WO2025209562A1

WO2025209562A1 - Tetrahydrofuran pyridone compound serving as nav1.8 inhibitor

Info

Publication number: WO2025209562A1
Application number: PCT/CN2025/087032
Authority: WO
Inventors: 张学军; 李金平; 徐招兵; 杨辉; 贾一民; 安丹; 杨俊�; 李莉娥
Original assignee: Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Current assignee: Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
Priority date: 2024-04-03
Filing date: 2025-04-03
Publication date: 2025-10-09
Anticipated expiration: 2026-10-03
Also published as: CN120774914A

Abstract

The present invention provides a compound as shown in formula (V), and a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof. The compound has a good Nav1.8 inhibition effect.

Description

Tetrahydrofuranpyridones as Nav1.8 inhibitors

本发明要求享有：The present invention claims:

于2024年4月3日向中国国家知识产权局提交的，专利申请号为202410405961.4,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权；Priority to the prior application, patent application number 202410405961.4, filed with the State Intellectual Property Office of China on April 3, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;

于2024年6月5日向中国国家知识产权局提交的，专利申请号为202410725452.X,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权；Priority to the prior application, patent application number 202410725452.X, filed with the State Intellectual Property Office of China on June 5, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;

于2024年7月11日向中国国家知识产权局提交的，专利申请号为202410931168.8,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权；Priority to the prior application, patent application number 202410931168.8, filed with the State Intellectual Property Office of China on July 11, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;

于2024年8月8日向中国国家知识产权局提交的，专利申请号为202411090328.7,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权；Priority to the prior application, patent application number 202411090328.7, filed with the State Intellectual Property Office of China on August 8, 2024, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”;

于2024年9月3日向中国国家知识产权局提交的，专利申请号为202411231872.9,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权；Priority to the prior application, patent application number 202411231872.9, filed with the State Intellectual Property Office of China on September 3, 2024, entitled “Tetrahydrofuran pyridone compounds as Nav1.8 inhibitors”;

于2024年11月22日向中国国家知识产权局提交的，专利申请号为202411690310.0,名称为“作为Nav1.8抑制剂的四氢呋喃吡啶酮类化合物”的在先申请的优先权。Priority to the prior application with patent application number 202411690310.0, entitled “Tetrahydrofuranpyridone compounds as Nav1.8 inhibitors”, filed with the State Intellectual Property Office of China on November 22, 2024.

上述在先申请的全文通过引用的方式结合于本申请中。The entire contents of the above-mentioned prior applications are incorporated into the present application by reference.

Technical Field

本发明属于医药领域，涉及四氢呋喃吡啶酮类化合物作为Nav1.8抑制剂及其用途。具体地，本发明涉及取代的四氢呋喃吡啶酮类化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药及其药物组合物作为Nav1.8抑制剂及其在制备治疗、缓解或预防疼痛药物中的用途。The present invention belongs to the field of medicine and relates to tetrahydrofuran pyridone compounds as Nav1.8 inhibitors and their uses. Specifically, the present invention relates to substituted tetrahydrofuran pyridone compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions thereof as Nav1.8 inhibitors and their use in the preparation of drugs for treating, alleviating or preventing pain.

Background Art

疼痛是“一种令人不快的感觉和情绪上的感受，伴有实质上的或潜在的组织损伤，它是一种主观感受”。疼痛可以作为一种警戒信号，提醒机体注意潜在的危险，对机体正常的生命活动具有不可或缺的保护作用。同时，疼痛也是一种常见的临床症状，在引发疼痛的外界刺激消失后，强烈或持久的疼痛会造成生理功能的紊乱，严重影响生命体的生活质量。据统计，全世界约五分之一的人患有中度至重度慢性疼痛。2018年全球镇痛药市场约为360亿美元，预计2023年将达到560亿美元。其中急性中重度未来将以2.5％的年复合增长率稳定增长，慢性疼痛未来市场将18％左右的年复合增长率增长，慢性疼痛是驱动未来十年全球疼痛市场持续增长的主要推动力。Pain is "an unpleasant sensory and emotional feeling, accompanied by actual or potential tissue damage, and it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers, and plays an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. In 2018, the global analgesic market was approximately US$36 billion and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

疼痛起源于周围神经系统的伤害感受器。这是一种游离的神经末梢，广泛分布于全身的皮肤、肌肉、关节和内脏组织中，它可以将感受到的热的、机械的或化学的刺激转化为神经冲动(动作电位)并经由传入神经纤维传递到其位于背根神经节(dorsal rootganglia，DRG)的胞体部分，最终传递到高级神经中枢，引起痛觉。而神经元中动作电位的产生和传导又依赖于细胞膜上的电压门控钠离子通道(voltage-gated sodiumchannels，NaV)。当细胞膜去极化时，钠离子通道激活，通道打开，引起钠离子内流，使细胞膜进一步去极化，导致动作电位的产生。因此，抑制异常的钠离子通道活动有助于疼痛的治疗、缓解。Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings that are widely distributed throughout the skin, muscles, joints, and internal organs of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies in the dorsal root ganglia (DRG), ultimately transmitting them to higher nerve centers, causing pain. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.

人类钠离子是一类跨膜离子通道蛋白，由分子量260kD的α亚基和分子量为30-40kD的β亚基组成，根据α亚基的不同可以分为9种亚型，分别为Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9是河豚毒素(tetrodotoxin，TTX)不敏感性钠通道，Nav1.5主要存在于心肌细胞中，Nav1.8、Navl.9存在于外周神经系统。其中Nav1.8是参与慢性疼痛、心房纤维性颤动、布加综合征的重要离子通道，是疼痛治疗的高选择性作用靶点。Human sodium channels are transmembrane ion channels composed of a 260kD α subunit and a 30-40kD β subunit. They are classified into nine subtypes based on the α subunits: Nav1.1 to Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is primarily found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Nav1.8 is a key ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, making it a highly selective target for pain treatment.

Nav1.8编码基因为SCN10A，位于人类染色体3p21-22区域，主要编码α亚单位。研究发现人与大鼠Nav1.8基因的同源性高达93％。Nav1.8主要存在于三叉神经节神经元和DRG神经元中，具有慢速失活、迅速恢复的电生理特征。在表达Nav1.8的神经元内，动作电位的上升主要由Nav1.8电流构成。在神经性疼痛的模型中，神经损伤会使Nav1.8在轴突和神经元胞体中的表达水平上升。使用Nav1.8反义寡核苷酸在降低Nav1.8表达的同时可以明显地缓解疼痛。大鼠爪内注射角叉菜胶后，DRG神经元中Nav1.8的表达有所上升。Nav1.8敲除小鼠不能表现出正常的内脏炎症痛。人类的Nav1.8基因产生功能增益突变后，会导致外周神经痛。根据一系列动物实验以及人类基因证据，选择性抑制Nav1.8具有成为新型镇痛疗法的潜力，可以用于炎性疼痛、神经疼痛、手术后疼痛和癌痛等多种疼痛类型的治疗。The gene encoding Nav1.8, SCN10A, is located in the human chromosome 3p21-22 region and primarily encodes the α subunit. Studies have found that the human and rat Nav1.8 genes share up to 93% homology. Nav1.8 is primarily present in trigeminal ganglion neurons and DRG neurons, exhibiting electrophysiological characteristics of slow inactivation and rapid recovery. In Nav1.8-expressing neurons, the rise of the action potential is primarily composed of Nav1.8 currents. In models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies. Nav1.8 antisense oligonucleotides significantly alleviate pain while simultaneously reducing Nav1.8 expression. Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons. Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy that can be used to treat various types of pain, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

一些已知的Nav’s抑制剂的主要缺点是它们的治疗窗口差，这可能是它们缺乏同种型选择性的结果。由于Navl.8主要限于感知疼痛的神经元，因此选择性Nav1.8阻断剂不太可能诱导非选择性Nav’s阻断剂常见的不良反应。因此，本领域仍然需要开发新的Nav1.8选择性抑制剂，优选对Nav1.8选择性更好、更有效、代谢稳定性增加、溶解度增加和副作用更少的Nav通道抑制剂。The main disadvantage of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce the adverse reactions common to non-selective Nav's blockers. Therefore, there is still a need to develop new Nav1.8 selective inhibitors in this area, preferably Nav channel inhibitors with better selectivity for Nav1.8, more effective, increased metabolic stability, increased solubility and fewer side effects.

Summary of the Invention

本发明旨在提出一种Nav1.8抑制剂，可用于制备治疗、缓解或预防疼痛的药物，所述疼痛包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛等。The present invention aims to propose a Nav1.8 inhibitor that can be used to prepare a drug for treating, alleviating or preventing pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

本发明的第一方面，本发明提供了式(V)所示化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药：
In the first aspect of the present invention, the present invention provides a compound represented by formula (V), its tautomers, stereoisomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

其中，in,

A选自H、C_1-6烷基或C_3-12环烷基；其中，所述的C_1-6烷基和C_3-12环烷基各自独立地任选被一个或多个R^D所取代；A is selected from H, C _1-6 alkyl or C _3-12 cycloalkyl; wherein the C _1-6 alkyl and C _3-12 cycloalkyl are each independently optionally substituted by one or more R ^D ;

R^D选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基；R ^D is selected from H, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy;

Y选自O、S或NH；Y is selected from O, S or NH;

Z为N或CR²；Z is N or CR ² ;

环B选自苯基或5-6元杂芳环，所述5-6元杂芳环中的杂原子或杂原子基团选自S、S(＝O)、S(＝O)₂、P(＝O)₂、O、N⁺-O^-、N或NH；Ring B is selected from phenyl or a 5-6 membered heteroaromatic ring, wherein the heteroatom or heteroatom group in the 5-6 membered heteroaromatic ring is selected from S, S(=O), S(=O) ₂ , P(=O) ₂ , O, N ⁺ —O ⁻ , N or NH;

R⁰选自H、卤素、羟基、氰基、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、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；其中，所述的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、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基各自独立地任选被一个或多个R^A所取代；R ⁰ is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, 5-12 membered heteroaryl, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, 4-12-membered heterocycloalkenyl, C _6-12 aryl, 5-12-membered heteroaryl are each independently optionally substituted with one or more ^RA ;

R¹选自H、羟基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基；其中，所述的C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基和5-12杂芳基各自独立地任选被一个或多个R^A所取代； ^R1 is selected from H, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl, 5-12 membered heteroaryl; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more ^RA ;

R^A选自H、卤素、羟基、氰基、硝基、氧代(C＝O)、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基； ^RA is selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy;

R²独立地选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基；其中，所述的C_1-6烷基、C_2-6烯基、C_2- ₆炔基、C_1-6烷氧基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基和5-12杂芳基各自独立地任选被一个或多个R^B所取代； ^R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, C3-12 cycloalkyl, _3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl, 5-12 membered heteroaryl; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 _alkynyl , _C1-6 alkoxy, C3-12 cycloalkyl, _3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R ^B ;

R^B选自H、卤素、羟基、氰基、硝基、氧代(C＝O)、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基； ^RB is selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy;

R³、R⁴和R⁵各自独立地选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基；其中，所述的C_1-6烷基、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基和5-12杂芳基各自独立地任选被一个或多个R^C所取代；R ³ , R ⁴ and R ⁵ are each independently selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, 5-12 membered heteroaryl; wherein the C _1-6 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R ^C ;

或者，R³、R⁴与它们所连接的原子一起形成C_3-12环烷基或3-12元杂环基，所述C_3-12环烷基和3-12元杂环基任选被一个或多个R^C所取代；Alternatively, R ³ , R ^{4 ,} together with the atoms to which they are attached, form a C _3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the C _3-12 cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted with one or more R ^C ;

R^C选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基；R ^C is selected from H, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy;

R^4b1和R^4b2各自独立地选自H、C_1-6烷基、C_3-6环烷基或C_1-6卤代烷基；R ^4b1 and R ^4b2 are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

或者，R^4b1和R^4b2与它们所连接的原子一起形成C_3-6饱和环，所述C_3-6饱和环任选地被一个或多个卤素、-OR⁴、-CN或-NR³R⁴所取代；Alternatively, R ^4b1 and R ^4b2 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

R^5b1和R^5b2各自独立地选自H、C_1-6烷基、C_3-6环烷基或C_1-6卤代烷基；R ^5b1 and R ^5b2 are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

或者，R^5b1和R^5b2与它们所连接的原子一起形成C_3-6饱和环，所述C_3-6饱和环任选地被一个或多个卤素、-OR⁴、-CN或-NR³R⁴所取代；Alternatively, R ^5b1 and R ^5b2 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

或者，R^4b1和R^5b1与它们所连接的原子一起形成C_3-6饱和环，所述C_3-6饱和环任选地被一个或多个卤素、-OR⁴、-CN或-NR³R⁴所取代；Alternatively, R ^4b1 and R ^5b1 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

R^6b选自H、-OH、卤素、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基；R ^6b is selected from H, -OH, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy;

R^7b选自H、-OH、卤素、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基；R ^7b is selected from H, -OH, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

R^2c选自H、-OH、卤素、C_1-6烷基、C_2-6烯基、C_1-6卤代烷基、C_1-6氘代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基、-NR³R⁴、-L¹-(C_1-6烷基)-OR⁴、-L¹-(C_1-6卤代烷基)-OR⁴、-L¹-(C_2-6烯基)-OR⁴、-L¹-(C_1-6烷基)-NR³R⁴、-L¹-(C_1-6烷基)-N＝S(O)(C_1-3烷基)₂、-L¹-(C_1-6烷基)-S(O)₂(C_1-6烷基)或-L¹-L²-R⁴；其中，所述的C_1-6卤代烷基和C_1-6卤代烷氧基中的氢任选地被0个、一个或多个氘取代；R ^2c is selected from H, -OH, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-OR ⁴ , -L ¹ -(C _1-6 haloalkyl)-OR ⁴ , -L ¹ -(C _2-6 alkenyl)-OR ⁴ , -L ¹ -(C _1-6 alkyl)-NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-N＝S(O)(C _1-3 alkyl) ₂ , -L ¹ -(C _1-6 alkyl)-S(O) ₂ (C _1-6 alkyl) or -L ¹ -L ² -R ⁴ ; wherein the hydrogen in the C _1-6 haloalkyl and C _1-6 haloalkoxy is optionally replaced by 0, one or more deuterium;

R^3c选自H、卤素、C_1-6烷基、C_1-6卤代烷基、或-(C_1-6亚烷基)-(C_1-6烷氧基)；R ^3c is selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, or -(C _1-6 alkylene)-(C _1-6 alkoxy);

R^4c选自H、卤素、C_1-6烷基、或C_1-6卤代烷基；R ^4c is selected from H, halogen, C _1-6 alkyl, or C _1-6 haloalkyl;

R^5c选自H、卤素、C_1-6烷基、或C_1-6卤代烷基；和R ^5c is selected from H, halogen, C _1-6 alkyl, or C _1-6 haloalkyl; and

R^6c选自H、卤素、C_1-6烷基、C_1-6卤代烷基、或C_1-6烷氧基；R ^6c is selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 alkoxy;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-；L ² is a bond or -(C _1-6 alkyl)-;

n选自0、1、2、3、4、5和6。在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(V)所示化合物
n is selected from 0, 1, 2, 3, 4, 5 and 6. In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (V)

其中，in,

Y选自O或S；Y is selected from O or S;

Z为N或CR²；Z is N or CR ² ;

R⁰选自H、卤素、羟基、氰基、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、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；其中，所述的C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基各自独立地任选被一个或多个R^A所取代；R ⁰ is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ;

R^A选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基； ^RA is selected from H, halogen, hydroxy, cyano, nitro, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy;

R^B选自H、卤素、羟基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_1-6卤代烷基、C_1-6卤代烷氧基； ^RB is selected from H, halogen, hydroxy, cyano, nitro, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

R^2c选自H、-OH、卤素、C_1-6烷基、C_2-6烯基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基、-NR³R⁴、-L¹-(C_1-6烷基)-OR⁴、-L¹-(C_1-6卤代烷基)-OR⁴、-L¹-(C_2-6烯基)-OR⁴、-L¹-(C_1-6烷基)-NR³R⁴、-L¹-(C_1-6烷基)-N＝S(O)(C_1-3烷基)₂、-L¹-(C_1-6烷基)-S(O)₂(C_1-6烷基)或-L¹-L²-R⁴；其中，所述的C_1-6卤代烷氧基中的氢任选地被0个、一个或多个氘取代；R ^2c is selected from H, -OH, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-OR ⁴ , -L ¹ -(C _1-6 haloalkyl)-OR ⁴ , -L ¹ -(C _2-6 alkenyl)-OR ⁴ , -L ¹ -(C _1-6 alkyl)-NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-N＝S(O)(C _1-3 alkyl) ₂ , -L ¹ -(C _1-6 alkyl)-S(O) ₂ (C _1-6 alkyl) or -L ¹ -L ² -R ⁴ ; wherein the C The hydrogen in the _1-6 haloalkoxy group is optionally substituted by 0, 1 or more deuteriums;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-；L ² is a bond or -(C _1-6 alkyl)-;

n选自0、1、2、3、4、5和6。n is selected from 0, 1, 2, 3, 4, 5 and 6.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(V)所示化合物
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (V)

其中，in,

Y选自O或S；Y is selected from O or S;

Z为N或CR²；Z is N or CR ² ;

R⁰选自H、卤素、羟基、氰基、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、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；R ⁰ is selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-；L ² is a bond or -(C _1-6 alkyl)-;

n选自0、1、2、3、4、5和6。n is selected from 0, 1, 2, 3, 4, 5 and 6.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(IV)所示化合物
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IV)

其中，in,

A选自C_1-6烷基或C_3-12环烷基；其中，所述的C_1-6烷基和C_3-12环烷基各自独立地任选被一个或多个R^D所取代；A is selected from C _1-6 alkyl or C _3-12 cycloalkyl; wherein the C _1-6 alkyl and C _3-12 cycloalkyl are each independently optionally substituted by one or more R ^D ;

Z为N或CR²；Z is N or CR ² ;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

R^2c选自H、-OH、卤素、C_1-6烷基、C_2-6烯基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基、-NR³R⁴、-L¹-(C_1-6烷基)-OR⁴、-L¹-(C_1-6卤代烷基)-OR⁴、-L¹-(C_2-6烯基)-OR⁴、-L¹-(C_1-6烷基)-NR³R⁴、-L¹-(C_1-6烷基)-N＝S(O)(C_1-3烷基)₂、-L¹-(C_1-6烷基)-S(O)₂(C_1-6烷基)或-L¹-L²-R⁴；R ^2c is selected from H, -OH, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-OR ⁴ , -L ¹ -(C _1-6 haloalkyl)-OR ⁴ , -L ¹ -(C _2-6 alkenyl)-OR ⁴ , -L ¹ -(C _1-6 alkyl)-NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-N＝S(O)(C _1-3 alkyl) ₂ , -L ¹ -(C _1-6 alkyl)-S(O) ₂ (C _1-6 alkyl) or -L ¹ -L ² -R ⁴ ;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-；L ² is a bond or -(C _1-6 alkyl)-;

n选自0、1、2、3、4、5和6。n is selected from 0, 1, 2, 3, 4, 5 and 6.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(III)所示化合物
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (III)

其中，in,

Z为N或CR²；Z is N or CR ² ;

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^3a、R^4a、R^5a各自独立地选自H、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；R ^3a , R ^4a , and R ^5a are each independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy;

R^6a为H、卤素、羟基、氰基、C_1-6烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；R ^6a is H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(═O)NR ³ R ⁴ , -C(═NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(═O) ₂ R ³ , -S(═O) ₂ NR ³ R ⁴ or -S(═O)(═NR ⁵ )R ³ ;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-。L ² is a bond or -(C _1-6 alkyl)-.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II)所示化合物
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II)

