. 22-3.17(m,2H),2.98-2.85(m,1H),2.76-2.63(m,2H),2.40(s,3H),2.35-2.1 7(m,6H),2.00(dd,J=14.1,3.4Hz,2H),1.82-1.73(m,2H),1.65-1.42(m,1H).

实施例113：化合物113的制备
Example 113: Preparation of compound 113

步骤1：25℃下，将化合物103-1(450mg,1.49mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入醋酸(2滴)和环丙基甲醛(156mg,2.23mmol)，搅拌2小时后，加入氰基硼氰化钠(252mg,2.23mmol)，继续搅拌18小时。通过LCMS监测反应。加入水(30mL)淬灭，用乙酸乙酯(2×30mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：20％-50％乙酸乙酯/石油醚梯度纯化，得到化合物113-1。MS m/z(ESI)：＝357.7[M+H]⁺。Step 1: At 25°C, compound 103-1 (450 mg, 1.49 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of acetic acid (2 drops) and cyclopropylformaldehyde (156 mg, 2.23 mmol). After stirring for 2 hours, sodium cyanoborocyanate (252 mg, 2.23 mmol) was added, and stirring continued for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (30 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 20%–50% ethyl acetate/petroleum ether to give compound 113-1. MS m/z (ESI): = 357.7 [M+H] ⁺ .

步骤2：20℃下，将化合物113-1(240mg,0.67mmol)溶于乙腈(2mL)和水(2mL)中，加入[双(三氟乙酰氧基)碘]苯(1.16g,2.70mmol)，搅拌2小时。通过LCMS监测反应。浓缩，得到化合物113-2。MS m/z(ESI)：＝329.4[M+H]⁺。Step 2: At 20°C, compound 113-1 (240 mg, 0.67 mmol) was dissolved in acetonitrile (2 mL) and water (2 mL), and [bis(trifluoroacetoxy)iodo]benzene (1.16 g, 2.70 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The solution was concentrated to obtain compound 113-2. MS m/z (ESI): = 329.4 [M+H] ⁺ .

步骤3：25℃下，将化合物113-2(200mg,0.61mmol)溶于乙腈(5mL)和醋酸(0.1mL)中，加入化合物1-14(264mg,0.91mmol)，搅拌1小时后，加入氰基硼氢化钠(194mg,0.91mmol)，继续搅拌2小时。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(2×10mL)萃取，合并的有机相用饱和食盐水(10mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物113-3。MS m/z(ESI)：＝602.7[M+H]⁺。Step 3: At 25°C, compound 113-2 (200 mg, 0.61 mmol) was dissolved in acetonitrile (5 mL) and acetic acid (0.1 mL), and compound 1-14 (264 mg, 0.91 mmol) was added. After stirring for 1 hour, sodium cyanoborohydride (194 mg, 0.91 mmol) was added, and stirring was continued for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (2 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 113-3. MS m/z (ESI): 602.7 [M+H] ⁺ .

步骤4：将化合物113-3(300mg,0.50mmol)溶于甲醇(5mL)和水(1mL)中，加入氢氧化锂(105mg,2.49mmol)，在60℃、氮气氛围下搅拌18小时。通过LCMS监测反应。浓缩，粗品通过反相色谱柱：25％-100％乙腈/缓冲液(0.01mol/L甲酸水溶液)梯度纯化，得到化合物113。MS m/z(ESI)：＝474.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.78(d,J＝7.9Hz,2H),7.40(d,J＝8.0Hz,2H),7.20(t,J＝2.8Hz,1H),6.64(s,1H),5.91(dd,J＝3.2,1.9Hz,1H),3.72-3.61(m,5H),3.44-3.41(m,2H),2.40(s,3H),2.38-2.19(m,7H),1.89-1.81(m,2H),1.70-1.51(m,1H),1.28-0.98(m,1H),0.53-0.47(m,2H),0.25-0.17(m,2H)。Step 4: Compound 113-3 (300 mg, 0.50 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (105 mg, 2.49 mmol) was added. The mixture was stirred at 60 °C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by a reverse-phase column using a gradient of 25%–100% acetonitrile/buffer (0.01 mol/L formic acid aqueous solution) to obtain compound 113. MS m/z (ESI): = 474.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(s,1H),7.78(d,J＝7.9Hz,2H),7.40(d,J＝8.0Hz,2H),7.20(t,J＝ 2.8Hz,1H),6.64(s,1H),5.91(dd,J＝3.2,1.9Hz,1H),3.72-3.61(m,5H), 3.44-3.41(m,2H),2.40(s,3H),2.38-2.19(m,7H),1.89-1.81(m,2H),1. 70-1.51(m,1H),1.28-0.98(m,1H),0.53-0.47(m,2H),0.25-0.17(m,2H).

实施例114：化合物114的制备
Example 114: Preparation of compound 114

步骤1：25℃下，将化合物103-1(500mg,1.65mmol)、环丙甲酸(157mg,1.82mmol)和N,N-二异丙基乙胺(0.86mL,4.96mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(692mg,1.82mmol)，搅拌2小时。通过LCMS监测反应。反应液倒入冰水(50mL)中，用乙酸乙酯(2×80mL)萃取，合并的有机相用水(2x80 mL)和饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物114-1。MS m/z(ESI)：＝371.3[M+H]⁺。Step 1: At 25°C, compound 103-1 (500 mg, 1.65 mmol), cyclopropionic acid (157 mg, 1.82 mmol), and N,N-diisopropylethylamine (0.86 mL, 4.96 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (692 mg, 1.82 mmol) was added, and the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction mixture was poured into ice water (50 mL), extracted with ethyl acetate (2 × 80 mL), and the combined organic phases were washed with water (2 × 80 mL) and saturated brine (80 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 114-1. MS m/z(ESI): =371.3[M+H] ⁺ .

步骤2：25℃下，将化合物114-1(475mg,1.28mmol)溶于乙腈(15mL)和水(15mL)中，再加入[双(三氟乙酰氧基)碘]苯(827mg,1.92mmol)，搅拌24小时。通过LCMS监测反应。反应液倒入饱和碳酸氢钠溶液(50mL)中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物114-2。MS m/z(ESI)：＝343.2[M+H]⁺。Step 2: At 25°C, compound 114-1 (475 mg, 1.28 mmol) was dissolved in acetonitrile (15 mL) and water (15 mL), followed by the addition of [bis(trifluoroacetoxy)iodo]benzene (827 mg, 1.92 mmol), and the mixture was stirred for 24 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (80 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to obtain compound 114-2. MS m/z (ESI): = 343.2 [M+H] ⁺ .

步骤3：25℃下，将化合物1-14(307mg,1.06mmol)、化合物114-2(363mg,1.06mmol)和乙酸(72mg,1.20mmol)溶于乙腈(8mL)中，搅拌24小时后，加入三乙酰氧基硼氢化钠(449mg,2.12mmol)，继续搅拌4小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(50mL)中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-60％乙酸乙酯/石油醚梯度纯化，得到化合物114-3。MS m/z(ESI)：＝616.4[M+H]⁺。Step 3: At 25°C, compounds 1-14 (307 mg, 1.06 mmol), 114-2 (363 mg, 1.06 mmol), and acetic acid (72 mg, 1.20 mmol) were dissolved in acetonitrile (8 mL). After stirring for 24 hours, sodium triacetoxyborohydride (449 mg, 2.12 mmol) was added, and stirring was continued for 4 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-60% ethyl acetate/petroleum ether to give compound 114-3. MS m/z (ESI): = 616.4 [M+H] ⁺ .

步骤4：将化合物114-3(567mg,0.92mmol)溶于甲醇(15mL)和水(3mL)中，加入氢氧化锂(193mg，4.60mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩。粗品通过反相色谱柱：18％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物114。MS m/z(ESI)：＝488.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.83(d,J＝2.3Hz,1H),8.05-7.87(m,2H),7.52(d,J＝8.4Hz,2H),7.22(t,J＝2.8Hz,1H),6.65(s,1H),5.93(dd,J＝3.1,1.9Hz,1H),4.67-4.41(m,2H),3.63(s,3H),3.54-3.41(m,2H),2.49-2.27(m,7H),2.04-1.85(m,4H),1.82-1.66(m,1H),0.80-0.54(m,4H)。Step 4: Compound 114-3 (567 mg, 0.92 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (193 mg, 4.60 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the solution was concentrated. The crude product was purified by a reverse-phase column using a gradient of 18%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 114. MS m/z (ESI): = 488.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.83(d,J＝2.3Hz,1H),8.05-7.87(m,2H),7.52(d,J＝8.4Hz,2H),7.22(t,J＝2.8Hz,1H),6.65(s,1H),5.93(dd,J＝3.1,1.9Hz,1H ),4.67-4.41(m,2H),3.63(s,3H),3.54-3.41(m,2H),2.49-2.27(m,7H),2.04-1.85(m,4H),1.82-1.66(m,1H),0.80-0.54(m,4H).

实施例115：化合物115的制备
Example 115: Preparation of compound 115

步骤1：将化合物115-1(400mg,4.44mmol)和三乙胺(1.15mL,8.88mmol)溶于二氯甲烷(15mL)中，在0℃、氮气氛围下加入对甲苯磺酰氯(931mg,4.88mmol)，升至25℃搅拌18小时。通过TLC监测反应。浓缩，粗品通过硅胶色谱柱：1％-20％乙酸乙酯/石油醚梯度纯化，得到化合物115-2。¹H NMR(400MHz,DMSO-d₆)δ7.81(d,J＝8.1Hz,2H),7.50(d,J＝8.0Hz,2H),4.39(d,J＝22.7Hz,2H),2.43(s,3H),1.13-1.01(m,2H),0.84-0.73(m,2H)。Step 1: Compound 115-1 (400 mg, 4.44 mmol) and triethylamine (1.15 mL, 8.88 mmol) were dissolved in dichloromethane (15 mL). p-Toluenesulfonyl chloride (931 mg, 4.88 mmol) was added at 0 °C under a nitrogen atmosphere, and the mixture was stirred at 25 °C for 18 hours. The reaction was monitored by TLC. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 1%–20% ethyl acetate/petroleum ether to obtain compound 115-2. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.81 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.39 (d, J = 22.7 Hz, 2H), 2.43 (s, 3H), 1.13–1.01 (m, 2H), 0.84–0.73 (m, 2H).

步骤2：25℃下，将化合物115-2(848mg,3.47mmol)、化合物103-1(350mg,1.16mmol)和碳酸铯(754mg,2.32mmol)溶于N,N-二甲基甲酰胺(10mL)中，搅拌18小时。通过LCMS监测反应。反应液倒入水(60mL)中淬灭，用乙酸乙酯(2×80mL)萃取，合并的有机相用水(2x100 mL)和饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％甲醇/二氯甲烷梯度纯化，得到化合物115-3。MS m/z(ESI)：＝375.2[M+H]⁺。Step 2: Compound 115-2 (848 mg, 3.47 mmol), compound 103-1 (350 mg, 1.16 mmol), and cesium carbonate (754 mg, 2.32 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 25 °C and stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was quenched in water (60 mL), extracted with ethyl acetate (2 × 80 mL), and the combined organic phases were washed with water (2 × 100 mL) and saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–20% methanol/dichloromethane gradient to give compound 115-3. MS m/z (ESI): = 375.2 [M+H] ⁺ .

步骤3：25℃下，将化合物115-3(390mg,1.04mmol)溶于乙腈(10mL)和水(10mL)中，加入[双(三氟乙酰氧基)碘]苯(672mg,1.56mmol)，搅拌24小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-20％甲醇/二氯甲烷梯度纯化，得到化合物115-4。MS m/z(ESI)：＝347.2[M+H]⁺。Step 3: At 25°C, compound 115-3 (390 mg, 1.04 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and [bis(trifluoroacetoxy)iodide]benzene (672 mg, 1.56 mmol) was added. The mixture was stirred for 24 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a 0%-20% methanol/dichloromethane gradient to give compound 115-4. MS m/z (ESI): = 347.2 [M+H] ⁺ .

步骤4：25℃下，将化合物115-4(460mg,1.33mmol)、化合物1-14(320mg,1.11mmol)和乙酸(0.21mL,2.19mmol)溶于乙腈(10mL)中，搅拌2小时后，加入三乙酰氧基硼氢化钠(469mg,2.21mmol)，继续搅拌16小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(50mL)中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物115-5。MS m/z(ESI)：＝620.6[M+H]⁺。Step 4: At 25°C, compound 115-4 (460 mg, 1.33 mmol), compound 1-14 (320 mg, 1.11 mmol), and acetic acid (0.21 mL, 2.19 mmol) were dissolved in acetonitrile (10 mL). After stirring for 2 hours, sodium triacetoxyborohydride (469 mg, 2.21 mmol) was added, and stirring was continued for 16 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 115-5. MS m/z (ESI): = 620.6 [M+H] ⁺ .

步骤5：将化合物115-5(500mg,0.81mmol)溶于甲醇(15mL)和水(3mL)中，加入氢氧化锂(169mg,4.03mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，浓缩，粗品通过反相色谱柱：5％-78％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物115。MS m/z(ESI)：＝492.4[M+H]⁺。¹H NMR(400MHz,甲醇-d₄)δ8.21(d,J＝8.3Hz,2H),7.75(d,J＝8.6Hz,2H),7.23(t,J＝1.6Hz,1H),6.82(s,1H),5.82(d,J＝3.2Hz,1H),4.54-4.42(m,2H),4.24-4.14(m,1H),3.94(s,3H),3.72(d,J＝21.3Hz,3H),3.29-3.03(m,4H),2.79-2.60(m,2H),2.51-2.48(m,4H),2.43-2.34(m,1H),1.36-1.25(m,3H),1.10-1.02(m,2H)。Step 5: Compound 115-5 (500 mg, 0.81 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (169 mg, 4.03 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 5%–78% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 115. MS m/z (ESI): = 492.4 [M+H] ⁺ . ¹ H NMR (400MHz, methanol-d ₄ )δ8.21(d,J＝8.3Hz,2H),7.75(d,J＝8.6Hz,2H),7.23(t,J＝1.6Hz,1H),6.8 2(s,1H),5.82(d,J＝3.2Hz,1H),4.54-4.42(m,2H),4.24-4.14(m,1H),3.9 4(s,3H),3.72(d,J＝21.3Hz,3H),3.29-3.03(m,4H),2.79-2.60(m,2H),2. 51-2.48(m,4H),2.43-2.34(m,1H),1.36-1.25(m,3H),1.10-1.02(m,2H).

实施例117：化合物117的制备
Example 117: Preparation of Compound 117

步骤1：常温下，将化合物103-1(500mg,1.65mmol)溶于N,N-二甲基甲酰胺(10mL)中，加入环丁基甲醛(209mg,2.48mmol)和醋酸(1mL)，搅拌1小时后，加入氰基硼氢化钠(520mg,8.27mmol)，加热至50℃搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％乙酸乙酯/石油醚梯度纯化，得到化合物117-1。MS m/z(ESI)：＝371.4[M+H]⁺。Step 1: At room temperature, compound 103-1 (500 mg, 1.65 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of cyclobutylformaldehyde (209 mg, 2.48 mmol) and acetic acid (1 mL). After stirring for 1 hour, sodium cyanoborohydride (520 mg, 8.27 mmol) was added, and the mixture was heated to 50 °C and stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 2%–33% ethyl acetate/petroleum ether to obtain compound 117-1. MS m/z (ESI): = 371.4 [M+H] ⁺ .

步骤2：室温下，将化合物117-1(350mg,0.94mmol)溶于乙腈(5mL)和水(5mL)中，加入[双(三氟乙酰氧基)碘]苯(2.03g,4.72mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％甲醇/二氯甲烷梯度纯化，得到化合物117-2。MS m/z(ESI)：＝343.4[M+H]⁺。Step 2: At room temperature, compound 117-1 (350 mg, 0.94 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL), and [bis(trifluoroacetoxy)iodide]benzene (2.03 g, 4.72 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 2%–33% methanol/dichloromethane to obtain compound 117-2. MS m/z (ESI): = 343.4 [M+H] ⁺ .

步骤3：常温下，将化合物117-2(370mg,1.08mmol)溶于乙腈(10mL)中，加入化合物1-14(469mg,1.62mmol)和醋酸(2滴)，搅拌1小时后，加入三乙酰氧基硼氢化钠(1.14g,5.40mmol)，继续搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％甲醇/二氯甲烷梯度纯化，得到化合物117-3。MS m/z(ESI)：＝616.8[M+H]⁺。Step 3: At room temperature, compound 117-2 (370 mg, 1.08 mmol) was dissolved in acetonitrile (10 mL), compound 1-14 (469 mg, 1.62 mmol) and acetic acid (2 drops) were added, and the mixture was stirred for 1 hour. Then, sodium triacetoxyborohydride (1.14 g, 5.40 mmol) was added, and the mixture was stirred for another 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 2%–33% methanol/dichloromethane to obtain compound 117-3. MS m/z (ESI): = 616.8 [M+H] ⁺ .

步骤4：将化合物117-3(240mg,0.39mmol)溶于甲醇(10mL)和水(2mL)中，加入氢氧化锂(82mg,1.95mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/碳酸氢铵水溶液)梯度纯化，得到化合物117。MS m/z(ESI)：＝488.6[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ12.90(s,1H),10.86(s,1H),7.98(d,J＝8.2Hz,2H),7.60(d,J＝8.2Hz,2H),7.22(s,2H),6.65(s,1H),5.90(t,J＝2.4Hz,1H),3.96-3.83(m,2H),3.64(s,3H),3.44-3.37(m,2H),3.00(t,J＝6.4Hz,2H),2.77(p,J＝7.6Hz,1H),2.63-2.52(m,4H),2.48-2.40(m,2H),2.41(s,3H),2.13-1.98(m,4H),1.94-1.73(m,4H)。Step 4: Compound 117-3 (240 mg, 0.39 mmol) was dissolved in methanol (10 mL) and water (2 mL), and lithium hydroxide (82 mg, 1.95 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/Aqueous bicarbonate solution) to obtain compound 117. MS m/z (ESI): = 488.6 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ12.90(s,1H),10.86(s,1H),7.98(d,J＝8.2Hz,2H),7.60(d,J＝8.2Hz,2H),7 .22(s,2H),6.65(s,1H),5.90(t,J＝2.4Hz,1H),3.96-3.83(m,2H),3.64(s,3H ),3.44-3.37(m,2H),3.00(t,J＝6.4Hz,2H),2.77(p,J＝7.6Hz,1H),2.63-2.52 (m,4H),2.48-2.40(m,2H),2.41(s,3H),2.13-1.98(m,4H),1.94-1.73(m,4H).

实施例119：化合物119的制备
Example 119: Preparation of compound 119

步骤1：25℃下，将化合物119-1(50.00g,299.11mmol)和溴化苄(51.20g,299.11mmol)溶于N,N-二甲基甲酰胺(500mL)中，分批加入碳酸铯(116.70g,358.94mmol)，搅拌4小时。通过LCMS和TLC监测反应。加入水(500mL)淬灭，用乙酸乙酯(3×500mL)萃取，合并的有机相用饱和食盐水(1L)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-25％乙酸乙酯/石油醚梯度纯化，得到化合物119-2。Step 1: At 25°C, compound 119-1 (50.00 g, 299.11 mmol) and benzyl bromide (51.20 g, 299.11 mmol) were dissolved in N,N-dimethylformamide (500 mL), and cesium carbonate (116.70 g, 358.94 mmol) was added in portions. The mixture was stirred for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (500 mL), extracted with ethyl acetate (3 × 500 mL), and the combined organic phases were washed with saturated brine (1 L), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–25% ethyl acetate/petroleum ether to give compound 119-2.

步骤2：室温下，将化合物119-2(74.50g,289.56mmol)和N,N-二甲基甲酰胺二甲基缩醛(103.50g,868.67mmol)溶于N,N-二甲基甲酰胺(750mL)中，加入四氢吡咯(61.8g,868.67mmol)，升温至90℃搅拌16小时。通过LCMS和TLC监测反应。浓缩，得到化合物119-3。Step 2: At room temperature, compound 119-2 (74.50 g, 289.56 mmol) and N,N-dimethylformamide dimethyl acetal (103.50 g, 868.67 mmol) were dissolved in N,N-dimethylformamide (750 mL), and tetrahydropyrrole (61.8 g, 868.67 mmol) was added. The mixture was heated to 90 °C and stirred for 16 hours. The reaction was monitored by LCMS and TLC. The solution was concentrated to obtain compound 119-3.

步骤3：25℃下，将化合物119-3(95.00g,280.72mmol)溶于乙酸乙酯(1L)中，加入雷尼镍(10g)，氢气氛围下搅拌16小时。通过LCMS和TLC监测反应。过滤，浓缩，得到化合物119-4。MS m/z(ESI)：＝238.2[M+H]⁺。Step 3: At 25°C, compound 119-3 (95.00 g, 280.72 mmol) was dissolved in ethyl acetate (1 L), and Raney nickel (10 g) was added. The mixture was stirred for 16 hours under a hydrogen atmosphere. The reaction was monitored by LCMS and TLC. The solution was filtered and concentrated to give compound 119-4. MS m/z (ESI): = 238.2 [M+H] ⁺ .

步骤4：25℃下，将化合物119-4(65.00g,273.91mmol)和二碳酸二叔丁酯(119.60g,547.83mmol)溶于乙腈(650mL)中，加入4-二甲氨基吡啶(33.4g,273.91mmol)，搅拌16小时。通过LCMS和TLC监测反应。浓缩，加入水(300mL)淬灭，用乙酸乙酯(3×300mL)萃取，合并的有机相用饱和食盐水(500mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-25％乙酸乙酯/石油醚梯度纯化，得到化合物119-5。Step 4: At 25°C, compound 119-4 (65.00 g, 273.91 mmol) and di-tert-butyl dicarbonate (119.60 g, 547.83 mmol) were dissolved in acetonitrile (650 mL), and 4-dimethylaminopyridine (33.4 g, 273.91 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS and TLC. The mixture was concentrated, quenched with water (300 mL), extracted with ethyl acetate (3 × 300 mL), and the combined organic phases were washed with saturated brine (500 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–25% ethyl acetate/petroleum ether to give compound 119-5.

步骤5：将化合物119-5(46.30g,137.22mmol)和甲酸铵(8.60g,137.22mmol)溶于乙醇(500mL)中，加入钯碳(5g,10％)，50℃、氮气氛围下搅拌2小时。通过LCMS和TLC监测反应。过滤，浓缩，加入水(300mL)稀释，用乙酸乙酯(3×300mL)萃取，合并的有机相用饱和食盐水(500mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物119-6。MS m/z(ESI)：＝248.2[M+H]⁺。Step 5: Compound 119-5 (46.30 g, 137.22 mmol) and ammonium formate (8.60 g, 137.22 mmol) were dissolved in ethanol (500 mL), and palladium on carbon (5 g, 10%) was added. The mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS and TLC. The mixture was filtered, concentrated, diluted with water (300 mL), extracted with ethyl acetate (3 × 300 mL), and the combined organic phases were washed with saturated brine (500 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–50% ethyl acetate/petroleum ether to give compound 119-6. MS m/z (ESI): = 248.2 [M+H] ⁺ .

步骤6：20℃下，将多聚甲醛(44.40g,493.35mmol)和三乙胺(39.90g,394.68mmol)溶于四氢呋喃(500mL)中，加入氯化镁(35.20g,370.01mmol)，搅拌30分钟后，加入化合物119-6(30.50g,123.34mmol)，升温至70℃搅拌3小时。通过LCMS监测反应。过滤，浓缩，加入水(500mL)淬灭，用乙酸乙酯(3×500mL)萃取，合并的有机相用饱和食盐水(1L)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物119-7。MS m/z(ESI)：＝276.1[M+H]⁺。Step 6: At 20°C, paraformaldehyde (44.40 g, 493.35 mmol) and triethylamine (39.90 g, 394.68 mmol) were dissolved in tetrahydrofuran (500 mL), and magnesium chloride (35.20 g, 370.01 mmol) was added. After stirring for 30 minutes, compound 119-6 (30.50 g, 123.34 mmol) was added, and the mixture was heated to 70°C and stirred for 3 hours. The reaction was monitored by LCMS. The mixture was filtered, concentrated, quenched with water (500 mL), and extracted with ethyl acetate (3 × 500 mL). The combined organic phases were washed with saturated brine (1 L), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–50% ethyl acetate/petroleum ether to give compound 119-7. MS m/z (ESI): = 276.1 [M+H] ⁺ .

步骤7：室温下，将化合物119-7(3.00g,10.90mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入氘代碘甲烷(1.36mL,21.79mmol)，搅拌2小时。通过LCMS监测反应。加入水(20mL)淬灭，用乙酸乙酯(3×20mL)萃取，合并的有机相用饱和食盐水(40mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：10％-20％乙酸乙酯/石油醚梯度纯化，得到化合物119-8。MS m/z(ESI)：＝293.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.52(d,J＝1.0Hz,1H),7.80(dd,J＝3.7,1.8Hz,1H),7.31(dd,J＝3.7,1.0Hz,1H),7.05-7.00(m,1H),2.61(d,J＝1.4Hz,3H),1.60(s,9H)。Step 7: At room temperature, compound 119-7 (3.00 g, 10.90 mmol) was dissolved in N,N-dimethylformamide (30 mL), and deuterated iodomethane (1.36 mL, 21.79 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (40 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 10%–20% ethyl acetate/petroleum ether gradient to give compound 119-8. MS m/z (ESI): = 293.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.52(d,J＝1.0Hz,1H),7.80(dd,J＝3.7,1.8Hz,1H),7.31(dd,J＝3.7,1.0Hz,1H),7.05-7.00(m,1H),2.61(d,J＝1.4Hz,3H),1.60(s,9H).