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^6a为H、卤素、羟基、C_1-6烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；R ^6a is H, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(═O)NR ³ R ⁴ , -C(═NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(═O) ₂ R ³ , -S(═O) ₂ NR ³ R ⁴ or -S(═O)(═NR ⁵ )R ³ ;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-。L ² is a bond or -(C _1-6 alkyl)-.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-D)、式(II-E)、式(II-F)或(II-G)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II-D), formula (II-E), formula (II-F) or (II-G):

其中，in,

Z为N或CR²；Z is N or CR ² ;

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^3a、R^4a各自独立地选自H、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；R ^3a and R ^4a are each independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R^5a和R^6a各自独立地选自H、卤素、羟基、氰基、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、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；其中，所述的C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基各自独立地任选被一个或多个R^A所取代；R ^5a and R ^6a are each independently selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ;

W选自S、S(＝O)、S(＝O)₂、P(＝O)₂、O或NH；W is selected from S, S(=O), S(=O) ₂ , P(=O) ₂ , O or NH;

R¹、R²、R³、R⁴、R⁵、R^4b1、R^4b2、R^5b1、R^5b2、R^6b、R^7b、R^A、A的定义如本发明所述。在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-A)、式(II-C)、式(II-D)或式(II-E)所示化合物：
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , RA and ^A are as defined herein. In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is represented by Formula (II-A), Formula (II-C), Formula (II-D) or Formula (II-E):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^6a为H、卤素、羟基、氰基、C_1-6烷基、C_1-6烷氧基、被一个或多个羟基取代的C_1-6烷基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；R ^6a is H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkyl substituted by one or more hydroxy groups, -NR ³ R ⁴ , -C(═O)NR ³ R ⁴ , -C(═NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(═O) ₂ R ³ , -S(═O) ₂ NR ³ R ⁴ or -S(═O)(═NR ⁵ )R ³ ;

R¹、R²、R³、R⁴、R⁵、R^4b1、R^4b2、R^5b1、R^5b2、R^6b、R^7b、A的定义如本发明所述。R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b and A are as defined in the present invention.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-A)、式(II-C)、式(II-D)或式(II-E)所示化合物：

In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II-A), formula (II-C), formula (II-D) or formula (II-E):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-A)、式(II-C)或式(II-D)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II-A), formula (II-C) or formula (II-D):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-B)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II-B):

其中，X^3a、X^4a、X^5a、X^6a、R¹、R²、R^4b1、R^4b2、R^5b1、R^5b2、R^6b、R^7b、A的定义如本发明所述。Wherein, ^X3a , ^X4a , ^X5a , ^X6a , ^R1 , ^R2 , ^R4b1 , ^R4b2 , ^R5b1 , ^R5b2 , ^R6b , ^R7b and A are as defined in the present invention.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(II-A)或式(II-C)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (II-A) or formula (II-C):

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(I)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (I):

其中，X^3a、X^4a、X^5a、X^6a、R¹、R²、R^4b1、R^4b2、R^5b1、R^5b2、R^6b、R^7b、X^2c、X^3c、X^4c、X^5c和X^6c的定义如本发明所述。wherein ^X3a , ^{X4a, X5a} , ^X6a , ^R1 , ^R2 , ^R4b1 , ^R4b2 , ^R5b1 , ^R5b2 , ^R6b , ^R7b , ^X2c , ^X3c , ^X4c , ^X5c and ^X6c ^are as defined in the present invention.

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^5b1和R^5b2各自独立地选自H、C_1-6烷基、C_3-6环烷基或C₁-C₆卤代烷基；R ^5b1 and R ^5b2 are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or C ₁ -C ₆ haloalkyl;

X^2c选自N或C-R^2c；X ^2c is selected from N or CR ^2c ;

X^3c选自N或C-R^3c；X ^3c is selected from N or CR ^3c ;

X^4c选自N或C-R^4c；X ^4c is selected from N or CR ^4c ;

X^5c选自N或C-R^5c；X ^5c is selected from N or CR ^5c ;

X^6c选自N或C-R^6c；X ^6c is selected from N or CR ^6c ;

R^2c选自H、-OH、卤素、C_1-6烷基、C₂-C₆烯基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6氘代烷氧基、C_1-6卤代烷氧基、-L¹-(C_1-6烷基)-OR⁴、-L¹-(C_1-6卤代烷基)-OR⁴、-L¹-(C_2-6烯基)-OR⁴、-L¹-(C_1-6烷基)-NR³R⁴、-L¹-(C_1-6烷基)-N＝S(O)(C_1-3烷基)₂、-L¹-(C_1-6烷基)-S(O)₂(C_1-6烷基)或-L¹-L²-R⁴；R ^2c is selected from H, -OH, halogen, C _1-6 alkyl, C ₂ -C ₆ alkenyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, -L ¹ -(C _1-6 alkyl)-OR ⁴ , -L ¹ -(C _1-6 haloalkyl)-OR ⁴ , -L ¹ -(C _2-6 alkenyl)-OR ⁴ , -L ¹ -(C _1-6 alkyl)-NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-N＝S(O)(C _1-3 alkyl) ₂ , -L ¹ -(C _1-6 alkyl)-S(O) ₂ (C _1-6 alkyl) or -L ¹ -L ² -R ⁴ ;

L¹是键或-O-；L ¹ is a bond or -O-;

L²是键或-(C_1-6烷基)-。L ² is a bond or -(C _1-6 alkyl)-.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(I-C)、式(I-D)、式(I-F)或式(I-G)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IC), formula (ID), formula (IF) or formula (IG):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R^5a和R^6a各自独立地选自H、卤素、羟基、氰基、C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；所述的C_1-6烷基、C_1- ₆卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基各自独立地任选被一个或多个R^A所取代；R ^5a and R ^6a are each independently selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; the _C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ;

R¹、R²、R³、R⁴、R⁵、R^4b1、R^4b2、R^5b1、R^5b2、R^6b、R^7b、X^2c、X^3c、X^4c、X^5c和X^6c的定义如本发明所述。R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^2c , X ^3c , X ^4c , X ^5c and X ^6c are as defined in the present invention.

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(I-A)、式(I-B)、式(I-C)或式(I-D)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA), formula (IB), formula (IC) or formula (ID):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(I-A)、式(I-B)或式(I-C)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA), formula (IB) or formula (IC):

其中，in,

X^3a为N或CR^3a；X ^3a is N or CR ^3a ;

X^4a为N或CR^4a；X ^4a is N or CR ^4a ;

X^5a为N或CR^5a；X ^5a is N or CR ^5a ;

X^6a为N、N⁺-O^-或CR^6a；X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

在本发明一任选实施方案中，本发明所述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药，为式(I-A)或式(I-B)所示化合物：
In an optional embodiment of the present invention, the compound of the present invention, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA) or formula (IB):

在本发明一任选实施方案中，R¹为H、羟基或C_1-6烷氧基；较佳的，R¹为H或羟基。In an optional embodiment of the present invention, R ¹ is H, hydroxy or C _1-6 alkoxy; preferably, R ¹ is H or hydroxy.

在本发明一任选实施方案中，R¹为H。In an optional embodiment of the present invention, R ¹ is H.

在本发明一任选实施方案中，Z为N或CR²，R²的定义如本发明所述。In an optional embodiment of the present invention, Z is N or CR ² , and R ² is as defined herein.

在本发明一任选实施方案中，R²独立地选自H、卤素、羟基、氰基、C_1-6烷基、C_1-6烷氧基；所述的C_1-6烷基、C_1-6烷氧基各自独立地任选被一个或多个R^B所取代；R^B的定义如本发明所述。In an optional embodiment of the present invention, ^R2 is independently selected from H, halogen, hydroxy, cyano, _C1-6 alkyl, _C1-6 alkoxy; the _C1-6 alkyl and _C1-6 alkoxy are each independently optionally substituted by one or more ^RB ; ^RB is as defined in the present invention.

在本发明一任选实施方案中，R²独立地选自H、卤素、羟基、C_1-3烷基、C_1-3烷氧基；所述的C_1-3烷基、C_1-3烷氧基各自独立地任选被一个或多个R^B所取代；R^B的定义如本发明所述。In an optional embodiment of the present invention, ^R2 is independently selected from H, halogen, hydroxy, _C1-3 alkyl, _C1-3 alkoxy; the _C1-3 alkyl and _C1-3 alkoxy are each independently optionally substituted with one or more ^RB ; ^RB is as defined in the present invention.

在本发明一任选实施方案中，R²独立地选自H、F、Cl、羟基、甲基、甲氧基；所述的甲基、甲氧基各自独立地任选被一个或多个R^B所取代；R^B的定义如本发明所述。In an optional embodiment of the present invention, R ² is independently selected from H, F, Cl, hydroxy, methyl, methoxy; the methyl and methoxy groups are each independently optionally substituted with one or more ^RB ; ^RB is as defined in the present invention.

在本发明一任选实施方案中，R^B选自H、卤素、羟基、C_1-6烷基、C_1-6烷氧基。In an optional embodiment of the present invention, ^RB is selected from H, halogen, hydroxy, _C1-6 alkyl, _C1-6 alkoxy.

在本发明一任选实施方案中，R^B选自H、F、Cl、羟基、C_1-3烷基、C_1-3烷氧基。In an optional embodiment of the present invention, ^RB is selected from H, F, Cl, hydroxy, _C1-3 alkyl, and _C1-3 alkoxy.

在本发明一任选实施方案中，R^B选自H、F、Cl、羟基、甲基、甲氧基。In an optional embodiment of the present invention, ^RB is selected from H, F, Cl, hydroxy, methyl, and methoxy.

在本发明一任选实施方案中，R²为H、卤素、羟基、C_1-6烷基、C_1-6烷氧基；较佳的，R²为H、F、Cl、羟基、甲基、甲氧基。In an optional embodiment of the present invention, R ² is H, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy; preferably, R ² is H, F, Cl, hydroxy, methyl, methoxy.

在本发明一任选实施方案中，R²为H、卤素、C_1-6烷基、C_1-6烷氧基；较佳的，R²为H、F、Cl、甲基、甲氧基。In an optional embodiment of the present invention, R ² is H, halogen, C _1-6 alkyl, C _1-6 alkoxy; preferably, R ² is H, F, Cl, methyl, methoxy.

在本发明一任选实施方案中，R²为H。In an optional embodiment of the present invention, ^R2 is H.

在本发明一任选实施方案中，选自 In an optional embodiment of the present invention, Selected from

X^3a、X^4a、X^5a、X^6a、W的定义如本发明所述。X ^3a , X ^4a , X ^5a , X ^6a and W are as defined in the present invention.

在本发明一些实施方案中，X^3a为N或CR^3a；X^4a为N或CR^4a；X^5a为N或CR^5a；X^6a为N、N⁺-O^-或CR^6a；R^3a、R^4a、R^5a和R^6a各自独立地选自H、卤素、羟基、氰基、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、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；其中，所述的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、C_3-12环烷基、3-12元杂环基、4-12元杂环烯基、C_6-12芳基、5-12元杂芳基各自独立地任选被一个或多个R^A所取代；其中R³、R⁴、R⁵、R^A的定义如本发明所述。在本发明的一些实施方案中，R^3a、R^4a、R^5a和R^6a各自独立地选自H、卤素、C_1-6烷基，R^6a、R^5a各自独立地选自氰基、-CH(OH)CH₂OH、-OCH₂CH(OH)CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³、-S(＝O)(＝NH)R³或-OR⁴，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代；In some embodiments of the present invention, X ^3a is N or CR ^3a ; X ^4a is N or CR ^4a ; X ^5a is N or CR ^5a ; X ^6a is N, N ⁺ —O ^— , or CR ^6a ; R ^3a , R ^4a , R ^5a , and R ^6a are each independently selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl, —NR ³ R ⁴ , —C(═O)NR ³ R ⁴ , —C(═NR ⁵ )NR ³ R ⁴ , —OR ⁴ , —S(═O) ₂ R ³ , —S(═O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, and 5-12 membered heteroaryl are each independently optionally substituted by one or more ^RA ; wherein R ³ , R ⁴ , R ⁵ , and ^RA are as defined in the present invention. In some embodiments of the present invention, R ^3a , R ^4a , R ^5a and R ^6a are each independently selected from H, halogen, C _1-6 alkyl, R ^6a and R ^5a are each independently selected from cyano, -CH(OH)CH ₂ OH, -OCH ₂ CH(OH)CH ₂ OH, -C(═O)NHR ³ , -C(═NH)NHR ³ , -S(═O) ₂ R ³ , -S(═O) ₂ NHR ³ , -S(═O)(═NH)R ³ or -OR ⁴ , R ³ is H, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, and the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted with one or more R ^C ;

在本发明一些实施方案中，X^3a为N或CR^3a；X^4a为N或CR^4a；X^5a为N或CR^5a；X^6a为N、N⁺-O^-或CR^6a；R^3a、R^4a各自独立地选自H、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；R^5a和R^6a各自独立地选自H、卤素、羟基、氰基、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、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；其中，所述的C_1-6烷基、C_1-6卤代烷基、C_1-6烷氧基、C_1-6卤代烷氧基各自独立地任选被一个或多个R^A所取代；其中R³、R⁴、R⁵、R^A的定义如本发明所述。In some embodiments of the present invention, X ^3a is N or CR ^3a ; X ^4a is N or CR ^4a ; X ^5a is N or CR ^5a ; X ^6a is N, N ⁺ -O ^- , or CR ^6a ; R ^3a , R ^4a are each independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy; R ^5a and R ^6a are each independently selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -C(═O)NR ³ R ⁴ , -C(═NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(═O) ₂ R ³ , -S(═O) ₂ NR ³ R ⁴ or -S(=O)(=NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ; wherein R ³ , R ⁴ , R ⁵ , and ^RA are as defined in the present invention.

在本发明一任选实施方案中，为X^3a、X^4a、X^5a、X^6a的定义如本发明所述。In an optional embodiment of the present invention, for X ^3a , X ^4a , X ^5a , and X ^6a are as defined in the present invention.

在本发明一任选实施方案中，为X^4a、X^5a、X^6a的定义如本发明所述。In an optional embodiment of the present invention, for X ^4a , X ^5a , and X ^6a are as defined in the present invention.

在本发明一任选实施方案中，R^6a独立地选自H、卤素、羟基、氰基、C_1-6烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；所述的C_1-6烷基、C_1- ₆烷氧基各自独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代；R³、R⁴、R⁵的定义如本发明所述。In an optional embodiment of the present invention, R ^6a is independently selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; the C _1-6 alkyl and _C _1-6 alkoxy are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen or hydroxy; R ³ , R ⁴ and R ⁵ are as defined herein.

在本发明一任选实施方案中，R^6a独立地选自H、羟基、氰基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；R³、R⁴、R⁵的定义如本发明所述。In an optional embodiment of the present invention, R ^6a is independently selected from H, hydroxy, cyano, -NR ³ R ⁴ , -C(=O)NR ³ R ⁴ , -C(=NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(=O) ₂ NR ³ R ⁴ or -S(=O)(=NR ⁵ )R ³ ; R ³ , R ⁴ and R ⁵ are as defined herein.

在本发明一任选实施方案中，R^6a独立地选自H、羟基、氰基、 In an optional embodiment of the present invention, R ^6a is independently selected from H, hydroxy, cyano,

在本发明一任选实施方案中，R^5a独立地选自H、卤素、羟基、氰基、C_1-6烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；所述的C_1-6烷基、C_1- ₆烷氧基各自独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代；R³、R⁴、R⁵的定义如本发明所述。In an optional embodiment of the present invention, R ^5a is independently selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; the C _1-6 alkyl and _C _1-6 alkoxy are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen or hydroxy; R ³ , R ⁴ and R ⁵ are as defined herein.

在本发明一任选实施方案中，R^5a独立地选自H、羟基、氰基、C_1-6烷基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；所述的C_1-6烷基、独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代；R³、R⁴、R⁵的定义如本发明所述。In an optional embodiment of the present invention, R ^5a is independently selected from H, hydroxy, cyano, C _1-6 alkyl, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; said C _1-6 alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen or hydroxy; R ³ , R ⁴ and R ⁵ are as defined herein.

在本发明一任选实施方案中，R^5a独立地选自H、C_1-6烷基、-C(＝O)NR³R⁴、所述的C_1-6烷基独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代；R³、R⁴、R⁵的定义如本发明所述。In an optional embodiment of the present invention, R ^5a is independently selected from H, C _1-6 alkyl, -C(=O)NR ³ R ⁴ , said C _1-6 alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxyl; R ³ , R ⁴ and R ⁵ are as defined herein.

在本发明一任选实施方案中，R^5a独立地选自H、羟基、氰基、 In an optional embodiment of the present invention, R ^5a is independently selected from H, hydroxy, cyano,

在本发明一任选实施方案中，R³、R⁴、R⁵各自独立地选自H、卤素、羟基、C_1-6烷基、C_1-6烷氧基；所述的C_1-6烷基、C_1-6烷氧基各自独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代。In an optional embodiment of the present invention, R ³ , R ⁴ , and R ⁵ are each independently selected from H, halogen, hydroxy, C _1-6 alkyl, and C _1-6 alkoxy; and the C _1-6 alkyl and C _1-6 alkoxy are each independently optionally substituted with 1, 2, 3, 4, 5, or 6 H, halogen, or hydroxy.

在本发明一任选实施方案中，R³、R⁴、R⁵各自独立地选自H、羟基、C_1-6烷基、C_1-6烷氧基；所述的C_1-6烷基、C_1-6烷氧基各自独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代。In an optional embodiment of the present invention, R ³ , R ⁴ and R ⁵ are each independently selected from H, hydroxy, C _1-6 alkyl and C _1-6 alkoxy; the C _1-6 alkyl and C _1-6 alkoxy are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen or hydroxy.

在本发明一任选实施方案中，R³、R⁴、R⁵各自独立地选自H、羟基、C_1-6烷基；所述的C_1-6烷基独立地任选被1、2、3、4、5或6个H、卤素、羟基所取代。In an optional embodiment of the present invention, R ³ , R ⁴ and R ⁵ are each independently selected from H, hydroxyl and C _1-6 alkyl; said C _1-6 alkyl is independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen or hydroxyl.

在本发明一任选实施方案中，R³、R⁴、R⁵各自独立地选自H、羟基、甲基、 In an optional embodiment of the present invention, R ³ , R ⁴ and R ⁵ are each independently selected from H, hydroxy, methyl,

在本发明一任选实施方案中，R^4a各自独立地选自H、卤素、C_1-6烷基。In an optional embodiment of the present invention, R ^4a is independently selected from H, halogen, and C _1-6 alkyl.

在本发明一任选实施方案中，R^4a各自独立地选自H、F、Cl、甲基、乙基、正丙基、异丙基。In an optional embodiment of the present invention, R ^4a is independently selected from H, F, Cl, methyl, ethyl, n-propyl, isopropyl.

在本发明一任选实施方案中，R^4a为H。In an optional embodiment of the present invention, R ^4a is H.

在本发明一任选实施方案中，选自其中，X^3a为N或CR^3a；X^4a为N或CR^4a；X^5a为N或CR^5a；X^6a为N、N⁺-O^-或CR^6a；R^3a、R^4a、R^5a各自独立地选自H、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；R^6a为H、卤素、羟基、C_1-6烷基、C_1-6烷氧基、-NR³R⁴、-C(＝O)NR³R⁴、-C(＝NR⁵)NR³R⁴、-OR⁴、-S(＝O)₂R³、-S(＝O)₂NR³R⁴或-S(＝O)(＝NR⁵)R³；W选自S、S(＝O)、S(＝O)₂、P(＝O)₂、O或NH。In an optional embodiment of the present invention, Selected from wherein X ^3a is N or CR ^3a ; X ^4a is N or CR ^4a ; X ^5a is N or CR ^5a ; X ^6a is N, N ⁺ -O ^- , or CR ^6a ; R ^3a , R ^4a , and R ^5a are each independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, or C _1-6 haloalkoxy; and R ^6a is H, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(═O)NR ³ R ⁴ , -C(═NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(═O) ₂ R ³ , -S(═O) ₂ NR ³ R ⁴ , or -S(═O)(═NR ⁵ )R ³ ; W is selected from S, S(=O), S(=O) ₂ , P(=O) ₂ , O or NH.