步骤8：将化合物103-1(1.00g,3.31mmol)和2,2,2-三氟乙基三氟甲烷磺酸酯(1.15g,4.96mmol)溶于二氯甲烷(200mL)中，0℃下加入三乙胺(0.86mL,6.61mmol)，升至室温搅拌18个小时。通过LCMS监测反应。加入水(20mL)淬灭，用二氯甲烷(3×60mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物119-9。MS m/z(ESI)：＝385.2[M+H]⁺。Step 8: Compound 103-1 (1.00 g, 3.31 mmol) and 2,2,2-trifluoroethyltrifluoromethane sulfonate (1.15 g, 4.96 mmol) were dissolved in dichloromethane (200 mL). Triethylamine (0.86 mL, 6.61 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL), extracted with dichloromethane (3 × 60 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–50% ethyl acetate/petroleum ether to give compound 119-9. MS m/z (ESI): = 385.2 [M+H] ⁺ .

步骤9：25℃下，将化合物119-9(1.00g,2.60mmol)溶于乙腈(10ml)和水(10ml)中，加入[双(三氟乙酰氧基)碘]苯(1.23g,2.86mmol)，搅拌3小时。通过LCMS监测反应。反应液倒入饱和碳酸氢钠(50mL)溶液中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物119-10。MS m/z(ESI)：＝357.3[M+H]⁺。Step 9: At 25°C, compound 119-9 (1.00 g, 2.60 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and [bis(trifluoroacetoxy)iodo]benzene (1.23 g, 2.86 mmol) was added. The mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (80 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 119-10. MS m/z (ESI): = 357.3 [M+H] ⁺ .

步骤10：25℃下，将化合物119-10(240mg,0.67mmol)和化合物119-8(196.9mg,0.67mmol)溶于乙腈(5mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(285.5mg,1.35mmol)，继续搅拌17小时。通过LCMS监测反应。加入饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物119-11。MS m/z(ESI)：＝633.4[M+H]⁺。Step 10: Compounds 119-10 (240 mg, 0.67 mmol) and 119-8 (196.9 mg, 0.67 mmol) were dissolved in acetonitrile (5 mL) at 25 °C. After stirring for 1 hour, sodium triacetoxyborohydride (285.5 mg, 1.35 mmol) was added, and stirring was continued for 17 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 119-11. MS m/z (ESI): = 633.4 [M+H] ⁺ .

步骤11：将化合物119-11(380mg,0.60mmol)溶于甲醇(5mL)和水(1mL)，加入氢氧化锂(75.6mg,1.80mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩。粗品通过反相色谱柱：5％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物119。MS m/z(ESI)：＝505.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.93(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.62(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.40(s,2H),3.28(d,J＝4.6Hz,2H),3.04(q,J＝10.1Hz,2H),2.40(s,3H),2.29-2.20(m,4H),2.02(dd,J＝13.8,3.4Hz,2H),1.78-1.72(m,2H)。Step 11: Compound 119-11 (380 mg, 0.60 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (75.6 mg, 1.80 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LC-MS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the solution was concentrated. The crude product was purified by a reverse-phase column using a gradient of 5%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 119. MS m/z (ESI): = 505.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.81(s,1H),7.93(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.62(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.40(s ,2H),3.28(d,J＝4.6Hz,2H),3.04(q,J＝10.1Hz,2H),2.40(s,3H),2.29-2.20(m,4H),2.02(dd,J＝13.8,3.4Hz,2H),1.78-1.72(m,2H).

实施例122：化合物122的制备
Example 122: Preparation of compound 122

步骤1：室温下，将化合物119-10(6.00g,16.84mmol)和化合物1-14(4.63g,16.00mmol)溶于乙腈(30mL)中，滴加乙酸(0.96g,16.84mmol)，搅拌20分钟后，加入三乙酰氧基硼氢化钠(7.14g,33.67mmol)，继续搅拌3小时。通过LCMS监测反应。浓缩，加水(30mL)淬灭，用乙酸乙酯(3×30mL)萃取，合并的有机相用饱和食盐水(30mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物122-1。MS m/z(ESI)：＝630.2[M+H]⁺。Step 1: At room temperature, compounds 119-10 (6.00 g, 16.84 mmol) and 1-14 (4.63 g, 16.00 mmol) were dissolved in acetonitrile (30 mL), and acetic acid (0.96 g, 16.84 mmol) was added dropwise. After stirring for 20 minutes, sodium triacetoxyborohydride (7.14 g, 33.67 mmol) was added, and stirring was continued for 3 hours. The reaction was monitored by LCMS. The mixture was concentrated, quenched with water (30 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 122-1. MS m/z (ESI): = 630.2 [M+H] ⁺ .

步骤2：将化合物122-1(7.30g,11.59mmol溶于甲醇(100mL)和水(20mL)中，加入氢氧化锂(2.43g,57.95mmol)，加热至60℃搅拌12个小时。通过LCMS监测反应。浓缩，加入盐酸(1N)调节体系pH至中性，过滤，浓缩，粗品通过反相色谱柱：25％-95％乙腈/缓冲液(0.1mol/碳酸氢铵水溶液)梯度纯化，得到化合物122。MS m/z(ESI)：＝502.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.83(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.90(t,J＝2.5Hz,1H),3.61(s,3H),3.39(s,2H),3.28(s,2H),3.04(q,J＝10.1Hz,2H),2.39(s,3H),2.28-2.20(m,4H),2.06-1.96(m,2H),1.80-1.69(m,2H)。Step 2: Compound 122-1 (7.30 g, 11.59 mmol) was dissolved in methanol (100 mL) and water (20 mL), and lithium hydroxide (2.43 g, 57.95 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours. The reaction was monitored by LCMS. The solution was concentrated, and the pH of the system was adjusted to neutral by adding hydrochloric acid (1 N). The solution was filtered, concentrated, and the crude product was purified by a reversed-phase chromatography column using a gradient of 25%–95% acetonitrile/buffer (0.1 mol/Aqueous bicarbonate solution) to obtain compound 122. MS m/z (ESI): = 502.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.83(s,1H),7.93(d,J＝8.3Hz,2H),7.53(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.90(t,J＝2.5Hz,1H),3.61( s,3H),3.39(s,2H),3.28(s,2H),3.04(q,J＝10.1Hz,2H),2.39(s,3H),2.28-2.20(m,4H),2.06-1.96(m,2H),1.80-1.69(m,2H).

实施例123：化合物123的制备
Example 123: Preparation of compound 123

步骤1：20℃下，将化合物1-6(5.00g,16.38mmol)和碳酸钾(6.79g,49.13mmol)溶于N,N-二甲基甲酰胺(80mL)中，滴加碘甲烷(4.65g,32.75mmol)，搅拌3小时。通过LCMS和TLC监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物123-1。MS m/z(ESI)：＝320[M+H]⁺。Step 1: At 20 °C, compounds 1-6 (5.00 g, 16.38 mmol) and potassium carbonate (6.79 g, 49.13 mmol) were dissolved in N,N-dimethylformamide (80 mL), and iodomethane (4.65 g, 32.75 mmol) was added dropwise, followed by stirring for 3 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 123-1. MS m/z (ESI): = 320 [M+H] ⁺ .

步骤2：将化合物123-1(5.20g,16.28mmol)溶于甲醇(120mL)中，0℃下缓慢加入硼氘化钠(1.37g,32.57mmol)，升至20℃搅拌4小时。通过LCMS和TLC监测反应。0℃下加入十水合硫酸钠，搅拌2小时，过滤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物123-2。MS m/z(ESI)：＝176[M-17]⁺。Step 2: Compound 123-1 (5.20 g, 16.28 mmol) was dissolved in methanol (120 mL), and sodium borodeuteride (1.37 g, 32.57 mmol) was slowly added at 0 °C. The mixture was then heated to 20 °C and stirred for 4 hours. The reaction was monitored by LC-MS and TLC. Sodium sulfate decahydrate was added at 0 °C, and the mixture was stirred for 2 hours. The mixture was filtered, dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–50% ethyl acetate/petroleum ether to give compound 123-2. MS m/z (ESI): = 176 [M-17] ⁺ .

步骤3：室温下，将化合物123-2(3.00g,15.52mmol)溶于二氯甲烷(120mL)中，加入二氧化锰(1.48g,17.08mmol)，升至50℃搅拌24小时。通过LCMS和TLC监测反应。过滤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物123-3。MS m/z(ESI)：＝191[M+H]⁺。Step 3: At room temperature, compound 123-2 (3.00 g, 15.52 mmol) was dissolved in dichloromethane (120 mL), and manganese dioxide (1.48 g, 17.08 mmol) was added. The mixture was heated to 50 °C and stirred for 24 hours. The reaction was monitored by LCMS and TLC. The product was filtered, dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–50% ethyl acetate/petroleum ether to give compound 123-3. MS m/z (ESI): = 191 [M+H] ⁺ .

步骤4：20℃下，将化合物123-3(480mg,2.52mmol)和化合物119-10(1.08g,3.03mmol)溶于甲醇(30mL)中，加入乙酸(5滴)，搅拌1小时后，0℃下缓慢加入硼氘化钠(211mg,5.05mmol)，升至常温搅拌4小时。通过LCMS和TLC监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物123-4。MS m/z(ESI)：＝532[M+H]⁺。Step 4: At 20°C, compound 123-3 (480 mg, 2.52 mmol) and compound 119-10 (1.08 g, 3.03 mmol) were dissolved in methanol (30 mL), and acetic acid (5 drops) was added. After stirring for 1 hour, sodium borodeuteride (211 mg, 5.05 mmol) was slowly added at 0°C, and the mixture was heated to room temperature and stirred for 4 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-50% ethyl acetate/petroleum ether to give compound 123-4. MS m/z (ESI): 532 [M+H] ⁺ .

步骤5：将化合物123-4(1.00g,1.88mmol)溶于甲醇(20mL)、水(20mL)和四氢呋喃(20mL)中，加入氢氧化锂(135mg,5.64mmol)，50℃搅拌3小时。通过LCMS监测反应。加入盐酸(1N)调节pH至5，加入水(100mL)，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物123。MS m/z(ESI)：＝504[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.94(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.20(t,J＝2.7Hz,1H),6.63(s,1H),5.98-5.86(m,1H),3.61(s,3H),3.28(s,2H),3.04(d,J＝10.1Hz,2H),2.40(s,3H),2.24(d,J＝8.1Hz,4H),2.02(d,J＝11.2Hz,2H),1.82-1.67(m,2H)。Step 5: Compound 123-4 (1.00 g, 1.88 mmol) was dissolved in methanol (20 mL), water (20 mL), and tetrahydrofuran (20 mL). Lithium hydroxide (135 mg, 5.64 mmol) was added, and the mixture was stirred at 50 °C for 3 hours. The reaction was monitored by LCMS. The pH was adjusted to 5 with hydrochloric acid (1 N), and water (100 mL) was added. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–100% ethyl acetate/petroleum ether to give compound 123. MS m/z (ESI): = 504 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.81(s,1H),7.94(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.20(t,J＝2.7Hz,1H),6.63(s,1H),5.98-5.86(m,1H),3.61( s,3H),3.28(s,2H),3.04(d,J＝10.1Hz,2H),2.40(s,3H),2.24(d,J＝8.1Hz,4H),2.02(d,J＝11.2Hz,2H),1.82-1.67(m,2H).

实施例124：化合物124的制备
Example 124: Preparation of Compound 124

步骤1：冰浴下将化合物124-1(30.3g，154.64mmol)溶于硫酸(120mL)和硝酸(8mL)中，保持0℃搅拌2小时。通过LCMS监测反应。加入水(1000mL)淬灭，加入碳酸钠固体调节pH至中性，用乙酸乙酯(3×500mL)萃取，合并的有机相用饱和食盐水(500mL)洗涤，再用无水硫酸钠干燥并浓缩。粗品通过硅胶色谱柱：10％-16％乙酸乙酯/石油醚梯度纯化，得到化合物124-2。MS m/z(ESI)：＝241.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ8.63(s,1H),8.15(s,1H),2.58(s,3H)。Step 1: Compound 124-1 (30.3 g, 154.64 mmol) was dissolved in sulfuric acid (120 mL) and nitric acid (8 mL) under ice bath conditions and stirred at 0 °C for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (1000 mL), and the pH was adjusted to neutral with sodium carbonate solid. Extraction was performed with ethyl acetate (3 × 500 mL). The combined organic phases were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 10%–16% ethyl acetate/petroleum ether to give compound 124-2. MS m/z (ESI): = 241.0 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.63 (s, 1H), 8.15 (s, 1H), 2.58 (s, 3H).

步骤2：在-20℃氮气保护下将化合物124-2(1.5g，6.25mmol)溶于无水四氢呋喃(15mL)，加入乙烯基溴化镁的四氢呋喃溶液(25mL，1M，25mmol)，升至室温搅拌1.5小时。通过LCMS监测反应。加入饱和氯化铵溶液(100mL)淬灭，加入水(100mL)，并用乙酸乙酯(3×100mL)萃取。合并的有机相用饱和食盐水(100mL)洗涤，再用无水硫酸钠干燥并浓缩。粗品通过硅胶色谱柱：20％-30％乙酸乙酯/石油醚梯度纯化，得到化合物124-3。MS m/z(ESI)：＝235.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ11.96(s,1H),7.69(t,J＝2.9Hz,1H),7.33(s,1H),6.57(dd,J＝3.1,1.8Hz,1H),2.56(s,3H)。Step 2: Compound 124-2 (1.5 g, 6.25 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) under nitrogen protection at -20 °C. A tetrahydrofuran solution of vinyl magnesium bromide (25 mL, 1 M, 25 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated ammonium chloride solution (100 mL), water (100 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a 20%–30% ethyl acetate/petroleum ether gradient to give compound 124-3. MS m/z (ESI): = 235.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.96 (s, 1H), 7.69 (t, J = 2.9 Hz, 1H), 7.33 (s, 1H), 6.57 (dd, J = 3.1, 1.8 Hz, 1H), 2.56 (s, 3H).

步骤3：将化合物124-3(2.0g，8.51mmol)溶于1,4-二氧六环(15mL)和水(5mL)，加入碳酸铯(5.6g，17.19mmol)，[1,1'-双(二苯基膦)二茂铁]二氯化钯(625mg，0.86mmol)和环丙基硼酸(1.1g，12.81mmol)，反应在90℃下搅拌16小时。通过TLC监测反应。加入水(20mL)淬灭，用乙酸乙酯(3×15mL)萃取。合并的有机相用饱和食盐水(20mL)洗涤，再用无水硫酸钠干燥并浓缩。粗品通过硅胶色谱柱：10％-20％乙酸乙酯/石油醚梯度纯化，得到化合物124-4。¹H NMR(400MHz,DMSO-d₆)δ11.59(s,1H),7.55(t,J＝2.9Hz,1H),6.60(s,1H),6.50-6.44(m,1H),2.49(s,3H),2.21(m,1H),1.09-1.03(m,2H),0.81-0.76(m,2H)。Step 3: Compound 124-3 (2.0 g, 8.51 mmol) was dissolved in 1,4-dioxane (15 mL) and water (5 mL), and cesium carbonate (5.6 g, 17.19 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (625 mg, 0.86 mmol) and cyclopropylboronic acid (1.1 g, 12.81 mmol) were added. The reaction was stirred at 90 °C for 16 hours. The reaction was monitored by TLC. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography using a 10%–20% ethyl acetate/petroleum ether gradient to give compound 124-4. ¹ H NMR (400MHz, DMSO-d ₆ )δ11.59(s,1H),7.55(t,J＝2.9Hz,1H),6.60(s,1H),6.50-6.44(m,1H),2.49(s,3H),2.21(m,1H),1.09-1.03(m,2H),0.81-0.76(m,2H).

步骤4：在-78℃氮气保护下将化合物124-4(200mg，1.02mmol)溶于甲苯(4mL)，加入二异丁基氢化铝的己烷溶液(1.6mL，1M，1.60mmol)，反应在-78℃下搅拌1.5小时。通过LCMS监测反应。加入十水硫酸钠淬灭，搅拌30分钟后过滤并浓缩。粗品通过硅胶色谱柱：10％-20％乙酸乙酯/石油醚梯度纯化，得到化合物124-5。MS m/z(ESI)：＝200.0[M+H]⁺。Step 4: Compound 124-4 (200 mg, 1.02 mmol) was dissolved in toluene (4 mL) under nitrogen protection at -78 °C. A hexane solution of diisobutylaluminum hydride (1.6 mL, 1 M, 1.60 mmol) was added, and the reaction was stirred at -78 °C for 1.5 h. The reaction was monitored by LC-MS. The mixture was quenched with sodium sulfate decahydrate, stirred for 30 min, filtered, and concentrated. The crude product was purified by silica gel column chromatography using a 10%–20% ethyl acetate/petroleum ether gradient to give compound 124-5. MS m/z (ESI): = 200.0 [M+H] ⁺ .

步骤5：将化合物124-5(917mg，4.60mmol)溶于二氯甲烷(10mL)中，加入三乙胺(1.92mL，13.81mmol)、4-二甲氨基吡啶(112mg，0.92mmol)和二碳酸二叔丁酯(1.5g，6.90mmol)，室温搅拌30分钟。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×50mL)萃取。合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-15％乙酸乙酯/石油醚梯度纯化，得到化合物124-6。MS m/z(ESI)：＝300.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.87(s,1H),7.80(d,J＝3.7Hz,1H),6.94(s,1H),6.70(d,J＝3.7Hz,1H),2.56(s,3H),2.25-2.15(m,1H),1.60(s,9H),1.06-1.02(m,2H),0.90-0.84(m,2H)。Step 5: Compound 124-5 (917 mg, 4.60 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.92 mL, 13.81 mmol), 4-dimethylaminopyridine (112 mg, 0.92 mmol), and di-tert-butyl dicarbonate (1.5 g, 6.90 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–15% ethyl acetate/petroleum ether to give compound 124-6. MS m/z (ESI): = 300.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.87(s,1H),7.80(d,J＝3.7Hz,1H),6.94(s,1H),6.70(d,J＝3.7Hz,1H),2.5 6(s,3H),2.25-2.15(m,1H),1.60(s,9H),1.06-1.02(m,2H),0.90-0.84(m,2H).

步骤6：室温下，将化合物119-10(830mg,2.33mmol)和化合物124-6(700mg,2.34mmol)溶于乙腈(30mL)中，加入乙酸(0.14mL,2.34mmol)，搅拌30分钟后，加入三乙酰氧基硼氢化钠(1.48g,7.01mmol)，继续搅拌12小时。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×30mL)萃取，合并的有机相用饱和食盐水(30mL)洗涤，干燥并浓缩。粗品用甲醇打浆纯化，得到化合物124-7。MS m/z(ESI)：＝640.2[M+H]⁺。Step 6: At room temperature, compounds 119-10 (830 mg, 2.33 mmol) and 124-6 (700 mg, 2.34 mmol) were dissolved in acetonitrile (30 mL), and acetic acid (0.14 mL, 2.34 mmol) was added. After stirring for 30 minutes, sodium triacetoxyborohydride (1.48 g, 7.01 mmol) was added, and stirring was continued for 12 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine (30 mL), dried, and concentrated. The crude product was purified by slurrying with methanol to give compound 124-7. MS m/z (ESI): 640.2 [M+H] ⁺ .

步骤7：将化合物124-7(1.00g,1.56mmol)溶于甲醇(80mL)和水(8mL)中，加入氢氧化锂(328mg,7.82mmol)，加热至60℃搅拌12小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，浓缩，粗品通过反相色谱柱：25％-95％乙腈/缓冲液(0.1mol/L碳酸氢铵水溶液)梯度纯化，得到化合物124。MS m/z(ESI)：＝512.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.91(d,J＝8.0Hz,2H),7.53(d,J＝8.1Hz,2H),7.14(t,J＝2.8Hz,1H),6.38(s,1H),5.80(t,J＝2.5Hz,1H),3.62(s,2H),3.27(s,2H),3.04(q,J＝10.1Hz,2H),2.33(s,5H),2.27(d,J＝7.2Hz,2H),2.03(dd,J＝14.0,3.5Hz,2H),1.85-1.71(m,2H),1.52(td,J＝8.5,4.3Hz,1H),0.54(dt,J＝8.8,2.9Hz,2H),0.48-0.35(m,2H)。Step 7: Compound 124-7 (1.00 g, 1.56 mmol) was dissolved in methanol (80 mL) and water (8 mL), and lithium hydroxide (328 mg, 7.82 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase column using a gradient of 25%–95% acetonitrile/buffer (0.1 mol/L ammonium bicarbonate aqueous solution) to obtain compound 124. MS m/z (ESI): = 512.2 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(s,1H),7.91(d,J＝8.0Hz,2H),7.53(d,J＝8.1Hz,2H),7.14(t,J＝2.8Hz,1H ),6.38(s,1H),5.80(t,J＝2.5Hz,1H),3.62(s,2H),3.27(s,2H),3.04(q,J＝10.1Hz, 2H),2.33(s,5H),2.27(d,J＝7.2Hz,2H),2.03(dd,J＝14.0,3.5Hz,2H),1.85-1.71( m,2H),1.52(td,J＝8.5,4.3Hz,1H),0.54(dt,J＝8.8,2.9Hz,2H),0.48-0.35(m,2H).

实施例131：化合物131的制备
Example 131: Preparation of compound 131

步骤1：将化合物129-1(8.41g,56.24mmol)和乙酸钠(26.54g,323.53mmol)溶于水(100mL)中，0℃下加入1,3-丙酮二羧酸(9.33g,63.86mmol)和盐酸(64mL,1N)，搅拌1小时后，缓慢滴加丁二醛水溶液(11g,51.11mmol,40％)的四氢呋喃溶液(100mL)，升至40℃搅拌18小时。通过LCMS监测反应。用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-10％乙酸乙酯/石油醚梯度纯化，得到化合物129-2。MS m/z(ESI)：＝222.2[M+H]⁺。Step 1: Compound 129-1 (8.41 g, 56.24 mmol) and sodium acetate (26.54 g, 323.53 mmol) were dissolved in water (100 mL). 1,3-propanone dicarboxylic acid (9.33 g, 63.86 mmol) and hydrochloric acid (64 mL, 1 N) were added at 0 °C. After stirring for 1 hour, a tetrahydrofuran solution (100 mL) of succinaldehyde aqueous solution (11 g, 51.11 mmol, 40%) was slowly added dropwise. The mixture was then heated to 40 °C and stirred for 18 hours. The reaction was monitored by LC-MS. The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 5%–10% ethyl acetate/petroleum ether gradient to give compound 129-2. MS m/z (ESI): = 222.2 [M+H] ⁺ .

步骤2：将化合物129-2(5.50g,24.86mmol)、对甲基苯磺酰甲基异腈(7.28g,37.29mmol)、叔丁醇(3.57mL,37.29mmol)溶于乙二醇二甲醚(55mL)中，0℃、氮气氛围下滴加叔丁醇钾的四氢呋喃溶液(49.72mL,49.72mmol,1.0M)，搅拌1小时后，升至25℃搅拌24小时。通过LCMS监测反应。加入水(50mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-10％乙酸乙酯/石油醚梯度纯化，得到化合物129-3。MS m/z(ESI)：＝233.2[M+H]⁺。Step 2: Compound 129-2 (5.50 g, 24.86 mmol), p-toluenesulfonylmethylisocyanate (7.28 g, 37.29 mmol), and tert-butanol (3.57 mL, 37.29 mmol) were dissolved in ethylene glycol dimethyl ether (55 mL). A tetrahydrofuran solution of potassium tert-butoxide (49.72 mL, 49.72 mmol, 1.0 M) was added dropwise under a nitrogen atmosphere at 0 °C. After stirring for 1 hour, the mixture was raised to 25 °C and stirred for 24 hours. The reaction was monitored by LC-MS. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 5%–10% ethyl acetate/petroleum ether gradient to give compound 129-3. MS m/z (ESI): = 233.2 [M+H] ⁺ .

步骤3：将化合物129-3(3.00g,12.92mmol)、对氟苯甲酸乙酯(3.78mL,25.83mmol)溶于四氢呋喃(30mL)中，在0℃、氮气氛围下滴加双三甲基硅基胺基锂的四氢呋喃溶液(25.83mL,25.83mmol,1.0M)，升至25℃搅拌2小时。通过LCMS和TLC监测反应。加入饱和氯化铵溶液(50mL)淬灭，用乙酸乙酯(3×30mL)萃取，合并的有机相用饱和食盐水(50mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-10％乙酸乙酯/石油醚梯度纯化，得到化合物129-4。MS m/z(ESI)：＝381.2[M+H]⁺。Step 3: Compound 129-3 (3.00 g, 12.92 mmol) and ethyl p-fluorobenzoate (3.78 mL, 25.83 mmol) were dissolved in tetrahydrofuran (30 mL). A tetrahydrofuran solution of lithium bis(trimethylsilylamino)amine (25.83 mL, 25.83 mmol, 1.0 M) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was then heated to 25 °C and stirred for 2 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–10% ethyl acetate/petroleum ether to give compound 129-4. MS m/z (ESI): = 381.2 [M+H] ⁺ .

步骤4：将化合物129-4(3.20g,8.41mmol)和碳酸钾(2.33g,16.82mmol)溶于二甲基亚砜(33mL)中，0℃下滴加入双氧水(3.38mL,30％)，升至25℃搅拌16小时。通过LCMS和TLC监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×50mL)萃取，合并的有机相用饱和食盐水(30mL)洗涤，干燥并浓缩。粗品通过乙酸乙酯/石油醚(50mL,1/5)打浆纯化，得到化合物129-5。MS m/z(ESI)：＝399.2[M+H]⁺。Step 4: Compound 129-4 (3.20 g, 8.41 mmol) and potassium carbonate (2.33 g, 16.82 mmol) were dissolved in dimethyl sulfoxide (33 mL). Hydrogen peroxide (3.38 mL, 30%) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine (30 mL), dried, and concentrated. The crude product was purified by slurry mixing with ethyl acetate/petroleum ether (50 mL, 1/5) to give compound 129-5. MS m/z (ESI): ＝399.2 [M+H] ⁺ .

步骤5：常温下，将化合物129-5(2.20g,5.52mmol)溶于乙腈(20mL)和水(20mL)中，加入[双(三氟乙酰氧基)碘]苯(2.61g,6.07mmol)，搅拌3小时。通过LCMS监测反应。加入饱和碳酸钠溶液(40mL)淬灭，用二氯甲烷(3×50mL)萃取，合并的有机相用饱和食盐水(40mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：30％-50％乙酸乙酯/石油醚梯度纯化，得到化合物129-6。MS m/z(ESI)：＝371.2[M+H]⁺。Step 5: At room temperature, compound 129-5 (2.20 g, 5.52 mmol) was dissolved in acetonitrile (20 mL) and water (20 mL), and [bis(trifluoroacetoxy)iodide]benzene (2.61 g, 6.07 mmol) was added. The mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (40 mL), extracted with dichloromethane (3 × 50 mL), and the combined organic phases were washed with saturated brine (40 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 30%–50% ethyl acetate/petroleum ether to give compound 129-6. MS m/z (ESI): = 371.2 [M+H] ⁺ .

步骤7：25℃下，将化合物129-6(148mg,0.40mmol)溶于乙腈(5mL)中，加入化合物1-14(98mg,0.34mmol)、乙酸(0.02mL,0.40mmol)，搅拌16小时后，加入三乙酰氧基硼氢化钠(343mg,1.62mmol)，继续搅拌6小时。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×10mL)萃取，合并的有机相用饱和食盐水(10mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％乙酸乙酯/石油醚梯度纯化，得到化合物131-1。MS m/z(ESI)：＝644.4[M+H]⁺。Step 7: At 25°C, compound 129-6 (148 mg, 0.40 mmol) was dissolved in acetonitrile (5 mL), and compound 1-14 (98 mg, 0.34 mmol) and acetic acid (0.02 mL, 0.40 mmol) were added. After stirring for 16 hours, sodium triacetoxyborohydride (343 mg, 1.62 mmol) was added, and stirring was continued for 6 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-10% ethyl acetate/petroleum ether to give compound 131-1. MS m/z (ESI): = 644.4 [M+H] ⁺ .

步骤8：将化合物131-1(170mg,0.26mmol)溶于乙醇(5mL)和水(2mL)中，加入氢氧化锂(55mg,1.32mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物131。MS m/z(ESI)：＝516.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.94(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.19(s,1H),6.66-6.57(m,1H),5.90(s,1H),3.59(s,3H),3.47-3.43(m,1H),3.42-3.35(m,3H),3.12-3.01(m,1H),2.39(s,3H),2.27-2.14(m,4H),1.97(d,J＝13.4Hz,2H),1.79-1.65(m,1H),1.62-1.47(m,1H),1.10(d,J＝6.3Hz,3H)。Step 8: Compound 131-1 (170 mg, 0.26 mmol) was dissolved in ethanol (5 mL) and water (2 mL), and lithium hydroxide (55 mg, 1.32 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 131. MS m/z (ESI): = 516.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(s,1H),7.94(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.19(s,1H ),6.66-6.57(m,1H),5.90(s,1H),3.59(s,3H),3.47-3.43(m,1H),3.42-3 .35(m,3H),3.12-3.01(m,1H),2.39(s,3H),2.27-2.14(m,4H),1.97(d,J＝ 13.4Hz, 2H), 1.79-1.65 (m, 1H), 1.62-1.47 (m, 1H), 1.10 (d, J = 6.3Hz, 3H).

实施例132：化合物132的制备
Example 132: Preparation of compound 132

步骤1：25℃下，将化合物129-6(300mg,0.81mmol)溶于乙腈(6mL)中，加入化合物119-8(237mg,0.81mmol)、乙酸(0.01mL,0.24mmol)，搅拌1小时后，加入三乙酰氧基硼氢化钠(343mg,1.62mmol)，搅拌6小时。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×10mL)萃取，合并的有机相用饱和食盐水(10mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％乙酸乙酯/石油醚梯度纯化，得到化合物132-1。MS m/z(ESI)：＝647.4[M+H]⁺。Step 1: At 25°C, compound 129-6 (300 mg, 0.81 mmol) was dissolved in acetonitrile (6 mL), and compound 119-8 (237 mg, 0.81 mmol) and acetic acid (0.01 mL, 0.24 mmol) were added. After stirring for 1 hour, sodium triacetoxyborohydride (343 mg, 1.62 mmol) was added, and the mixture was stirred for 6 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–10% ethyl acetate/petroleum ether to give compound 132-1. MS m/z (ESI): = 647.4 [M+H] ⁺ .

步骤2：将化合物132-1(500mg,0.77mmol)溶于乙醇(5mL)和水(2mL)中，加入氢氧化锂(162mg,3.87mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物132。MS m/z(ESI)：＝519.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(d,J＝2.6Hz,1H),7.93(d,J＝8.5Hz,2H),7.53(d,J＝8.4Hz,2H),7.20(t,J＝2.8Hz,1H),6.62(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.50(d,J＝6.6Hz,1H),3.45-3.38(m,3H),3.12(p,J＝7.1Hz,1H),2.40(s,3H),2.25(q,J＝11.4,10.3Hz,4H),1.99(d,J＝13.5Hz,2H),1.81-1.71(m,1H),1.64-1.52(m,1H),1.13(d,J＝6.8Hz,3H)。Step 2: Compound 132-1 (500 mg, 0.77 mmol) was dissolved in ethanol (5 mL) and water (2 mL), and lithium hydroxide (162 mg, 3.87 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 132. MS m/z (ESI): = 519.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(d,J＝2.6Hz,1H),7.93(d,J＝8.5Hz,2H),7.53(d,J＝8.4Hz,2H),7.20(t,J ＝2.8Hz,1H),6.62(s,1H),5.90(dd,J＝3.1,1.9Hz,1H),3.50(d,J＝6.6Hz,1H),3.45 -3.38(m,3H),3.12(p,J＝7.1Hz,1H),2.40(s,3H),2.25(q,J＝11.4,10.3Hz,4H),1. 99(d,J＝13.5Hz,2H),1.81-1.71(m,1H),1.64-1.52(m,1H),1.13(d,J＝6.8Hz,3H).

实施例133：化合物133的制备
Example 133: Preparation of compound 133

步骤1：25℃下，将化合物129-6(300mg,0.81mmol)溶于乙腈(6mL)中，加入化合物124-6(242mg,0.81mmol)、乙酸(0.05mL,0.81mmol)，搅拌16小时后，加入三乙酰氧基硼氢化钠(343mg,1.62mmol)，继续搅拌6小时。通过LCMS监测反应。加入水(10mL)淬灭，用乙酸乙酯(3×10mL)萃取，合并的有机相用饱和食盐水(10mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％乙酸乙酯/石油醚梯度纯化，得到化合物133-1。MS m/z(ESI)：＝654.4[M+H]⁺。Step 1: At 25°C, compound 129-6 (300 mg, 0.81 mmol) was dissolved in acetonitrile (6 mL), followed by compound 124-6 (242 mg, 0.81 mmol) and acetic acid (0.05 mL, 0.81 mmol). After stirring for 16 hours, sodium triacetoxyborohydride (343 mg, 1.62 mmol) was added, and stirring continued for 6 hours. The reaction was monitored by LCMS. The reaction was quenched with water (10 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (10 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–10% ethyl acetate/petroleum ether to give compound 133-1. MS m/z (ESI): = 654.4 [M+H] ⁺ .

步骤2：将化合物133-1(427mg,0.65mmol)溶于乙醇(5mL)和水(2mL)中，加入氢氧化锂(137mg,3.27mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物133。MS m/z(ESI)：＝526.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.91(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.13(t,J＝2.7Hz,2H),6.38(s,1H),5.79(s,1H),3.62(s,2H),3.54-3.49(m,1H),3.43(s,1H),3.12(p,J＝6.9Hz,1H),2.41-2.21(m,7H),2.01(d,J＝13.2Hz,2H),1.86-1.74(m,1H),1.69-1.58(m,1H),1.58-1.49(m,1H),1.13(d,J＝6.7Hz,3H),0.55(t,J＝7.2Hz,2H),0.41(q,J＝5.5Hz,2H)。Step 2: Compound 133-1 (427 mg, 0.65 mmol) was dissolved in ethanol (5 mL) and water (2 mL), and lithium hydroxide (137 mg, 3.27 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 133. MS m/z (ESI): = 526.4 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(s,1H),7.91(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.13(t,J＝2.7Hz,2H),6 .38(s,1H),5.79(s,1H),3.62(s,2H),3.54-3.49(m,1H),3.43(s,1H),3.12(p,J＝6.9Hz ,1H),2.41-2.21(m,7H),2.01(d,J＝13.2Hz,2H),1.86-1.74(m,1H),1.69-1.58(m,1H), 1.58-1.49(m,1H),1.13(d,J＝6.7Hz,3H),0.55(t,J＝7.2Hz,2H),0.41(q,J＝5.5Hz,2H).

实施例135：化合物135的制备
Example 135: Preparation of compound 135

步骤1：将化合物134-1(9.99g,61.83mmol)和醋酸钠(29.19g,355.87mmol)溶于水(150mL)中，在0℃、氮气氛围下依次加入1,3-丙酮二羧酸(8.02mL,70.28mmol)和盐酸(4.18mL,1N)，搅拌1小时后，加入丁二醛水溶液(11.36mL,56.21mmol,40％)的四氢呋喃溶液(150ml)，升至40℃搅拌18小时。通过LCMS监测反应。用乙酸乙酯(2×200mL)萃取，合并的有机相用饱和食盐水(250mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-20％乙酸乙酯/石油醚梯度纯化，得到化合物134-2。MS m/z(ESI)：＝234.0[M+H]⁺。Step 1: Compound 134-1 (9.99 g, 61.83 mmol) and sodium acetate (29.19 g, 355.87 mmol) were dissolved in water (150 mL). Under a nitrogen atmosphere at 0 °C, 1,3-propanone dicarboxylic acid (8.02 mL, 70.28 mmol) and hydrochloric acid (4.18 mL, 1N) were added sequentially. After stirring for 1 hour, a tetrahydrofuran solution (150 mL) of succinaldehyde aqueous solution (11.36 mL, 56.21 mmol, 40%) was added, and the mixture was stirred at 40 °C for 18 hours. The reaction was monitored by LC-MS. The mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were washed with saturated brine (250 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–20% ethyl acetate/petroleum ether to give compound 134-2. MS m/z (ESI): = 234.0 [M+H] ⁺ .

步骤2：将化合物134-2(4.20g,18.01mmol)、叔丁醇(2.58mL,27.01mmol)和对甲基苯磺酰甲基异腈(5.27g,27.01mmol)溶于乙二醇二甲醚(60mL)中，在0℃、氮气氛围下，滴加叔丁醇钾的四氢呋喃溶液(36.02mL,36.02mmol,1.0M)，升至25℃搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(150mL)中，用乙酸乙酯(2×150mL)萃取，合并的有机相用饱和食盐水(200mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物134-3。¹H NMR(400MHz,Chloroform-d)δ3.52(dd,J＝4.6,2.8Hz,2H),2.75(tt,J＝11.9,5.8Hz,1H),1.98-1.79(m,6H),1.54(t,J＝7.5Hz,2H),1.03-0.96(m,2H),0.86-0.78(m,2H)。Step 2: Compound 134-2 (4.20 g, 18.01 mmol), tert-butanol (2.58 mL, 27.01 mmol), and p-toluenesulfonylmethylisocyanate (5.27 g, 27.01 mmol) were dissolved in ethylene glycol dimethyl ether (60 mL). Under a nitrogen atmosphere at 0 °C, a tetrahydrofuran solution of potassium tert-butoxide (36.02 mL, 36.02 mmol, 1.0 M) was added dropwise, and the mixture was stirred at 25 °C for 18 hours. The reaction was monitored by LC-MS. The reaction mixture was poured into a saturated ammonium chloride solution (150 mL), extracted with ethyl acetate (2 × 150 mL), and the combined organic phases were washed with saturated brine (200 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to obtain compound 134-3. ¹ H NMR (400MHz, Chloroform-d) δ3.52 (dd, J＝4.6, 2.8Hz, 2H), 2.75 (tt, J＝11.9, 5.8Hz, 1H), 1.98-1.79 (m, 6H), 1.54 (t, J = 7.5Hz, 2H), 1.03-0.96 (m, 2H), 0.86-0.78 (m, 2H).

步骤3：将化合物134-3(1.40g,5.73mmol)和对氟苯甲酸乙酯(1.68mL,11.46mmol)溶于四氢呋喃(60mL)中，在0℃、氮气氛围下，滴加双三甲基硅基胺基锂的四氢呋喃溶液(8.06mL,8.06mmol,1.0M)，升至25℃搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(100mL)中，用乙酸乙酯(2×100mL)萃取，合并的有机相用饱和食盐水(150mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物134-4。MS m/z(ESI)：＝393.2[M+H]⁺。Step 3: Compound 134-3 (1.40 g, 5.73 mmol) and ethyl p-fluorobenzoate (1.68 mL, 11.46 mmol) were dissolved in tetrahydrofuran (60 mL). Under a nitrogen atmosphere at 0 °C, a tetrahydrofuran solution of lithium bis(trimethylsilylamino)amine (8.06 mL, 8.06 mmol, 1.0 M) was added dropwise, and the mixture was stirred at 25 °C for 18 hours. The reaction was monitored by LCMS. The reaction mixture was poured into a saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic phases were washed with saturated brine (150 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 134-4. MS m/z (ESI): = 393.2 [M+H] ⁺ .

步骤4：将化合物134-4(1.50g,3.82mmol)溶于乙醇(30mL)和氢氧化钠的水溶液(30mL,10M)中，90℃下搅拌72小时。通过LCMS监测反应。浓缩，倒入水(30mL)中，加入盐酸(2N)调节pH至5-6，过滤，固体用水洗涤，真空干燥，得到化合物134-5。MS m/z(ESI)：＝383.2[M+H]⁺。Step 4: Compound 134-4 (1.50 g, 3.82 mmol) was dissolved in ethanol (30 mL) and an aqueous solution of sodium hydroxide (30 mL, 10 M), and stirred at 90 °C for 72 hours. The reaction was monitored by LCMS. The solution was concentrated, poured into water (30 mL), and the pH was adjusted to 5-6 with hydrochloric acid (2 N). The mixture was filtered, the solid was washed with water, and dried under vacuum to obtain compound 134-5. MS m/z (ESI): ＝383.2[M+H] ⁺ .

步骤5：25℃下，将化合物134-5(1.35g,3.53mmol)、碘乙烷(0.56mL,7.06mmol)和碳酸钾(976mg,7.06mmol)溶于N,N-二甲基甲酰胺(15mL)中，搅拌18小时。通过LCMS监测反应。反应液倒入冰水(100mL)中，用乙酸乙酯(2x100 mL)萃取，合并的有机相用水(2×150mL)和饱和食盐水(150mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物134-6。MS m/z(ESI)：＝411.2[M+H]⁺。Step 5: At 25°C, compound 134-5 (1.35 g, 3.53 mmol), iodoethane (0.56 mL, 7.06 mmol), and potassium carbonate (976 mg, 7.06 mmol) were dissolved in N,N-dimethylformamide (15 mL) and stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (2 x 100 mL), and the combined organic phases were washed with water (2 x 150 mL) and saturated brine (150 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 134-6. MS m/z (ESI): = 411.2 [M+H] ⁺ .

步骤6：25℃下，将化合物134-6(1.20g,2.92mmol)溶于乙腈(15mL)和水(15mL)中，加入[双(三氟乙酰氧基)碘]苯(1.89g,4.39mmol)，搅拌18小时。通过LCMS监测反应。反应液倒入饱和碳酸氢钠溶液(50mL)中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物134-7。MS m/z(ESI)：＝383.2[M+H]⁺。Step 6: At 25°C, compound 134-6 (1.20 g, 2.92 mmol) was dissolved in acetonitrile (15 mL) and water (15 mL), and [bis(trifluoroacetoxy)iodo]benzene (1.89 g, 4.39 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The reaction mixture was poured into saturated sodium bicarbonate solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (80 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 134-7. MS m/z (ESI): = 383.2 [M+H] ⁺ .

步骤7：25℃下，将化合物134-7(300mg,0.78mmol)、化合物1-14(227mg,0.78mmol)和乙酸(47mg,0.78mmol)溶于乙腈(8mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(333mg,1.57mmol)，继续搅拌17小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(50mL)中，用乙酸乙酯(2×60mL)萃取，合并的有机相用饱和食盐水(60mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物135-1。MS m/z(ESI)：＝656.4[M+H]⁺。Step 7: At 25°C, compound 134-7 (300 mg, 0.78 mmol), compound 1-14 (227 mg, 0.78 mmol), and acetic acid (47 mg, 0.78 mmol) were dissolved in acetonitrile (8 mL). After stirring for 1 hour, sodium triacetoxyborohydride (333 mg, 1.57 mmol) was added, and stirring was continued for 17 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (2 × 60 mL), and the combined organic phases were washed with saturated brine (60 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 135-1. MS m/z (ESI): = 656.4 [M+H] ⁺ .

步骤8：将化合物135-1(490mg,0.75mmol)溶于甲醇(15mL)和水(3mL)中，加入氢氧化锂(157mg,3.74mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，浓缩。粗品通过反相色谱柱：32％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物135。MS m/z(ESI)：＝528.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(t,J＝2.3Hz,1H),7.94(d,J＝8.2Hz,2H),7.51(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.89(dd,J＝3.1,1.9Hz,1H),3.61(s,3H),3.48-3.39(m,4H),2.40(s,3H),2.35-2.27(m,2H),2.25-2.17(m,2H),2.08-1.99(m,2H),1.53-1.41(m,2H),1.02-0.85(m,4H)。Step 8: Compound 135-1 (490 mg, 0.75 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (157 mg, 3.74 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), and the solution was concentrated. The crude product was purified by a reverse-phase column using a gradient of 32%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 135. MS m/z (ESI): = 528.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(t,J＝2.3Hz,1H),7.94(d,J＝8.2Hz,2H),7.51(d,J＝8.2Hz,2H),7.20(t,J＝2.8Hz,1H),6.63(s,1H),5.89(dd,J＝3.1,1.9Hz,1H),3. 61(s,3H),3.48-3.39(m,4H),2.40(s,3H),2.35-2.27(m,2H),2.25-2 .17(m,2H),2.08-1.99(m,2H),1.53-1.41(m,2H),1.02-0.85(m,4H).

实施例136：化合物136的制备
Example 136: Preparation of compound 136

步骤1：25℃下，将化合物134-7(203mg,0.53mmol)、化合物124-6(159mg,0.53mmol)和乙酸(32mg,0.53mmol)溶于乙腈(8mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(222mg,1.05mmol)，继续搅拌17小时。通过LCMS监测反应。反应液倒入饱和氯化铵溶液(30mL)中，用乙酸乙酯(2×50mL)萃取，合并的有机相用饱和食盐水(30mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物136-1。MS m/z(ESI)：＝666.5[M+H]⁺。Step 1: At 25°C, compound 134-7 (203 mg, 0.53 mmol), compound 124-6 (159 mg, 0.53 mmol), and acetic acid (32 mg, 0.53 mmol) were dissolved in acetonitrile (8 mL). After stirring for 1 hour, sodium triacetoxyborohydride (222 mg, 1.05 mmol) was added, and stirring continued for 17 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (2 × 50 mL), and the combined organic phases were washed with saturated brine (30 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 136-1. MS m/z (ESI): = 666.5 [M+H] ⁺ .

步骤2：将化合物136-1(315mg,0.47mmol)溶于甲醇(15mL)、四氢呋喃(10mL)和水(3mL)中，加入氢氧化锂(100mg,2.38mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节pH至中性，过滤，滤饼真空干燥，得到化合物136-2。MS m/z(ESI)：＝582.5[M-56+H]⁺。Step 2: Compound 136-1 (315 mg, 0.47 mmol) was dissolved in methanol (15 mL), tetrahydrofuran (10 mL), and water (3 mL). Lithium hydroxide (100 mg, 2.38 mmol) was added, and the mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH was adjusted to neutral by adding hydrochloric acid (1 N), filtered, and the filter cake was dried under vacuum to obtain compound 136-2. MS m/z (ESI): 582.5 [M-56+H] ⁺ .

步骤3：25℃下，将化合物136-2(200mg,0.31mmol)溶于氯化氢的甲醇溶液(10mL,3M)，搅拌2小时。通过LCMS监测反应。浓缩，粗品通过反相色谱柱：45％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物136。MS m/z(ESI)：＝538.8[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.80(s,1H),7.91(d,J＝8.4Hz,2H),7.51(d,J＝8.3Hz,2H),7.12(t,J＝2.8Hz,1H),6.37(s,1H),5.76(dd,J＝3.1,1.9Hz,1H),3.61(s,2H),3.50-3.41(m,2H),2.45-2.36(m,3H),2.32(s,3H),2.24(d,J＝7.1Hz,2H),2.08-2.00(m,2H),1.57-1.47(m,3H),1.01-0.94(m,2H),0.92-0.86(m,2H),0.58-0.49(m,2H),0.41(td,J＝5.9,4.0Hz,2H)。Step 3: Compound 136-2 (200 mg, 0.31 mmol) was dissolved in a methanol solution of hydrogen chloride (10 mL, 3 M) at 25 °C and stirred for 2 hours. The reaction was monitored by LC-MS. The crude product was concentrated and purified by a reverse-phase column using a gradient of 45%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 136. MS m/z (ESI): = 538.8 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.80(s,1H),7.91(d,J＝8.4Hz,2H),7.51(d,J＝8.3Hz,2H),7.12(t,J＝2.8Hz,1H) ,6.37(s,1H),5.76(dd,J＝3.1,1.9Hz,1H),3.61(s,2H),3.50-3.41(m,2H),2.45-2.3 6(m,3H),2.32(s,3H),2.24(d,J＝7.1Hz,2H),2.08-2.00(m,2H),1.57-1.47(m,3H),1 .01-0.94(m,2H),0.92-0.86(m,2H),0.58-0.49(m,2H),0.41(td,J=5.9,4.0Hz,2H).

实施例138：化合物138的制备
Example 138: Preparation of compound 138

步骤1：室温下，将化合物103-1(6.70g,22.16mmol)溶于N,N-二甲基甲酰胺(40mL)中，加入3,3,3-三氟丙醛(2.86mL,33.24mmol)和醋酸(2滴)，搅拌1小时后，分批加入氰基硼氢化钠(5.63g,94.17mmol)，继续搅拌18小时。通过LCMS监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×50mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-50％乙酸乙酯/石油醚梯度纯化，得到化合物138-1。MS m/z(ESI)：＝399.2[M+H]⁺。Step 1: At room temperature, compound 103-1 (6.70 g, 22.16 mmol) was dissolved in N,N-dimethylformamide (40 mL), followed by the addition of 3,3,3-trifluoropropionaldehyde (2.86 mL, 33.24 mmol) and acetic acid (2 drops). After stirring for 1 hour, sodium cyanoborohydride (5.63 g, 94.17 mmol) was added in portions, and stirring was continued for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–50% ethyl acetate/petroleum ether to give compound 138-1. MS m/z (ESI): = 399.2 [M+H] ⁺ .

步骤2：常温下，将化合物138-1(11.4g,28.61mmol)溶于乙腈(110mL)和水(110mL)中，分批加入[双(三氟乙酰氧基)碘]苯(14.77g,34.34mmol)，搅拌3小时。通过LCMS监测反应。加入饱和碳酸钠溶液(80mL)淬灭，用二氯甲烷(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：30％-50％乙酸乙酯/石油醚梯度纯化，得到化合物138-2。MS m/z(ESI)：＝371.2[M+H]⁺。Step 2: At room temperature, compound 138-1 (11.4 g, 28.61 mmol) was dissolved in acetonitrile (110 mL) and water (110 mL). [bis(trifluoroacetoxy)iodide]benzene (14.77 g, 34.34 mmol) was added in portions, and the mixture was stirred for 3 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (80 mL), extracted with dichloromethane (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 30%–50% ethyl acetate/petroleum ether to give compound 138-2. MS m/z (ESI): = 371.2 [M+H] ⁺ .

步骤3：室温下，将化合物138-2(3.00g,8.10mmol)溶于N,N-二甲基甲酰胺(50mL)中，加入化合物1-14(2.34g,8.09mmol)、醋酸(2滴)，搅拌1小时后，加入三乙酰氧基硼氢化钠(5.15g,24.3mmol)，搅拌16小时后，再加入氰基硼氢化钠(2.54g,40.49mmol)，继续搅拌2小时。通过LCMS监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×50mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-30％乙酸乙酯/石油醚梯度纯化，得到化合物138-3。MS m/z(ESI)：＝644.4[M+H]⁺。Step 3: At room temperature, compound 138-2 (3.00 g, 8.10 mmol) was dissolved in N,N-dimethylformamide (50 mL), compound 1-14 (2.34 g, 8.09 mmol) and acetic acid (2 drops) were added. After stirring for 1 hour, sodium triacetoxyborohydride (5.15 g, 24.3 mmol) was added, and after stirring for 16 hours, sodium cyanoborohydride (2.54 g, 40.49 mmol) was added, and stirring continued for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-30% ethyl acetate/petroleum ether to give compound 138-3. MS m/z (ESI): = 644.4 [M+H] ⁺ .

步骤4：将化合物138-3(5.30g,8.23mmol)溶于乙醇(90mL)和水(30mL)中，加入氢氧化锂(1.73g,41.17mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至弱酸性，继续搅拌2小时。过滤，得到的固体在甲醇(20mL)中打浆1小时，过滤，干燥，得到化合物138。MS m/z(ESI)：＝516.3[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.79(s,1H),7.98(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),7.19(d,J＝2.7Hz,1H),6.64(s,1H),5.91(d,J＝2.9Hz,1H),3.62(s,3H),3.40(s,2H),3.14(dd,J＝13.9,5.5Hz,2H),2.84-2.73(m,2H),2.64-2.51(m,6H),2.39(s,3H),2.36-2.28(m,2H),2.07-2.00(m,2H)。Step 4: Compound 138-3 (5.30 g, 8.23 mmol) was dissolved in ethanol (90 mL) and water (30 mL), and lithium hydroxide (1.73 g, 41.17 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to weakly acidic by adding hydrochloric acid (1 N), and stirring was continued for 2 hours. The mixture was filtered, and the resulting solid was slurried in methanol (20 mL) for 1 hour, filtered, and dried to obtain compound 138. MS m/z (ESI): 516.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.79(s,1H),7.98(d,J＝8.4Hz,2H),7.58(d,J＝8.4Hz,2H),7.19(d,J＝2.7Hz,1H),6.64(s,1H),5.91(d,J＝2.9Hz,1H),3.62(s,3H) ,3.40(s,2H),3.14(dd,J＝13.9,5.5Hz,2H),2.84-2.73(m,2H),2.64-2.51(m,6H),2.39(s,3H),2.36-2.28(m,2H),2.07-2.00(m,2H).