在本发明一任选实施方案中，为其中，R^4a为H、卤素、C_1-6烷基，R^6a、R^5a各自独立地选自H、卤素、C_1-6烷基、氰基、-CH(OH)CH₂OH、-OCH₂CH(OH)CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³、-S(＝O)(＝NH)R³或-OR⁴，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代，R^C的定义如本发明所述，R⁴为H或C_1-6烷基，所述C_1-6烷基选被一个或多个R^C所取代，R^C的定义如本发明所述。In an optional embodiment of the present invention, for wherein R ^4a is H, halogen, or C _1-6 alkyl; R ^6a and R ^5a are each independently selected from H, halogen, C _1-6 alkyl, cyano, -CH(OH)CH ₂ OH, -OCH ₂ CH(OH)CH ₂ OH, -C(═O)NHR ³ , -C(═NH)NHR ³ , -S(═O) ₂ R ³ , -S(═O) ₂ NHR ³ , -S(═O)(═NH)R ³ or -OR ⁴ ; R ³ is H, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted with one or more ^RC , and ^RC is as defined herein; R ⁴ is H or C _1-6 alkyl, wherein the C _1-6 alkyl is optionally substituted with one or more ^RC , and ^RC is as defined herein;

在本发明一任选实施方案中，为 R^4a、R^5a、R^6a定义如本发明所述。In an optional embodiment of the present invention, for R ^4a , R ^5a , and R ^6a are as defined in the present invention.

在本发明一任选实施方案中，为其中，R^4a、R^5a各自独立地选自H、卤素、C_1-6烷基，R^6a为氰基、-CH(OH)CH₂OH、-OCH₂CH(OH)CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³、-S(＝O)(＝NH)R³或-OR⁴，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代，R^C的定义如本发明所述，R⁴为H或C_1-6烷基，所述C_1-6烷基选被一个或多个R^C所取代，R^C的定义如本发明所述。在本发明一任选实施方案中，为其中，R^4a、R^5a各自独立地选自H、卤素、C_1-6烷基，R^6a为氰基、-OCH₂CH(OH)CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³、-S(＝O)(＝NH)R³或-OR⁴，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代，R^C的定义如本发明所述，R⁴为H或C_1-6烷基，所述C_1-6烷基任选被一个或多个R^C所取代，R^C的定义如本发明所述。In an optional embodiment of the present invention, for wherein R ^4a and R ^5a are each independently selected from H, halogen, C _1-6 alkyl, R ^6a is cyano, -CH(OH)CH ₂ OH, -OCH ₂ CH(OH)CH ₂ OH, -C(═O)NHR ³ , -C(═NH)NHR ³ , -S(═O) ₂ R ³ , -S(═O) ₂ NHR ³ , -S(═O)(═NH)R ³ or -OR ⁴ , R ³ is H, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, said C _1-6 alkyl and C _1-6 alkoxy are optionally substituted with one or more ^RC , ^{and RC} is as defined in the present invention, R ⁴ is H or C _1-6 alkyl, said C _1-6 alkyl is optionally substituted with one or more ^RC , and ^RC is as defined in the present invention. In an optional embodiment of the present invention, for wherein R ^4a and R ^5a are each independently selected from H, halogen, C _1-6 alkyl; R ^6a is cyano, -OCH ₂ CH(OH)CH ₂ OH, -C(＝O)NHR ³ , -C(＝NH)NHR ³ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NHR ³ , -S(＝O)(＝NH)R ³ or -OR ⁴ ; R ³ is H, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy, the C _1-6 alkyl and C _1-6 alkoxy being optionally substituted with one or more ^RC , and ^RC being as defined herein; R ⁴ is H or C _1-6 alkyl, the C _1-6 alkyl being optionally substituted with one or more ^RC , and ^RC being as defined herein.

在本发明一任选实施方案中，为其中，R^4a、R^5a各自独立地选自H、卤素、C_1-6烷基，R^6a为-OCH₂CH(OH)CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³或-S(＝O)(＝NH)R³，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代，R^C的定义如本发明所述。In an optional embodiment of the present invention, for wherein R ^4a and R ^5a are each independently selected from H, halogen, and C _1-6 alkyl; R ^6a is -OCH ₂ CH(OH)CH ₂ OH, -C(＝O)NHR ³ , -C(＝NH)NHR ³ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NHR ³ , or -S(＝O)(＝NH)R ³ ; and R ³ is H, hydroxyl, C _1-6 alkyl, or C _1-6 alkoxy; the C _1-6 alkyl and C _1-6 alkoxy groups are optionally substituted with one or more ^RC , and ^RC is as defined herein.

在本发明一任选实施方案中，为

In an optional embodiment of the present invention, for

在本发明一任选实施方案中，选自其中，R^6a为-OCH₂CH(OH)CH₂OH、-OCH₂CH₂OH、-C(＝O)NHR³、-C(＝NH)NHR³、-S(＝O)₂R³、-S(＝O)₂NHR³或-S(＝O)(＝NH)R³，R³为H、羟基、C_1-6烷基或C_1-6烷氧基，所述C_1-6烷基和C_1-6烷氧基任选被一个或多个R^C所取代，R^C的定义如本发明所述。In an optional embodiment of the present invention, Selected from Wherein, R ^6a is -OCH ₂ CH(OH)CH ₂ OH, -OCH ₂ CH ₂ OH, -C(＝O)NHR ³ , -C(＝NH)NHR ³ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NHR ³ or -S(＝O)(＝NH)R ³ , R ³ is H, hydroxyl, C _1-6 alkyl or C _1-6 alkoxy, and the C _1-6 alkyl and C _1-6 alkoxy groups are optionally substituted with one or more ^RC , and ^RC is as defined in the present invention.

在本发明一任选实施方案中，为其中R^4b1、R^4b2、R^5b1、R^5b2、R^6b和R^7b的定义如本发明所述。In an optional embodiment of the present invention, for wherein R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b and R ^7b are as defined in the present invention.

在本发明一任选实施方案中，R^5b1和R^5b2各自独立地选自C_1-6烷基或C_1-6卤代烷基；较佳地，R^5b1和R^5b2各自独立地选自甲基或三氟甲基；更佳地，R^5b1为甲基，R^5b2为三氟甲基。In an optional embodiment of the present invention, R ^5b1 and R ^5b2 are each independently selected from C _1-6 alkyl or C _1-6 haloalkyl; preferably, R ^5b1 and R ^5b2 are each independently selected from methyl or trifluoromethyl; more preferably, R ^5b1 is methyl and R ^5b2 is trifluoromethyl.

在本发明一任选实施方案中，R^4b1和R^4b2各自独立地选自H、C_1-6烷基或C_1-6卤代烷基；较佳地，R^4b1和R^4b2各自独立地选自H、甲基、乙基、正丙基、异丙基；更佳地，R^4b1为H，R^4b2为甲基。In an optional embodiment of the present invention, R ^4b1 and R ^4b2 are each independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; preferably, R ^4b1 and R ^4b2 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl; more preferably, R ^4b1 is H and R ^4b2 is methyl.

在本发明一任选实施方案中，R^6b为H。In an optional embodiment of the present invention, R ^6b is H.

在本发明一任选实施方案中，R^7b为H。In an optional embodiment of the present invention, R ^7b is H.

在本发明一任选实施方案中，A为H。In an optional embodiment of the present invention, A is H.

在本发明一任选实施方案中，A为其中X^2c、X^3c、X^4c、X^5c和X^6c的定义如本发明所述。In an optional embodiment of the present invention, A is wherein X ^2c , X ^3c , X ^4c , X ^5c and X ^6c are as defined in the present invention.

在本发明一任选实施方案中，为其中R^2c、R^3c和R^4c的定义如本发明所述。In an optional embodiment of the present invention, for wherein R ^2c , R ^3c and R ^4c are as defined in the present invention.

在本发明一任选实施方案中，R^2c为被一个或多个卤素取代的3-6元杂环基、被一个或多个卤素取代的C_3-6环烷基、C_1-6烷基、C_1-6烷氧基、C_1-6氘代烷氧基、-N(C_1-6烷基)₂；较佳地，R^2c为甲基、乙基、正丙基、异丙基、甲氧基、乙基氧基、正丙基氧基、异丙基氧基、-O-CD₃、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃)、-N(CH₃)₂、更佳地，R^2c为甲基、甲氧基、-O-CD₃、-N(CH₃)₂、 In an optional embodiment of the present invention, R ^2c is a 3-6 membered heterocyclyl substituted by one or more halogens, a C _3-6 cycloalkyl substituted by one or more halogens, a C _1-6 alkyl, a C _1-6 alkoxy, a C _1-6 deuterated alkoxy, or -N(C _1-6 alkyl) ₂ ; preferably, R ^2c is methyl, ethyl, n-propyl, isopropyl, methoxy, ethyloxy, n-propyloxy, isopropyloxy, -O-CD ₃ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ ) ₂ , More preferably, R ^2c is methyl, methoxy, -O-CD ₃ , -N(CH ₃ ) ₂ ,

在本发明一任选实施方案中，R^2c为被一个或多个卤素取代的3-6元杂环基、C_1-6烷氧基、-N(C_1-6烷基)₂；较佳地，R^2c为甲氧基、乙基氧基、正丙基氧基、异丙基氧基、-N(CH₂CH₃)₂、-N(CH₃)(CH₂CH₃)、-N(CH₃)₂、更佳地，R^2c为甲氧基、-N(CH₃)₂或 In an optional embodiment of the present invention, R ^2c is a 3-6 membered heterocyclyl substituted by one or more halogens, C _1-6 alkoxy, or -N(C _1-6 alkyl) ₂ ; preferably, R ^2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ ) ₂ , More preferably, R ^2c is methoxy, -N(CH ₃ ) ₂ or

在本发明一任选实施方案中，R^2c为C_1-6烷氧基；较佳地，R^2c为甲氧基、乙基氧基、正丙基氧基、异丙基氧基，更佳地，R^2c为甲氧基。In an optional embodiment of the present invention, R ^2c is C _1-6 alkoxy; preferably, R ^2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, and more preferably, R ^2c is methoxy.

在本发明一任选实施方案中，R^3c为H或卤素；较佳地，R^3c为H、F或Cl；更佳地，R^3c为H或F。In an optional embodiment of the present invention, R ^3c is H or halogen; preferably, R ^3c is H, F or Cl; more preferably, R ^3c is H or F.

在本发明一任选实施方案中，R^3c为卤素；较佳地，R^3c为F或Cl；更佳地，R^3c为F。In an optional embodiment of the present invention, R ^3c is halogen; preferably, R ^3c is F or Cl; more preferably, R ^3c is F.

在本发明一任选实施方案中，R^4c为卤素；较佳地，R^4c为F或Cl；更佳地，R^4c为F。In an optional embodiment of the present invention, R ^4c is halogen; preferably, R ^4c is F or Cl; more preferably, R ^4c is F.

在本发明一任选实施方案中，A为C_1-6烷基；较佳的，A为甲基、乙基、正丙基或异丙基；更佳的，A为甲基；In an optional embodiment of the present invention, A is C _1-6 alkyl; preferably, A is methyl, ethyl, n-propyl or isopropyl; more preferably, A is methyl;

在本发明一任选实施方案中，A为环丙基、环丁基、环戊基、环己基；较佳的，A为环丙基。In an optional embodiment of the present invention, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably, A is cyclopropyl.

在本发明一任选实施方案中，所述化合物具有选自下列任一结构，或任一结构的互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药：

In an optional embodiment of the present invention, the compound has any one of the following structures, or a tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug of any one of the structures:

本发明还提供了所述化合物的制备方法，其中通式的取代基具有上文所述的含义。这些方法旨在例示本发明，而并非将本发明的主题及所保护的化合物的范围限定于所述实施例。如果未说明起始化合物的制备，则其市售购得或可通过与已知化合物或本文所述方法类似的方式制备。文献中所述的物质根据已公开的合成方法制备。依据本发明，通式(V)的化合物可根据方案1描述的方法制备，包括如下步骤：

The present invention also provides methods for preparing the compounds, wherein the substituents of the general formula have the meanings described above. These methods are intended to illustrate the present invention and are not intended to limit the scope of the subject matter of the present invention and the protected compounds to the examples described. If the preparation of the starting compound is not described, it is commercially available or can be prepared in a manner similar to known compounds or methods described herein. The substances described in the literature are prepared according to published synthetic methods. According to the present invention, the compound of general formula (V) can be prepared according to the method described in Scheme 1, comprising the following steps:

方案1Solution 1

使其中式(Int1)和式(Int2)在钯催化剂(例如Pd2(dba)3、Pd(dba)2)、膦配体(例如Xphos或Xantphos)以及强碱(例如NaOH、NaOtBu、Cs₂CO₃、K₃PO₄、K₂CO₃、Na₂CO₃、KOAc中的一种或多种)的作用下在非极性有机溶剂(例如二氧六环，甲苯)中，反应得到式(V)化合物；较佳地，所述反应可在无氧环境下进行；较佳地，所述反应温度为90℃～110℃；所述反应时间为8-30小时，Formula (Int1) and Formula (Int2) are reacted in the presence of a palladium catalyst (e.g., Pd2(dba)3, Pd(dba)2), a phosphine ligand (e.g., Xphos or Xantphos), and a strong base ( _e.g. , one or more of NaOH, _NaOtBu , _Cs2CO3 , _K3PO4 , _K2CO3 , _Na2CO3 , KOAc) in a non-polar organic solvent (e.g., dioxane, toluene) to obtain _a compound _of Formula (V); preferably, the reaction can be carried out in an oxygen-free environment; preferably, the reaction temperature is 90°C to 110°C; and the reaction time is 8-30 hours.

依据本发明，通式(V)的化合物还可根据方案2描述的方法制备，包括如下步骤：
According to the present invention, the compound of formula (V) can also be prepared according to the method described in Scheme 2, comprising the following steps:

方案2Option 2

使其中式(Int3)和式(Int4)在酰化剂(例如酸酐(例如醋酸酐)或酰氯(例如草酰氯))和有机碱(例如N,N-二甲基甲酰胺)的作用下反应得到式(Int5)化合物；较佳地，所述反应在无氧环境下进行；较佳地，所述反应温度为20℃～30℃；所述反应时间为1-4小时。Formula (Int3) and Formula (Int4) are reacted in the presence of an acylating agent (e.g., an acid anhydride (e.g., acetic anhydride) or an acid chloride (e.g., oxalyl chloride)) and an organic base (e.g., N,N-dimethylformamide) to obtain a compound of Formula (Int5); preferably, the reaction is carried out in an anaerobic environment; preferably, the reaction temperature is 20°C to 30°C; and the reaction time is 1-4 hours.

式(Int5)化合物在强碱(例如NaOH、NaOtBu、Cs₂CO₃、K₃PO4、K₂CO₃、Na₂CO₃、KOAc)的作用下，形成式(V)化合物。The compound of formula (Int5) forms the compound of formula (V) under the action of a strong base (eg, NaOH, NaOtBu, Cs ₂ CO ₃ , K ₃ PO 4 , K ₂ CO ₃ , Na ₂ CO ₃ , KOAc).

本发明的第二方面，本发明提出了一种药物组合物，所述药物组合物包括治疗有效量的上述化合物，其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药以及药学上可接受的药用载体、稀释剂或赋形剂。In the second aspect of the present invention, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of the above-mentioned compound, its tautomers, stereoisomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

本发明的第三方面，本发明提出了上述化合物、其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备用于抑制电压门控钠离子通道相关药物中的用途，所述电压门控钠离子通道包括Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9，优选为Nav1.8。In the third aspect of the present invention, the present invention proposes the use of the above-mentioned compound, its tautomers, stereoisomers, nitrogen oxides, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical composition in the preparation of drugs related to inhibiting voltage-gated sodium ion channels, wherein the voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8.

根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备药物中的用途，所述药物可用于治疗、缓解或预防疼痛，所述疼痛包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug, the drug can be used to treat, relieve or prevent pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

根据本发明的具体实施例，上述化合物或其互变异构体、立体异构体、氮氧化物、水合物、溶剂化物、药学上可接受的盐或前药或上述药物组合物在制备药物中的用途，所述药物可用于治疗、缓解或预防疼痛，所述疼痛包括急性疼痛尤其是术后疼痛等，慢性疼痛，炎性疼痛，癌症疼痛，神经性疼痛，肌肉骨骼痛，肠痛，特发性疼痛，原发性疼痛如纤维肌痛症，原发性疼痛如头痛及颌面痛等。According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a medicament, the medicament can be used to treat, relieve or prevent pain, the pain including acute pain, especially postoperative pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, intestinal pain, idiopathic pain, primary pain such as fibromyalgia, primary pain such as headache and maxillofacial pain, etc.

本发明第四方面，提供一种抑制电压门控钠离子通道，或预防和/或治疗电压门控钠离子通道相关的疾病的方法，包括步骤：给需要的对象施用本发明第一方面所述的式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药或本发明的第二方面所述的药物组合物。In a fourth aspect, the present invention provides a method for inhibiting voltage-gated sodium ion channels, or preventing and/or treating diseases related to voltage-gated sodium ion channels, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect of the present invention.

所述电压门控钠离子通道包括Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9，优选为Nav1.8。所述电压门控钠离子通道相关的疾病为疼痛，包括急性疼痛、慢性疼痛、炎性疼痛、癌症疼痛、神经性疼痛、肌肉骨骼痛、原发性疼痛、肠痛和特发性疼痛。The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. The diseases associated with the voltage-gated sodium ion channels are pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

所述电压门控钠离子通道包括Nav1.1～Nav1.9，Nav1.5、Nav1.8和Nav1.9，优选为Nav1.8。所述电压门控钠离子通道相关的疾病为疼痛，包括急性疼痛尤其是术后疼痛等，慢性疼痛，炎性疼痛，癌症疼痛，神经性疼痛，肌肉骨骼痛，肠痛，特发性疼痛，原发性疼痛如纤维肌痛症，原发性疼痛如头痛及颌面痛等。The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. Diseases associated with the voltage-gated sodium ion channels are pain, including acute pain, especially postoperative pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, intestinal pain, idiopathic pain, primary pain such as fibromyalgia, and primary pain such as headache and maxillofacial pain.

Beneficial effects:

根据本发明的实施例，本发明至少具有如下技术效果至少之一：According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

提供了结构新颖、药代动力学性质优良、药效或成药性好的Nav1.8抑制剂，可以用于有效治疗Nav1.8相关的疾病、病症。Provided are Nav1.8 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat Nav1.8-related diseases and conditions.

本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

术语和定义Terms and Definitions

除非另有说明，用于本发明申请，包括本申请说明书和权利要求书中记载的术语和定义如下。Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

本领域技术人员可以理解，根据本领域中使用的惯例，在本申请的结构式中，用于描绘化学键，所述化学键为部分或取代基与核心结构或骨架结构相连的点。Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

除非另有规定，术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

除非另有规定，术语“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐，包括无机酸和碱、有机酸和碱的盐。Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

除了药学可接受的盐外，本发明还考虑其他盐。它们可以在化合物纯化中或在制备其它药学上课接受的盐中充当中间体或可用于本发明化合物的鉴别、表征或纯化。In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

除非另有规定，术语“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物，其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein, or their physiologically/pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

除非另有规定，术语“辅料”是指可药用惰性成分。术语“赋形剂”的种类实例非限制性地包括粘合剂、崩解剂、润滑剂、助流剂、稳定剂、填充剂和稀释剂等。赋形剂能增强药物制剂的操作特性，即通过增加流动性和/或粘着性使制剂更适于直接压缩。Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and/or cohesiveness, making the formulation more suitable for direct compression.