实施例140：化合物140的制备
Example 140: Preparation of Compound 140

步骤1：室温下，将化合物138-2(2.76g,7.45mmol)溶于N,N-二甲基甲酰胺(30mL)中，加入化合物124-6(2.23g,7.45mmol)和醋酸(0.08mL,1.49mmol)，搅拌1小时后，加入三乙酰氧基硼氢化钠(3.16g,14.90mmol)，搅拌18小时后，加入氰基硼氢化钠(2.34g,37.26mmol)，继续搅拌2小时。通过LCMS监测反应。加入水(50mL)淬灭，用乙酸乙酯(3×40mL)萃取，合并的有机相用饱和食盐水(50mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：5％-30％乙酸乙酯/石油醚梯度纯化，得到化合物140-1。MS m/z(ESI)：＝654.4[M+H]⁺。Step 1: At room temperature, compound 138-2 (2.76 g, 7.45 mmol) was dissolved in N,N-dimethylformamide (30 mL), compound 124-6 (2.23 g, 7.45 mmol) and acetic acid (0.08 mL, 1.49 mmol) were added. After stirring for 1 hour, sodium triacetoxyborohydride (3.16 g, 14.90 mmol) was added, and after stirring for 18 hours, sodium cyanoborohydride (2.34 g, 37.26 mmol) was added, and stirring continued for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL), extracted with ethyl acetate (3 × 40 mL), and the combined organic phases were washed with saturated brine (50 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 5%–30% ethyl acetate/petroleum ether to give compound 140-1. MS m/z (ESI): = 654.4 [M+H] ⁺ .

步骤2：将化合物140-1(3.50g,5.35mmol)溶于乙醇(30mL)和水(10mL)中，加入氢氧化锂(1.10g,26.77mmol)，加热至60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH值至弱酸性，继续搅拌2小时。过滤，得到的固体在甲醇(15mL)中打浆1小时，过滤，得到的固体在水(20mL)中打浆1小时，过滤并干燥，得到化合物140。MS m/z(ESI)：＝526.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.90(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.14(t,J＝2.6Hz,1H),6.39(s,1H),5.81(s,1H),3.62(s,2H),2.68-2.57(m,2H),2.57-2.50(m,2H),2.50-2.42(m,2H),2.41-2.34(m,2H),2.33(s,3H),2.30(d,J＝7.0Hz,2H),2.07(d,J＝12.4Hz,2H),1.92-1.81(m,2H),1.59-1.49(m,1H),0.59-0.51(m,2H),0.46-0.37(m,2H)。Step 2: Compound 140-1 (3.50 g, 5.35 mmol) was dissolved in ethanol (30 mL) and water (10 mL), and lithium hydroxide (1.10 g, 26.77 mmol) was added. The mixture was heated to 60 °C and stirred for 16 hours. The reaction was monitored by LCMS. Hydrochloric acid (1 N) was added to adjust the pH of the system to weakly acidic, and stirring was continued for 2 hours. The mixture was filtered, and the resulting solid was slurried in methanol (15 mL) for 1 hour. After filtration, the solid was slurried in water (20 mL) for 1 hour, filtered, and dried to obtain compound 140. MS m/z (ESI): 526.4 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ10.82(s,1H),7.90(d,J＝8.3Hz,2H),7.52(d,J＝8.3Hz,2H),7.14(t,J＝2.6Hz,1H) ,6.39(s,1H),5.81(s,1H),3.62(s,2H),2.68-2.57(m,2H),2.57-2.50(m,2H),2.50- 2.42(m,2H),2.41-2.34(m,2H),2.33(s,3H),2.30(d,J＝7.0Hz,2H),2.07(d,J＝12.4 Hz,2H),1.92-1.81(m,2H),1.59-1.49(m,1H),0.59-0.51(m,2H),0.46-0.37(m,2H).

实施例141：化合物141的制备
Example 141: Preparation of compound 141

步骤1：25℃下，将化合物141-1(2.00g,14.27mmol)溶于二氯甲烷(15mL)中，依次加入三乙胺(3.69mL,28.55mmol)和对甲苯磺酰氯(2.99g,15.70mmol)，搅拌18小时。通过LCMS监测反应。加入水(30mL)淬灭，用二氯甲烷(2×30mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物141-2。Step 1: Compound 141-1 (2.00 g, 14.27 mmol) was dissolved in dichloromethane (15 mL) at 25 °C, followed by the sequential addition of triethylamine (3.69 mL, 28.55 mmol) and p-toluenesulfonyl chloride (2.99 g, 15.70 mmol), and the mixture was stirred for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (30 mL), extracted with dichloromethane (2 × 30 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to give compound 141-2.

步骤2：25℃下，将化合物141-2(1.46g,4.96mmol)溶于N,N-二甲基甲酰胺(10mL)中，依次加入碳酸铯(1.07g,3.31mmol)和化合物103-1(500mg,1.65mmol)，搅拌18小时。通过LCMS监测反应。加入水(30mL)淬灭，用乙酸乙酯(2×30mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物141-3。MS m/z(ESI)：＝425.7[M+H]⁺。Step 2: At 25°C, compound 141-2 (1.46 g, 4.96 mmol) was dissolved in N,N-dimethylformamide (10 mL), followed by the sequential addition of cesium carbonate (1.07 g, 3.31 mmol) and compound 103-1 (500 mg, 1.65 mmol), and the mixture was stirred for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (30 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 141-3. MS m/z (ESI): = 425.7 [M+H] ⁺ .

步骤3：25℃下，将化合物141-3(263mg,0.62mmol)溶于乙腈(5mL)和水(5mL)中，加入[双(三氟乙酰氧基)碘]苯(1.33g,3.10mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物141-4。MS m/z(ESI)：＝397.7[M+H]⁺。Step 3: At 25°C, compound 141-3 (263 mg, 0.62 mmol) was dissolved in acetonitrile (5 mL) and water (5 mL), and [bis(trifluoroacetoxy)iodo]benzene (1.33 g, 3.10 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 141-4. MS m/z (ESI): = 397.7 [M+H] ⁺ .

步骤4：25℃、氮气氛围下，将化合物141-4(182mg,0.46mmol)溶于N,N-二甲基甲酰胺(5mL)和醋酸(0.1mL)中，加入化合物1-14(199mg,0.69mmol)，搅拌1小时后，加入氰基硼氢化钠(43mg,0.69mmol)，继续搅拌18小时。通过LCMS监测反应。加入水(30mL)淬灭，用乙酸乙酯(2×30mL)萃取，合并的有机相用饱和食盐水(20mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物141-5。MS m/z(ESI)：＝670.5[M+H]⁺。Step 4: Under a nitrogen atmosphere at 25°C, compound 141-4 (182 mg, 0.46 mmol) was dissolved in N,N-dimethylformamide (5 mL) and acetic acid (0.1 mL). Compound 1-14 (199 mg, 0.69 mmol) was added, and the mixture was stirred for 1 hour. Then, sodium cyanoborohydride (43 mg, 0.69 mmol) was added, and the mixture was stirred for another 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (30 mL), extracted with ethyl acetate (2 × 30 mL), and the combined organic phases were washed with saturated brine (20 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 141-5. MS m/z (ESI): 670.5 [M+H] ⁺ .

步骤5：将化合物141-5(250mg,0.37mmol)溶于甲醇(5mL)和水(1mL)中，加入氢氧化锂(78mg,1.87mmol)，在60℃、氮气氛围下搅拌18小时。通过LCMS监测反应。浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物141。MS m/z(ESI)：＝542.3[M+H]⁺。¹H NMR(400MHz,甲醇-d₄)δ8.04(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,2H),7.14(d,J＝3.1Hz,1H),6.70(s,1H),5.86(d,J＝3.2Hz,1H),3.78(s,3H),3.70(s,2H),3.67-3.56(m,2H),2.91-2.74(m,2H),2.68-2.55(m,2H),2.45(s,3H),2.44-2.19(m,4H),2.13-2.05(m,2H),1.02-0.88(m,2H),0.86-0.69(m,2H)。Step 5: Compound 141-5 (250 mg, 0.37 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (78 mg, 1.87 mmol) was added. The mixture was stirred at 60 °C under a nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by a reverse-phase column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 141. MS m/z (ESI): = 542.3 [M+H] ⁺ . ¹ H NMR (400MHz, methanol-d ₄ )δ8.04(d,J＝8.2Hz,2H),7.53(d,J＝8.2Hz,2H),7.14(d,J＝3.1Hz,1H),6.70(s,1H),5.86(d,J＝3.2Hz,1H),3.78(s,3H),3.70(s,2H),3.67-3 .56(m,2H),2.91-2.74(m,2H),2.68-2.55(m,2H),2.45(s,3H),2.44- 2.19(m,4H),2.13-2.05(m,2H),1.02-0.88(m,2H),0.86-0.69(m,2H).

实施例147：化合物147-P1、147-P2的制备
Example 147: Preparation of compounds 147-P1 and 147-P2

步骤1：25℃下，将化合物103-1(2.00g,6.61mmol)、4,4,4-三氟-2-丁酮(2.08g,16.53mmol)和钛酸四异丙脂(2.82g,9.92mmol)溶于N,N-二甲基甲酰胺(30mL)中，搅拌1小时后，加入氰基硼氢化钠(1.25g,19.83mmol)，继续搅拌17小时。通过LCMS监测反应。反应液倒入冰水(100mL)中，用乙酸乙酯(2×100mL)萃取，合并的有机相用水(2×150mL)和饱和食盐水(150mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物147-1。MS m/z(ESI)：＝413.2[M+H]⁺。Step 1: At 25 °C, compound 103-1 (2.00 g, 6.61 mmol), 4,4,4-trifluoro-2-butanone (2.08 g, 16.53 mmol), and tetraisopropyl titanate (2.82 g, 9.92 mmol) were dissolved in N,N-dimethylformamide (30 mL). After stirring for 1 hour, sodium cyanoborohydride (1.25 g, 19.83 mmol) was added, and stirring continued for 17 hours. The reaction was monitored by LCMS. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic phases were washed with water (2 × 150 mL) and saturated brine (150 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 147-1. MS m/z (ESI): = 413.2 [M+H] ⁺ .

步骤2：25℃下，将化合物147-1(2.00g,4.85mmol)溶于乙腈(30mL)和水(30mL)中，加入[双(三氟乙酰氧基)碘]苯(4.17g,9.70mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物147-2。MS m/z(ESI)：＝385.2[M+H]⁺。Step 2: At 25°C, compound 147-1 (2.00 g, 4.85 mmol) was dissolved in acetonitrile (30 mL) and water (30 mL), and [bis(trifluoroacetoxy)iodide]benzene (4.17 g, 9.70 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 147-2. MS m/z (ESI): = 385.2 [M+H] ⁺ .

步骤3：25℃下，将化合物147-2(2.12g,5.51mmol)、化合物1-14(1.33g,4.60mmol)和乙酸(0.26mL,4.60mmol)溶于乙腈(30mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(1.95g,9.19mmol)，继续搅拌17小时。通过LCMS监测反应。反应液倒入饱和氯化铵(100mL)溶液中，用乙酸乙酯(2×80mL)萃取，合并的有机相用饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物147-3。MS m/z(ESI)：＝658.2[M+H]⁺。Step 3: At 25°C, compound 147-2 (2.12 g, 5.51 mmol), compound 1-14 (1.33 g, 4.60 mmol), and acetic acid (0.26 mL, 4.60 mmol) were dissolved in acetonitrile (30 mL). After stirring for 1 hour, sodium triacetoxyborohydride (1.95 g, 9.19 mmol) was added, and stirring continued for 17 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride (100 mL) solution and extracted with ethyl acetate (2 × 80 mL). The combined organic phases were washed with saturated brine (80 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-50% ethyl acetate/petroleum ether to give compound 147-3. MS m/z (ESI): = 658.2 [M+H] ⁺ .

步骤4：化合物147-3(1.80g,2.74mmol)再经过手性分离(色谱柱：ChiralPak IG,300×50mm I.D.,10μm；流动相：A：二氧化碳，B：[0.1％氨-甲醇]；梯度：B％：45％)，得到化合物147-3-P1和147-3-P2。Step 4: Compound 147-3 (1.80 g, 2.74 mmol) was further separated by chirality (chromatographic column: ChiralPak IG, 300 × 50 mm I.D., 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-methanol]; gradient: B%: 45%) to obtain compounds 147-3-P1 and 147-3-P2.

SFC分析检测方法：色谱柱：ChiralPak IG,100×4.6mm I.D.,3μm，流动相：A：二氧化碳，B：甲醇(0.05％二乙胺)，梯度：B％：50％，梯度流动4分钟，流速：2mL/min，拆分波长220nm。SFC analysis and detection method: Column: ChiralPak IG, 100×4.6mm I.D., 3μm, mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine), gradient: B%: 50%, gradient flow for 4 minutes, flow rate: 2mL/min, resolution wavelength 220nm.

化合物147-3-P1：保留时间：1.948分钟，MS m/z(ESI)：＝658.4[M+H]⁺。Compound 147-3-P1: Retention time: 1.948 min, MS m/z (ESI): 658.4 [M+H] ⁺ .

化合物147-3-P2：保留时间：2.482分钟，MS m/z(ESI)：＝658.4[M+H]⁺。Compound 147-3-P2: Retention time: 2.482 min, MS m/z (ESI): 658.4 [M+H] ⁺ .

步骤5：将化合物147-3-P1(700mg，1.06mmol)溶于甲醇(15mL)和水(3mL)中，加入氢氧化锂(233mg,5.31mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，过滤，滤饼用水打浆，过滤得到的固体冻干后，得到化合物147-P1。MS m/z(ESI)：＝530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.93(d,J＝8.5Hz,2H),7.54(d,J＝8.4Hz,2H),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.92(dd,J＝3.1,1.8Hz,1H),3.61(s,3H),3.57-3.44(m,2H),3.41(s,2H),2.80-2.68(m,1H),2.60-2.51(m,1H),2.40(s,3H),2.29-2.09(m,5H),2.06-1.94(m,2H),1.82-1.64(m,2H),1.11(d,J＝6.1Hz,3H)。Step 5: Compound 147-3-P1 (700 mg, 1.06 mmol) was dissolved in methanol (15 mL) and water (3 mL), and lithium hydroxide (233 mg, 5.31 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was filtered. The filter cake was slurried with water, and the resulting solid was lyophilized to obtain compound 147-P1. MS m/z (ESI): 530.2 [M+H] ⁺ . ^¹H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(s,1H),7.93(d,J＝8.5Hz,2H),7.54(d,J＝8.4Hz,2H),7.21(t,J＝2. 8Hz,1H),6.63(s,1H),5.92(dd,J＝3.1,1.8Hz,1H),3.61(s,3H),3.57-3.44( m,2H),3.41(s,2H),2.80-2.68(m,1H),2.60-2.51(m,1H),2.40(s,3H),2.2 9-2.09(m,5H),2.06-1.94(m,2H),1.82-1.64(m,2H),1.11(d,J=6.1Hz,3H).

按照由147-3-P1制得147-P1的方法，由化合物147-3-P2得到化合物147-P2。MS m/z(ESI)：＝530.2[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.94(d,J＝8.2Hz,2H),7.54(d,J＝8.1Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.92(dd,J＝3.1,1.8Hz,1H),3.62(s,3H),3.58-3.46(m,2H),3.42(s,2H),2.79-2.68(m,1H),2.62-2.53(m,1H),2.41(s,3H),2.30-2.12(m,5H),2.08-1.94(m,2H),1.80-1.63(m,2H),1.12(d,J＝6.2Hz,3H)。Compound 147-P2 was obtained from compound 147-3-P2 using the same method as 147-P1 to 147-P1. MS m/z (ESI): 530.2 [M+H] ⁺ . ^¹H NMR (400MHz, DMSO-d6 ₎ )δ10.82(s,1H),7.94(d,J＝8.2Hz,2H),7.54(d,J＝8.1Hz,2H),7.21(t,J＝2. 8Hz,1H),6.64(s,1H),5.92(dd,J＝3.1,1.8Hz,1H),3.62(s,3H),3.58-3.46( m,2H),3.42(s,2H),2.79-2.68(m,1H),2.62-2.53(m,1H),2.41(s,3H),2.3 0-2.12(m,5H),2.08-1.94(m,2H),1.80-1.63(m,2H),1.12(d,J＝6.2Hz,3H).

实施例148：化合物148-P1、148-P2的制备
Example 148: Preparation of compounds 148-P1 and 148-P2

步骤1：25℃下，将化合物103-1(2.00g,6.61mmol)、4,4,4-三氟-3-甲基丁醛(2.50g,17.84mmol)和钛酸四异丙脂(2.82g,9.92mmol)溶于N,N-二甲基甲酰胺(30mL)中，搅拌1小时后，加入氰基硼氢化钠(1.25g,19.84mmol)，继续搅拌17小时。通过LCMS监测反应。反应液倒入冰水(100mL)中，用乙酸乙酯(2×100mL)萃取，合并的有机相用水(2×150mL)和饱和食盐水(150mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物148-1。MS m/z(ESI)：＝413.2[M+H]⁺。Step 1: At 25 °C, compound 103-1 (2.00 g, 6.61 mmol), 4,4,4-trifluoro-3-methylbutanal (2.50 g, 17.84 mmol), and tetraisopropyl titanate (2.82 g, 9.92 mmol) were dissolved in N,N-dimethylformamide (30 mL). After stirring for 1 hour, sodium cyanoborohydride (1.25 g, 19.84 mmol) was added, and stirring continued for 17 hours. The reaction was monitored by LCMS. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic phases were washed with water (2 × 150 mL) and saturated brine (150 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a 0%–10% methanol/dichloromethane gradient to give compound 148-1. MS m/z (ESI): = 413.2 [M+H] ⁺ .

步骤2：25℃下，将化合物148-1(1.50g,3.64mmol)溶于乙腈(30mL)和水(30mL)中，加入[双(三氟乙酰氧基)碘]苯(3.13g,7.27mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-10％甲醇/二氯甲烷梯度纯化，得到化合物148-2。MS m/z(ESI)：＝385.2[M+H]⁺。Step 2: At 25°C, compound 148-1 (1.50 g, 3.64 mmol) was dissolved in acetonitrile (30 mL) and water (30 mL), and [bis(trifluoroacetoxy)iodide]benzene (3.13 g, 7.27 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a 0%-10% methanol/dichloromethane gradient to give compound 148-2. MS m/z (ESI): = 385.2 [M+H] ⁺ .

步骤3：25℃下，将化合物148-2(1.46g,3.80mmol)、化合物1-14(1.00g,3.46mmol)和乙酸(0.20mL,3.46mmol)溶于乙腈(30mL)中，搅拌1小时后，加入三乙酰氧基硼氢化钠(1.47g,6.91mmol)，继续搅拌18小时。通过LCMS监测反应。反应液倒入饱和氯化铵(100mL)溶液中，用乙酸乙酯(2×80mL)萃取，合并的有机相用饱和食盐水(80mL)洗涤，干燥并浓缩。粗品通过反相色谱柱：50％-95％乙腈/缓冲液(0.1％甲酸)梯度纯化，得到化合物148-3。MS m/z(ESI)：＝658.2[M+H]⁺。Step 3: At 25°C, compound 148-2 (1.46 g, 3.80 mmol), compound 1-14 (1.00 g, 3.46 mmol), and acetic acid (0.20 mL, 3.46 mmol) were dissolved in acetonitrile (30 mL). After stirring for 1 hour, sodium triacetoxyborohydride (1.47 g, 6.91 mmol) was added, and stirring continued for 18 hours. The reaction was monitored by LCMS. The reaction solution was poured into a saturated ammonium chloride (100 mL) solution and extracted with ethyl acetate (2 × 80 mL). The combined organic phases were washed with saturated brine (80 mL), dried, and concentrated. The crude product was purified by a reversed-phase column using a gradient of 50%–95% acetonitrile/buffer (0.1% formic acid) to obtain compound 148-3. MS m/z (ESI): = 658.2 [M+H] ⁺ .

步骤4：化合物148-3(550mg,0.84mmol)通过手性分离(色谱柱：ChiralPak IG,250×30mm I.D.,10μm；流动相：A：二氧化碳，B：[0.1％氨-甲醇]；梯度：B％：40％)，得到化合物148-3-P1和148-3-P2。Step 4: Compound 148-3 (550 mg, 0.84 mmol) was separated by chirality (column: ChiralPak IG, 250 × 30 mm I.D., 10 μm; mobile phase: A: carbon dioxide, B: [0.1% ammonia-methanol]; gradient: B%: 40%) to give compounds 148-3-P1 and 148-3-P2.

SFC分析检测方法：色谱柱：ChiralPak IG,100×4.6mm I.D.,3μm，流动相：A：二氧化碳，B：甲醇(0.05％二乙胺)，梯度：B％：5-40％，梯度流动6分钟，流速：2.5mL/min，拆分波长220nm。SFC analysis and detection method: Column: ChiralPak IG, 100×4.6mm I.D., 3μm; Mobile phase: A: carbon dioxide, B: methanol (0.05% diethylamine); Gradient: B%: 5-40%; Gradient flow for 6 minutes; Flow rate: 2.5mL/min; Resolution wavelength: 220nm.

化合物148-3-P1：保留时间：3.799分钟，MS m/z(ESI)：＝658.4[M+H]⁺。Compound 148-3-P1: Retention time: 3.799 min, MS m/z (ESI): 658.4 [M+H] ⁺ .

化合物148-3-P2：保留时间：4.206分钟，MS m/z(ESI)：＝658.4[M+H]⁺。Compound 148-3-P2: Retention time: 4.206 min, MS m/z (ESI): 658.4 [M+H] ⁺ .

步骤5：将化合物148-3-P1(210mg,0.32mmol)溶于甲醇(6mL)和水(1.2mL)中，加入氢氧化锂(67mg,1.60mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，过滤，滤饼用甲醇打浆，过滤得到的固体冻干后，得到化合物148-P1。MS m/z(ESI)：＝530.0[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.81(s,1H),7.93(d,2H),7.53(d,J＝8.3Hz,2H),7.21(t,J＝2.8Hz,1H),6.63(s,1H),5.91(dd,J＝3.1,1.9Hz,1H),3.61(s,3H),3.41(s,2H),3.21(d,J＝12.5Hz,2H),2.57(dd,J＝12.4,4.3Hz,1H),2.49-2.43(m,1H),2.40(s,3H),2.27-2.15(m,5H),2.09-1.92(m,2H),1.85-1.70(m,2H),1.11(d,J＝6.8Hz,3H)。Step 5: Compound 148-3-P1 (210 mg, 0.32 mmol) was dissolved in methanol (6 mL) and water (1.2 mL), and lithium hydroxide (67 mg, 1.60 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), filtered, and the filter cake was slurried with methanol. The filtered solid was lyophilized to obtain compound 148-P1. MS m/z (ESI): 530.0 [M+H] ⁺ . ^1H NMR (400 MHz, DMSO-d6 ₎ )δ10.81(s,1H),7.93(d,2H),7.53(d,J＝8.3Hz,2H),7.21(t,J＝2.8Hz,1H),6 .63(s,1H),5.91(dd,J＝3.1,1.9Hz,1H),3.61(s,3H),3.41(s,2H),3.21(d,J＝ 12.5Hz,2H),2.57(dd,J＝12.4,4.3Hz,1H),2.49-2.43(m,1H),2.40(s,3H),2. 27-2.15(m,5H),2.09-1.92(m,2H),1.85-1.70(m,2H),1.11(d,J＝6.8Hz,3H).

按照由148-3-P1制得148-P1的方法，由化合物148-3-P2得到化合物148-P2。MS m/z(ESI)：＝530.2[M+H]⁺。¹H NMR(500MHz,DMSO-d₆)δ10.86(s,1H),8.00(s,2H),7.62(s,2H),7.23(s,1H),6.66(s,1H),5.96-5.90(m,1H),4.30(s,2H),3.66(s,3H),3.42(s,1H),3.32(s,1H),3.23-3.13(m,1H),2.76-2.57(m,5H),2.45-2.36(m,5H),2.16-1.92(m,3H),1.42(d,J＝6.6Hz,3H)。Compound 148-P2 was obtained from compound 148-3-P2 using the same method as that used to prepare 148-P1. MS m/z (ESI): 530.2 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ10.86(s,1H),8.00(s,2H),7.62(s,2H),7.23(s,1H),6.66(s,1H),5.96-5.90(m,1H),4.30(s,2H),3.66(s,3H),3.42 (s,1H),3.32(s,1H),3.23-3.13(m,1H),2.76-2.57(m,5H),2.45-2.36(m,5H),2.16-1.92(m,3H),1.42(d,J＝6.6Hz,3H).

实施例149：化合物149-P1、149-P2的制备
Example 149: Preparation of compounds 149-P1 and 149-P2

步骤1：室温下，将化合物103-1(1.00g,3.31mmol)溶于乙醇(20mL)中，加入1,1,1-三氟-2,3-环氧丙烷(1.11g,9.92mmol)和N,N-二异丙基乙胺(2.14g,16.54mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％甲醇/二氯甲烷梯度纯化，得到化合物149-1。MS m/z(ESI)：＝415.4[M+H]⁺。Step 1: At room temperature, compound 103-1 (1.00 g, 3.31 mmol) was dissolved in ethanol (20 mL), and 1,1,1-trifluoro-2,3-epoxypropane (1.11 g, 9.92 mmol) and N,N-diisopropylethylamine (2.14 g, 16.54 mmol) were added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by a silica gel column using a gradient of 2%–33% methanol/dichloromethane to give compound 149-1. MS m/z (ESI): = 415.4 [M+H] ⁺ .

步骤2：室温下，将化合物149-1(1.20g,2.90mmol)溶于乙腈(10mL)和水(10mL)中，加入[双(三氟乙酰氧基)碘]苯(2.49g,5.79mmol)，搅拌18小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％甲醇/二氯甲烷梯度纯化，得到化合物149-2。MS m/z(ESI)：＝387.4[M+H]⁺。Step 2: At room temperature, compound 149-1 (1.20 g, 2.90 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and [bis(trifluoroacetoxy)iodide]benzene (2.49 g, 5.79 mmol) was added. The mixture was stirred for 18 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 2%–33% methanol/dichloromethane to give compound 149-2. MS m/z (ESI): = 387.4 [M+H] ⁺ .

步骤3：室温下，将化合物149-2(2.60g,6.73mmol)溶于乙腈(20mL)中，加入化合物1-14(2.14g,7.40mmol)、醋酸(1mL)和钛酸四乙酯(0.5mL)，搅拌18小时后，加入三乙酰氧基硼氢化钠(4.28g,20.19mmol)，继续搅拌6小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：2％-33％甲醇/二氯甲烷梯度纯化，得到化合物149-3。MS m/z(ESI)：＝660.7[M+H]⁺。Step 3: At room temperature, compound 149-2 (2.60 g, 6.73 mmol) was dissolved in acetonitrile (20 mL), and compound 1-14 (2.14 g, 7.40 mmol), acetic acid (1 mL), and tetraethyl titanate (0.5 mL) were added. After stirring for 18 hours, sodium triacetoxyborohydride (4.28 g, 20.19 mmol) was added, and stirring was continued for 6 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 2%–33% methanol/dichloromethane to obtain compound 149-3. MS m/z (ESI): = 660.7 [M+H] ⁺ .

步骤4：化合物149-3(2.60g,3.94mmol)再经过手性分离(色谱柱：ChiralPak AD,250×30mm I.D.,10μm；流动相：Α：二氧化碳，B：乙醇；梯度：B％：35％)，得到化合物149-3-P1和化合物149-3-P2。Step 4: Compound 149-3 (2.60 g, 3.94 mmol) was further separated by chirality (chromatographic column: ChiralPak AD, 250 × 30 mm I.D., 10 μm; mobile phase: A: carbon dioxide, B: ethanol; gradient: B%: 35%) to obtain compounds 149-3-P1 and 149-3-P2.

SFC分析检测方法：色谱柱：ChiralPakAD,50×4.6mm I.D.,3μm，流动相：Α：二氧化碳，B：乙醇(0.05％二乙氨)，梯度：B％：40％，梯度流动3.0分钟，流速：3.0mL/min，拆分波长220nm。SFC analysis and detection method: Column: ChiralPakAD, 50×4.6mm I.D., 3μm, mobile phase: A: carbon dioxide, B: ethanol (0.05% diethylamine), gradient: B%: 40%, gradient flow for 3.0 min, flow rate: 3.0 mL/min, resolution wavelength 220 nm.

化合物149-3-P1：保留时间：0.447分钟，MS m/z(ESI)：＝660.7[M+H]⁺。Compound 149-3-P1: Retention time: 0.447 min, MS m/z (ESI): 660.7 [M+H] ⁺ .

化合物149-3-P2：保留时间：0.576分钟，MS m/z(ESI)：＝660.7[M+H]⁺。Compound 149-3-P2: Retention time: 0.576 min, MS m/z (ESI): 660.7 [M+H] ⁺ .

步骤5：将化合物149-3-P1(100mg,0.15mmol)溶于甲醇(5mL)和水(1mL)中，加入氢氧化锂(31.8mg,0.76mmol)，加热至60℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物149-P1。MS m/z(ESI)：＝532.5[M+H]⁺。¹H NMR(500MHz,DMSO-d₆)δ10.82(s,1H),7.90(d,J＝7.9Hz,2H),7.51(d,J＝8.1Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.92(d,J＝2.7Hz,1H),4.07(s,1H),3.62(s,3H),3.44-3.34(m,4H),2.63-2.57(m,1H),2.48-2.38(m,4H),2.27-2.18(m,4H),2.08(t,J＝15.4Hz,2H),1.85-1.72(m,2H),1.52(s,1H)。Step 5: Compound 149-3-P1 (100 mg, 0.15 mmol) was dissolved in methanol (5 mL) and water (1 mL), and lithium hydroxide (31.8 mg, 0.76 mmol) was added. The mixture was heated to 60 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 149-P1. MS m/z (ESI): = 532.5 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ10.82(s,1H),7.90(d,J＝7.9Hz,2H),7.51(d,J＝8.1Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.92(d,J＝2.7Hz,1H),4.07(s,1H),3.62( s,3H),3.44-3.34(m,4H),2.63-2.57(m,1H),2.48-2.38(m,4H),2.27 -2.18(m,4H),2.08(t,J＝15.4Hz,2H),1.85-1.72(m,2H),1.52(s,1H).

按照由149-3-P1制得149-P1的方法，由化合物149-3-P2得到化合物149-P2。MS m/z(ESI)：＝532.5[M+H]⁺。¹H NMR(500MHz,DMSO-d₆)δ10.82(s,1H),7.90(s,2H),7.52(d,J＝7.8Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.92(d,J＝2.7Hz,1H),4.10(s,1H),3.62(s,3H),3.42(s,3H),3.30(s,1H),2.63-2.56(m,1H),2.46-2.34(m,4H),2.34-1.99(m,6H),1.89-1.70(m,2H),1.63-1.40(m,1H)。Compound 149-P2 was obtained from compound 149-3-P2 using the same method as that used to prepare 149-P1. MS m/z (ESI): 532.5 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ )δ10.82(s,1H),7.90(s,2H),7.52(d,J＝7.8Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.92(d,J＝2.7Hz,1H),4.10(s,1H),3.62 (s,3H),3.42(s,3H),3.30(s,1H),2.63-2.56(m,1H),2.46-2.34(m,4H),2.34-1.99(m,6H),1.89-1.70(m,2H),1.63-1.40(m,1H).

实施例150：化合物150的制备
Example 150: Preparation of Compound 150

步骤1：将化合物150-1(900mg,9.37mmol)和三乙胺(2.60mL,18.73mmol)溶于二氯甲烷(10mL)中，0℃下加入对甲苯磺酰氯(2.68g,14.05mmol)，升至25℃搅拌18小时。通过TLC监测反应。浓缩，粗品通过硅胶色谱柱：0％-15％乙酸乙酯/石油醚梯度纯化，得到化合物150-2。Step 1: Compound 150-1 (900 mg, 9.37 mmol) and triethylamine (2.60 mL, 18.73 mmol) were dissolved in dichloromethane (10 mL). p-Toluenesulfonyl chloride (2.68 g, 14.05 mmol) was added at 0 °C, and the mixture was stirred at 25 °C for 18 hours. The reaction was monitored by TLC. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%–15% ethyl acetate/petroleum ether to obtain compound 150-2.

步骤2：将化合物103-1(1.61g,5.32mmol)和化合物150-2(2.00g,7.99mmol)溶于N,N-二甲基甲酰胺(32mL)中，加入碳酸铯(3.47g,10.65mmol)，在50℃下搅拌18小时。通过LCMS监测反应。加入水(150mL)淬灭，用乙酸乙酯(3×150mL)萃取，合并的有机相用饱和食盐水(180mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-15％甲醇/二氯甲烷梯度纯化，得到化合物150-3。MS m/z(ESI)：＝381.2[M+H]⁺。Step 2: Compound 103-1 (1.61 g, 5.32 mmol) and compound 150-2 (2.00 g, 7.99 mmol) were dissolved in N,N-dimethylformamide (32 mL), and cesium carbonate (3.47 g, 10.65 mmol) was added. The mixture was stirred at 50 °C for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with water (150 mL), extracted with ethyl acetate (3 × 150 mL), and the combined organic phases were washed with saturated brine (180 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–15% methanol/dichloromethane to give compound 150-3. MS m/z (ESI): = 381.2 [M+H] ⁺ .

步骤3：常温下，将化合物150-3(500mg,1.31mmol)溶于乙腈(10mL)和水(10mL)中，加入[双(三氟乙酰氧基)碘]苯(1.13g,2.63mmol)，搅拌2小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-20％甲醇/二氯甲烷梯度纯化，得到化合物150-4。MS m/z(ESI)：＝353.2[M+H]⁺。Step 3: At room temperature, compound 150-3 (500 mg, 1.31 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and [bis(trifluoroacetoxy)iodide]benzene (1.13 g, 2.63 mmol) was added. The mixture was stirred for 2 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a 0%-20% methanol/dichloromethane gradient to obtain compound 150-4. MS m/z (ESI): = 353.2 [M+H] ⁺ .

步骤4：25℃下，将化合物150-4(585mg,1.66mmol)和化合物1-14(480mg,1.66mmol)溶于乙腈(10mL)中，加入醋酸(0.09mL,1.66mmol)，搅拌30分钟后，加入三乙酰氧基硼氢化钠(703mg,3.32mmol)，继续搅拌18小时。通过LCMS监测反应。加入饱和碳酸钠溶液(30mL)淬灭，用乙酸乙酯(3×30mL)萃取，合并的有机相用饱和食盐水(40mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-40％乙酸乙酯/石油醚梯度纯化，得到化合物150-5。MS m/z(ESI)：＝626.4[M+H]⁺。Step 4: At 25°C, compound 150-4 (585 mg, 1.66 mmol) and compound 1-14 (480 mg, 1.66 mmol) were dissolved in acetonitrile (10 mL), and acetic acid (0.09 mL, 1.66 mmol) was added. After stirring for 30 minutes, sodium triacetoxyborohydride (703 mg, 3.32 mmol) was added, and stirring was continued for 18 hours. The reaction was monitored by LCMS. The reaction was quenched with saturated sodium carbonate solution (30 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine (40 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%-40% ethyl acetate/petroleum ether to give compound 150-5. MS m/z (ESI): = 626.4 [M+H] ⁺ .

步骤5：将化合物150-5(680mg,1.09mmol)溶于甲醇(10mL)和水(2.5mL)中，加入氢氧化锂(228mg,5.43mmol)，加热至50℃搅拌18小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至中性，过滤浓缩。粗品通过反相色谱柱：10％-95％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物150。MS m/z(ESI)：＝498.4[M+H]⁺。¹HNMR(400MHz,DMSO-d₆)δ10.82(d,J＝2.7Hz,1H),7.90(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),6.14(tt,J＝57.0,4.6Hz,1H),5.95-5.88(m,1H),3.62(s,3H),3.42(s,2H),3.33(s,2H),2.50-2.48(m,2H),2.41(s,3H),2.29-2.17(m,4H),2.12-1.94(m,4H),1.85-1.75(m,2H)。Step 5: Compound 150-5 (680 mg, 1.09 mmol) was dissolved in methanol (10 mL) and water (2.5 mL), and lithium hydroxide (228 mg, 5.43 mmol) was added. The mixture was heated to 50 °C and stirred for 18 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to neutral by adding hydrochloric acid (1 N), and the mixture was concentrated by filtration. The crude product was purified by a reversed-phase column using a gradient of 10%–95% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 150. MS m/z (ESI): = 498.4 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ10.82(d,J＝2.7Hz,1H),7.90(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),6.14(tt,J＝57.0,4.6Hz,1H),5.95 -5.88(m,1H),3.62(s,3H),3.42(s,2H),3.33(s,2H),2.50-2.48(m,2H) ,2.41(s,3H),2.29-2.17(m,4H),2.12-1.94(m,4H),1.85-1.75(m,2H).

实施例151：化合物151-P1、151-P2的制备
Example 151: Preparation of compounds 151-P1 and 151-P2

步骤1：20℃下，将化合物103-1(1.00g,3.31mmol)和氟代丙酮(0.50g,6.61mmol)溶于乙腈(30mL)和乙酸(0.5mL)中，加入三乙酰氧基硼氢化钠(2.10g,9.92mmol)，搅拌16小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物151-1。MS m/z(ESI)：＝363.5[M+H]⁺。Step 1: At 20°C, compound 103-1 (1.00 g, 3.31 mmol) and fluoroacetone (0.50 g, 6.61 mmol) were dissolved in acetonitrile (30 mL) and acetic acid (0.5 mL), and sodium triacetoxyborohydride (2.10 g, 9.92 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%–100% ethyl acetate/petroleum ether to give compound 151-1. MS m/z (ESI): = 363.5 [M+H] ⁺ .

步骤2：20℃下，将化合物151-1(1.15g,3.17mmol)溶于乙腈(20mL)和水(20mL)中，加入[双(三氟乙酰氧基)碘]苯(2.05g,4.76mmol)，搅拌16小时。通过LCMS监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物151-2。MS m/z(ESI)：＝335.4[M+H]⁺。Step 2: At 20°C, compound 151-1 (1.15 g, 3.17 mmol) was dissolved in acetonitrile (20 mL) and water (20 mL), and [bis(trifluoroacetoxy)iodo]benzene (2.05 g, 4.76 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–100% ethyl acetate/petroleum ether to give compound 151-2. MS m/z (ESI): = 335.4 [M+H] ⁺ .

步骤3：20℃下，将化合物151-2(1.00g,2.99mmol)和化合物1-14(1.30g,4.49mmol)溶于乙腈(30mL)和乙酸(0.5mL)中，加入三乙酰氧基硼氢化钠(1.90g,8.97mmol)，搅拌16小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物151-3。MS m/z(ESI)：＝608.7[M+H]⁺。Step 3: At 20°C, compound 151-2 (1.00 g, 2.99 mmol) and compound 1-14 (1.30 g, 4.49 mmol) were dissolved in acetonitrile (30 mL) and acetic acid (0.5 mL), and sodium triacetoxyborohydride (1.90 g, 8.97 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%-100% ethyl acetate/petroleum ether to give compound 151-3. MS m/z (ESI): = 608.7 [M+H] ⁺ .

步骤4：将化合物151-3(1.20g,1.97mmol)溶于甲醇(30mL)和水(20mL)中，加入氢氧化锂(0.50g,11.85mmol)，60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH至弱酸性，过滤浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物151-P1，MS m/z(ESI)：＝492.0[M+H]⁺。HPLC(测定条件四)保留时间：2.570min。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.80(d,J＝8.2Hz,2H),7.39(d,J＝8.1Hz,2H),7.19(t,J＝2.7Hz,1H),6.64(s,1H),5.93-5.85(m,1H),3.84-3.76(m,2H),3.63(s,3H),3.41(s,2H),3.27-3.26(m,5H),2.92-2.87(m,1H),2.40(s,3H),2.34(d,J＝6.3Hz,2H),2.31-2.21(m,4H),1.87-1.79(m,2H),1.16(d,J＝6.1Hz,3H)。Step 4: Compound 151-3 (1.20 g, 1.97 mmol) was dissolved in methanol (30 mL) and water (20 mL), and lithium hydroxide (0.50 g, 11.85 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to weakly acidic by adding hydrochloric acid (1 N), and the mixture was filtered and concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 151-P1. MS m/z (ESI): = 492.0 [M+H] ⁺ . HPLC (determination condition 4) retention time: 2.570 min. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(s,1H),7.80(d,J＝8.2Hz,2H),7.39(d,J＝8.1Hz,2H),7.19(t,J＝2 .7Hz,1H),6.64(s,1H),5.93-5.85(m,1H),3.84-3.76(m,2H),3.63(s,3H) ,3.41(s,2H),3.27-3.26(m,5H),2.92-2.87(m,1H),2.40(s,3H),2.34(d, J＝6.3Hz,2H),2.31-2.21(m,4H),1.87-1.79(m,2H),1.16(d,J＝6.1Hz,3H).

得到化合物151-P2，MS m/z(ESI)：＝492.0[M+H]⁺。HPLC(测定条件四)保留时间：2.677min。¹H NMR(400MHz,DMSO-d₆)δ10.82(s,1H),7.85(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),7.20(t,J＝2.7Hz,1H),6.64(s,1H),5.95-5.86(m,1H),3.62(s,3H),3.42-3.40(m,5H),3.25(s,3H),2.64-2.56(m,1H),2.47-2.43(m,1H),2.40(s,3H),2.30-2.22(m,4H),2.20-2.13(m,2H),1.89-1.80(m,2H),1.09(d,J＝6.1Hz,3H)。Compound 151-P2 was obtained, MS m/z (ESI): 492.0 [M+H] ⁺ . HPLC (determination condition 4) retention time: 2.677 min. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.82(s,1H),7.85(d,J＝8.3Hz,2H),7.44(d,J＝8.3Hz,2H),7.20(t,J＝ 2.7Hz,1H),6.64(s,1H),5.95-5.86(m,1H),3.62(s,3H),3.42-3.40(m,5H ),3.25(s,3H),2.64-2.56(m,1H),2.47-2.43(m,1H),2.40(s,3H),2.30- 2.22(m,4H),2.20-2.13(m,2H),1.89-1.80(m,2H),1.09(d,J＝6.1Hz,3H).

实施例152：化合物152的制备
Example 152: Preparation of compound 152

步骤1：20℃下，将化合物152-1(900mg,6.92mmol)和三乙胺(2.10g,20.76mmol)溶于二氯甲烷(30mL)中，加入对甲苯磺酰氯(1.98g,10.38mmol)，搅拌16小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-20％乙酸乙酯/石油醚梯度纯化，得到化合物152-2。Step 1: At 20°C, compound 152-1 (900 mg, 6.92 mmol) and triethylamine (2.10 g, 20.76 mmol) were dissolved in dichloromethane (30 mL), and p-toluenesulfonyl chloride (1.98 g, 10.38 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%–20% ethyl acetate/petroleum ether to obtain compound 152-2.

步骤2：20℃下，将化合物152-2(1.00g,3.52mmol)和化合物103-1(0.53g,1.75mmol)溶于N,N-二甲基甲酰胺(40mL)中，加入N,N-二异丙基乙胺(1.36g,10.55mmol)，搅拌48小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-50％乙酸乙酯/石油醚梯度纯化，得到化合物152-3。MS m/z(ESI)：＝415.7[M+H]⁺。Step 2: At 20°C, compound 152-2 (1.00 g, 3.52 mmol) and compound 103-1 (0.53 g, 1.75 mmol) were dissolved in N,N-dimethylformamide (40 mL), and N,N-diisopropylethylamine (1.36 g, 10.55 mmol) was added. The mixture was stirred for 48 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%-50% ethyl acetate/petroleum ether to give compound 152-3. MS m/z (ESI): = 415.7 [M+H] ⁺ .

步骤3：20℃下，将化合物152-3(680mg,1.64mmol)溶于乙腈(15mL)和水(15mL)中，加入[双(三氟乙酰氧基)碘](1.06g,2.46mmol)，搅拌16小时。通过LCMS监测反应。加入水(100mL)淬灭，用乙酸乙酯(3×100mL)萃取，合并的有机相用饱和食盐水(100mL)洗涤，干燥并浓缩。粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物152-4。MS m/z(ESI)：＝387.4[M+H]⁺。Step 3: At 20°C, compound 152-3 (680 mg, 1.64 mmol) was dissolved in acetonitrile (15 mL) and water (15 mL), and [bis(trifluoroacetoxy)iodine] (1.06 g, 2.46 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with water (100 mL), extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated brine (100 mL), dried, and concentrated. The crude product was purified by silica gel column chromatography using a gradient of 0%–100% ethyl acetate/petroleum ether to give compound 152-4. MS m/z (ESI): = 387.4 [M+H] ⁺ .

步骤4：20℃下，将化合物152-4(500mg,1.29mmol)和化合物1-14(449mg,1.55mmol)溶于N,N-二甲基甲酰胺(20mL)和乙酸(0.2mL)中，加入三乙酰氧基硼氢化钠(823mg,3.88mmol)，搅拌16小时。通过LCMS监测反应。加入水(1mL)淬灭，浓缩，粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物152-5。MS m/z(ESI)：＝658.0[M+H]⁺。Step 4: At 20°C, compound 152-4 (500 mg, 1.29 mmol) and compound 1-14 (449 mg, 1.55 mmol) were dissolved in N,N-dimethylformamide (20 mL) and acetic acid (0.2 mL), and sodium triacetoxyborohydride (823 mg, 3.88 mmol) was added. The mixture was stirred for 16 hours. The reaction was monitored by LCMS. The reaction was quenched with water (1 mL), concentrated, and the crude product was purified by silica gel column chromatography using a gradient of 0%-100% ethyl acetate/petroleum ether to obtain compound 152-5. MS m/z (ESI): = 658.0 [M+H] ⁺ .

步骤5：20℃下，将化合物152-5(500mg,0.76mmol)溶于甲醇(20mL)中，加入硼氢化钠(28.9mg,0.76mmol)，搅拌3小时。通过LCMS监测反应。浓缩，粗品通过硅胶色谱柱：0％-100％乙酸乙酯/石油醚梯度纯化，得到化合物152-6。MS m/z(ESI)：＝660.5[M+H]⁺。Step 5: At 20°C, compound 152-5 (500 mg, 0.76 mmol) was dissolved in methanol (20 mL), and sodium borohydride (28.9 mg, 0.76 mmol) was added. The mixture was stirred for 3 hours. The reaction was monitored by LCMS. The crude product was concentrated and purified by silica gel column chromatography using a gradient of 0%-100% ethyl acetate/petroleum ether to give compound 152-6. MS m/z (ESI): = 660.5 [M+H] ⁺ .

步骤6：将化合物152-6(500mg,0.76mmol)溶于甲醇(20mL)和水(10mL)中，加入氢氧化锂(90.8mg,3.79mmol)，60℃搅拌16小时。通过LCMS监测反应。加入盐酸(1N)调节体系pH为弱酸性，浓缩，粗品通过反相色谱柱：15％-100％乙腈/缓冲液(0.01mol/L碳酸氢铵水溶液)梯度纯化，得到化合物152。MS m/z(ESI)：＝532.4[M+H]⁺。¹H NMR(400MHz,DMSO-d₆)δ10.83(s,1H),7.94(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.91(dd,J＝2.8,1.9Hz,1H),4.10(t,J＝5.7Hz,2H),3.62(s,3H),3.41(s,2H),3.34(s,2H),2.68-2.61(m,2H),2.40(s,3H),2.31-2.14(m,4H),2.02(d,J＝11.5Hz,2H),1.88-1.69(m,2H)。Step 6: Compound 152-6 (500 mg, 0.76 mmol) was dissolved in methanol (20 mL) and water (10 mL), and lithium hydroxide (90.8 mg, 3.79 mmol) was added. The mixture was stirred at 60 °C for 16 hours. The reaction was monitored by LCMS. The pH of the system was adjusted to weakly acidic by adding hydrochloric acid (1 N), and the mixture was concentrated. The crude product was purified by a reverse-phase chromatography column using a gradient of 15%–100% acetonitrile/buffer (0.01 mol/L ammonium bicarbonate aqueous solution) to obtain compound 152. MS m/z (ESI): = 532.4 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ )δ10.83(s,1H),7.94(d,J＝8.4Hz,2H),7.54(d,J＝8.4Hz,2H),7.21(t,J＝2.8Hz,1H),6.64(s,1H),5.91(dd,J＝2.8,1.9Hz,1H),4.10(t,J＝5.7 Hz,2H),3.62(s,3H),3.41(s,2H),3.34(s,2H),2.68-2.61(m,2H),2.4 0(s,3H),2.31-2.14(m,4H),2.02(d,J＝11.5Hz,2H),1.88-1.69(m,2H).

本发明的其他化合物可以通过与以上实施例所述的方法类似的方法(必要时，进行适当的修改)制备。Other compounds of the present invention can be prepared by methods similar to those described in the above embodiments (with appropriate modifications if necessary).

生物学测试：Biological tests:

实验例1：人FB蛋白竞争结合实验Experimental Example 1: Competitive Binding Experiment of Human FB Protein

使用Echo(Beckman 665)在384白色浅孔板(PerkinElmer 6008280)中加入梯度稀释的20nL实施例化合物(10μM开始，3倍稀释，2个复孔)，添加以10μL试验缓冲液[pH值7.4，20mM Tris-HCl，0.005％(v/v)Tween-20]溶解的2倍反应浓度FB蛋白(Sinobiological，D470–L764，终浓度：5nM)，密封浅孔板，震荡后1000rpm离心1分钟，室温孵育1小时；然后加入5μL Cy5标记的小分子探针(CN105579444A的生物学实施例2.6)(终浓度：37.5nM)和5μLEu标记的链霉亲和素(PerkinElmer，AD0060终浓度：1.25nM)，密封浅孔板，震荡后1000rpm离心1分钟，室温孵育1小时，使用酶标仪(PerkinElmer 2105)在激发光337nm、发射光620/665nm波长下读取数值。Using an Echo (Beckman 665), 20 nL of serially diluted example compounds (starting at 10 μM, 3-fold dilution, 2 replicates) were added to 384 white shallow-well plates (PerkinElmer 6008280). Then, FB protein (Sinobiological, D470–L764, final concentration: 5 nM) dissolved in 10 μL of test buffer [pH 7.4, 20 mM Tris-HCl, 0.005% (v/v) Tween-20] at twice the reaction concentration was added. The shallow-well plates were sealed, and the plates were shaken for 100 minutes. Centrifuge at 0 rpm for 1 minute and incubate at room temperature for 1 hour; then add 5 μL of Cy5-labeled small molecule probe (Biological Example 2.6 of CN105579444A) (final concentration: 37.5 nM) and 5 μL of Leu-labeled streptavidin (PerkinElmer, AD0060, final concentration: 1.25 nM), seal the shallow well plate, shake, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 1 hour. Use a microplate reader (PerkinElmer 2105) to read the values at excitation wavelength of 337 nm and emission wavelength of 620/665 nm.

抑制百分比是使用以下公式计算：抑制％＝100％×[1-(X-min)/(max-min)]，The inhibition percentage is calculated using the following formula: Inhibition % = 100% × [1 - (X - min) / (max - min)],

其中X是原始数据读数，min是最大浓度阳性对照化合物(LNP023)的对照孔(n＝2)的平均值，max是DMSO对照孔(n＝2)的平均值。Where X is the raw data reading, min is the average value of the control wells (n=2) for the highest concentration of the positive control compound (LNP023), and max is the average value of the DMSO control wells (n=2).