除非另有规定，术语“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明化合物。本发明的前药通过修饰在该化合物中的功能基团来制备，该修饰可以按常规的操作或者在体内被除去，而得到母体化合物。前药包括本发明化合物中的一个羟基或者氨基连接到任何基团上所形成的化合物，当本发明化合物的前药被施予哺乳动物个体时，前药被割裂而分别形成游离的羟基、游离的氨基。Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

除非另有规定，术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体、非对应异构体和构象异构体。Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

依据原料和方法的选择，本发明化合物可以以可能的异构体中的一个或它们的混合物的形式存在，例如作为纯旋光异构体，或作为异构体混合物，如作为外消旋和非对映异构体混合物，这取决于不对称碳原子的数量。当描述具有光学活性的化合物时，使用前缀D和L或R和S来表示就分子中的手性中心(或多个手性中心)而言分子的绝对构型。前缀D和L或(+)和(–)是用于指定化合物所致平面偏振光旋转的符号，其中(–)或L表示化合物是左旋的。前缀为(+)或D的化合物是右旋的。就给定的化学结构而言，除了这些立体异构体互为镜像外，这些立体异构体是相同的。具体的立体异构体也可称为对映异构体，并且所述异构体的混合物通常称作对映异构体的混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋体，当在化学反应或方法中没有立体选择性或立体特异性时，可出现所述外消旋混合物或外消旋体。烯烃、C＝N双键等的许多几何异构体也可以存在于本文所述的化合物中，且所有这种稳定的异构体在本发明中均被考虑。当本文所描述化合物含有烯双键时，除非另外说明，否则，这种双键包括E和Z几何异构体。如果化合物中含有二取代的环烷基，环烷基的取代基可能为顺式或反式(cis-或trans-)构型。Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

当将本发明式中与手性碳的键描写成直线时，应当理解为，手性碳的(R)和(S)两种构型和由此产生的其对映体纯的化合物和混合物两者包括在该通式范围内。本文中消旋体或者对映体纯的化合物的图示法来自Maehr，J.Chem.Ed.1985，62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。When the bonds to chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

旋光性的(R)-或(S)-异构体可使用手性合成子或手性制剂制备，或使用常规技术拆分。含有不对称取代的碳原子的本发明化合物能够以旋光活性形式或外消旋形式分离。化合物的外消旋混合物的拆分可以通过本领域已知的许多方法中的任一种来进行。示例性方法包括使用手性拆分酸的分级重结晶，该手性拆分酸是旋光活性的成盐有机酸。用于分级重结晶方法的适合的拆分剂例如是旋光活性酸，例如酒石酸、二乙酰基酒石酸、二苯甲酰基酒石酸、扁桃酸、苹果酸、乳酸或各种旋光活性樟脑磺酸如β-樟脑磺酸的D和L形式。适合于分级结晶方法的其它的拆分剂包括立体异构纯形式的α-甲基-苄胺(例如，S和R形式或者非对映异构纯形式)、2-苯基甘氨醇、降麻黄碱、麻黄碱、N-甲基麻黄碱、环己基乙胺、1，2-二氨基环己烷等。外消旋混合物的拆分还可以通过在填充有旋光活性拆分剂(例如，二硝基苯甲酰基苯基甘氨酸)的色谱柱上洗脱来进行。可以采用高效液相色谱(HPLC)法也可以采用超临界流体色谱法(SFC)进行。具体方法的选择以及洗脱条件、色谱柱的选择可以由本领域技术人员根据化合物的结构以及试验结果选择。进一步的，还可以使用已知构型的光学纯的起始原料或试剂，通过立体有机合成，获得本发明所描述化合物的任何对映体或非对映体。Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

除非另有规定，术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。Unless otherwise specified, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型。Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。本发明化合物可表现出互变异构现象。互变异构的化合物可以存在两种或多种可相互转化的种类。质子移变互变异构体来自两个原子之间共价键合的氢原子的迁移。互变异构体一般以平衡形式存在，尝试分离单一互变异构体时通常产生一种混合物，其理化性质与化合物的混合物是一致的。平衡的位置取决于分子内的化学特性。例如，在很多脂族醛和酮如乙醛中，酮型占优势；而在酚中，烯醇型占优势。本发明包含化合物的所有互变异构形式。例如：
The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds. For example:

酮型与烯醇型互变。Keto and enol forms interconvert.

本发明的实例中，质子可以占据杂环体系的两个或多个位置的环状形式，例如，1H-和3H-咪唑，1H-、2H-和4H-1，2，4-三唑，1H-和2H-异吲哚，四氮唑，以及1H-和2H-吡唑。互变异构形式可以通过适当的取代而处于平衡或空间上固定于一种形式。例如：
In embodiments of the present invention, protons can occupy two or more positions of the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

由于共振的原因，四氮唑上氮的氢可以在四个氮的任何一个上。Due to resonance, the hydrogen atoms of the tetrazole nitrogen can be on any of the four nitrogen atoms.

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(²H)，氚(³H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换(即“同位素标记物”)，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( ² H), tritium ( ³ H), iodine-125 ( 125I), or C-14 ( 14C). All isotopic variations of the compounds of the present invention (i.e., "isotopically labeled materials"), whether radioactive or not, are included within the scope of the present invention.

针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

除非另有规定，术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个(两个，三个或更多)氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。当限定取代基为一个或多个时，所述多个包括两个，三个，四个或更多个。Unless otherwise specified, the term "substituted" means that any one or more (two, three or more) hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. When the substituent is limited to one or more, the plurality includes two, three, four or more.

除非另有规定，术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。Unless otherwise specified, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。例如，R¹被g个R^a取代，当g为2、3或4个时，每一个R^a是独立的选项，可以相同或者不同。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R, then the group may be optionally substituted with up to two R, and each occurrence of R is an independent choice. For example, ^if R is substituted with g ^Ra , when g is 2, 3, or 4, each ^Ra is an independent choice and may be the same or different.

此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。另外，当多环(并环、螺环或桥环)被取代基取代时，表示每一个环上的氢原子均可能会被取代。In addition, combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds. In addition, when multiple rings (parallel rings, spiro rings, or bridged rings) are substituted with substituents, each hydrogen atom on the ring may be substituted.

除非另有规定，术语“C_1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C_1-6烷基包括C_1-5、C_1-4、C_1-3、C_1-2、C_2-6、C_2-4、C₆和C₅烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C_1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。Unless otherwise specified, the term "C _1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group includes C _1-5 , C _1-4 , C _1-3 , C 1-2, C _2-6 , C _2-4 , C ₆ and C ₅ alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of _C _1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.

除非另有规定，术语“C_1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C_1-3烷基包括C_1-2和C_2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C_1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C _1-3 alkyl" is used to refer to a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C _1-3 alkyl group includes C _1-2 and C _2-3 alkyl groups, and can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of C _1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

在单独或作为其他取代基一部分时，术语“卤代”可与术语“卤素取代”互换使用。The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

除非另有规定，“卤代烷基”或“卤素取代的烷基”指包括具有特定数目的碳原子、被一或多个卤素取代的支链和直链的饱和脂族烃基。Unless otherwise specified, "haloalkyl" or "halo-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

除非另有规定，“C_2-6烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至6个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C_2-6烯基包括C_2-4、C_2-3、C₄、C₃和C₂烯基等；其可以是一价、二价或者多价。C_2-6烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基、己间二烯基等。Unless otherwise specified, " _C2-6 alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position within the group. The _C2-6 alkenyl group includes _C2-4 , _C2-3 , _C4 , _C3 , and _C2 alkenyl groups, and may be monovalent, divalent, or polyvalent. Examples of _C2-6 alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentyladienyl, and hexadienyl.

除非另有规定，“C_2-3烯基”用于表示直链或支链的包含至少一个碳-碳双键的由2至3个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C_2-3烯基包括C₃和C₂烯基；所述C_2-3烯基可以是一价、二价或者多价。C_2-3烯基的实例包括但不限于乙烯基、丙烯基等。Unless otherwise specified, " _C2-3 alkenyl" refers to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position within the group. The _C2-3 alkenyl group includes _C3 and C2 _alkenyl groups; the _C2-3 alkenyl group may be monovalent, divalent, or polyvalent. Examples of _C2-3 alkenyl groups include, but are not limited to, ethenyl and propenyl.

除非另有规定，“C_2-6炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至6个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C_2-6炔基包括C_2-4、C_2-3、C₄、C₃和C₂炔基等。其可以是一价、二价或者多价。C_2-6炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。Unless otherwise specified, " _C2-6 alkynyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position within the group. The _C2-6 alkynyl group includes _C2-4 , _C2-3 , _C4 , _C3 , and _C2 alkynyl groups. It may be monovalent, divalent, or polyvalent. Examples of _C2-6 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and pentynyl.

除非另有规定，“C_2-3炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至3个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。其可以是一价、二价或者多价。所述C_2-3炔基包括C₃和C₂炔基。C_2-3炔基的实例包括但不限于乙炔基、丙炔基等。Unless otherwise specified, " _C2-3 alkynyl" refers to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position within the group. It may be monovalent, divalent, or polyvalent. The _C2-3 alkynyl group includes _C3 and _C2 alkynyl groups. Examples of _C2-3 alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

除非另有规定，术语“C_1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C_1-6烷氧基包括C_1-4、C_1-3、C_1-2、C_2-6、C_2-4、C₆、C₅、C₄和C₃烷氧基等。C_1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。Unless otherwise specified, the term "C _1-6 alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ , and C ₃ alkoxy groups. Examples of C _1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), pentoxy (including n-pentoxy, isopentoxy, and neopentoxy), hexyloxy, and the like.

除非另有规定，术语“C_1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C_1-3烷氧基包括C_1-2、C_2-3、C₃和C₂烷氧基等。C_1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C _1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms that is attached to the rest of the molecule via an oxygen atom. The C _1-3 alkoxy group includes C _1-2 , C _2-3 , C ₃ and C ₂ alkoxy groups. Examples of C _1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

除非另有规定，术语“C_3-12环烷基”或“C_3-12饱和环”表示由3至12个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C_3-12环烷基包括C_3-10、C_3-8、C_3-6、C_3- ₅、C_4-8、C_4-6、C_4-5、C_5-8或C_5-6环烷基等；其可以是一价、二价或者多价。C_3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。Unless otherwise specified, the term "C _3-12 cycloalkyl" or "C _3-12 saturated ring" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. The C _3-12 cycloalkyl group includes C _3-10 , C _3-8 , C _3-6 , C _3-5 , C _4-8 , C _4-6 , C _4-5 _{, C 5-8} _or C _5-6 cycloalkyl groups, etc.; and can be monovalent, divalent or polyvalent. Examples of _{C 3-8} cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, etc.

除非另有规定，术语“C_3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C_3-8环烷基包括C_3-6、C_3-5、C_4-8、C_4-6、C_4-5、C_5-8或C_5-6环烷基等；其可以是一价、二价或者多价。C_3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。Unless otherwise specified, the term " _C3-8 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused, and bridged rings. The _C3-8 cycloalkyl group includes _C3-6 , _C3-5 , _C4-8 , _C4-6 , _C4-5 , _C5-8 , or _C5-6 cycloalkyl groups, and can be monovalent, divalent, or polyvalent. Examples of _C3-8 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

除非另有规定，术语“C_3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C_3-6环烷基包括C_3-5、C_4-5和C_5-6环烷基等；其可以是一价、二价或者多价。C_3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, the term " _C3-6 cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems. Such _C3-6 cycloalkyl groups include _C3-5 , _C4-5 , and _C5-6 cycloalkyl groups, and may be monovalent, divalent, or polyvalent. Examples of _C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

除非另有规定，本发明术语“C_6-12芳环”和“C_6-12芳基”可以互换使用，术语“C_6-12芳环”或“C_6-12芳基”表示由6至12个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中至少一个环为芳香性的，其他环为任意环，任意环可以为环烷基、环烯基、杂环烷基、杂环烯基、芳基和杂芳基。其可以是一价、二价或者多价，C_6-12芳基包括C_6-10、C_6-9、C_6-8、C₁₂、C₁₀和C₆芳基等。C_6-12芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。Unless otherwise specified, the terms "C _6-12 aromatic ring" and "C _6-12 aryl" are used interchangeably herein. The term "C _6-12 aromatic ring" or "C _6-12 aryl" refers to a cyclic hydrocarbon group consisting of 6 to 12 carbon atoms and having a conjugated π electron system. It can be a monocyclic, fused bicyclic, or fused tricyclic ring system, wherein at least one ring is aromatic and the other rings are any rings, which can be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl. It can be monovalent, divalent, or polyvalent. C _6-12 aryl groups include C _6-10 , C _6-9 , C _6-8 , C ₁₂ , C ₁₀ , and C ₆ aryl groups. Examples of C _6-12 aryl groups include, but are not limited to, phenyl and naphthyl (including 1-naphthyl and 2-naphthyl).

除非另有规定，术语“4-12元杂环烯基”表示包含一个或多个独立地选自O、N和S的杂原子并且指定环原子数目的、至少包含一个双键的稳定非芳环结构(单环或多环)。非芳环结构可以具有4至12个环成员(例如4,5,6,7,8,9,10,11,12个环成员)，并且特别4至7个环成员。稠合的杂环环系可以包含碳环并且仅需包含一个杂环。Unless otherwise specified, the term "4-12 membered heterocycloalkenyl" refers to a stable non-aromatic ring structure (monocyclic or polycyclic) containing at least one double bond, one or more heteroatoms independently selected from O, N and S and the specified number of ring atoms. The non-aromatic ring structure may have 4 to 12 ring members (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12 ring members), and particularly 4 to 7 ring members. The fused heterocyclic ring system may contain carbocyclic rings and need only contain one heterocyclic ring.

除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C_1-12包括C₁、C₂、C₃、C₄、C₅、C₆、C₇、C₈、C₉、C₁₀、C₁₁、和C₁₂，也包括n至n+m中的任何一个范围，例如C_1-12包括C_1- ₃、C_1-6、C_1-9、C_3-6、C_3-9、C_3-12、C_6-9、C_6-12、和C_9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbon atoms, for example _{, C1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10} _, _C11 _, _and _C12 _, _and _also _includes _any _range _from n to n+m, for example _, _C1-12 includes _C1-3 , _C1-6 , _C1-9 , _C3-6 , _C3-9 , _C3-12 , _C6-9 , _C6-12 , and C13. _9-12 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

除非另有规定，术语“3-12元杂环基”或“3-12元杂环烷基”本身或者与其他术语联合分别表示由3至12个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-12元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。例如3-12元杂环烷基包括但不限于3元、4元、5元、6元、7元、8元、9元、10元、11元、12元、3-10元、3-8元、3-6元、4-6元等。“3-12元杂环烷基”的实例包括但不限于氧杂环丙基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基。Unless otherwise specified, the term "3-12 membered heterocyclyl" or "3-12 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-12 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 3-12 membered heterocycloalkyl includes, but is not limited to, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 3-10-membered, 3-8-membered, 3-6-membered, 4-6-membered, etc. Examples of “3-12 membered heterocycloalkyl” include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

除非另有规定，术语“4-8元杂环烷基”本身或者与其他术语联合分别表示由4至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“6-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。例如4-8元杂环烷基包括但不限于4元、5元、6元、7元、8元、4-6元等。4-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基。Unless otherwise specified, the term "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 4-8 membered heterocycloalkyl includes but is not limited to 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 4-6-membered, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

除非另有规定，本发明术语“5-12元杂芳环”和“5-12元杂芳基”可以互换使用，术语“5-12元杂芳基”表示由5至12个环原子组成的具有共轭π电子体系的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-12元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-12元杂芳基包括5-10元、5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-12元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1，2，3-三唑基、2H-1，2，3-三唑基、1H-1，2，4-三唑基和4H-1，2，4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-1吡啶基等)、吡嗪基、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" are used interchangeably herein, and the term "5-12 membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-12 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-12 membered heteroaryl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl) 1-oxazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S、P和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮、磷和硫杂原子可任选被氧化(即NO，P(O)p，和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1，2，3-三唑基、2H-1，2，3-三唑基、1H-1，2，4-三唑基和4H-1，2，4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, P and N, and the remainder are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen, phosphorus and sulfur heteroatoms are optionally oxidized (i.e., NO, P(O)p, and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

除非另有规定，术语“5,6并环”为5元环并6元环。Unless otherwise specified, the term "5,6-membered ring" refers to a 5-membered ring and a 6-membered ring.

除非另有规定，术语“卤代基”或“卤素”为氟、氯、溴和碘。Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“……独立地”应作广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“……独立地”既可以是指在不同基团中，相同符合之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

除非另有规定，术语“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

除非另有规定，术语“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、系统、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。Unless otherwise specified, the term "therapeutically effective amount" means the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevent disease, e.g., prevent a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibit disease, e.g., inhibit the disease, disorder, or condition (i.e., prevent further development of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviate disease, e.g., alleviate the disease, disorder, or condition (i.e., reverse the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting the disease or condition, i.e., curbing its development;

(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

(iv)减轻该疾病或病症所造成的症状。(iv) Alleviate the symptoms of the disease or condition.

术语“任选”或“任选地”意思是随后所述的事件或情形可发生或可不发生，且所述描述包括其中所述事件或情形发生的情况以及其中所述事件或情形不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

DETAILED DESCRIPTION

下面将结合实施例对本发明的方案进行解释。本领域技术人员将会理解，下面的实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。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。Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

如无特别说明，本发明的化合物均是通过核磁共振(NMR)和/或质谱(MS)来确定其结构的。NMR位移的单位为10^-6(ppm)。NMR测定的溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl₃)、氘代甲醇(MeOD)、重水(D₂O)等，内标为四甲基硅烷(TMS)。Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 ^{<-6 >} (ppm). The solvents used for NMR measurements are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl ₃ ), deuterated methanol (MeOD), heavy water (D ₂ O), etc., and tetramethylsilane (TMS) is the internal standard.

本发明的缩写定义如下：The abbreviations of the present invention are defined as follows:

PE：石油醚(Petroleum Ether)PE: Petroleum Ether

EA：乙酸乙酯(Ethyl Acetate)EA：Ethyl Acetate

brine：饱和食盐水(盐水)brine: saturated salt water (brine)

DMF：二甲基甲酰胺(Dimethylformamide)DMF: Dimethylformamide

NBS：N-溴代丁二酰亚胺(N-Bromosuccinimide)NBS: N-Bromosuccinimide

BPO：过氧化苯甲酰(Benzoyl Peroxide)BPO：Benzoyl Peroxide

NMO：N-甲氧基邻苯二甲酰亚胺(N-Methoxyphthalimide)NMO: N-Methoxyphthalimide

THF：四氢呋喃(Tetrahydrofuran)THF: Tetrahydrofuran

DCM：二氯甲烷(Dichloromethane)DCM: Dichloromethane

Dioxane：1,4-二氧六环(1,4-Dioxane)Dioxane：1,4-Dioxane

Xantphos：2,9-二甲基-4,7-二苯基-1,10-菲咯啉Xantphos: 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline

TLC：薄层色谱TLC: Thin layer chromatography

LC-MS：液质联用色谱LC-MS: Liquid chromatography-mass spectrometry

M：摩尔浓度，例如1M盐酸表示每升溶液中含有1mol的HClM: molar concentration, for example, 1M hydrochloric acid means that there is 1 mol of HCl per liter of solution

N：当量浓度，例如2N盐酸表示2mol/L盐酸溶液N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution

IC50：半数抑制浓度，指达到最大抑制效果一半时的浓度IC50: half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

本领域技术人员应当理解，本发明通过柱拆分得到的同一化合物的不同手性结构以同一化合物的不同后缀P1、P2、P3、P4等进行区分。Those skilled in the art should understand that different chiral structures of the same compound obtained by column separation in the present invention are distinguished by different suffixes P1, P2, P3, P4, etc. of the same compound.