在Prism GraphPad 9软件中，使用标准四参数曲线拟合算法计算IC₅₀值。In Prism GraphPad 9 software, the IC ₅₀ value is calculated using the standard four-parameter curve fitting algorithm.

部分实验结果概述于表1。Some of the experimental results are summarized in Table 1.

表1：本发明实施例化合物对FB酶活性的抑制作用(IC₅₀)

Table 1: Inhibitory effect of the compounds in the embodiments of the present invention on FB enzyme activity ( _IC50 )

结论：本发明的化合物对FB酶活性具有较好的抑制作用。Conclusion: The compounds of this invention have a good inhibitory effect on FB enzyme activity.

实验例2：小鼠血清旁路途径补体沉降实验Experimental Example 2: Complement Sedimentation Experiment via Alternate Pathway in Mouse Serum

本实验中试剂来自补体系统旁路途径检测试剂盒(下文中简称为“AP”)。The reagents used in this experiment were from the complement system bypass pathway detection kit. (Hereinafter referred to as "AP").

将正常小鼠血清用DiluteAP稀释至1/75(v/v)。将95μL稀释后的小鼠血清和5μL实施例化合物(10μM开始，3倍稀释，2个复孔，DMSO终含量0.1％)添加到LPS包被的AP 96孔板中，混匀后37℃孵育60分钟。弃掉上清液并用300μLAP wash solution洗涤3次，加入300μL StartingBlock^TMT20(PBS)1X(Thermo Scientific^TM37539)室温孵育15分钟。弃掉上清液并用300μLAP wash solution洗涤3次，每孔加入100μL TBST稀释的大鼠抗小鼠C3b/iC3b/C3c单克隆抗体(clone 2/11，Hycult Biotech，HM1065，浓度为2μg/mL)，室温孵育60分钟。弃掉上清液并用300μLAP wash solution洗涤3次后，每孔加入100μL辣根过氧化物酶(HRP)标记的山羊抗大鼠IgG抗体(Cell Signaling 7077S，TBS-T稀释1/1000)，室温下孵育60分钟。弃掉上清液并用300μLAP wash solution洗涤3次后，每孔加入100μL Quantablu Substrate Solution(Thermo pierce 15169)，室温下反应20分钟后加入100μL Quantablu Stop Solution终止反应。使用酶标仪(PerkinElmer 2105)，在激发光320nm和发射光420nm下读取数值。Normal mouse serum was diluted to 1/75 (v/v) with DiluteAP. 95 μL of the diluted mouse serum and 5 μL of the example compound (starting at 10 μM, 3-fold dilution, 2 replicates, 0.1% DMSO final concentration) were added to an LPS-coated AP 96-well plate, mixed, and incubated at 37°C for 60 min. The supernatant was discarded, and the plate was washed three times with 300 μL of LAP wash solution. 300 μL of StartingBlock ^™ T20 (PBS) 1X (Thermo Scientific ^™ 37539) was added, and the plate was incubated at room temperature for 15 min. The supernatant was discarded, and the plate was washed three times with 300 μL of LAP wash solution. 100 μL of TBST-diluted rat anti-mouse C3b/iC3b/C3c monoclonal antibody (clone 2/11, Hycult Biotech, HM1065, 2 μg/mL) was added to each well, and the plate was incubated at room temperature for 60 min. After discarding the supernatant and washing three times with 300 μL LAP wash solution, add 100 μL of horseradish peroxidase (HRP)-labeled goat anti-rat IgG antibody (Cell Signaling 7077S, TBS-T diluted 1/1000) to each well and incubate at room temperature for 60 minutes. After discarding the supernatant and washing three times with 300 μL LAP wash solution, add 100 μL of Quantablu Substrate Solution (Thermo Pierce 15169) to each well and react at room temperature for 20 minutes. Then, stop the reaction by adding 100 μL of Quantablu Stop Solution. Read the values using a microplate reader (PerkinElmer 2105) at excitation light at 320 nm and emission light at 420 nm.

其中X是原始数据读数，min是最大浓度阳性对照化合物的对照孔(n＝2)的平均值，max是DMSO对照孔(n＝2)的平均值。Where X is the raw data reading, min is the average value of the control wells (n=2) with the highest concentration of the positive control compound, and max is the average value of the DMSO control wells (n=2).

采用GraphPad Prism软件计算IC₅₀值。在Prism GraphPad 9软件中，使用标准四参数曲线拟合算法计算IC₅₀值。The _IC50 value was calculated using GraphPad Prism software. In Prism GraphPad 9 software, the standard four-parameter curve fitting algorithm was used to calculate the _IC50 value.

部分实验结果概述于表2。Some of the experimental results are summarized in Table 2.

表2：本发明实施例化合物对小鼠补体旁路途径测得的IC₅₀值
Table 2: _IC50 values of the compounds in the embodiments of the present invention against the mouse complement bypass pathway.

结论：本发明的化合物对鼠血清旁路途径激活的抑制活性明显。Conclusion: The compounds of this invention exhibit significant inhibitory activity against activation of the bypass pathway in mouse serum.

实验例3：人血清旁路途径补体沉降实验Experimental Example 3: Human Serum Alternate Pathway Complement Sedimentation Experiment

本实验试剂耗材来自补体系统旁路途径检测试剂盒(COMPLAP330RUO)，下述AP皆指代本试剂盒。The reagents and consumables used in this experiment are from the Complement System Bypass Pathway Detection Kit (COMPLAP330RUO). AP in the following text refers to this kit.

将正常人血清用DiluteAP稀释至1/18(v/v)，取95μL稀释后的人血清和5μL实施例化合物(1μM开始，3倍稀释，2个复孔，DMSO终含量0.1％)添加到LPS包被的AP 96孔板中，混匀后37℃孵育60分钟。弃掉上清液并用300μLAP wash solution洗涤3次，每孔加入100μL含有碱性磷酸酶标记的抗C5b-9抗体的偶联物，室温孵育30分钟。弃掉上清液并用300μLAP wash solution洗涤3次后，每孔加入100μL底物溶液，室温下孵育30分钟。使用酶标仪(PerkinElmer 2105)，在吸光度405nm下读取数值。Normal human serum was diluted to 1/18 (v/v) with Dilute AP. 95 μL of the diluted human serum and 5 μL of the example compound (starting at 1 μM, 3-fold dilution, 2 replicates, DMSO final concentration 0.1%) were added to an LPS-coated AP 96-well plate. After mixing, the plate was incubated at 37°C for 60 minutes. The supernatant was discarded, and the plate was washed three times with 300 μL of LAP wash solution. 100 μL of a conjugate containing alkaline phosphatase-labeled anti-C5b-9 antibody was added to each well, and the plate was incubated at room temperature for 30 minutes. The supernatant was discarded, and the plate was washed three times with 300 μL of LAP wash solution. 100 μL of substrate solution was added to each well, and the plate was incubated at room temperature for 30 minutes. The absorbance was read at 405 nm using a microplate reader (PerkinElmer 2105).

抑制百分比是使用以下公式计算：抑制％＝100％×[1-(X-min)/(max-min)]；其中X是原始数据读数，min是最大浓度阳参化合物的对照孔(n＝4)的平均值，max是DMSO对照孔(n＝4)的平均值。The inhibition percentage is calculated using the following formula: Inhibition% = 100% × [1 - (X - min) / (max - min)]; where X is the raw data reading, min is the average value of the control wells (n = 4) with the highest concentration of yangshen compound, and max is the average value of the DMSO control wells (n = 4).

采用GraphPad Prism软件计算IC₅₀值。在Prism GraphPad 9软件中，使用标准四参数曲线拟合算法计算IC₅₀值。部分实验结果概述于表3。The _IC50 value was calculated using GraphPad Prism software. The standard four-parameter curve fitting algorithm was used to calculate the _IC50 value in Prism GraphPad 9 software. Some experimental results are summarized in Table 3.

表3：本发明实施例化合物对人补体旁路途径测得的IC₅₀值
Table 3: _IC50 values of the compounds in the embodiments of the present invention against the human complement bypass pathway.

注：A表示IC₅₀≤100nM；B表示100nM<IC₅₀≤500nM；C表示IC₅₀>500nM。Note: A indicates IC ₅₀ ≤ 100 nM; B indicates 100 nM < IC ₅₀ ≤ 500 nM; C indicates IC ₅₀ > 500 nM.

结论：本发明的化合物对人血清旁路途径激活的抑制活性明显。Conclusion: The compounds of this invention exhibit significant inhibitory activity against activation of the human serum bypass pathway.

实验例4：肝微粒体稳定性实验Experiment Example 4: Liver Microsomal Stability Experiment

将各种属的肝微粒体(人/大鼠/小鼠)及实施例化合物的乙腈溶液以100mM磷酸缓冲液(pH7.4)配制成反应母液，使化合物在反应体系终浓度为1.5μM。混匀后，各取30μL分装至新的96深孔板中设为含NADPH的0、5、15、30和45min反应组(n＝2)，及0和45min不加NADPH的对照组(n＝1)。Liver microsomes of various genera (human/rat/mouse) and acetonitrile solutions of the compounds in the examples were prepared into a stock solution using 100 mM phosphate buffer (pH 7.4) to achieve a final concentration of 1.5 μM in the reaction system. After mixing, 30 μL of each solution was aliquoted into new 96-well plates to form reaction groups (n = 2) containing NADPH at 0, 5, 15, 30, and 45 min, and a control group (n = 1) without NADPH at 0 and 45 min.

将以上样品37℃水浴振荡预孵育5min后，分别加入15μLNADPH启动反应，使NADPH终浓度为3mM，无NADPH对照组加入15μL的磷酸缓冲溶液。混匀后，继续孵育相应的时间。以200μL含内标的冰乙腈终止反应。涡旋混匀，4℃下以4000rpm离心50min，取上清用超纯水稀释，待UPLC-MS/MS检测分析。After pre-incubating the above samples in a 37°C water bath with shaking for 5 min, 15 μL of NADPH was added to each sample to initiate the reaction, bringing the final NADPH concentration to 3 mM. For the NADPH-free control group, 15 μL of phosphate buffer solution was added. After mixing, incubation was continued for the appropriate time. The reaction was terminated with 200 μL of ice-cold acetonitrile containing the internal standard. The mixture was vortexed, centrifuged at 4000 rpm for 50 min at 4°C, and the supernatant was diluted with ultrapure water for UPLC-MS/MS analysis.

以测试物剩余百分率的对数值对孵育时间作图，采用T_1/2＝0.693/K计算测试物消除半衰期(MMS(人/大鼠/小鼠，T_1/2，min))。部分实验结果概述于表4。Plot the logarithm of the remaining percentage of the test substance against incubation time, and calculate the elimination half-life of the test substance (MMS(human/rat/mouse, T _1/2 , min)) using T _1/2 = 0.693/K. Some experimental results are summarized in Table 4.

表4：本发明实施例化合物的肝微粒体消除半衰期
Table 4: Hepatic microsomal elimination half-life of compounds in the embodiments of the present invention

结论：本发明的化合物具有较好的肝微粒体稳定性。Conclusion: The compounds of this invention exhibit good liver microsomal stability.

实验例5：小鼠药代动力学研究实验Experiment Example 5: Pharmacokinetic Study in Mice

实验动物：将5-6周龄的体重21-28克的健康状况良好的雄性ICR小鼠(上海必凯科翼生物科技有限公司)分为口服(PO)和静脉(IV)给药两组，每组各3只。IV组动物不禁食不禁水，PO组动物给药前禁食过夜，给药后4h喂食，自由饮水。Experimental animals: Healthy male ICR mice (Shanghai Bikai Keyi Biotechnology Co., Ltd.) aged 5-6 weeks and weighing 21-28 grams were divided into two groups: oral (PO) and intravenous (IV) administration, with 3 mice in each group. Animals in the IV group were allowed free access to food and water, while animals in the PO group were fasted overnight before administration, fed 4 hours after administration, and allowed free access to water.

配制给药制剂：根据给药剂量称量待测实施例化合物，以溶媒[待测实施例化合物：IV&PO,5％DMSO+10％Solutol+85％生理盐水；LNP023:IV,10％propylene glycol+5％solutol+85％phosphatebuffered saline；PO,0.5％methylcellulose+0.5％Tween 80)Deionized water]配制成适量浓度的给药制剂(静脉和口服给药剂量分别为1mg/kg和10mg/kg，给药体积分别为5mL/kg和10mL/kg)。静脉注射剂为澄清溶液，口服剂为澄清溶液或均一的混悬液。Preparation of Dosing Formulations: Weigh the compound of the test example according to the dosage, and prepare a dosage formulation of appropriate concentration using the solvent [compound of the test example: IV & PO, 5% DMSO + 10% Solutol + 85% physiological saline; LNP023: IV, 10% propylene glycol + 5% solubilol + 85% phosphate-buffered saline; PO, 0.5% methylcellulose + 0.5% Tween 80) Deionized water] (intravenous and oral dosages are 1 mg/kg and 10 mg/kg, respectively, with administration volumes of 5 mL/kg and 10 mL/kg, respectively). The intravenous injection is a clear solution, and the oral dosage is a clear solution or a homogeneous suspension.

动物给药及血样采集：通过静脉注射和口服灌胃进行动物给药，并于静脉注射给药后0.033、0.083、0.25、0.5、1、2、4、8和24h及口服给药后0.083、0.25、0.5、1、2、4、6、8和24h采集血样。将全血在4℃下以6800g离心6min，取上层血浆并保存于-80℃冰箱待分析。Animal drug administration and blood sample collection: Animals were administered drugs via intravenous injection and oral gavage. Blood samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 minutes at 4°C, and the supernatant plasma was collected and stored at -80°C for analysis.

血浆样本检测：取待测物的DMSO储备液以甲醇溶液稀释成系列工作溶液，加入空白血浆基质中，配制标准曲线及质控样品。取适量体积的血浆样本，根据响应加入适量倍数的含内标的甲醇进行蛋白沉淀。将所有样本在4℃下以18000g离心10min后，取适量上清用于LC-MS/MS分析。Plasma sample testing: Dilute the DMSO stock solution of the analyte with methanol to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample and add an appropriate amount of methanol containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 18000g for 10 min at 4℃, and take an appropriate amount of supernatant for LC-MS/MS analysis.

参数计算：根据测试浓度绘制血药浓度-时间曲线，通过WinNonlin(PhoenixTM，版本8.3)软件，按非房室模型计算参数，包括：清除率(CL)、半衰期(T_1/2)、达峰浓度(C_max)、血药浓度-时间曲线下面积(AUC_0-t)、生物利用度(F)等药代动力学参数。Parameter calculation: Based on the test concentration, a blood drug concentration-time curve was plotted. Using WinNonlin (Phoenix™, version 8.3) software, parameters were calculated according to the non-compartmental model, including: clearance (CL), half-life (T _1/2 ), peak concentration (C _max ), area under the blood drug concentration-time curve (AUC _0-t ), bioavailability (F), and other pharmacokinetic parameters.

结论：本发明的至少部分化合物具有较好的药代动力学性质。Conclusion: At least some of the compounds of the present invention have good pharmacokinetic properties.

实验例6A：大鼠药代动力学研究实验-1 Experiment Example 6A: Rat Pharmacokinetic Study Experiment-1

实验动物：将6-8周龄的体重200-300克的健康状况良好的雄性Wistar-Han大鼠或Lewis大鼠(维通利华实验动物技术有限公司)分为口服和静脉给药两组，每组各3只。IV组动物不禁食不禁水。PO组动物禁食过夜，给药后4h喂食，不禁水。Laboratory animals: Healthy male Wistar-Han or Lewis rats (Vitollife Laboratory Animal Technology Co., Ltd.) aged 6-8 weeks and weighing 200-300 grams were randomly divided into two groups: oral administration and intravenous administration, with 3 animals in each group. Animals in group IV were allowed free access to food and water. Animals in group PO were fasted overnight, fed 4 hours after administration, and allowed free access to water.

配制给药制剂：根据给药剂量称量待测实施例化合物，以溶媒[待测实施例化合物：IV&PO,5％DMSO+10％Solutol+85％生理盐水(Wistar-Han大鼠)，或5％DMA+10％Solutol+85％去离子水(Lewis大鼠)；LNP023:IV&PO,30％PEG300/10％Cremphor EL/60％PBS，并以1N HCl调节到pH>4]配制成适量浓度的给药制剂(静脉和口服给药剂量分别为1mg/kg和30mg/kg，给药体积分别为5mL/kg和10mL/kg)。静脉注射剂为澄清溶液，口服剂为澄清溶液或均一的混悬液。Preparation of Dosing Formulations: Weigh the compound of the test example according to the dosage, and prepare a dosage formulation of appropriate concentration using the solvent [test example compound: IV&PO, 5% DMSO + 10% Solutol + 85% physiological saline (Wistar-Han rat), or 5% DMA + 10% Solutol + 85% deionized water (Lewis rat); LNP023: IV&PO, 30% PEG300/10% Cremphor EL/60% PBS, adjusted to pH > 4 with 1N HCl] (intravenous and oral dosages are 1 mg/kg and 30 mg/kg, respectively, with administration volumes of 5 mL/kg and 10 mL/kg, respectively). The intravenous injection formulation is a clear solution, and the oral formulation is a clear solution or a homogeneous suspension.

动物给药及血样采集：通过静脉注射和口服灌胃进行动物给药，并于静脉注射给药后0.033、0.083、0.25、0.5、1、2、4、8和24h及口服给药后0.083、0.25、0.5、1、2、4、6、8和24h采集血样。将全血在2-8℃(设置为4℃)，6800g条件下离心6min，取上层血浆并保存于-80℃冰箱待分析。Animal drug administration and blood sample collection: Animals were administered drugs via intravenous injection and oral gavage. Blood samples were collected at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at the same time after oral administration. Whole blood was centrifuged at 6800g for 6 minutes at 2-8℃ (set to 4℃), and the supernatant plasma was collected and stored at -80℃ for analysis.

血浆样本检测：取待测物的DMSO储备液以甲醇溶液稀释成系列工作溶液，加入空白血浆基质中，配制标准曲线及质控样品。取适量体积的血浆样本，根据响应加入适量倍数的含内标的甲醇进行蛋白沉淀。将所有样本在2-8℃(设置为4℃)，4000g条件下离心10min后，取适量上清液用于LC-MS/MS分析。Plasma sample testing: Dilute the DMSO stock solution of the analyte with methanol to prepare a series of working solutions, add them to the blank plasma matrix, and prepare a standard curve and quality control samples. Take an appropriate volume of plasma sample, and add an appropriate amount of methanol containing internal standard according to the response to precipitate proteins. Centrifuge all samples at 2-8℃ (set to 4℃) at 4000g for 10 min, and take an appropriate amount of supernatant for LC-MS/MS analysis.

参数计算：根据测试浓度绘制血药浓度-时间曲线，通过WinNonlin(PhoenixTM，版本8.3)软件，按非房室模型计算参数，包括：清除率(CL)、半衰期(T_1/2)、达峰浓度(C_max)、血药浓度-时间曲线下面积(AUC_0-t)、生物利用度(F)等药代动力学参数。部分实验结果概述于表5。Parameter calculation: Based on the test concentrations, plasma concentration-time curves were plotted. Parameters, including clearance (CL), half-life (T _{1/2} ), peak concentration (C _{max} ), area under the plasma concentration-time curve (AUC _{0-t} ), and bioavailability (F), were calculated using WinNonlin (Phoenix™, version 8.3) software according to a non-compartmental model. Some experimental results are summarized in Table 5.

表5：本发明实施例化合物与对照化合物PK结果对比
Table 5: Comparison of PK results between compounds in the embodiments of the present invention and control compounds

结论：本发明的化合物药代动力学性质良好，与阳性对照化合物相当或更优，口服暴露量尤佳。Conclusion: The compounds of this invention exhibit good pharmacokinetic properties, comparable to or better than the positive control compounds, with particularly good oral exposure.

实验例6B：大鼠药代动力学研究实验-2 Experiment 6B: Rat Pharmacokinetic Study Experiment-2

实验动物：将6-8周龄的体重200-300克的健康状况良好的雄性Lewis大鼠(维通利华实验动物技术有限公司)分为口服和静脉给药两组，每组各3只。IV组动物不禁食不禁水。PO组动物禁食过夜，给药后4h喂食，不禁水。Laboratory animals: Healthy male Lewis rats (Vitollife Laboratory Animal Technology Co., Ltd.) aged 6-8 weeks and weighing 200-300 grams were randomly divided into two groups: one receiving oral administration and the other receiving intravenous administration, with 3 rats in each group. Group IV animals were allowed unrestricted food and water. Group PO animals were fasted overnight, fed 4 hours after administration, and allowed unrestricted water.

配制给药制剂：根据给药剂量称量待测实施例化合物，以溶媒[待测实施例化合物:IV&PO,5％DMA+10％Solutol+85％去离子水；LNP023:IV&PO,5％DMA+10％Solutol+85％去离子水]配制成适量浓度的给药制剂[静脉和口服给药剂量分别为1mg/kg和20mg/kg(或30mg/kg)，给药体积分别为5mL/kg和10mL/kg]。静脉注射剂为澄清溶液，口服剂为澄清溶液或均一的混悬液。Preparation of Dosing Formulations: Weigh the compound of the test example according to the dosage, and prepare a dosage formulation of appropriate concentration using the solvent [compound of the test example: IV&PO, 5% DMA + 10% Solutol + 85% deionized water; LNP023: IV&PO, 5% DMA + 10% Solutol + 85% deionized water] [intravenous and oral dosages are 1 mg/kg and 20 mg/kg (or 30 mg/kg), respectively, with administration volumes of 5 mL/kg and 10 mL/kg, respectively]. The intravenous injection is a clear solution, and the oral dosage is a clear solution or a homogeneous suspension.

参数计算：根据测试浓度绘制血药浓度-时间曲线，通过WinNonlin(PhoenixTM，版本8.3)软件，按非房室模型计算参数，包括：清除率(CL)、半衰期(T_1/2)、达峰浓度(C_max)、血药浓度-时间曲线下面积(AUC_0-t)、生物利用度(F)等药代动力学参数。部分实验结果概述于表6。Parameter calculation: Based on the test concentrations, plasma concentration-time curves were plotted. Parameters, including clearance (CL), half-life (T _{1/2} ), peak concentration (C _{max} ), area under the plasma concentration-time curve (AUC _{0-t} ), and bioavailability (F), were calculated using WinNonlin (Phoenix™, version 8.3) software according to a non-compartmental model. Some experimental results are summarized in Table 6.

表6：本发明实施例化合物与对照化合物PK结果对比
Table 6: Comparison of PK results between compounds in the embodiments of the present invention and control compounds

注：^a 30mpk(PO)Note: ^a 30mpk(PO)

结论：本发明的化合物药代动力学性质良好，与阳性对照化合物相当或更优，例如口服暴露量和/或生物利用度。Conclusion: The compounds of the present invention exhibit favorable pharmacokinetic properties, comparable to or better than those of the positive control compounds, such as oral exposure and/or bioavailability.

实验例7：LPS诱导小鼠体内补体激活的PD模型Experimental Example 7: LPS-induced complement activation PD model in mice

实验目的：评估阳性对照化合物LNP023和本发明实施例化合物对脂多糖诱导的小鼠体内补体激活的抑制作用。Experimental objective: To evaluate the inhibitory effect of positive control compound LNP023 and compounds from the embodiments of this invention on lipopolysaccharide-induced complement activation in mice.

实验材料：实验用雌性C57BL/6J小鼠，7-9周龄，体重17-21克,由维通利华实验动物技术有限公司提供；脂多糖(LPS,Sigma,L6386)。Experimental materials: Female C57BL/6J mice, 7-9 weeks old, weighing 17-21 grams, were provided by Vital River Laboratory Animal Technology Co., Ltd.; lipopolysaccharide (LPS, Sigma, L6386).

实验方法：实验动物适应环境3天后开始实验。动物根据体重进行随机分组，每组3只，空白对照组动物通过腹腔单次注射等体积无菌DPBS，其余组的动物通过腹腔单次注射50μg脂多糖来诱导动物补体激活。待测化合物在脂多糖诱导3.5小时后，经口服单次给药；空白对照组给予溶媒(0.5％(w/v)的甲基纤维素和0.5％(v/v)的吐温80)。脂多糖诱导动物补体激活7.5小时后收集血浆，迅速置于干冰中，在-80℃低温冰箱中保存，用于后续Western blot分析。取动物血浆各5μL，分别加入35μL裂解液裂解30分钟，12500rpm离心15分钟，通过BCA方法进行蛋白定量，取25μL上清液加入13.5μL reducing buffer和SDS buffer的混合液，100℃煮10分钟，Western Blot每孔的上样量为10μg，经转膜和C3d抗体(R&D,AF2655)孵育后，用凝胶成像仪读取C3d信号，采用ImageJ软件对目标蛋白进行灰度分析。本实验通过检测血浆中C3d的表达水平，来检验阳性对照化合物LNP023和本发明化合物对脂多糖LPS诱导的小鼠补体激活的抑制作用。Experimental Methods: Animals were acclimatized to the environment for 3 days before the experiment began. Animals were randomly divided into groups of 3 animals each based on their body weight. The blank control group received a single intraperitoneal injection of an equal volume of sterile DPBS, while the other groups received a single intraperitoneal injection of 50 μg of lipopolysaccharide (LPS) to induce complement activation. The test compound was administered orally 3.5 hours after LPS induction; the blank control group received a solvent (0.5% (w/v) methylcellulose and 0.5% (v/v) Tween 80). Plasma was collected 7.5 hours after LPS-induced complement activation, rapidly placed on dry ice, and stored at -80°C for subsequent Western blot analysis. Five μL of animal plasma was taken from each sample and lysed for 30 minutes with 35 μL of lysis buffer. The mixture was centrifuged at 12500 rpm for 15 minutes, and protein quantification was performed using the BCA method. 25 μL of the supernatant was added to a mixture of 13.5 μL reducing buffer and SDS buffer, and the mixture was boiled at 100°C for 10 minutes. 10 μg of sample was loaded per well for Western blotting. After transfer to a membrane and incubation with C3d antibody (R&D, AF2655), the C3d signal was read using a gel imaging system, and the target protein was analyzed using ImageJ software. This experiment aimed to examine the inhibitory effects of the positive control compound LNP023 and the compound of this invention on LPS-induced complement activation in mice by detecting the expression level of C3d in plasma.