实施例1：目标化合物I-1的制备Example 1: Preparation of target compound I-1

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-1)
2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-1)

目标化合物I-1路线如下所示：
The route of target compound I-1 is as follows:

第一步：N-(叔丁基)-4-氯-3-碘吡啶酰胺的合成
Step 1: Synthesis of N-(tert-butyl)-4-chloro-3-iodopyridineamide

将N-(叔丁基)-4-氯吡啶酰胺(5.00g,23.5mmol)溶于四氢呋喃(50mL)中，于-65℃和氮气保护下，向反应液中加入滴加二异丙基胺锂(2M,15.2mL)，并反应1小时。将碘单质(8.95g,35.2mmol)分批次加入反应液中，反应液在-65℃搅拌1小时。反应完成后,在氮气保护下，将反应液缓慢倒入到零度的饱和氯化铵水溶液(50mL)中淬灭，然后用乙酸乙酯(45mL*3)萃取，有机相用饱和氯化钠溶液(50mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到黄色固体，粗品经柱层析纯化(流动相：石油醚/乙酸乙酯＝100:1/5:1)得到N-(叔丁基)-4-氯-3-碘吡啶酰胺(5.20g，65.3％收率)。Dissolve N-(tert-butyl)-4-chloropicolinamide (5.00 g, 23.5 mmol) in tetrahydrofuran (50 mL). Add lithium diisopropylamine (2 M, 15.2 mL) dropwise to the reaction mixture at -65°C under nitrogen and allow to react for 1 hour. Add iodine (8.95 g, 35.2 mmol) in batches to the reaction mixture, which is then stirred at -65°C for 1 hour. After the reaction was completed, under nitrogen protection, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (50 mL) at zero degree to quench, and then extracted with ethyl acetate (45 mL*3). The organic phase was washed with a saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate, then filtered and concentrated to obtain a yellow solid. The crude product was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:1/5:1) to obtain N-(tert-butyl)-4-chloro-3-iodopicolinamide (5.20 g, 65.3% yield).

LC-MS,M/Z:339.0(M+H⁺)LC-MS, M/Z: 339.0 (M+H ⁺ )

第二步：3-乙酰基-N-(叔丁基)-4-氯吡啶酰胺的合成
Step 2: Synthesis of 3-acetyl-N-(tert-butyl)-4-chloropyridineamide

将N-(叔丁基)-4-氯-3-碘吡啶酰胺(2.00g,5.91mmol)溶于二氧六环(20mL)中，然后加入三丁基(1-乙氧基乙烯)锡(2.24g,6.20mmol,2.10mL)和三苯基膦二氯化钯(414mg,590μmol)，并氮气置换三次。反应液在100℃搅拌12小时。反应完成后，将反应液滴入饱和氟化钾溶液中，搅拌0.5小时。用乙酸乙酯(20mL*3)萃取，有机相用饱和氯化钠溶液(50mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到黄色固体的粗品，粗品溶于四氢呋喃(10mL)，并加入2M盐酸(10mL)，搅拌1小时。水解完全后，用乙酸乙酯(20mL*3)萃取，无水硫酸钠干燥后，过滤浓缩得到粗品，其经柱层析纯化(流动相：石油醚/乙酸乙酯＝100:1/5:1)得到3-乙酰基-N-(叔丁基)-4-氯吡啶酰胺(1.10g，71.1％收率)。Dissolve N-(tert-butyl)-4-chloro-3-iodopicolinamide (2.00 g, 5.91 mmol) in dioxane (20 mL), then add tributyl(1-ethoxyethylene)tin (2.24 g, 6.20 mmol, 2.10 mL) and triphenylphosphine palladium dichloride (414 mg, 590 μmol). The atmosphere is purged with nitrogen three times. The reaction mixture is stirred at 100°C for 12 hours. After completion, the reaction mixture is added dropwise to a saturated potassium fluoride solution and stirred for 0.5 hours. Extraction is performed with ethyl acetate (20 mL x 3). The organic phase is washed with a saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The mixture is filtered and concentrated to yield a crude yellow solid. This crude product is dissolved in tetrahydrofuran (10 mL), 2M hydrochloric acid (10 mL) is added, and the mixture is stirred for 1 hour. After complete hydrolysis, the mixture was extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product, which was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:1/5:1) to give 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (1.10 g, 71.1% yield).

LC-MS,M/Z:255.0(M+H⁺)LC-MS, M/Z: 255.0 (M+H ⁺ )

第三步：(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成
Step 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

将(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(100mg,282μmol)溶于二氯甲烷(2mL)和N,N-二甲基甲酰胺(2.06mg,28.2μmol)中，然后加入草酰氯(71.6mg,564μmol)，并于室温下搅拌0.5小时。将反应液浓缩干后溶于二氯甲烷(2mL)中，在氮气保护下，降温至0℃，再加入氯化铵(30.2mg,564μmol)和三乙胺(85.6mg,846μmol)。反应液在25℃搅拌2小时。反应完成后，使用饱和碳酸氢钠溶液(5mL)淬灭反应液，然后用乙酸乙酯(10mL*3)萃取，有机相用饱和氯化钠溶液(20mL)洗涤和无水硫酸钠干燥后，过滤浓缩得到黄色油状物的粗品，粗品经柱层析纯化(流动相：石油醚/乙酸乙酯＝20:1/1:1)得到(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(97.0mg，97.2％收率)。(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 282 μmol) was dissolved in dichloromethane (2 mL) and N,N-dimethylformamide (2.06 mg, 28.2 μmol). Oxalyl chloride (71.6 mg, 564 μmol) was then added and stirred at room temperature for 0.5 hours. The reaction mixture was concentrated to dryness and dissolved in dichloromethane (2 mL). Under nitrogen, the temperature was lowered to 0°C, followed by the addition of ammonium chloride (30.2 mg, 564 μmol) and triethylamine (85.6 mg, 846 μmol). The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium bicarbonate solution (5 mL), and then extracted with ethyl acetate (10 mL*3). The organic phase was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to give a crude yellow oil. The crude product was purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 20:1/1:1) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (97.0 mg, 97.2% yield).

LC-MS,M/Z:354.0(M+H⁺)LC-MS, M/Z: 354.0 (M+H ⁺ )

第四步：N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 4: Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

将(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(95.0mg,268μmol)溶于甲苯(5mL)中，然后加入双(二亚苄基丙酮)钯(15.4mg,26.8μmol)，磷酸钾(285mg,1.34mmol)和二环己基(2,4,6-三异丙基-[1,1-二联苯]-2-基)膦(30.0mg,62.9μmol),氮气置换三次，反应液在100℃搅拌12小时。反应完成后，将反应液过滤浓缩得到粗品，粗品先经柱层析纯化(流动相：石油醚/乙酸乙酯＝100:1/10:1，Rf＝0.45)得到N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(50.0mg，33.6％收率)。(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (95.0 mg, 268 μmol) was dissolved in toluene (5 mL), and then bis(dibenzylideneacetone)palladium (15.4 mg, 26.8 μmol), potassium phosphate (285 mg, 1.34 mmol) and dicyclohexyl(2,4,6-triisopropyl-[1,1-biphenyl]-2-yl)phosphine (30.0 mg, 62.9 μmol) were added. The atmosphere was replaced with nitrogen three times, and the reaction solution was stirred at 100 ° C for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated to obtain a crude product, which was first purified by column chromatography (mobile phase: petroleum ether/ethyl acetate = 100:1/10:1, Rf = 0.45) to obtain N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (50.0 mg, 33.6% yield).

LC-MS,M/Z:554.2(M+H⁺)LC-MS, M/Z: 554.2 (M+H ⁺ )

第五步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-1)
Step 5: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-1)

将N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(50.0mg,90.3μmol)溶于甲苯(2mL)中，再向其中加入叔丁基二甲硅基三氟甲磺酸酯(477mg,1.81mmol)。氮气保护下，反应液在65℃搅拌12小时。反应完成后，将反应液浓缩得到粗品，粗品经反相高效液相色谱法进行分离纯化(色谱柱:column:Phenomenex luna C18150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:38％-68％,11min)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(15.7mg,34.9％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (50.0 mg, 90.3 μmol) was dissolved in toluene (2 mL), and tert-butyldimethylsilyl trifluoromethanesulfonate (477 mg, 1.81 mmol) was added. The reaction mixture was stirred at 65°C for 12 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was separated and purified by reverse-phase high performance liquid chromatography (chromatographic column: column: Phenomenex luna C18150*25mm*10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 38%-68%, 11min) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (15.7 mg, 34.9% yield).

LC-MS,M/Z:498.3(M+H⁺)LC-MS, M/Z: 498.3 (M+H ⁺ )

¹H NMR(CDCl₃,400MHz)δ15.4(s,1H),8.89-8.92(m,1H),8.58(d,1H,J＝5.6Hz),7.99(br d,1H,J＝5.3Hz),6.82(dd,J＝16.8,8.8Hz,1H),6.10(br s,1H),5.58(d,1H,J＝11.0Hz),4.15(dd,J＝11.0,7.8Hz,1H),3.91(d,3H,J＝2.5Hz),2.80-2.89(m,1H),1.75(s,3H),0.87-0.89(m,3H) ¹ H NMR (CDCl ₃ , 400MHz) δ 15.4 (s, 1H), 8.89-8.92 (m, 1H), 8.58 (d, 1H, J = 5.6Hz), 7.99 (br d, 1H, J = 5.3Hz), 6.82 (dd, J = 16.8, 8.8Hz, 1H), 6.10 (br s,1H),5.58(d,1H,J＝11.0Hz),4.15(dd,J＝11.0,7.8Hz,1H),3.91(d,3H,J＝2.5Hz),2.80-2.89(m,1H),1.75(s,3H),0.87-0.89(m,3H)

实施例2：目标化合物I-4的制备Example 2: Preparation of target compound I-4

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-4)的合成
Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-4)

目标化合物I-4的合成路线如下所示：
The synthetic route of target compound I-4 is as follows:

第一步:N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-碘-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 1: Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-iodo-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

把N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(80.0mg,144μmol)溶解于醋酸(2mL)中，加入N-碘琥珀酰亚胺(29.2mg,130μmol)，反应于55℃搅拌2小时。反应完全后，将反应液倒入碳酸氢钠(20mL)中，调节pH＝7，用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，过滤直接浓缩得到粗品，经薄层色谱(流动相：石油醚/乙酸乙酯＝3/1)得到N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-碘-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(58.0mg,59.0％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (80.0 mg, 144 μmol) was dissolved in acetic acid (2 mL), and N-iodosuccinimide (29.2 mg, 130 μmol) was added. The reaction was stirred at 55 °C for 2 hours. After the reaction was complete, the reaction solution was poured into sodium bicarbonate (20 mL), the pH was adjusted to 7, and the product was extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3/1) gave N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-iodo-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (58.0 mg, 59.0% yield).

LC-MS,M/Z(ESI):680.1(M+H⁺).LC-MS, M/Z (ESI): 680.1 (M+H ⁺ ).

第二步:N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 2: Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

把N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-碘-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(58.0mg,85.4μmol)溶解于二氧六环(2mL)中，加入甲基硼酸(25.5mg,427μmol)，四三苯基膦钯(19.7mg,17.1μmol)和磷酸钾(90.6mg,427μmol)，反应置换三次氮气于110℃搅拌2小时。反应完全后，将反应液直接浓缩得到粗品，经薄层色谱(流动相：石油醚/乙酸乙酯＝3/1)得到N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(20.0mg,41.2％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-iodo-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (58.0 mg, 85.4 μmol) was dissolved in dioxane (2 mL), and methylboric acid (25.5 mg, 427 μmol), tetrakistriphenylphosphine palladium (19.7 mg, 17.1 μmol) and potassium phosphate (90.6 mg, 427 μmol) were added. The reaction was purged with nitrogen three times and stirred at 110°C for 2 hours. After the reaction was completed, the reaction solution was directly concentrated to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3/1) to give N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (20.0 mg, 41.2% yield).

LC-MS,M/Z(ESI):568.2(M+H⁺).LC-MS, M/Z (ESI): 568.2 (M+H ⁺ ).

第三步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-4)的合成
Step 3: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-4)

把N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(20.0mg,35.2μmol)溶解于甲苯(1mL)中，加入叔丁基二甲基硅基三氟甲基磺酸酯(465mg,1.76mmol)，60℃搅拌1小时。反应完全后，将反应液浓缩干，粗品经高效液相色谱制备纯化(柱子:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:35％-65％,9min)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-甲基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(5.44mg,29.4％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (20.0 mg, 35.2 μmol) was dissolved in toluene (1 mL), tert-butyldimethylsilyl trifluoromethylsulfonate (465 mg, 1.76 mmol) was added, and the mixture was stirred at 60°C for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 35%-65%, 9min) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (5.44 mg, 29.4% yield).

LC-MS,M/Z(ESI):512.3(M+H⁺).LC-MS, M/Z (ESI): 512.3 (M+H ⁺ ).

¹H NMR(400MHz,CDCl₃)δ8.85-8.91(m,1H),8.78-8.79(br m,1H),8.50-8.70(m,1H),7.00-7.20(m,1H),6.70-7.00(m,2H),5.85(d,J＝10.4Hz,1H),4.76(br t,J＝11.1Hz,1H),3.91(s,3H),3.10-3.50(m,1H),2.13(br s,3H),1.87(br s,3H),0.92(br d,J＝6.8Hz,3H) ¹ H NMR (400MHz, CDCl ₃ ) δ8.85-8.91(m,1H),8.78-8.79(br m,1H),8.50-8.70(m,1H),7.00-7.20(m,1H),6.70-7.00(m,2H),5.85(d,J＝10.4Hz,1H),4.76(br t,J＝11.1Hz,1H),3.91(s,3H),3.10-3.50(m,1H),2.13(br s,3H),1.87(br s,3H),0.92(br d,J＝6.8Hz,3H)

实施例3：目标化合物I-6的制备Example 3: Preparation of target compound I-6

3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-6)的合成
Synthesis of 3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-6)

目标化合物I-6的合成路线如下所示：
The synthetic route of target compound I-6 is as follows:

第一步:N-(叔丁基)-3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 1: Synthesis of N-(tert-butyl)-3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

把N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(200mg,361μmol)溶解于醋酸(4mL)中，加入N-氯代丁二酰亚胺(43.4mg,325μmol)，反应于50℃搅拌12小时。反应完全后，将反应液倒入碳酸氢钠(50mL)中，调节pH＝7，用乙酸乙酯(10mL*3)萃取，有机相用无水硫酸钠干燥，过滤直接浓缩得到粗品，经薄层色谱(流动相：石油醚/乙酸乙酯＝3/1)得到N-(叔丁基)-3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(60.0mg,28.2％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (200 mg, 361 μmol) was dissolved in acetic acid (4 mL), and N-chlorosuccinimide (43.4 mg, 325 μmol) was added. The reaction was stirred at 50 °C for 12 hours. After the reaction was complete, the reaction solution was poured into sodium bicarbonate (50 mL), the pH was adjusted to 7, and the product was extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. Thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 3/1) gave N-(tert-butyl)-3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60.0 mg, 28.2% yield).

LC-MS,M/Z(ESI):588.1(M+H⁺).LC-MS, M/Z (ESI): 588.1 (M+H ⁺ ).

第二步：3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-6)的合成
Step 2: Synthesis of 3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-6)

把N-(叔丁基)-3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(3)(30.0mg,51.02μmol)溶解于甲苯(1mL)中，加入叔丁基二甲基硅基三氟甲基磺酸酯(1.35g,5.10mmol)，55℃搅拌1小时。反应完全后，将反应液浓缩干，粗品经高效液相色谱制备纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:38％-68％,9min)得到产物3-氯-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(7.80mg,28.3％收率)。N-(tert-Butyl)-3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (3) (30.0 mg, 51.02 μmol) was dissolved in toluene (1 mL), tert-butyldimethylsilyl trifluoromethylsulfonate (1.35 g, 5.10 mmol) was added, and the mixture was stirred at 55°C for 1 hour. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 38%-68%, 9min) to obtain the product 3-chloro-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (7.80 mg, 28.3% yield).

LC-MS,M/Z(ESI):532.2(M+H⁺).LC-MS, M/Z (ESI): 532.2 (M+H ⁺ ).

¹H NMR(400MHz,CDCl₃)δ8.98-9.03(m,1H),8.73-8.76(m,1H),8.28-8.38(m,1H),6.99-7.03(m,1H),6.83(q,J＝8.5Hz,1H),6.41-6.51(m,1H),6.16(d,J＝10.1Hz,1H),4.82(t,J＝9.2Hz,1H),3.95(d,J＝2.0Hz,3H),2.99-3.12(m,1H),1.81(s,3H),0.91(br d,J＝5.9Hz,3H) ¹ H NMR (400MHz, CDCl ₃ )δ8.98-9.03(m,1H),8.73-8.76(m,1H),8.28-8.38(m,1H),6.99-7.03(m,1H),6.83(q,J＝8.5Hz,1H),6.41-6.51(m ,1H),6.16(d,J＝10.1Hz,1H),4.82(t,J＝9.2Hz,1H),3.95(d,J＝2.0Hz,3H),2.99-3.12(m,1H),1.81(s,3H),0.91(br d,J＝5.9Hz,3H)

实施例4：目标化合物I-7的制备Example 4: Preparation of target compound I-7

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-氟-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-7)的合成
Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-fluoro-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-7)

目标化合物I-7合成路线如下所示：
The synthetic route of target compound I-7 is as follows:

第一步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-氟-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-7)的合成
Step 1: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-fluoro-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-7)

把2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(40.0mg,80.4μmol)溶解于N,N二甲基甲酰胺(3mL)中，然后加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(37.0mg,104μmol)，微波反应于140℃搅拌2小时。反应完全后，将反应液经高效液相色谱制备纯化(柱子:Phenomenex luna C18 150*25mm*10um；流动相:溶剂A＝水+0.1％甲酸，B＝乙腈；梯度:42％-72％,9min)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-氟-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(4.98mg,9.61μmol,11.9％收率)。2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (40.0 mg, 80.4 μmol) was dissolved in N,N-dimethylformamide (3 mL), and then 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt (37.0 mg, 104 μmol) was added and the mixture was stirred at 140°C for 2 hours in a microwave oven. After the reaction was completed, the reaction solution was purified by HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 42%-72%, 9min) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-fluoro-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (4.98 mg, 9.61 μmol, 11.9% yield).

LC-MS,M/Z(ESI):516.2(M+H⁺)LC-MS, M/Z (ESI): 516.2 (M+H ⁺ )

¹H NMR(400MHz,CDCl₃)δ15.8(br s,1H),8.89(br s,1H),8.59(d,J＝6.0Hz,1H),8.07(d,J＝5.4Hz,1H),7.00-7.04(m,1H),6.75-6.82(q,J＝8.8Hz,1H),6.18-6.19(m,1H),5.92(d,J＝11.2Hz,1H),4.71-4.76(dd,J＝7.6,11.2Hz,1H),3.97(d,J＝2.4Hz,3H),2.91(br t,J＝7.8Hz,1H),1.76(s,3H),0.91(br dd,3H,J＝1.6,7.4Hz). ¹ H NMR (400MHz, CDCl ₃ ) δ15.8(br s,1H),8.89(br s,1H),8.59(d,J＝6.0Hz,1H),8.07(d,J＝5.4Hz,1H),7.00-7.04(m,1H),6.75-6.82(q,J＝8.8Hz,1H),6.18 -6.19(m,1H),5.92(d,J＝11.2Hz,1H),4.71-4.76(dd,J＝7.6,11.2Hz,1H),3.97(d,J＝2.4Hz,3H),2.91(br t,J＝7.8Hz,1H),1.76(s,3H),0.91(br dd,3H,J＝1.6,7.4Hz).