实验结论：本发明的至少一些化合物能够显著抑制LPS诱导的补体激活，与阳性对照化合物相当或更优。Experimental conclusions: At least some of the compounds of the present invention can significantly inhibit LPS-induced complement activation, which is comparable to or better than the positive control compounds.

实验例8A：PHN(被动海曼肾炎)大鼠肾炎药效模型-1Experimental Example 8A: PHN (Passive Heyman Nephritis) Rat Nephritis Efficacy Model - 1

实验目的：评估阳性对照化合物LNP023和本发明实施例化合物对绵羊抗大鼠FxlA血清诱导的大鼠被动海曼肾炎(Passive Heymann nephritis)的治疗作用。Experimental objective: To evaluate the therapeutic effects of the positive control compound LNP023 and the compounds of the present invention on passive Heymann nephritis induced by sheep anti-rat FxlA serum in rats.

实验材料：实验用雄性Lewis大鼠，6-8周龄，由维通利华实验动物技术有限公司提供；绵羊抗大鼠FxlA血清(购于Probetex,PTX-002S)。Experimental materials: Male Lewis rats, 6-8 weeks old, provided by Vital River Laboratory Animal Technology Co., Ltd.; sheep anti-rat FxlA serum (purchased from Probetex, PTX-002S).

实验方法：Experimental methods:

实验动物适应环境3天后，在造模前收集动物尿液来检测尿蛋白，并根据体重和尿蛋白进行随机分组，每组6只。空白对照组动物通过尾静脉单次注射5mL/kg空白绵羊血清，其余组的动物通过尾静脉单次注射5mL/kg绵羊抗大鼠FxlA血清来诱导大鼠PHN肾炎。治疗组一天两次口服给药待测化合物，空白对照组和模型组给予溶媒(5％DMA+10％Solutol+85％去离子水)。连续给药14天。在实验过程中包括造模前(Day-3～-2)、Day 4-5、Day 6-7、Day 8-9、Day 11-12、Day 14-15对动物尿液进行收集，试验终点收集动物双侧肾脏。测定收集的动物尿液中ALB、肌酐、尿素氮和总蛋白；收集的肾脏进行HE染色和PAS染色以考察肾小球病变及评分。本次实验通过对动物尿液中尿蛋白/肌酐比值以及肾脏的免疫组化，来评判空白对照组、模型组和治疗组的肾功能的损伤程度，并且检测阳性对照化合物LNP023以及本发明化合物(例如化合物138和化合物140)在PHN模型中起到的保护和治疗作用。Three days after acclimatization, urine was collected from the animals before modeling to detect urinary protein. Animals were randomly assigned to groups of six based on body weight and urinary protein levels. Animals in the control group received a single intravenous injection of 5 mL/kg of blank sheep serum, while animals in the other groups received a single intravenous injection of 5 mL/kg of sheep anti-rat FxlA serum to induce PHN nephritis in rats. The treatment group received the test compound orally twice daily, while the control and model groups received a solvent (5% DMA + 10% Solutol + 85% deionized water). Administration continued for 14 days. Urine was collected from the animals before modeling (Day 3-2), Days 4-5, 6-7, 8-9, 11-12, and 14-15. Bilateral kidneys were collected at the end of the experiment. ALB, creatinine, urea nitrogen, and total protein were measured in the collected urine. The collected kidneys were stained with hematoxylin and eosin (HE) and eosin (PAS) to examine glomerular lesions and assess their scores. This experiment assessed the degree of renal function impairment in the blank control group, model group, and treatment group by measuring the urine protein/creatinine ratio and the immunohistochemistry of the kidneys. It also detected the protective and therapeutic effects of the positive control compound LNP023 and the compounds of this invention (e.g., compounds 138 and 140) in the PHN model.

部分具体实验结果见图1A、1B。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将造模组与给药组数据进行分析比较，判断是否存在显著统计学意义，^#p<0.05，表示给药组与造模组比较具有显著性差异，^##p<0.01，表示给药组与造模组比较具有高度显著性差异，^###p<0.001，表示给药组与造模组比较具有极高度显著性差异。^$p<0.05，表示造模组与空白对照组比较具有显著性差异，^$$p<0.01，表示造模组与空白对照组比较具有高度显著性差异，^$$$p<0.001，表示造模组与空白对照组比较具有极高度显著性差异。Some specific experimental results are shown in Figures 1A and 1B. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using the t-test in Excel software. Data from the model group and the drug-treated group were analyzed and compared to determine statistical significance: ^# p < 0.05 indicated a significant difference between the drug-treated group and the model group; ^## p < 0.01 indicated a highly significant difference; ^### p < 0.001 indicated an extremely highly significant difference; ^$ p < 0.05 indicated a significant difference between the model group and the blank control group; ^$$ p < 0.01 indicated a highly significant difference; and ^$$$ p < 0.001 indicated an extremely highly significant difference.

实验结论：根据病理评分结果，与模型组相比，20mg/kg的本发明化合物能明显改善模型动物肾脏的病变程度。本发明的至少一些化合物能够降低大鼠尿蛋白水平，改善肾功能，与阳性对照化合物相当或更优，因此能够用于治疗补体FB相关疾病。Experimental conclusion: Based on pathological scoring results, compared with the model group, 20 mg/kg of the compounds of this invention significantly improved the degree of kidney lesions in the model animals. At least some compounds of this invention can reduce urinary protein levels and improve renal function in rats, comparable to or better than the positive control compounds, and therefore can be used to treat complement FB-related diseases.

实验例8B：PHN(被动海曼肾炎)大鼠肾炎药效模型-2Experimental Example 8B: PHN (Passive Heyman Nephritis) Rat Nephritis Efficacy Model - 2

实验方法：Experimental methods:

实验动物适应环境3天后，在造模前收集动物尿液来检测尿蛋白，并根据体重和尿蛋白进行随机分组，每组6只。空白对照组动物通过尾静脉单次注射5mL/kg空白绵羊血清，其余组的动物通过尾静脉单次注射5mL/kg绵羊抗大鼠FxlA血清来诱导大鼠PHN肾炎。治疗组一天两次口服给药实施例化合物(溶媒:5％DMA+10％Solutol+85％去离子水)，空白对照组和模型组给予溶媒(5％DMA+10％Solutol+85％去离子水)。连续给药14天。在实验过程中包括造模前(Day-3～-2)、Day 4-5、Day 6-7、Day 8-9、Day 11-12、Day 13-14对动物尿液进行收集，试验终点收集动物双侧肾脏。测定收集的动物尿液中ALB、肌酐、尿素氮和总蛋白；收集的肾脏进行HE染色和PAS染色以考察肾小球病变及评分。本次实验通过对动物尿液中尿蛋白/肌酐比值以及肾脏的免疫组化，来评判空白对照组、模型组和治疗组的肾功能的损伤程度，并且检测阳性对照化合物LNP023以及本发明化合物(例如化合物5和化合物20)在PHN模型中起到的保护和治疗作用。Three days after acclimatization, urine was collected from the animals before modeling to detect urinary protein. Animals were randomly assigned to groups of six based on body weight and urinary protein levels. The control group received a single intravenous injection of 5 mL/kg of blank sheep serum, while the other groups received a single intravenous injection of 5 mL/kg of sheep anti-rat FxlA serum to induce PHN nephritis in rats. The treatment group received the compound (solvent: 5% DMA + 10% Solutol + 85% deionized water) orally twice daily, while the control and model groups received the solvent (5% DMA + 10% Solutol + 85% deionized water). Administration continued for 14 days. Urine was collected from the animals before modeling (Day 3-2), Days 4-5, 6-7, 8-9, 11-12, and 13-14. Bilateral kidneys were collected at the end of the experiment. ALB, creatinine, urea nitrogen, and total protein were measured in collected animal urine. Kidneys were stained with hematoxylin and eosin (HE) and plasmolysis (PAS) to examine glomerular lesions and assess their scores. This experiment assessed the degree of renal function impairment in the blank control group, model group, and treatment group by analyzing the urine protein/creatinine ratio and immunohistochemistry of the kidneys. It also examined the protective and therapeutic effects of the positive control compound LNP023 and the compounds of this invention (e.g., compounds 5 and 20) in the PHN model.

部分具体实验结果见图2A、2B。ACR＝ALB/肌酐、PCR＝总蛋白/肌酐。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将造模组与给药组数据进行分析比较，判断是否存在显著统计学意义，^#p<0.05，表示给药组与造模组比较具有显著性差异，^##p<0.01，表示给药组与造模组比较具有高度显著性差异，^###p<0.001，表示给药组与造模组比较具有极高度显著性差异。^$p<0.05，表示造模组与空白对照组比较具有显著性差异，^$$p<0.01，表示造模组与空白对照组比较具有高度显著性差异，^$$$p<0.001，表示造模组与空白对照组比较具有极高度显著性差异。Some specific experimental results are shown in Figures 2A and 2B. ACR = ALB/creatinine, PCR = total protein/creatinine. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using the t-test in Excel software. Data from the model group and the drug-treated group were analyzed and compared to determine statistical significance: ^# ^p < 0.05 indicated a significant difference between the drug-treated group and the model group; ^## p < 0.01 indicated a highly significant difference; ### p < 0.001 indicated an extremely highly significant difference; ^$ p < 0.05 indicated a significant difference between the model group and the blank control group; ^$$ p < 0.01 indicated a highly significant difference; ^$$$ p < 0.001 indicated an extremely highly significant difference.

实验例8C：PHN(被动海曼肾炎)大鼠肾炎药效模型-3Experimental Example 8C: PHN (Passive Heyman Nephritis) Rat Nephritis Efficacy Model - 3

实验方法：Experimental methods:

实验动物适应环境3天后，在造模前收集动物尿液来检测尿蛋白，并根据体重和尿蛋白进行随机分组，每组6只。空白对照组动物通过尾静脉单次注射5mL/kg空白绵羊血清，其余组的动物通过尾静脉单次注射5mL/kg绵羊抗大鼠FxlA血清来诱导大鼠PHN肾炎。治疗组一天两次或一天一次口服给药实施例化合物(溶媒:5％DMA+10％Solutol+85％去离子水)，空白对照组和模型组给予溶媒(5％DMA+10％Solutol+85％去离子水)。连续给药14天。在实验过程中包括造模前(Day-3～-2)、Day 4-5、Day 6-7、Day 8-9、Day 11-12、Day 13-14对动物尿液进行收集，试验终点收集动物双侧肾脏。测定收集的动物尿液中ALB、肌酐、尿素氮和总蛋白；收集的肾脏进行HE染色和PAS染色以考察肾小球病变及评分。本次实验通过对动物尿液中尿蛋白/肌酐比值以及肾脏的免疫组化，来评判空白对照组、模型组和治疗组的肾功能的损伤程度，并且检测阳性对照化合物LNP023以及本发明化合物(例如化合物5、化合物20)在PHN模型中起到的保护和治疗作用。Three days after acclimatization, urine was collected from the animals before modeling to detect urinary protein. Animals were randomly assigned to groups of six based on body weight and urinary protein levels. Animals in the control group received a single intravenous injection of 5 mL/kg of blank sheep serum, while animals in the other groups received a single intravenous injection of 5 mL/kg of sheep anti-rat FxlA serum to induce PHN nephritis in rats. The treatment group received the compound (solvent: 5% DMA + 10% Solutol + 85% deionized water) orally twice or once daily, while the control and model groups received the solvent (5% DMA + 10% Solutol + 85% deionized water). Administration continued for 14 days. Urine was collected from the animals before modeling (Day 3-2), Days 4-5, 6-7, 8-9, 11-12, and 13-14. Bilateral kidneys were collected at the end of the experiment. ALB, creatinine, urea nitrogen, and total protein were measured in collected animal urine. Kidneys were stained with hematoxylin and eosin (HE) and plasmolysis (PAS) to examine glomerular lesions and assess their scores. This experiment assessed the degree of renal function impairment in the blank control group, model group, and treatment group by analyzing the urine protein/creatinine ratio and immunohistochemistry of the kidneys. It also examined the protective and therapeutic effects of the positive control compound LNP023 and the compounds of this invention (e.g., compounds 5 and 20) in the PHN model.

部分具体实验结果见图3A、3B、3C、3D、3E、3F、4A、4B、4C和4D。ACR＝ALB/肌酐、PCR＝总蛋白/肌酐。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将造模组与给药组数据进行分析比较，判断是否存在显著统计学意义，^#p<0.05，表示给药组与造模组比较具有显著性差异，^##p<0.01，表示给药组与造模组比较具有高度显著性差异，^###p<0.001，表示给药组与造模组比较具有极高度显著性差异。^$p<0.05，表示造模组与空白对照组比较具有显著性差异，^$$p<0.01，表示造模组与空白对照组比较具有高度显著性差异，^$$$p<0.001，表示造模组与空白对照组比较具有极高度显著性差异。Some specific experimental results are shown in Figures 3A, 3B, 3C, 3D, 3E, 3F, 4A, 4B, 4C, and 4D. ACR = ALB/creatinine, PCR = total protein/creatinine. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using the t-test in Excel software. Data from the model group and the drug-treated group were analyzed and compared to determine statistical significance: ^# ^p < 0.05 indicated a significant difference between the drug-treated group and the model group; ^## p < 0.01 indicated a highly significant difference; ### p < 0.001 indicated an extremely highly significant difference; ^$ p < 0.05 indicated a significant difference between the model group and the blank control group; ^$$ p < 0.01 indicated a highly significant difference; ^$$$ p < 0.001 indicated an extremely highly significant difference.

实验结论：根据病理评分结果，与模型组相比，5mg/kg、20mg/kg、60mg/kg的本发明化合物均能明显改善模型动物肾脏的病变程度。本发明的至少一些化合物能够降低大鼠尿蛋白水平，改善肾功能，在多个剂量组与阳性对照化合物相当或更优，因此能够用于治疗补体FB相关疾病。Experimental conclusions: Based on pathological scoring results, compared with the model group, the compounds of this invention at doses of 5 mg/kg, 20 mg/kg, and 60 mg/kg significantly improved the degree of kidney lesions in the model animals. At least some compounds of this invention can reduce urinary protein levels and improve renal function in rats, showing comparable or better performance than the positive control compounds in multiple dose groups, and therefore can be used to treat complement-related liver failure (FB).

实验例9A：LPS诱导大鼠体内补体激活的PD模型-1Experimental Example 9A: LPS-induced PD model of complement activation in rats - 1

实验目的：评估阳参化合物LNP023和本发明实施例化合物对脂多糖诱导大鼠体内补体激活的抑制作用。Experimental objective: To evaluate the inhibitory effect of Yangshen compound LNP023 and the compounds of the present invention on lipopolysaccharide-induced complement activation in rats.

实验材料：实验用雄性lewis大鼠，6-8周龄，由维通利华实验动物技术有限公司提供；脂多糖(LPS,Sigma,L6386)Experimental materials: Male Lewis rats, 6-8 weeks old, provided by Vital River Laboratory Animal Technology Co., Ltd.; lipopolysaccharide (LPS, Sigma, L6386).

实验方法：实验动物到达动物房后适应3天后开始实验。实验动物根据体重进行随机分组，空白对照组动物通过腹腔单次注射等体积无菌DPBS，其余组的动物通过腹腔单次注射2.5mg/kg脂多糖来诱导动物补体激活；实施例化合物在脂多糖诱导3.5小时和9.5小时后，分别口服给予对应的实施例化合物，空白对照组给予溶媒(0.5％(w/v)的甲基纤维素和0.5％(v/v)的吐温80)；脂多糖诱导动物补体激活7.5小时和27.5小时后收集血浆，迅速置于干冰中，在-80度低温冰箱中保存，用于后续Westernblot分析；取动物血浆各5μL，分别加入35μL裂解液裂解30分钟，12500rpm离心15分钟，通过BCA方法进行蛋白定量，取25μL上清液加入13.5μLreducingbuffer和SDS buffer的混合液，100℃煮10分钟，WesternBlot每孔的上样量为10μg，经转膜和C3d抗体(R&D,AF2655)孵育后，用凝胶成像仪读取C3d信号，采用ImageJ软件对目标蛋白进行灰度分析。本实验通过检测血浆中C3d的表达水平，来检验阳参化合物LNP023和本发明化合物对脂多糖LPS诱导的大鼠补体激活的抑制作用。Experimental Methods: Animals were acclimatized for 3 days after arrival at the animal facility before the experiment began. Animals were randomly assigned to groups based on body weight. The blank control group received a single intraperitoneal injection of an equal volume of sterile DPBS, while the other groups received a single intraperitoneal injection of 2.5 mg/kg lipopolysaccharide (LPS) to induce complement activation. Compounds from the examples were administered orally 3.5 and 9.5 hours after LPS induction, respectively. The blank control group received a solvent (0.5% (w/v) methylcellulose and 0.5% (v/v) Tween 80). Plasma was collected 7.5 and 27.5 hours after LPS-induced complement activation, rapidly placed on dry ice, and stored at -80°C for later use. Western blot analysis continued; 5 μL of animal plasma was taken from each well, and 35 μL of lysis buffer was added to each well for lysis for 30 minutes. The mixture was then centrifuged at 12500 rpm for 15 minutes, and protein quantification was performed using the BCA method. 25 μL of the supernatant was added to a mixture of 13.5 μL reducing buffer and SDS buffer, and the mixture was boiled at 100°C for 10 minutes. The loading volume for each well in the Western blot was 10 μg. After transfer to a membrane and incubation with C3d antibody (R&D, AF2655), the C3d signal was read using a gel imaging system, and the target protein was analyzed using ImageJ software. This experiment aimed to examine the inhibitory effects of Yangshen compound LNP023 and the compound of this invention on LPS-induced complement activation in rats by detecting the expression level of C3d in plasma.

实验结果：本次实验以诺华公司的Factor B抑制剂LNP023作为参比药物，测试化合物为参比化合物LNP023、本申请化合物(例如化合物138)。结果显示，参比化合物LNP023、化合物138、化合物140在4h和24h均能显著抑制C3d水平，即能够抑制LPS诱导的补体激活作用。部分具体实验结果见图5A和5B。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将模型组与给药组数据进行分析比较，判断是否存在显著统计学意义，*p<0.05，表示给药组与模型组比较具有显著性差异，**p<0.01，表示给药组与模型组比较具有高度显著性差异，***p<0.001，表示给药组与模型组比较具有极高度显著性差异，****p<0.0001，表示给药组与模型组比较具有超高度显著性差异，ns表示给药组与模型组比较没有统计学差异。^#p<0.05，表示模型组与空白对照组比较具有显著性差异，^##p<0.01，表示模型组与空白对照组比较具有高度显著性差异，^###p<0.001，表示模型组与空白对照组比较具有极高度显著性差异，^####p<0.0001，表示模型组与空白对照组比较具有超高度显著性差异。Experimental Results: Novartis' Factor B inhibitor LNP023 was used as the reference drug in this experiment. The tested compounds were the reference compound LNP023 and compounds from this application (e.g., compound 138). The results showed that reference compound LNP023, compound 138, and compound 140 significantly inhibited C3d levels at both 4 h and 24 h, indicating that they could inhibit LPS-induced complement activation. Some specific experimental results are shown in Figures 5A and 5B. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using an Excel t-test. Data from the model group and the treatment group were analyzed and compared to determine if there was statistical significance. *p<0.05 indicates a significant difference between the treatment group and the model group; **p<0.01 indicates a highly significant difference; ***p<0.001 indicates an extremely highly significant difference; ****p<0.0001 indicates a very high degree of significance; ns indicates no statistical difference. ^#p <0.05 indicates a significant difference between the model group and the blank control group; ^## p<0.01 indicates a highly significant difference; ^### p<0.001 indicates an extremely high degree of significance; ^#### p<0.0001 indicates a very high degree of significance.

实验结论：本发明的一些化合物能够显著抑制LPS诱导的补体激活，与阳性对照化合物相当或更优。Experimental conclusions: Some compounds of the present invention can significantly inhibit LPS-induced complement activation, and are comparable to or better than the positive control compounds.

实验例9B：LPS诱导大鼠体内补体激活的PD模型-2Experimental Example 9B: LPS-induced PD model of complement activation in rats - 2

实验方法：实验动物到达动物房后适应3天后开始实验。实验动物根据体重进行随机分组，空白对照组动物通过腹腔单次注射等体积无菌DPBS，其余组的动物通过腹腔单次注射2.5mg/kg脂多糖来诱导动物补体激活；实施例化合物在脂多糖诱导3.5小时和9.5小时后，分别口服给予对应的实施例化合物(溶媒:5％DMA+10％Solutol+85％去离子水)，空白对照组给予溶媒(5％DMA+10％Solutol+85％去离子水)；脂多糖诱导动物补体激活7.5小时和27.5小时后收集血浆，迅速置于干冰中，在-80度低温冰箱中保存，用于后续Western blot分析；取动物血浆各5μL，分别加入35μL裂解液裂解30分钟，12500rpm离心15分钟，通过BCA方法进行蛋白定量，取25μL上清液加入13.5μL reducing buffer和SDS buffer的混合液，100℃煮10分钟，Western Blot每孔的上样量为10μg，经转膜和C3d抗体(R&D,AF2655)孵育后，用凝胶成像仪读取C3d信号，采用ImageJ软件对目标蛋白进行灰度分析。本实验通过检测血浆中C3d的表达水平，来检验阳参化合物LNP023和本发明化合物对脂多糖LPS诱导的大鼠补体激活的抑制作用。Experimental Methods: Animals were acclimatized for 3 days after arrival at the animal facility before the experiment began. Animals were randomly assigned to groups based on body weight. The blank control group received a single intraperitoneal injection of an equal volume of sterile DPBS, while the other groups received a single intraperitoneal injection of 2.5 mg/kg lipopolysaccharide (LPS) to induce complement activation. The corresponding compound from the examples was administered orally (solvent: 5% DMA + 10% Solutol + 85% deionized water) 3.5 hours and 9.5 hours after LPS induction, respectively. The blank control group received the same solvent (5% DMA + 10% Solutol + 85% deionized water). Plasma was collected 7.5 hours and 27.5 hours after LPS-induced complement activation and rapidly placed on dry ice at -80°C. Stored in a refrigerator for subsequent Western blot analysis; 5 μL of animal plasma was taken from each well, and lysed with 35 μL of lysis buffer for 30 minutes, centrifuged at 12500 rpm for 15 minutes, and protein quantification was performed using the BCA method. 25 μL of supernatant was added to a mixture of 13.5 μL reducing buffer and SDS buffer, and boiled at 100℃ for 10 minutes. The sample loading volume per well for Western blot was 10 μg. After transfer to a membrane and incubation with C3d antibody (R&D, AF2655), the C3d signal was read using a gel imaging system, and the target protein was analyzed using ImageJ software. This experiment examines the inhibitory effect of Yangshen compound LNP023 and the compound of this invention on LPS-induced complement activation in rats by detecting the expression level of C3d in plasma.

实验结果：本次实验以诺华公司的Factor B抑制剂LNP023作为参比药物，测试化合物为参比化合物LNP023、本申请化合物(例如化合物5、化合物20)。结果显示，参比化合物LNP023、化合物5至化合物11、化合物15至化合物20、化合物22、化合物23在4h和24h均能显著抑制C3d水平，即能够抑制LPS诱导的补体激活作用。部分具体实验结果见图6A～6F。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将模型组与给药组数据进行分析比较，判断是否存在显著统计学意义，*p<0.05，表示给药组与模型组比较具有显著性差异，**p<0.01，表示给药组与模型组比较具有高度显著性差异，***p<0.001，表示给药组与模型组比较具有极高度显著性差异，****p<0.0001，表示给药组与模型组比较具有超高度显著性差异，ns表示给药组与模型组比较没有统计学差异。^#p<0.05，表示模型组与空白对照组比较具有显著性差异，^##p<0.01，表示模型组与空白对照组比较具有高度显著性差异，^###p<0.001，表示模型组与空白对照组比较具有极高度显著性差异，^####p<0.0001，表示模型组与空白对照组比较具有超高度显著性差异。Experimental Results: Novartis' Factor B inhibitor LNP023 was used as the reference drug in this experiment. The tested compounds were the reference compound LNP023 and the compounds of this application (e.g., compounds 5 and 20). The results showed that reference compound LNP023, compounds 5 to 11, compounds 15 to 20, compounds 22, and compounds 23 significantly inhibited C3d levels at both 4 h and 24 h, indicating that they could inhibit LPS-induced complement activation. Some specific experimental results are shown in Figures 6A-6F. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using an Excel t-test. Data from the model group and the treatment group were analyzed and compared to determine if there was statistical significance. *p<0.05 indicates a significant difference between the treatment group and the model group; **p<0.01 indicates a highly significant difference; ***p<0.001 indicates an extremely highly significant difference; ****p<0.0001 indicates a very high degree of significance; ns indicates no statistical difference. ^#p <0.05 indicates a significant difference between the model group and the blank control group; ^## p<0.01 indicates a highly significant difference; ^### p<0.001 indicates an extremely high degree of significance; ^#### p<0.0001 indicates a very high degree of significance.

实验例9C：LPS诱导大鼠体内补体激活的PD模型-3Experimental Example 9C: LPS-induced PD model of complement activation in rats - 3

实验结果：本次实验以诺华公司的Factor B抑制剂LNP023作为参比药物，测试化合物为参比化合物LNP023、本申请化合物(例如化合物5)。结果显示，参比化合物LNP023、化合物5在4h和24h均能显著抑制C3d水平，即能够抑制LPS诱导的补体激活作用。部分具体实验结果见图7。实验数据表示为平均值(Mean)±标准误差(SEM)。采用Excel软件t检验进行统计比较。将模型组与给药组数据进行分析比较，判断是否存在显著统计学意义，*p<0.05，表示给药组与模型组比较具有显著性差异，**p<0.01，表示给药组与模型组比较具有高度显著性差异，***p<0.001，表示给药组与模型组比较具有极高度显著性差异，****p<0.0001，表示给药组与模型组比较具有超高度显著性差异，ns表示给药组与模型组比较没有统计学差异。^#p<0.05，表示模型组与空白对照组比较具有显著性差异，^##p<0.01，表示模型组与空白对照组比较具有高度显著性差异，^###p<0.001，表示模型组与空白对照组比较具有极高度显著性差异，^####p<0.0001，表示模型组与空白对照组比较具有超高度显著性差异。Experimental Results: Novartis' Factor B inhibitor LNP023 was used as the reference drug in this experiment. The tested compounds were the reference compound LNP023 and the compounds of this application (e.g., compound 5). The results showed that both the reference compound LNP023 and compound 5 significantly inhibited C3d levels at both 4h and 24h, i.e., they inhibited LPS-induced complement activation. Some specific experimental results are shown in Figure 7. Experimental data are expressed as mean ± standard error (SEM). Statistical comparisons were performed using the t-test in Excel software. Data from the model group and the treated group were analyzed and compared to determine if there was a statistically significant difference. *p<0.05 indicated a significant difference between the treated group and the model group; **p<0.01 indicated a highly significant difference; ***p<0.001 indicated an extremely highly significant difference; ****p<0.0001 indicated a very highly significant difference; and ns indicated no statistically significant difference between the treated group and the model group. ^# p<0.05 indicates a significant difference between the model group and the blank control group; ^## p<0.01 indicates a highly significant difference between the model group and the blank control group; ^### p<0.001 indicates an extremely highly significant difference between the model group and the blank control group; ^#### p<0.0001 indicates an extremely highly significant difference between the model group and the blank control group.

除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。In addition to those described herein, various modifications of the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

Compounds of formula (I):

Or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts.

in:

^R1 is independently selected from deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 alkoxy, -NH ( _{C1-6 haloalkyl), -N (C1-6} _haloalkyl ) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterated alkyl), -N ( _C1-6 deuterated alkyl) ₂ , _C1-6 deuterated alkyl, _C1-6 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

^R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterated alkyl), -N ( _C1-6 deuterated alkyl) ₂ , _C1-6 deuterated alkyl, _C1-6 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

^R3 is selected from hydrogen, deuterium, halogen, OH, SH, CN, ^-NR3a ^R3b , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 deuteralkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, C1-6 deuteralkyl, -S ( _C1-6 alkyl), _C3-6 cycloalkyl, _4-7 membered heterocyclic, _C6-10 aryl, 5-10 membered heteroaryl, _-C1-6 alkylene- _OC1-6 alkyl, _-OC1-6 alkylene- _OC1-6 alkyl, _-C1-6 alkylene-OH, _-C1-6 alkylene-CN or _-C1-6 alkylene- ^NR3a ^R3b ;

^R3a and ^R3b are independently selected from H, _C1-6 alkyl, _C1-6 haloalkyl, or _C1-6 deuteralkyl each time they appear;

^R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, NH2, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -S ( _C1-6 alkyl), -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- _C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, -S ( _C1-6 alkyl), -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl)2, _C3-10 cycloalkyl, 3-12 membered heterocyclic, _-C1-6 alkylene- _C3-10 cycloalkyl, -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene-C3-10 cycloalkyl, -N ( _C1-6 haloalkyl)2, - ... The _3-10 cycloalkyl or _-C1-6 alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, ₅ , 6 or more groups selected from deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 alkyl), -S( _C1-6 haloalkyl), -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -NH( _C1-6 haloalkyl), -N( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

Indicates a single or double bond;

The condition is that the compound is not

According to claim 1, a compound of formula (I), or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R1 is independently selected from deuterium, _C1-6 alkyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, _C1-6 haloalkoxy, -NH ( _C1-6 deuterium alkyl), -N ( _C1-6 deuterium alkyl) ₂ , _C1-6 deuterium alkyl, _C1-6 deuterium alkoxy, _C3-6 cycloalkyl or 4-7 membered heterocyclic group;

^R4 is selected from hydrogen, deuterium, halogen, OH, CN, SH, _NH2 , _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -S ( _C1-6 alkyl), -NH (C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene- _C3-10 cycloalkyl, or -C1-6 alkylene-3-12 membered heterocyclic; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkoxy, -S ( _C1-6 alkyl), -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl)2, _C3-10 cycloalkyl, 3-12 membered heterocyclic, _-C1-6 alkylene- _C3-10 cycloalkyl, -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, -C1-6 alkylene-C3-10 cycloalkyl, -N ( _C1-6 haloalkyl)2, - ... The _3-10 cycloalkyl or _-C1-6 alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3, 4, ₅ , 6 or more groups selected from deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 alkyl), -S( _C1-6 haloalkyl), -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -NH( _C1-6 haloalkyl), -N( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to claim 1 or 2, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R2 is selected from deuterium, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C1-6 haloalkyl, C1-6 haloalkoxy, _{-NH (C1-6 deuterium alkyl), -N (C1-6} _deuterium _alkyl ) ₂ , _C1-6 deuterium alkyl, _C1-6 deuterium alkoxy, or 4-7 membered heterocyclic groups;

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to any one of claims 1-3, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

R ³ is selected from deuterium, 4-7 membered heterocyclic groups, C _6-10 aryl groups, 5-10 membered heteroaryl groups, or -C _1-6 alkylene-CN;

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to any one of claims 1-4, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R3a and ^R3b are each independently selected from _C1-6 haloalkyl or _C1-6 deuteralkyl when they appear;

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to any one of claims 1-5, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R4 is selected from deuterium or -S ( _C1-6 alkyl); said -S ( _C1-6 alkyl) is optionally selected from 1, 2, 3, 4, ₅ , 6 or more of deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S ( _C1-6 alkyl), -S ( _C1-6 haloalkyl), -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to any one of claims 1-6, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R4 is selected from deuterium or -S ( _C1-6 alkyl), wherein -S ( _C1-6 alkyl) is optionally composed of 1, 2, 3, 4, ₅ , 6 or more of deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S ( _C1-6 alkyl), -S ( _C1-6 haloalkyl), -NH ( _C1-6 alkyl), -N ( _C1-6 alkyl) ₂ , -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ ( _C1-6 haloalkyl), -O(C1-6 alkyl) Substitution with substituents of _-3-6 cycloalkyl), -O (C _3-6 halocycloalkyl), -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

^Rg and ^Rh are each independently selected from hydrogen or deuterium;

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound of formula (I) according to any one of claims 1-7, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts,

in:

^R1 is independently selected from halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl) or -N ( _C1-6 alkyl) ₂ ;

^R2 is selected from hydrogen, halogen, OH, SH, CN, _NH2 , -NH ( _C1-6 alkyl), _-N ( _C1-6 alkyl), _C1-6 alkyl, or _C3-6 cycloalkyl;

^R3 is selected from hydrogen, halogen, OH, SH, CN, ^-NR3a ^R3b , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 deuterated alkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, _C1-6 deuterated alkoxy, -S ( _C1-6 alkyl), _C3-6 cycloalkyl, -C1-6 alkylene _- _OC1-6 alkyl, -OC1-6 alkylene _-OC1-6 _alkyl , _-C1-6 alkylene-OH, or _-C1-6 alkylene- ^NR3a ^R3b ;

^R3a and ^R3b are independently selected from H or _C1-6 alkyl groups each time they appear;

^R4 is selected from hydrogen, halogen, OH, CN, SH, NH2, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 _cycloalkyl , 3-12 membered heterocyclic, _-C1-6 alkylene- _C3-10 cycloalkyl, or -C1-6 alkylene- _3-12 membered heterocyclic; wherein _{the C1-6} _alkyl , _C2-6 alkenyl, _C2-6 alkoxy, -NH ( _C1-6 haloalkyl), -N ( _C1-6 haloalkyl) ₂ , _C3-10 cycloalkyl, 3-12 membered heterocyclic, _-C1-6 alkylene _- _C3-10 _cycloalkyl , or -C _{The 1-6} alkylene-3-12-membered heterocyclic group is optionally surrounded by 1, 2, 3 _, 4, ₅ , 6 or more groups selected from deuterium, halogen, OH, CN, NH2, _SF5 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, _C1-6 haloalkoxy, -S( _C1-6 alkyl), -S( _C1-6 haloalkyl), -NH( _C1-6 alkyl), -N( _C1-6 alkyl) ₂ , -NH( _C1-6 haloalkyl), -N( _C1-6 haloalkyl) ₂ , -S(=O)( _C1-6 alkyl), -S(=O) ₂ ( _C1-6 alkyl), -S(=O)( _C1-6 haloalkyl), -S(=O) ₂ _(C1-6 _haloalkyl ), -O(C3-6 cyclo ... Substitution with substituents of _3-6 halocycloalkyl, -S (C _3-6 cycloalkyl) or -S (C _3-6 halocycloalkyl);

^Rg and ^Rh are each independently selected from hydrogen or deuterium; preferably, both ^Rg and ^Rh are hydrogen.

n is selected from 0, 1, 2, 3 or 4;

It indicates a single or double bond.

The compound according to any one of claims 1-8, wherein the compound is not:

The compound according to any one of claims 1-9, wherein the compound of formula (I) has the structure shown in formula (I-1) or (I-2):

Preferably, it has the structure shown in (I-3) or (I-4):

The compound according to any one of claims 1-10, wherein:

n is selected from 0, 1, or 2;

Preferably, n is selected from 0 or 1;

Preferably, n is 0.

The compound according to any one of claims 1-11, wherein the compound has a structure shown in one of formulas (II-1)-(II-6):

Preferred

Preferably, it has a structure shown in one of formulas (II-7)-(II-18):

Preferred

More preferably, it has a structure shown in one of formulas (II-19)-(II-30):

Preferred

The compound according to any one of claims 1-12, wherein:

^R1 is selected from deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C1-4 haloalkyl, _C1-4 haloalkoxy, -NH ( _C1-4 deuterated alkyl), -N ( _C1-4 deuterated alkyl) ₂ , _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

Preferably, ^R1 is selected from halogens or _C1-4 alkyl groups;

Preferably, ^R1 is selected from F, Cl or methyl.

The compound according to any one of claims 1-13, wherein:

^R2 is selected from hydrogen, deuterium, halogen, OH, SH, CN, _NH2 , -NH ( _C1-4 alkyl), -N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C1-4 haloalkyl, _C1-4 haloalkoxy, -NH ( _C1-4 deuterated alkyl), -N ( _C1-4 deuterated alkyl) ₂ , _C1-4 deuterated alkyl, _C1-4 deuterated alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

Preferably, ^R2 is selected from hydrogen, halogen, or _C1-4 alkyl;

Preferably, ^R2 is selected from hydrogen or halogen;

Preferably, ^R2 is selected from hydrogen, F, or Cl;

Preferably, ^R2 is hydrogen.

The compound according to any one of claims 1-14, wherein:

R ³ is selected from hydrogen, deuterium, halogen, OH, SH, CN, -NR ^3a R ^3b , C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteralkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, C _1-4 deuteralkyl, -S (C _1-4 alkyl), C _3-6 cycloalkyl, 4-7 heterocyclic, C _6-10 aryl, 5-6 heteroaryl, -C _1-4 alkylene-OC _1-4 alkyl, -OC _1-4 alkylene-OC _1-4 alkyl, -C _1-4 alkylene-OH, _{-C 1-4} _alkylene -CN or -C _1-4 alkylene-NR ^3a R ^3b ; and/or

^R3a and ^R3b are each independently selected from H, _C1-4 alkyl, _C1-4 haloalkyl, or _C1-4 deuteralkyl when they appear;

Preferably, ^R3 is selected from halogens, CN, _C1-4 alkyl, -S ( _C1-4 alkyl), ^-NR3a ^R3b , _C1-4 alkoxy, _C3-6 cycloalkyl, 4-7 membered heterocyclic or _-C1-4 alkylene- _OC1-4 alkyl; and/or ^R3a and ^R3b are independently selected from H or _C1-4 alkyl each time they appear;

Preferably, ^R3 is selected from F, Cl, CN, _C1-4 alkyl, -S ( _C1-4 alkyl), ^-NR3a ^R3b , _C1-4 alkoxy, _C3-6 cycloalkyl, 4-7 membered heterocyclic or _-C1-4 alkylene- _OC1-4 alkyl; and/or

^R3a and ^R3b are each independently selected from H or _C1-4 alkyl groups when they appear; preferably, one of ^R3a and ^R3b is H and the other is a _C1-4 alkyl group.

Preferably, ^R3 is selected from CN, _C1-4 alkyl, _C1-4 alkoxy, and _C3-6 cycloalkyl;

Preferably, ^R3 is a _C1-4 alkyl group;

Preferably, ^R3 is selected from CN, _C1-4 alkyl, -S ( _C1-4 alkyl), _C1-4 alkoxy, _C3-6 cycloalkyl, or 4-7 membered heterocyclic groups;

Preferably, ^R3 is selected from F, Cl, -CN, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , _-SCH3 , -NHCH3, _-OCH3 , _-OCH2CH3 , _-OCH ( _CH3 ) ₂ , _-CH2OCH3 , cyclopropyl, _cyclobutyl , oxacyclobutyl (e.g. ₎ ), thioheterobutyl (e.g.) ) or nitrogen-containing heterocyclic butyl (e.g. );

Preferably, ^R3 is selected from CN, _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , _-SCH3 , cyclobutyl, oxacyclobutyl, _-OCH3 , cyclopropyl or _-OCH2CH3 _;

More preferably, ^R3 is selected from _CN , _-CH3 , _-CH2CH3 , -CH( _CH3 ) ₂ , _-SCH3 , cyclobutyl or oxacyclobutyl.

The compound according to any one of claims 1-15, wherein:

^R4 is selected from _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, -S ( _C1-4 alkyl), -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C3-6 cycloalkyl, 4-7 membered heterocyclic group, _-C1-4 alkylene- _C3-6 cycloalkyl, or -C1-4 alkylene _- 4-7 membered heterocyclic group; wherein the _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkoxy, _-S ( _C1-4 alkyl), -NH ( _C1-4 haloalkyl), -N ( _C1-4 haloalkyl) ₂ , _C3-6 cycloalkyl, 4-7 membered heterocyclic group, _-C1-4 alkylene- _C3-6 _cycloalkyl , or _-C1- _{The 4} -alkylene-4-7-membered heterocyclic group is optionally substituted with 1, 2, 3, 4, ₅ or 6 substituents selected from deuterium, halogen, OH, CN, _NH2 , _C1-4 alkyl, _C1-4 haloalkyl, _C1-4 alkoxy, C1-4 haloalkoxy, -S( _C1-4 alkyl), -S( _C1-4 haloalkyl), -NH( _C1-4 _{alkyl), -N(C1-4} _alkyl ) ₂ , -NH( _C1-4 haloalkyl), -N( _C1-4 haloalkyl) ₂ , -S(=O)( _C1-4 alkyl), -S(=O) ₂ ( _C1-4 alkyl), -S(=O)( _C1-4 haloalkyl), -S(=O) ₂ ( _C1-4 haloalkyl), -O(C3-6 cycloalkyl) or -O( _C3-6 halocycloalkyl);

Preferably, ^R4 is selected from _C1-6 alkyl, _C3-10 cycloalkyl, _-C1-6 alkylene- _C3-10 cycloalkyl; the _C1-6 alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from halogen, _C1-6 alkoxy, _C1-6 haloalkoxy, -S ( _C1-6 haloalkyl), -S(O) ( _C1-6 haloalkyl), -S(O) ₂ ( _C1-6 haloalkyl), -O ( _C3-6 halocycloalkyl); the C3-10 cycloalkyl in the _C3-10 cycloalkyl and _-C1-6 alkylene- _C3-10 cycloalkyl is optionally substituted with 1, 2, 3 _, 4, 5 or 6 substituents selected from halogen, _C1-6 haloalkyl or _C1-6 haloalkoxy;

Preferably, ^R4 is selected from _C1-4 alkyl, _C3-6 cycloalkyl, or _-C1-4 alkylene- _C3-6 cycloalkyl; the _C1-4 alkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halogen, _C1-4 alkoxy, _C1-4 haloalkoxy, -S ( _C1-4 haloalkyl), -S(=O) ( _C1-4 haloalkyl), -S(=O) ₂ ( _C1-4 haloalkyl), or -O ( _C3-6 halocycloalkyl); the _C3-6 cycloalkyl in the _C3-6 cycloalkyl or _-C1-4 alkylene- _C3-6 cycloalkyl is optionally substituted with 1, 2, ₃ , 4, 5, or 6 substituents selected from halogen, _C1-4 haloalkyl, or _C1-4 haloalkoxy.

Preferably, ^R4 is selected from _C1-4 alkyl; the _C1-4 alkyl is optionally substituted by 1, 2, 3, ₄ , 5 or 6 substituents selected from halogen, C1-4 alkoxy, _C1-4 haloalkoxy, -S ( _C1-4 haloalkyl) or -O ( _C3-6 halocycloalkyl);

Preferably, ^R4 is selected from _C1-4 alkyl; the _C1-4 alkyl is optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from halogen, _C1-4 alkoxy or _C1-4 haloalkoxy.

Preferably, ^R4 is selected from (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ), (Preferred) ),

Preferably, ^R4 is selected from (Preferred) ), (Preferred) ), (Preferred) )or (Preferred) );

Preferably, ^R4 is selected from (Preferred) )or (Preferred) ).

The compound according to any one of claims 1-16, wherein the compound has the structure shown in formula (III-1):

in:

n is selected from 0 or 1;

p is selected from 0, 1, 2, or 3;

Q is selected from halogens, _C1-6 haloalkyl, _C1-6 haloalkoxy, -S ( _C1-6 haloalkyl), -S(=O) ( _C1-6 haloalkyl), or -S(=O) ₂ ( _C1-6 haloalkyl);

^Ra and ^Rb are each independently selected from H, deuterium, halogen, _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy or _C1-6 haloalkoxy;

L is selected from -CR ^L1 R ^L2 -, -C _3-6 cycloalkyl-, -C _3-6 halocycloalkyl-, -OC _3-6 cycloalkyl-*, -OC _3-6 halocycloalkyl-*, -SC _3-6 cycloalkyl-* or -SC _3-6 halocycloalkyl-*, wherein the bond marked with "*" is connected to Q;

^RL1 and ^RL2 are each independently selected from H, deuterium, halogen, CN, OH, _NH2 , _C1-6 alkyl, _C1-6 haloalkyl, _C1-6 alkoxy, or _C1-6 haloalkoxy; or ^RL1 , ^RL2 and the carbon atoms they are attached to form _C3-6 cycloalkyl or 4-7 membered heterocyclic groups;

^R1 , ^R2 , ^R3 , ^Rg , ^Rh are as defined in any one of claims 1-15;

Preferably, it has the structure shown in formula (III-2) or (III-3):

Preferably, it has the structure shown in any of formulas (III-4)-(III-7):

Preferably, it has the structure shown in any of formulas (III-8)-(III-11):

The compound according to claim 17, wherein:

n is selected from 0;

p is selected from 0, 1, or 2;

Preferably, p is 1.

The compound according to claim 17 or 18, wherein:

Q is selected from F, Cl, Br, _C1-3 haloalkyl, _C1-3 haloalkoxy, -S ( _C1-3 haloalkyl), -S(=O) ( _C1-3 haloalkyl), or -S(=O) ₂ ( _C1-3 haloalkyl);

Preferably, Q is selected from _C1-3 haloalkyl (e.g., _C1-3 fluoroalkyl) or _C1-3 haloalkoxy (e.g., _C1-3 fluoroalkoxy);

Preferably, Q is selected from _C1-3 haloalkyl (e.g., _C1-3 fluoroalkyl);

Preferably, Q is selected from F, _-OCF3 , _-OCF2H , _-CF3 , _-CF2H , _-SCF3 , _-SCF2H , _-S (=O) _CF3 , -S(=O) _2CF3 or _-OCH2CF3 _;

More preferably, Q is selected from -OCF ₃ or -CF ₃ , preferably -CF ₃ .

The compound according to any one of claims 17-19, wherein:

^Ra and ^Rb are each independently selected from H, deuterium, halogen, _C1-6 alkyl or _C1-6 haloalkyl;

Preferably, ^Ra and ^Rb are each independently selected from H or _C1-6 alkyl groups;

Preferably, ^Ra and ^Rb are each independently selected from H or _C1-3 alkyl groups;

Preferably, ^Ra and ^Rb are both H, or one of ^Ra and ^Rb is H and the other is a _C1-3 alkyl group;

More preferably, ^Ra and ^Rb are both H.

The compound according to any one of claims 17-20, wherein:

L is selected from -CR ^L1 R ^L2 -, -C _3-6 cycloalkylene- or -OC _3-6 halocycloalkylene-*; wherein the bond indicated by "*" is connected to Q;

Preferably, L is selected from -CR ^L1 R ^L2 -; and/or

^RL1 and ^RL2 are each independently selected from H, _C1-6 alkyl or _C1-6 alkoxy; or ^RL1 , ^RL2 and the carbon atoms they are attached to form _C3-6 cycloalkyl groups;

Preferably, ^RL1 and ^RL2 are each independently selected from H, _C1-3 alkyl, or _C1-3 alkoxy.

Preferably, both ^RL1 and ^RL2 are H, or one of ^RL1 and ^RL2 is H and the other is a _C1-3 alkyl or _C1-3 alkoxy group;

Preferably, one of ^RL1 and ^RL2 is H, and the other is a _C1-3 alkoxy group;

Preferably, L is selected from -CR ^L1 R ^L2 -,

Preferably, L is selected from _-CH2- , -CH( _CH3 )-, -CH( _OCH3 )-,

More preferably, L is selected from _-CH2- , -CH( _CH3 )- or -CH( _OCH3 )-; preferably -CH( _OCH3 )-.

The compound according to any one of claims 17-21, wherein the compound has the structure shown in formula (IV-1):

Preferably, it has the structure shown in formula (IV-2)

More preferably, it has the structure shown in formula (IV-3)

Wherein ^R1 , ^R2 , ^R3 , ^Rg , ^Rh , n are defined as in any one of claims 1-15, and ^Ra , ^Rb , ^RL1 , ^RL2 are defined as in any one of claims 17-21.

The compound according to any one of claims 1-8, 10-22, wherein the compound is selected from:

The compound according to any one of claims 1-23, wherein the compound is selected from:

Preferred

A pharmaceutical composition comprising a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

A pharmaceutical combination comprising a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate or pharmaceutically acceptable salt, and another therapeutically active agent.

A method for modulating the activity of the complement bypass pathway in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to claim 25; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to claim 26.

A method for preventing or treating diseases, disorders, or conditions mediated by complement activation, particularly those mediated by activation of the complement alternative pathway, in an individual, wherein the method comprises: administering to the individual a therapeutically effective amount of a compound according to any one of claims 1-24, or a stereoisomer, tautomer, diastereomer, racemic compound, cis-trans isomer, isotopically labeled compound (preferably deuterated), N-oxide, metabolite, ester, prodrug, crystal form, hydrate, solvate, or pharmaceutically acceptable salt thereof; or administering to the individual a therapeutically effective amount of a pharmaceutical composition according to claim 25; or administering to the individual a therapeutically effective amount of a pharmaceutical combination according to claim 26.

Preferably, the disease, disorder, or condition is selected from age-related macular degeneration (AMD), geographic macular atrophy, diabetic retinopathy, uveitis, retinitis pigmentosa, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harada syndrome, intermediate uveitis, skeletal retinochoroiditis, sympathetic ophthalmia, ocular cicatricial pemphigoid, ocular pemphigoid, non-arterial ischemic optic neuropathy, postoperative inflammation, retinal vein occlusion, neurological diseases, multiple sclerosis, and other conditions. Wind, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, symptoms caused by inappropriate or unintended complement activation, complications of hemodialysis, hyperacute allogeneic transplant rejection, xenotransplant rejection, IL-2-induced toxicity during interleukin-2 (IL-2) therapy, inflammatory diseases, inflammation in autoimmune diseases, Crohn's disease, adult respiratory distress syndrome, myocarditis, ischemia-reperfusion syndrome, myocardial infarction, balloon angioplasty, post-pump syndrome during cardiopulmonary bypass or renal bypass, atherosclerosis, hemodialysis. Renal ischemia, mesenteric artery reperfusion after aortic reconstruction, infectious diseases or sepsis, immune complex disorders and autoimmune diseases, rheumatoid arthritis, systemic lupus erythematosus (SLE), lupus nephritis (LN), proliferative glomerulonephritis, C3 glomerular disease (C3G), immunoglobulin A nephropathy (IgAN) or other nephropathy with evidence of glomerular C3 deposition (e.g., membranous nephropathy (MN) and hemolytic uremic syndrome (HUS)), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aH) US), immune thrombocytopenic purpura (ITP), cold agglutinin disease (CAD), liver fibrosis, hemolytic anemia, myasthenia gravis, tissue regeneration, nerve regeneration, dyspnea, hemoptysis, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrotic dust disease, pulmonary fibrosis, allergy, bronchoconstriction, hypersensitivity pneumonia, parasitic diseases, pulmonary hemorrhage nephritis syndrome, pulmonary vasculitis, Pauci immune vasculitis, immune complex-related inflammation, antiphospholipid syndrome, glomerulonephritis, or obesity.

The compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic derivatives, cis-trans isomers, isotopically labeled compounds (preferably deuterated compounds), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 25, or the pharmaceutical composition according to claim 26, is used as a drug.

Use of any compound according to any one of claims 1-24, or its stereoisomers, tautomers, diastereomers, racemic compounds, cis-trans isomers, isotopically labeled compounds (preferably deuterated), N-oxides, metabolites, esters, prodrugs, crystal forms, hydrates, solvates, or pharmaceutically acceptable salts, or the pharmaceutical composition according to claim 25, or the pharmaceutical composition according to claim 26, in the preparation of a medicament for treating diseases, disorders, or conditions mediated by complement activation in an individual, particularly diseases, disorders, or conditions mediated by activation of the complement alternative pathway.