实施例5：目标化合物I-8的制备Example 5: Preparation of target compound I-8

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(2,3-二羟基丙氧基)-1,6-萘啶-4(1H)-酮(目标化合物I-8)
2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (target compound I-8)

目标化合物I-8的合成路线如下所示：
The synthetic route of target compound I-8 is as follows:

第一步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲基磺酰基)-1,6-萘啶-4(1H)-酮的合成
Step 1: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)-1,6-naphthyridin-4(1H)-one

将2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲硫基)-1,6-萘啶-4(1H)-酮(50.0mg,99.9μmol)溶于二氯甲烷(1mL)中，然后在0℃下，缓慢加入间氯过氧化苯甲酸(44.6mg,219μmol,85％purity)，氮气置换三次后升温至25℃搅拌2小时。反应完成后，在0℃下将反应液倒入饱和亚硫酸钠(30mL)中淬灭，混合液用二氯甲烷(10mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲基磺酰基)-1,6-萘啶-4(1H)-酮(50.0mg,94％收率)2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one (50.0 mg, 99.9 μmol) was dissolved in dichloromethane (1 mL). Then, m-chloroperoxybenzoic acid (44.6 mg, 219 μmol, 85% purity) was slowly added at 0°C. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 25°C, followed by stirring for 2 hours. After completion of the reaction, the reaction solution was poured into saturated sodium sulfite (30 mL) at 0°C to quench the mixture. The mixture was then extracted with dichloromethane (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)-1,6-naphthyridin-4(1H)-one (50.0 mg, 94% yield).

LC-MS,M/Z(ESI):533.1(M+H⁺)。LC-MS, M/Z(ESI): 533.1(M+H ⁺ ).

第二步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)-1,6-萘啶-4(1H)-酮的合成
Step 2: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one

将原料2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲基磺酰基)-1,6-萘啶-4(1H)-酮(50.0mg,93.9μmol)和(2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲醇(24.8mg,187μmol)溶在四氢呋喃(2mL)中，将反应体系用氮气置换三次，在0℃下，缓慢加入氢化钠(7.51mg,187μmol,60％纯度)，然后在0℃下搅拌2小时。反应完毕后加入饱和氯化铵(10mL)淬灭，用乙酸乙酯(5.00mL*3)萃取，饱和氯化钠(10mL)洗涤，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝1:2)，得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)-1,6-萘啶-4(1H)-酮(50.0mg，90.1％收率)。The raw materials 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylsulfonyl)-1,6-naphthyridin-4(1H)-one (50.0 mg, 93.9 μmol) and (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (24.8 mg, 187 μmol) were dissolved in tetrahydrofuran (2 mL). The reaction system was replaced with nitrogen three times. Sodium hydride (7.51 mg, 187 μmol, 60% purity) was slowly added at 0°C, and then stirred at 0°C for 2 hours. After completion of the reaction, saturated ammonium chloride (10 mL) was added to quench the reaction, followed by extraction with ethyl acetate (5.00 mL*3), washed with saturated sodium chloride (10 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to afford 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one (50.0 mg, 90.1% yield).

LC-MS,M/Z(ESI):585.3(M+H⁺)。LC-MS, M/Z(ESI): 585.3(M+H ⁺ ).

第三步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(2,3-二羟基丙氧基)-1,6-萘啶-4(1H)-酮(I-8)的合成
Step 3: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridin-4(1H)-one (I-8)

将2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)-1,6-萘啶-4(1H)-酮(25.0mg,42.8μmol)溶于二氯甲烷(0.5mL)中，然后加入三氟乙酸(0.5mL)，氮气置换三次后升温至25℃搅拌2小时。反应完成后，反应液直接浓缩得到粗品。残留物通过高效液相色谱法进行分离纯化(柱子：Phenomenex luna C18 150*25mm*10μm；溶剂：A＝水+0.05体积甲酸(99％)，B＝乙腈；梯度：37％-67％,10分钟)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(2,3-二羟基丙氧基)-1,6-萘啶-4(1H)-酮(目标化合物I-8)(8.00mg，17％收率)。2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-1,6-naphthyridin-4(1H)-one (25.0 mg, 42.8 μmol) was dissolved in dichloromethane (0.5 mL), followed by the addition of trifluoroacetic acid (0.5 mL). The atmosphere was replaced with nitrogen three times, and the temperature was raised to 25°C and stirred for 2 hours. After completion of the reaction, the reaction solution was directly concentrated to obtain the crude product. The residue was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10μm; solvent: A = water + 0.05 volume of formic acid (99%), B = acetonitrile; gradient: 37%-67%, 10 minutes) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(2,3-dihydroxypropoxy)-1,6-naphthyridine-4(1H)-one (target compound I-8) (8.00 mg, 17% yield).

LC-MS,M/Z(ESI):545.3(M+H⁺).LC-MS, M/Z (ESI): 545.3 (M+H ⁺ ).

¹H NMR(400MHz,CD₃OD)δ8.11(d,J＝6.00Hz,1H),7.19-7.22(m,1H)7.10-7.17(m,1H),6.97-7.04(m,1H),6.22(s,1H),5.44(d,J＝11.10Hz,1H),4.49(d,J＝5.14Hz,2H),4.25(dd,J＝11.00,8.50Hz,1H),4.00-4.08(m,1H),3.96(d,J＝2.50Hz,3H),3.71(d,J＝5.26Hz,2H),2.88(m,1H),1.72(s,3H),0.82-0.94(m,3H). ¹ H NMR (400MHz, CD ₃ OD)δ8.11(d,J＝6.00Hz,1H),7.19-7.22(m,1H)7.10-7.17(m,1H),6.97-7 .04(m,1H),6.22(s,1H),5.44(d,J＝11.10Hz,1H),4.49(d,J＝5.14Hz,2H) ,4.25(dd,J＝11.00,8.50Hz,1H),4.00-4.08(m,1H),3.96(d,J＝2.50Hz,3 H),3.71(d,J＝5.26Hz,2H),2.88(m,1H),1.72(s,3H),0.82-0.94(m,3H).

实施例6：目标化合物I-9的制备Example 6: Preparation of target compound I-9

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺(目标化合物I-9)
2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (target compound I-9)

目标化合物I-9的合成路线如下所示：
The synthetic route of target compound I-9 is as follows:

第一步：2-(苄硫基)-3-溴-4-氯吡啶的合成
Step 1: Synthesis of 2-(benzylthio)-3-bromo-4-chloropyridine

将苄硫醇(3.19g,25.7mmol)溶在四氢呋喃(50mL)中，将反应体系用氮气置换三次，0℃下缓慢加入氢化钠(940mg,23.5mmol,60％purity)，在25℃下搅拌1小时。然后将2-氟-3-溴-4-氯吡啶(4.50g,21.4mmol)的四氢呋喃(50mL)的溶液，在0℃下缓慢滴加至反应液中，最后将反应液在25℃下搅拌2小时。反应完全后，将反应液缓慢加入到饱和的氯化铵溶液(60mL)中淬灭。然后用乙酸乙酯(40mL*3)萃取，饱和氯化钠溶液(60mL)洗涤,合并有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经柱层析(流动相：石油醚：乙酸乙酯＝50:1-10:1，R_fp1＝0.43)得到2-(苄硫基)-3-溴-4-氯吡啶(5.20g，77.0％收率)Dissolve benzyl mercaptan (3.19 g, 25.7 mmol) in tetrahydrofuran (50 mL). The reaction system was purged with nitrogen three times. Sodium hydride (940 mg, 23.5 mmol, 60% purity) was slowly added at 0°C and stirred at 25°C for 1 hour. A solution of 2-fluoro-3-bromo-4-chloropyridine (4.50 g, 21.4 mmol) in tetrahydrofuran (50 mL) was then slowly added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was slowly added to a saturated ammonium chloride solution (60 mL) to quench the reaction. The mixture was then extracted with ethyl acetate (40 mL x 3) and washed with saturated sodium chloride solution (60 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 50:1-10:1, R _fp1 = 0.43) to give 2-(benzylthio)-3-bromo-4-chloropyridine (5.20 g, 77.0% yield)

LC-MS,M/Z(ESI):315.8(M+H⁺)。LC-MS, M/Z(ESI): 315.8(M+H ⁺ ).

第二步：3-溴-4-氯吡啶-2-磺酰氯的合成
Step 2: Synthesis of 3-bromo-4-chloropyridine-2-sulfonyl chloride

将2-(苄硫基)-3-溴-4-氯吡啶(4.00g,12.7mmol)溶在二氯甲烷(75mL)、乙酸(10mL)和水(20mL)中，将反应体系用氮气置换三次，在0℃下，缓慢加入1,3-二氯-5,5-二甲基-咪唑烷-2,4-二酮(7.51g,38.1mmol)，然后在25℃下搅拌12小时。反应完毕后，在0℃下加入饱和碳酸氢钠(60mL)淬灭，用二氯甲烷(50mL*3)萃取，饱和氯化钠溶液(50mL)洗涤，合并的有机相用无水硫酸钠干燥，过滤，低温浓缩(温度不超过30℃)得到粗品3-溴-4-氯吡啶-2-磺酰氯(4.62g，粗品)。粗品直接用于下一步。2-(Benzylthio)-3-bromo-4-chloropyridine (4.00 g, 12.7 mmol) was dissolved in dichloromethane (75 mL), acetic acid (10 mL), and water (20 mL). The reaction system was purged with nitrogen three times. 1,3-Dichloro-5,5-dimethyl-imidazolidine-2,4-dione (7.51 g, 38.1 mmol) was slowly added at 0°C, and the mixture was stirred at 25°C for 12 hours. After completion of the reaction, saturated sodium bicarbonate (60 mL) was added to quench the reaction at 0°C. The mixture was extracted with dichloromethane (50 mL x 3) and washed with saturated sodium chloride solution (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated at low temperature (no higher than 30°C) to afford crude 3-bromo-4-chloropyridine-2-sulfonyl chloride (4.62 g, crude product). The crude product was used directly in the next step.

第三步：3-溴-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺的合成
Step 3: Synthesis of 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide

将3-溴-4-氯吡啶-2-磺酰氯(4.62g,15.9mmol)和N,N-二异丙基乙胺(6.16g,47.6mmol)溶在二氯甲烷(100mL)中，将反应体系用氮气置换三次，在0℃下，分批次加入加入双(4-甲氧基苄基)胺(2.45g,9.53mmol)，然后在25℃下搅拌2小时。反应完全后，将反应液直接浓缩得到粗品。粗品经正相制备进行纯化(柱子：Welch Ultimate XB-CN 250*70mm*10um溶剂：A＝正己烷+0.05％氨水(99％)，B＝乙醇；梯度10-50％,15min)，得到3-溴-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺(2.50g，30.7％收率)。Dissolve 3-bromo-4-chloropyridine-2-sulfonyl chloride (4.62 g, 15.9 mmol) and N,N-diisopropylethylamine (6.16 g, 47.6 mmol) in dichloromethane (100 mL). The reaction system was purged with nitrogen three times. Bis(4-methoxybenzyl)amine (2.45 g, 9.53 mmol) was added portionwise at 0°C, followed by stirring at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain the crude product. The crude product was purified by normal phase preparation (column: Welch Ultimate XB-CN 250*70mm*10um solvent: A = n-hexane + 0.05% ammonia water (99%), B = ethanol; gradient 10-50%, 15min) to obtain 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (2.50g, 30.7% yield).

LC-MS,M/Z(ESI):512.9(M+H⁺)。LC-MS, M/Z(ESI): 512.9(M+H ⁺ ).

第四步：3-乙酰基-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺的合成
Step 4: Synthesis of 3-acetyl-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide

将原料3-溴-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺(1.19g,3.28mmol)溶在二氧六环(20mL)中，将反应体系用氮气置换三次，在25℃下，分别加入二氯双(三苯基膦)钯(383mg,547μmol)和三丁基(1-乙氧基乙烯)锡(1.19g,3.28mmol)，然后在110℃下搅拌12小时。反应完全后直接浓缩得到粗品。将粗品稀释于四氢呋喃(20mL)中，缓慢向其滴加盐酸(1M,8.21mL)，最后在25℃下搅拌12小时。反应完成后，用氢氧化钠溶液(1N)调节反应液pH为12左右，然后用二氯甲烷(20mL*3)萃取，粗品利用柱层析分离纯化(石油醚：乙酸乙酯＝10:1-3:1，R_fp1＝0.43)，得到3-乙酰基-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺(650mg，50％收率)。The starting material, 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (1.19 g, 3.28 mmol), was dissolved in dioxane (20 mL). The reaction system was purged with nitrogen three times. Dichlorobis(triphenylphosphine)palladium (383 mg, 547 μmol) and tributyl(1-ethoxyethylene)tin (1.19 g, 3.28 mmol) were added at 25°C, respectively, and stirred at 110°C for 12 hours. After the reaction was complete, the mixture was concentrated to obtain the crude product. The crude product was diluted in tetrahydrofuran (20 mL), and hydrochloric acid (1 M, 8.21 mL) was slowly added dropwise. Finally, the mixture was stirred at 25°C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to about 12 with sodium hydroxide solution (1N), and then extracted with dichloromethane (20 mL*3). The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1-3:1, R _fp1 =0.43) to obtain 3-acetyl-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (650 mg, 50% yield).

LC-MS,M/Z(ESI):475.2(M+H⁺)。LC-MS, M/Z(ESI): 475.2(M+H ⁺ ).

第五步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-N,N-双(4-甲氧基苄基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺的合成
Step 5: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,N-bis(4-methoxybenzyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide

将原料(2R,3S,4S,5R)-3-(2-环丙基-4-氟苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(400mg,1.13mmol)和3-乙酰基-4-氯-N,N-双(4-甲氧基苄基)吡啶-2-磺酰胺(645mg,1.36mmol)溶在甲苯(6mL)中，将反应体系用氮气置换三次，在25℃下，分别加入2-二环己基磷-2,4,6-三异丙基联苯(215mg,452μmol)，碳酸铯(1.84g,5.66mmol)和双(二亚苄基丙酮)钯(130mg,226μmol)，然后在110℃下搅拌12小时。反应完全后直接浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝1:1，R_fp1＝0.43)，得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-N,N-双(4-甲氧基苄基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺(480mg，55％收率)。The starting materials (2R,3S,4S,5R)-3-(2-cyclopropyl-4-fluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (400 mg, 1.13 mmol) and 3-acetyl-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (645 mg, 1.36 mmol) were dissolved in toluene (6 mL). The reaction system was purged with nitrogen three times. 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (215 mg, 452 μmol), cesium carbonate (1.84 g, 5.66 mmol), and bis(dibenzylideneacetone)palladium (130 mg, 226 μmol) were added at 25°C, followed by stirring at 110°C for 12 hours. After completion of the reaction, the mixture was concentrated to obtain the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=1:1, R _fp1 =0.43) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,N-bis(4-methoxybenzyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (480 mg, 55% yield).

LC-MS,M/Z(ESI):774.0(M+H⁺)。LC-MS, M/Z(ESI):774.0(M+H ⁺ ).

第六步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺(目标化合物(I-9)的合成
Step 6: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (target compound (I-9)

将2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-N,N-双(4-甲氧基苄基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺(200mg,258μmol)溶于二氯甲烷(20mL)和三氟乙酸(3mL)中，氮气置换三次后25℃搅拌12小时。反应完成后，降温至室温后，将反应液直接浓缩(低于30℃)得到粗品。残留物通过高效液相色谱法进行分离纯化(柱子：Phenomenex luna C18 150*25mm*15um；溶剂：A＝水+0.05％三氟乙酸(99％)，B＝乙腈；梯度35-65％,15min)得到白色固体2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-磺酰胺(目标化合物I-9)(12.9mg，9.39％收率)。2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-N,N-bis(4-methoxybenzyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (200 mg, 258 μmol) was dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL). The atmosphere was replaced with nitrogen three times and stirred at 25°C for 12 hours. After the reaction was completed, the temperature was cooled to room temperature and the reaction solution was directly concentrated (below 30°C) to obtain the crude product. The residue was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*15um; solvent: A = water + 0.05% trifluoroacetic acid (99%), B = acetonitrile; gradient 35-65%, 15min) to give a white solid 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-sulfonamide (target compound I-9) (12.9 mg, 9.39% yield).

¹H NMR(400MHz,DMSO-d₆)δ12.11(s,1H),8.54(s,1H),7.52-7.78(m,2H),7.22-7.29(m,1H),7.07-7.17(m,1H),6.51(s,1H),5.37-5.54(m,1H),4.28-4.32(m,1H),3.92(d,J＝1.88Hz,3H),2.99-3.17(m,1H),2.79-2.90(m,1H),1.69(s,3H),0.78(br d,J＝6.75Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ )δ12.11(s,1H),8.54(s,1H),7.52-7.78(m,2H),7.22-7.29(m,1H),7.07-7.17(m,1H),6.51(s,1H),5.37-5.54 (m,1H),4.28-4.32(m,1H),3.92(d,J＝1.88Hz,3H),2.99-3.17(m,1H),2.79-2.90(m,1H),1.69(s,3H),0.78(br d,J＝6.75Hz,3H).

LC-MS,M/Z(ESI):534.2(M+H⁺).LC-MS, M/Z (ESI): 534.2 (M+H ⁺ ).

实施例7：目标化合物I-10的制备Example 7: Preparation of target compound I-10

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(S-甲基磺酰亚胺基)-1,6-萘啶-4(1H)-酮(目标化合物I-10)
2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (target compound I-10)

目标化合物I-10的合成路线如下所示：
The synthetic route of target compound I-10 is as follows:

第一步：3-碘-2-甲硫基吡啶-4-胺的合成
Step 1: Synthesis of 3-iodo-2-methylthiopyridin-4-amine

将原料2-氯-3-碘吡啶-4-胺(20.0g,78.6mmol)溶在四氢呋喃(200mL)中，将反应体系用氮气置换三次，在25℃下，缓慢加入甲硫醇钠(16.5g,235mmol)，然后在75℃下搅拌12小时。反应完毕后加入水(1.00L)淬灭，用乙酸乙酯(300mL*3)萃取，饱和氯化钠溶液(100mL)洗涤，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经柱层析分离纯化(流动相为：石油醚：乙酸乙酯＝10:1-1:1)，得到淡黄色油状化合物3-碘-2-甲硫基吡啶-4-胺(10.0g，收率43％)。The raw material, 2-chloro-3-iodopyridin-4-amine (20.0 g, 78.6 mmol), was dissolved in tetrahydrofuran (200 mL). The reaction system was purged with nitrogen three times. Sodium thiomethoxide (16.5 g, 235 mmol) was slowly added at 25°C, and then stirred at 75°C for 12 hours. After completion, the reaction was quenched with water (1.00 L), extracted with ethyl acetate (300 mL x 3), and washed with saturated sodium chloride solution (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1 to 1:1) to obtain 3-iodo-2-methylthiopyridin-4-amine (10.0 g, 43% yield) as a pale yellow oil.

LC-MS,M/Z(ESI):266.9(M+H⁺)。LC-MS, M/Z(ESI): 266.9(M+H ⁺ ).

¹H NMR(400MHz,DMSO-d₆)δ7.87(d,J＝5.50Hz,1H),6.40(d,J＝5.50Hz,1H),6.15(br s,2H),2.37(s,3H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.87 (d, J = 5.50 Hz, 1H), 6.40 (d, J = 5.50 Hz, 1H), 6.15 (br s, 2H), 2.37 (s, 3H).

第二步：1-(4-氨基-2-(甲硫基)吡啶-3-基)乙烷-1-酮的合成
Step 2: Synthesis of 1-(4-amino-2-(methylthio)pyridin-3-yl)ethan-1-one

将3-碘-2-甲硫基吡啶-4-胺(8.50g,31.9mmol)溶于1,4-二氧六环(80mL)中，分别加入三丁基(1-乙氧基乙烯基)锡烷(12.1g,33.5mmol)和二氯双(三苯基膦)钯(1.12g,1.60mmol)，将反应体系用氮气置换三次，然后在100℃下搅拌12小时。反应完成后，将反应液直接浓缩，然后稀释于四氢呋喃(80mL)，缓慢加入稀盐酸(1M,95.83mL)，然后在25℃下搅拌12小时。反应完全后加入饱和氟化钾(300mL)并室温搅拌12小时，然后用氢氧化钠(1N)调节pH＝10～12，然后用乙酸乙酯(200mL*3)萃取，饱和氯化钠溶液(200mL)洗涤，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝10:1-2:1)，得到1-(4-氨基-2-(甲硫基)吡啶-3-基)乙烷-1-酮(4.00g，68.7％收率)。3-Iodo-2-methylthiopyridin-4-amine (8.50 g, 31.9 mmol) was dissolved in 1,4-dioxane (80 mL), and tributyl(1-ethoxyvinyl)stannane (12.1 g, 33.5 mmol) and dichlorobis(triphenylphosphine)palladium (1.12 g, 1.60 mmol) were added. The reaction system was purged with nitrogen three times and stirred at 100°C for 12 hours. After completion of the reaction, the reaction solution was directly concentrated and then diluted with tetrahydrofuran (80 mL). Dilute hydrochloric acid (1 M, 95.83 mL) was slowly added, and then stirred at 25°C for 12 hours. After the reaction was complete, saturated potassium fluoride (300 mL) was added and stirred at room temperature for 12 hours. The pH was then adjusted to 10-12 with sodium hydroxide (1 N). The mixture was then extracted with ethyl acetate (200 mL x 3) and washed with saturated sodium chloride solution (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1-2:1) to afford 1-(4-amino-2-(methylthio)pyridin-3-yl)ethan-1-one (4.00 g, 68.7% yield).

LC-MS,M/Z(ESI):183.2(M+H⁺)。LC-MS, M/Z(ESI): 183.2(M+H ⁺ ).

第三步：(2R,3S,4S,5R)-N-(3-乙酰基-2-(甲硫基)吡啶-4-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成
Step 3: Synthesis of (2R,3S,4S,5R)-N-(3-acetyl-2-(methylthio)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

将原料(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(1)(1.30g,3.67mmol)和N,N-二甲基甲酰胺(536mg,7.34mmol)溶在二氯甲烷(15mL)中，将反应体系用氮气置换三次，在0℃下，缓慢加入草酰氯(931mg,7.34mmol)，然后在25℃下搅拌2小时。反应完毕后直接浓缩得到粗品。粗品稀释于二氯甲烷(20mL)中，在0℃下，缓慢滴加至1-(4-氨基-2-(甲硫基)吡啶-3-基)乙烷-1-酮(600mg,3.29mmol)和三乙胺(666mg,6.58mmol)的二氯甲烷(20mL)中，然后在25℃下搅拌2小时。反应完全后，将反应液直接浓缩，得到淡黄色油状的粗品。粗品经柱层析(流动相：石油醚：乙酸乙酯＝20:1-5:1)得到(2R,3S,4S,5R)-N-(3-乙酰基-2-(甲硫基)吡啶-4-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(1.00g，58.6％收率)。The raw material (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1) (1.30 g, 3.67 mmol) and N,N-dimethylformamide (536 mg, 7.34 mmol) were dissolved in dichloromethane (15 mL). The reaction system was purged with nitrogen three times. Oxalyl chloride (931 mg, 7.34 mmol) was slowly added at 0°C, and then stirred at 25°C for 2 hours. After completion of the reaction, the mixture was directly concentrated to obtain a crude product. The crude product was diluted in dichloromethane (20 mL) and slowly added dropwise to a solution of 1-(4-amino-2-(methylthio)pyridin-3-yl)ethan-1-one (600 mg, 3.29 mmol) and triethylamine (666 mg, 6.58 mmol) in dichloromethane (20 mL) at 0°C. The mixture was then stirred at 25°C for 2 hours. After the reaction was complete, the reaction solution was concentrated to yield the crude product as a pale yellow oil. The crude product was purified by column chromatography (mobile phase: petroleum ether:ethyl acetate = 20:1-5:1) to afford (2R,3S,4S,5R)-N-(3-acetyl-2-(methylthio)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (1.00 g, 58.6% yield).

LC-MS,M/Z(ESI):519.1(M+H⁺)。LC-MS, M/Z(ESI): 519.1(M+H ⁺ ).

第四步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲硫基)-1,6-萘啶-4(1H)-酮的合成
Step 4: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one

将原料(2R,3S,4S,5R)-N-(3-乙酰基-2-(甲硫基)吡啶-4-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(1.00g,1.93mmol)溶在1,4-二氧六环(10mL)中，将反应体系用氮气置换三次，缓慢加入氢氧化钠(385mg,9.64mmol,)然后在100℃下搅拌2小时。反应完毕后加入稀盐酸(1N),调节pH＝2～3，然后用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品4-(苄氧基)-2-(4-(叔丁基)-5-氯-2-甲基苯基)-5-(2-((四氢-2H-吡喃-2-基)氧基)乙氧基)-1,6-萘啶(800mg，83.0％收率)。The raw material (2R,3S,4S,5R)-N-(3-acetyl-2-(methylthio)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (1.00 g, 1.93 mmol) was dissolved in 1,4-dioxane (10 mL), the reaction system was replaced with nitrogen three times, sodium hydroxide (385 mg, 9.64 mmol) was slowly added, and then stirred at 100 ° C for 2 hours. After the reaction was completed, dilute hydrochloric acid (1N) was added to adjust the pH to 2-3, and then extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product of 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1,6-naphthyridine (800 mg, 83.0% yield).

LC-MS,M/Z(ESI):501.1(M+H⁺)。LC-MS, M/Z(ESI): 501.1(M+H ⁺ ).

第五步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(S-甲基磺酰亚胺基)-1,6-萘啶-4(1H)-酮(I-10)的合成
Step 5: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (I-10)

将2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲硫基)-1,6-萘啶-4(1H)-酮(25.0mg,44.5μmol)溶于二氯甲烷(0.5mL)和无水甲醇(0.5mL)中，在0℃下，分别加入醋酸碘苯(25.4mg,222μmol)和碳酸胺(25.4mg,222μmol)，氮气置换三次后升温至25℃搅拌2小时。反应完成后，反应液直接浓缩得到粗品。粗品经高效液相色谱法进行分离纯化(柱子：Waters Xbridge 150*25mm*5μm；溶剂：A＝水+0.05体积碳酸铵(99％)，B＝乙腈；梯度：30％-60％,15分钟)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(S-甲基磺酰亚胺基)-1,6-萘啶-4(1H)-酮(目标化合物I-10)(4.00mg，9.0％收率)。2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one (25.0 mg, 44.5 μmol) was dissolved in dichloromethane (0.5 mL) and anhydrous methanol (0.5 mL). Iodobenzene acetate (25.4 mg, 222 μmol) and ammonium carbonate (25.4 mg, 222 μmol) were added at 0°C. The atmosphere was replaced with nitrogen three times, then the temperature was raised to 25°C and stirred for 2 hours. After completion of the reaction, the reaction solution was directly concentrated to obtain the crude product. The crude product was separated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; solvent: A = water + 0.05 volume of ammonium carbonate (99%), B = acetonitrile; gradient: 30%-60%, 15 minutes) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(S-methylsulfonylimino)-1,6-naphthyridin-4(1H)-one (target compound I-10) (4.00 mg, 9.0% yield).

LC-MS,M/Z(ESI):532.1(M+H⁺).LC-MS, M/Z (ESI): 532.1 (M+H ⁺ ).

¹H NMR(400MHz,MeOD)δ8.55(d,J＝5.76Hz,1H),7.84(t,J＝6.20Hz,1H),7.12-7.24(m,1H),6.97-7.04(m,1H),6.39(d,J＝8.00Hz,1H),5.51-5.54(m,1H),4.20-4.32(m,1H),3.96(t,J＝2.94Hz,3H),3.42(s,4H),2.84-2.95(m,1H),1.73(s,3H),0.91(br d,J＝6.88Hz,3H). ^1H NMR (400MHz, MeOD) δ8.55(d,J＝5.76Hz,1H),7.84(t,J＝6.20Hz,1H),7.12-7.24(m,1H),6.97-7.04(m,1H),6.39(d,J＝8.00H z,1H),5.51-5.54(m,1H),4.20-4.32(m,1H),3.96(t,J＝2.94Hz,3H),3.42(s,4H),2.84-2.95(m,1H),1.73(s,3H),0.91(br d,J＝6.88Hz,3H).

实施例8：目标化合物I-14和I-14A的制备Example 8: Preparation of target compounds I-14 and I-14A

4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(I-14)
4-Oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-14)

4-氧代-2-((2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(I-14A)
4-Oxo-2-((2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-14A)

目标化合物I-14和I-14A的合成路线如下图所示:
The synthetic routes of target compounds I-14 and I-14A are shown below:

第一步：(4S,5R)-3,4,5-三甲基-5-(三氟甲基)二氢呋喃-2(3H)-酮的合成Step 1: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

在氮气保护，-78℃条件下，向(4S,5R)-4,5-二甲基-5-三氟甲基二氢呋喃-2(3H)-酮(800mg,4.3mmol)的无水四氢呋喃(20mL)溶液中滴加二异丙基氨基锂的四氢呋喃溶液(2.0M，2.6mL)。在-78℃反应30分钟后，向反应液中加入碘甲烷(738mg，5.2mmol)，并在-78℃条件下反应1小时，然后加入饱和氯化铵水溶液淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得到(4S,5R)-3,4,5-三甲基-5-(三氟甲基)二氢呋喃-2(3H)-酮(650mg，收率：77％)。To a solution of (4S,5R)-4,5-dimethyl-5-trifluoromethyldihydrofuran-2(3H)-one (800 mg, 4.3 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran (2.6 mL) under nitrogen at -78°C. After reacting at -78°C for 30 minutes, iodomethane (738 mg, 5.2 mmol) was added and the reaction mixture was allowed to react at -78°C for 1 hour. The reaction was then quenched by addition of saturated aqueous ammonium chloride. The organic phase was extracted with ethyl acetate, concentrated to dryness, and then purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:1) to afford (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (650 mg, yield: 77%).

¹H NMR(400MHz,CDCl₃)δ2.56–2.46(m,1H),2.10–2.0(m,1H),1.59–1.57(m,3H),1.25–1.23(m,6H)ppm ¹ H NMR (400MHz, CDCl ₃ ) δ2.56–2.46(m,1H),2.10–2.0(m,1H),1.59–1.57(m,3H),1.25–1.23(m,6H)ppm

第二步：(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-醇的合成Step 2: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

在氮气保护，-30℃条件下，向(4S,5R)-3,4,5-三甲基-5-(三氟甲基)二氢呋喃-2(3H)-酮(650mg，3.3mmol)的无水甲苯溶液(20mL)中加入二异丁基氢化铝的正己烷溶液(1.0M，6.6mL)，并在-30℃条件下反应2小时。将反应液温度升至0℃，分批次缓慢加入酒石酸钾钠四水合物(1g)，然后在室温条件下搅拌1小时，加水(20mL)，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得到(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-醇(400mg，收率：61％)。直接进行下一步反应。Under nitrogen, a solution of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (650 mg, 3.3 mmol) in anhydrous toluene (20 mL) was added with a 1.0 M solution of diisobutylaluminum hydride in n-hexane (6.6 mL) and allowed to react at -30°C for 2 hours. The reaction mixture was then heated to 0°C, and potassium sodium tartrate tetrahydrate (1 g) was slowly added portionwise. The mixture was stirred at room temperature for 1 hour, and water (20 mL) was added. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to dryness and then purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (400 mg, yield: 61%). This was directly carried out to the next step.

第三步：(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯的合成Step 3: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

在氮气保护，室温条件下，向(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-醇(400mg，2mmol)和4-二甲氨基吡啶(24mg，0.2mmol)的无水甲苯(10mL)溶液中加入无水乙酸酐(224mg，2.2mmol)和三乙胺(223mg，2.2mmol)。然后在室温条件下反应5小时，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得到(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯(410mg，收率：85％)。直接进行下一步反应。To a solution of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (400 mg, 2 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) in anhydrous toluene (10 mL) under nitrogen at room temperature were added anhydrous acetic anhydride (224 mg, 2.2 mmol) and triethylamine (223 mg, 2.2 mmol). The mixture was then allowed to react at room temperature for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 10:1) to obtain (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (410 mg, yield: 85%). The product was directly carried out to the next step.

第四步：(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈和(2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈的合成Step 4: Synthesis of (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile and (2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

在氮气保护，-30℃条件下，向(4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯(410mg，1.7mmol)的无水甲苯(9mL)溶液中依次加入三氟化硼乙醚(242mg,1.7mmol)和三甲基氰硅烷(239mg，2.4mmol)，然后在-20℃反应3小时，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得到(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈(200mg，收率：57％)和(2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈(60mg，收率：17％)。Under nitrogen protection, to a solution of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (410 mg, 1.7 mmol) in anhydrous toluene (9 mL) were added boron trifluoride etherate (242 mg, 1.7 mmol) and trimethylsilyl cyanide (239 mg, 2.4 mmol) in sequence at -30°C, and then reacted at -20°C for 3 hours. The reaction was quenched by adding water and ethyl acetate was added. The organic phase was extracted with ester, concentrated to dryness and mixed, and separated and purified by silica gel column (mobile phase: petroleum ether: ethyl acetate = 10:1) to give (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (200 mg, yield: 57%) and (2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (60 mg, yield: 17%).

(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈：(2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile:

¹H NMR(400MHz,CDCl₃)δ4.23(d,J＝9.6Hz,1H),2.58–2.45(m,1H),1.81–1.70(m,1H),1.42(s,3H),1.19–1.15(m,6H)ppm ¹ H NMR (400MHz, CDCl ₃ ) δ4.23(d,J＝9.6Hz,1H),2.58–2.45(m,1H),1.81–1.70(m,1H),1.42(s,3H),1.19–1.15(m,6H)ppm

(2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈：(2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile:

¹H NMR(400MHz,CDCl₃)δ4.84(d,J＝7.7Hz,1H),2.49–2.36(m,1H),2.03–1.93(m,1H),1.52(s,3H),1.22–1.19(m,3H),1.18–1.14(m,1H)ppm ¹ H NMR (400MHz, CDCl ₃ ) δ4.84(d,J＝7.7Hz,1H),2.49–2.36(m,1H),2.03–1.93(m,1H),1.52(s,3H),1.22–1.19(m,3H),1.18–1.14(m,1H)ppm

第五步：(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成Step 5: Synthesis of (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

在氮气保护条件下，向(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈(200mg，0.97mmol)和氢氧化钾(55mg，0.97mmol)的乙醇(4mL)溶液中加入30％的过氧化氢(1mL)，然后在55℃条件下反应1小时。加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝4：1)，得到(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(160mg，收率：73％)。Under nitrogen, 30% hydrogen peroxide (1 mL) was added to a solution of (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (200 mg, 0.97 mmol) and potassium hydroxide (55 mg, 0.97 mmol) in ethanol (4 mL). The mixture was then reacted at 55°C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 4:1) to obtain (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (160 mg, yield: 73%).

¹H NMR(400MHz,CDCl₃)δ6.44(brs,1H),5.37(brs,1H),3.99(d,J＝9.6Hz,1H),2.18–2.04(m,1H),1.85–1.74(m,1H),1.43(s,3H),1.23(d,J＝6.4Hz,3H),1.15–1.09(m,3H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ6.44(brs,1H),5.37(brs,1H),3.99(d,J＝9.6Hz,1H),2.18–2.04(m,1H), 1.85–1.74(m,1H),1.43(s,3H),1.23(d,J＝6.4Hz,3H),1.15–1.09(m,3H)ppm

第六步：N-(叔丁基)-4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺的合成Step 6: Synthesis of N-(tert-butyl)-4-oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide

在氮气保护条件下，向(2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(90mg，0.43mmol)、3-乙酰基-N-(叔丁基)-4-氯吡啶酰胺(109mg，0.43mmol)、碳酸铯(420mg，1.29mmol)、Pd(dba)₂(24mg，0.043mmol)和Xphos(41mg，0.086mmol)的混合物中加入无水甲苯(3mL)，然后在100℃反应16小时。待反应液冷却至室温后过滤除去无机盐，滤液浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：3)得到N-(叔丁基)-4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(60mg，收率：33％)。Under nitrogen protection, to a mixture of (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (90 mg, 0.43 mmol), 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (109 mg, 0.43 mmol), cesium carbonate (420 mg, 1.29 mmol), Pd(dba) ₂ (24 mg, 0.043 mmol) and Xphos (41 mg, 0.086 mmol) was added anhydrous toluene (3 mL), and the mixture was reacted at 100°C for 16 hours. After the reaction solution was cooled to room temperature, the inorganic salts were removed by filtration. The filtrate was concentrated to dryness and then mixed. The product was separated and purified by silica gel column (mobile phase: petroleum ether:ethyl acetate = 10:3) to give N-(tert-butyl)-4-oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, yield: 33%).

LC-MS,M/Z(ESI):426.19[M+H]⁺ LC-MS, M/Z(ESI):426.19[M+H] ⁺

第七步：4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(I-14)的合成Step 7: Synthesis of 4-oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-14)

在氮气保护条件下，向N-(叔丁基)-4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(60mg，0.14mmol)的无水甲苯(2mL)溶液中加入叔丁基二甲硅基三氟甲磺酸酯(932mg,3.53mmol)，然后在65℃反应16小时。待反应液冷却至室温后，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得到4-氧代-2-((2R,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(I-14)(20mg，收率：39％)。Under nitrogen protection, to a solution of N-(tert-butyl)-4-oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60 mg, 0.14 mmol) in anhydrous toluene (2 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (932 mg, 3.53 mmol), and then reacted at 65 ° C for 16 hours. After the reaction solution was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness and then mixed. The mixture was separated and purified by silica gel column (mobile phase: petroleum ether: ethyl acetate = 1:5) to obtain 4-oxo-2-((2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-14) (20 mg, yield: 39%).

LC-MS,M/Z(ESI):370.13[M+H]⁺ LC-MS, M/Z(ESI):370.13[M+H] ⁺

¹H NMR(400MHz,CDCl₃)δ8.93(brs,1H),8.58(d,J＝5.6Hz,1H),8.03(d,J＝5.6Hz,1H),7.29(s,1H),6.18(brs,1H),4.68(d,J＝9.9Hz,1H),2.14–2.02(m,1H),2.01–1.89(m,1H),1.52(s,3H),1.20–1.14(m,6H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ8.93(brs,1H),8.58(d,J＝5.6Hz,1H),8.03(d,J＝5.6Hz,1H),7.29(s,1H),6.18(brs,1H),4 .68(d,J＝9.9Hz,1H),2.14–2.02(m,1H),2.01–1.89(m,1H),1.52(s,3H),1.20–1.14(m,6H)ppm

4-氧代-2-((2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-基)-1,4-二氢-1,6-萘啶-5-甲酰胺(I-14A)的合成
Synthesis of 4-oxo-2-((2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-14A)

I-14A的合成以(2S,3R,4S,5R)-3,4,5-三甲基-5-(三氟甲基)四氢呋喃-2-腈(60mg)为原料，参考I-14的合成步骤五、六和七，最终得到I-14A(10mg)。The synthesis of I-14A was carried out using (2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (60 mg) as the starting material, and referring to the synthesis steps five, six and seven of I-14, I-14A (10 mg) was finally obtained.

LC-MS,M/Z(ESI):370.13[M+H]⁺ LC-MS, M/Z(ESI):370.13[M+H] ⁺

¹H NMR(400MHz,CDCl₃)δ8.95(brs,1H),8.59(d,J＝5.6Hz,1H),8.04(d,J＝5.6Hz,1H),7.07(s,1H),6.19(brs,1H),5.38(d,J＝9.5Hz,1H),2.77–2.64(m,1H),2.07–1.96(m,1H),1.70(s,3H),1.18–1.13(m,3H)，0.61(d,J＝6.9Hz,3H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ8.95(brs,1H),8.59(d,J＝5.6Hz,1H),8.04(d,J＝5.6Hz,1H),7.07(s,1H),6.19(brs,1H),5.38(d,J＝9. 5Hz,1H),2.77–2.64(m,1H),2.07–1.96(m,1H),1.70(s,3H),1.18–1.13(m,3H),0.61(d,J＝6.9Hz,3H)ppm

实施例9：目标化合物I-15的制备Example 9: Preparation of target compound I-15

目标化合物I-15的合成路线如下所示：

The synthetic route of target compound I-15 is as follows:

第一步：3-环丙基-4,5-二甲基-5-(三氟甲基)-4,5-二氢呋喃-2-甲酸乙酯的合成
Step 1: Synthesis of ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

将原料4,5-二甲基-5-(三氟甲基)-3-(((三氟甲基)磺酰基)氧基)-4,5-二氢呋喃-2-甲酸乙酯(6.00g,16.1mmol)和环丙基硼酸(4.15g,48.3mmol)溶于甲苯(30mL)中，再加入磷酸钾(10.2g,48.3mmol)，水(4mL)和四三苯基膦钯(250mg,216umol)。将反应体系用氮气置换三次，并在100℃下搅拌1小时。反应完毕后加入水(10mL)，用乙酸乙酯(15mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝10:1,Rfp1＝0.4)得到3-环丙基-4,5-二甲基-5-(三氟甲基)-4,5-二氢呋喃-2-甲酸乙酯(3.5g,收率82.1％)。Dissolve the starting materials, ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (6.00 g, 16.1 mmol) and cyclopropylboronic acid (4.15 g, 48.3 mmol) in toluene (30 mL). Add potassium phosphate (10.2 g, 48.3 mmol), water (4 mL), and tetrakistriphenylphosphine palladium (250 mg, 216 μmol). The reaction system was purged with nitrogen three times and stirred at 100°C for 1 hour. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=10:1, Rfp1=0.4) to give ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.5 g, yield 82.1%).

LC-MS,M/Z(ESI):279.1(M+H⁺)。LC-MS, M/Z(ESI): 279.1(M+H ⁺ ).

第二步：3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酸乙酯的合成
Step 2: Synthesis of ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

将3-环丙基-4,5-二甲基-5-(三氟甲基)-4,5-二氢呋喃-2-甲酸乙酯(1.00g,3.78mmol)溶于无水乙醇(10mL)中，在氩气保护下加入钯碳(402mg,10％含量)，氢气置换三次后，于25℃，压力20Psi下搅拌12小时。反应完成后，直接过滤浓缩得到3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酸乙酯(950mg,粗品)。直接用于下一步。Dissolve ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (1.00 g, 3.78 mmol) in anhydrous ethanol (10 mL). Add palladium on carbon (402 mg, 10% content) under argon protection. After replacing the atmosphere with hydrogen three times, stir at 25°C and 20 psi for 12 hours. After completion of the reaction, filter and concentrate to obtain ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (950 mg, crude product). Use directly in the next step.

LC-MS,M/Z(ESI):281.0(M+H⁺).LC-MS, M/Z (ESI): 281.0 (M+H ⁺ ).

第三步：3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸的合成
Step 3: Synthesis of 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

将3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酸乙酯(0.95g,3.57mmol)溶于无水四氢呋喃(10mL)中，于0℃氮气保护下，加入叔丁醇钾(800.74mg,7.14mmol)，升温至10℃搅拌0.5小时。反应完成后，向反应液中加入水1mL，在25℃下，搅拌1小时。将反应液倒入1N盐酸(10mL)中，混合液用乙酸乙酯(10mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(850mg,粗品)。直接用于下一步。Dissolve ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.95 g, 3.57 mmol) in anhydrous tetrahydrofuran (10 mL). Add potassium tert-butoxide (800.74 mg, 7.14 mmol) at 0°C under nitrogen, and stir at 10°C for 0.5 hours. After the reaction is complete, add 1 mL of water to the reaction mixture, and stir at 25°C for 1 hour. Pour the reaction mixture into 1N hydrochloric acid (10 mL), and extract the mixture with ethyl acetate (10 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (850 mg, crude). Use directly in the next step.

LC-MS,M/Z(ESI):251.1(M-H⁺).LC-MS, M/Z (ESI): 251.1 (MH ⁺ ).

第四步：3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成
Step 4: Synthesis of 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

将3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(520mg,2.06mmol)溶于无水四氢呋喃(5mL)中，然后加入羰基二咪唑(668.58mg,4.12mmol)，氮气置换三次后升温至25℃搅拌1小时。将氨水(1.20g,10.31mmol,1.32mL,30％含量)加入到反应液中，搅拌0.5小时，反应完成后，用乙酸乙酯(10mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得到3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(420mg,81.09％收率)。3-Cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (520 mg, 2.06 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), followed by the addition of carbonyldiimidazole (668.58 mg, 4.12 mmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 25°C and stirred for 1 hour. Aqueous ammonia (1.20 g, 10.31 mmol, 1.32 mL, 30% content) was added to the reaction mixture, and the mixture was stirred for 0.5 hour. After completion of the reaction, the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (420 mg, 81.09% yield).

LC-MS,M/Z(ESI):252.0(M+H⁺).LC-MS, M/Z (ESI): 252.0 (M+H ⁺ ).

第五步：N-(叔丁基)-2-((2R,3R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 5: Synthesis of N-(tert-butyl)-2-((2R,3R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

将3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(370mg,1.47mmol)和3-乙酰基-N-叔丁基-4-氯-吡啶-2-甲酰胺(498mg,1.96mmol)溶于无水甲苯(10mL)中，然后加入碳酸铯(2.40g,7.36mmol)，2-二环己基磷-2,4,6-三异丙基联苯(140mg,294μmol)和双(二亚苄基丙酮)钯(84.6mg,147μmol)，氮气置换三次后升温至110℃搅拌12小时。将反应液浓缩得到粗品，粗品经柱层析(流动相：石油醚：乙酸乙酯＝20:1-3:1，Rfp1＝0.35)得到N-(叔丁基)-2-((2R,3R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(150mg,22.5％收率)。3-Cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (370 mg, 1.47 mmol) and 3-acetyl-N-tert-butyl-4-chloro-pyridine-2-carboxamide (498 mg, 1.96 mmol) were dissolved in anhydrous toluene (10 mL), and then cesium carbonate (2.40 g, 7.36 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (140 mg, 294 μmol) and bis(dibenzylideneacetone)palladium (84.6 mg, 147 μmol) were added. After nitrogen replacement three times, the temperature was raised to 110 ° C and stirred for 12 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1-3:1, Rfp1 = 0.35) to give N-(tert-butyl)-2-((2R,3R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (150 mg, 22.5% yield).

LC-MS,M/Z(ESI):452.3(M+H⁺).LC-MS, M/Z (ESI): 452.3 (M+H ⁺ ).

第六步：2-((2R,3R,4S,5R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(目标化合物I-15P1/P2/P3/P4)
Step 6: 2-((2R,3R,4S,5R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-15P1/P2/P3/P4)

将N-(叔丁基)-2-((2R,3R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(5)(100mg,221μmol)溶于无水甲苯(3mL)中，然后加入叔丁基二甲基硅基三氟甲基磺酸酯(1.17g,4.43mmol,1.02mL)，氮气置换三次后升温至65℃搅拌12小时。反应完成后，将反应浓缩得到粗品。其通过高效液相色谱法进行分离纯化(柱子：Phenomenex luna C18 150*25mm*10um；溶剂：A＝水+0.2％甲酸，B＝乙腈；梯度：26％-56％,20分钟)后再经过超临界流体色谱分离(色谱柱:Chiralpak AD-3 50*4.6mm I.D.,3um；流动相A:[超临界流体二氧化碳]；流动相B：甲醇(0.05％二乙胺)，梯度洗脱:含有甲醇(0.05％二乙胺)的超临界流体二氧化碳，其比例由从5％到40％；流速：3mL/min；检测器：PDA；柱温：35℃；柱压：100bar)分别得到2-((2R,3R,4S,5R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(目标化合物I-15P1)(4.90mg，5.30％收率)和2-((2S,3S,4R,5S)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(目标化合物I-15P2)(4.52mg，5.02％收率)和2-((2R,3R,4R,5R)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(目标化合物I-15P3)(6.66mg，7.57％收率)和2-((2S,3S,4S,5S)-3-环丙基-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(目标化合物I-15P4)(7.25mg，8.01％收率)。N-(tert-butyl)-2-((2R,3R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (5) (100 mg, 221 μmol) was dissolved in anhydrous toluene (3 mL), and then tert-butyldimethylsilyl trifluoromethylsulfonate (1.17 g, 4.43 mmol, 1.02 mL) was added. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 65°C and stirred for 12 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product. The product was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10um; solvent: A = water + 0.2% formic acid, B = acetonitrile; gradient: 26%-56%, 20 minutes) and then separated by supercritical fluid chromatography (chromatographic column: Chiralpak AD-3 50*4.6mm I.D., 3um; mobile phase A: [supercritical fluid carbon dioxide]; mobile phase B: methanol (0. 05% diethylamine), gradient elution: supercritical fluid carbon dioxide containing methanol (0.05% diethylamine), the ratio of which was from 5% to 40%; flow rate: 3 mL/min; detector: PDA; column temperature: 35°C; column pressure: 100 bar) to obtain 2-((2R,3R,4S,5R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound) Compound I-15P1) (4.90 mg, 5.30% yield) and 2-((2S,3S,4R,5S)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-15P2) (4.52 mg, 5.02% yield) and 2-((2R,3R,4R,5R)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide )tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-15P3) (6.66 mg, 7.57% yield) and 2-((2S,3S,4S,5S)-3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-15P4) (7.25 mg, 8.01% yield).

LC-MS,M/Z(ESI):396.1(M+H⁺).LC-MS, M/Z (ESI): 396.1 (M+H ⁺ ).

I-15P1I-15P1

¹H NMR(400MHz,MeOD)δ8.51-8.72(m,1H),7.70(br d,1H,J＝3.6Hz),6.40-6.52(m,1H),5.51-5.72(m,1H),5.33-5.50(m,1H),2.51-2.53(m,1H),1.72-1.81(m,3H),1.47(s,3H),1.32-1.44(m,1H),1.31-1.34(m,1H),1.08(d,3H,J＝6.1Hz) ^1H NMR(400MHz,MeOD)δ8.51-8.72(m,1H),7.70(br d,1H,J＝3.6Hz),6.40-6.52(m,1H),5.51-5.72(m,1H),5.33-5.50(m,1H),2.51-2.53(m,1H) ,1.72-1.81(m,3H),1.47(s,3H),1.32-1.44(m,1H),1.31-1.34(m,1H),1.08(d,3H,J＝6.1Hz)

I-15P2I-15P2

¹H NMR(400MHz,MeOD)δ8.44(br d,1H,J＝2.9Hz),7.58(br s,1H),6.29(s,1H),5.41-5.63(m,1H),5.22-5.43(m,1H),2.42-2.45(m,1H),1.61-1.73(m,3H),1.37(s,3H),1.21-1.33(m,2H),0.98(d,3H,J＝6.1Hz) ¹ H NMR (400MHz, MeOD) δ8.44 (br d, 1H, J = 2.9Hz), 7.58 (br s,1H),6.29(s,1H),5.41-5.63(m,1H),5.22-5.43(m,1H),2.42-2.45(m,1H ),1.61-1.73(m,3H),1.37(s,3H),1.21-1.33(m,2H),0.98(d,3H,J＝6.1Hz)

I-15P3I-15P3

¹H NMR(400MHz,MeOD)δ8.52(d,1H,J＝6.0Hz),7.65(d,1H,J＝6.0Hz),6.32-6.51(m,1H),5.51-5.63(m,2H),4.57(br s,1H),3.10-3.21(m,1H),2.51-2.72(m,1H),1.73-1.74(m,3H),1.62(s,3H),1.33(br s,1H),1.13-1.21(m,3H),0.93 -1.04(m,1H) ¹ H NMR (400MHz, MeOD) δ8.52 (d, 1H, J = 6.0Hz), 7.65 (d, 1H, J = 6.0Hz), 6.32-6.51 (m, 1H), 5.51-5.63 (m, 2H), 4.57 (br s,1H),3.10-3.21(m,1H),2.51-2.72(m,1H),1.73-1.74(m,3H),1.62(s,3H),1.33(br s,1H),1.13-1.21(m,3H),0.93 -1.04(m,1H)

I-15P4I-15P4

¹H NMR(400MHz,MeOD)δ8.52(d,1H,J＝6.0Hz),7.65(d,1H,J＝5.9Hz),6.36(br s,1H),5.52-5.71(m,1H),5.34 -5.51(m,1H),4.62-4.73(m,1H),2.41-2.63(m,2H),1.72-1.84(m,3H),1.46(s,3H),1.31-1.42(m,1H),1.08(d,3H,J＝6.1Hz),0.85-1.03(m,1H) ¹ H NMR (400MHz, MeOD) δ8.52 (d, 1H, J = 6.0Hz), 7.65 (d, 1H, J = 5.9Hz), 6.36 (br s, 1H), 5.52-5.71 (m, 1H), 5.34 -5.51(m,1H),4.62-4.73(m,1H),2.41-2.63(m,2H),1.72-1.84(m,3H), 1.46(s,3H),1.31-1.42(m,1H),1.08(d,3H,J=6.1Hz),0.85-1.03(m,1H)

实施例10：目标化合物I-16的制备Example 10: Preparation of target compound I-16

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-羟基-1,6-萘啶-4(1H)-酮(目标化合物I-16)
2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,6-naphthyridin-4(1H)-one (target compound I-16)

目标化合物I-16的合成路线如下所示：
The synthetic route of target compound I-16 is as follows:

第一步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-羟基-1,6-萘啶-4(1H)-酮(I-16)的合成
Step 1: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-hydroxy-1,6-naphthyridin-4(1H)-one (I-16)

将2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-5-(甲硫基)-1,6-萘啶-4(1H)-酮(600mg,1.20mmol)溶于二氯甲烷(12mL)中，然后加入间氯过氧化苯甲酸(498mg,2.46mmol,85％纯度)，氮气置换三次后升温至25℃搅拌12小时。反应完成后，在0℃下将反应液倒入饱和亚硫酸钠(30mL)中淬灭，混合液用二氯甲烷(30mL*3)萃取。合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。残留物通过高效液相色谱法进行分离纯化(柱子：Phenomenex luna C18 150*40mm*15μm；溶剂：A＝水+0.05体积甲酸(99％)，B＝乙腈；梯度：52％-82％,15分钟)得到2-(4-(叔丁基)-5-氯-2-甲基苯基)-5-(2-羟基乙氧基)-1,6-萘啶-4(1H)-酮(目标化合物I-16)(150mg，26.6％收率)。Dissolve 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-(methylthio)-1,6-naphthyridin-4(1H)-one (600 mg, 1.20 mmol) in dichloromethane (12 mL). Then add m-chloroperoxybenzoic acid (498 mg, 2.46 mmol, 85% purity). After nitrogen substitution three times, warm the mixture to 25°C and stir for 12 hours. After completion of the reaction, pour the reaction mixture into saturated sodium sulfite (30 mL) at 0°C to quench the mixture. The mixture is extracted with dichloromethane (30 mL x 3). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated to yield the crude product. The residue was separated and purified by high performance liquid chromatography (column: Phenomenex luna C18 150*40mm*15μm; solvent: A = water + 0.05 volume of formic acid (99%), B = acetonitrile; gradient: 52%-82%, 15 minutes) to obtain 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-hydroxyethoxy)-1,6-naphthyridine-4(1H)-one (target compound I-16) (150 mg, 26.6% yield).

LC-MS,M/Z(ESI):471.1(M+H⁺).LC-MS, M/Z (ESI): 471.1 (M+H ⁺ ).

¹H NMR(400MHz,DMSO-d₆)δ13.54(s,1H),12.07(br s,1H),7.44(dd,J＝7.14,5.24Hz,1H),7.25-7.34(m,1H),7.06-7.15(m,1H),7.05(s,1H),6.57(d,J＝7.38Hz,1H),5.53(d,J＝11.0Hz,1H),4.31(dd,J＝11.0,7.50Hz,1H),3.88(d,J＝1.88Hz,3H),2.80(q,J＝7.50Hz,1H),1.66(s,3H),0.79(br d,J＝5.88Hz,3H). ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.54 (s, 1H), 12.07 (br s,1H),7.44(dd,J＝7.14,5.24Hz,1H),7.25-7.34(m,1H),7.06-7.15(m,1H),7.05(s,1H),6.57(d,J＝7.38Hz,1H),5.53 (d,J＝11.0Hz,1H),4.31(dd,J＝11.0,7.50Hz,1H),3.88(d,J＝1.88Hz,3H),2.80(q,J＝7.50Hz,1H),1.66(s,3H),0.79(br d,J=5.88Hz,3H).

实施例11：目标化合物I-20的制备Example 11: Preparation of target compound I-20

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-20)的合成
Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-20)

目标化合物I-20的合成路线如下所示：
The synthetic route of target compound I-20 is as follows:

第一步:乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯的合成
Step 1: Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

在室温下，向(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(940mg,2.65mmol)的乙醇(10mL)溶液滴加浓硫酸(208mg,2.12mmol)将反应液在80℃下搅拌3小时。反应结束后，将反应液加入冷的80mL 3％碳酸氢钠溶液中和，乙酸乙酯(30mL*2)萃取，有机相经过无水硫酸钠干燥，过滤浓缩得到粗品乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯(800mg,78.9％收率)。To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (940 mg, 2.65 mmol) in ethanol (10 mL) was added concentrated sulfuric acid (208 mg, 2.12 mmol) dropwise at room temperature, and the reaction mixture was stirred at 80°C for 3 hours. After the reaction, the reaction mixture was neutralized by adding 80 mL of cold 3% sodium bicarbonate solution, extracted with ethyl acetate (30 mL*2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (800 mg, 78.9% yield).

LC-MS,M/Z(ESI):383.2(M+H⁺)LC-MS, M/Z (ESI): 383.2 (M+H ⁺ )

第二步:乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-羟基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯的合成
Step 2: Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

在室温下，向乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯(800mg,2.09mmol)的二氯甲烷(10mL)溶液中加入三氯化铝(720mg,4.18mmol)，将反应液在25℃下搅拌16小时。反应结束后加水(60mL)淬灭，乙酸乙酯(15mL*2)萃取，有机相经过无水硫酸钠干燥，浓缩得到乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-羟基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯(400mg,51.9％收率)。To a solution of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (800 mg, 2.09 mmol) in dichloromethane (10 mL) was added aluminum chloride (720 mg, 4.18 mmol) at room temperature, and the reaction mixture was stirred at 25°C for 16 hours. After completion, the reaction was quenched with water (60 mL) and extracted with ethyl acetate (15 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to afford ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (400 mg, 51.9% yield).

LC-MS,M/Z(ESI):369.1(M+H⁺)LC-MS, M/Z (ESI): 369.1 (M+H ⁺ )

第三步:乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯的合成
Step 3: Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

在室温下，向乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-羟基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯(400mg,1.09mmol)和碳酸钾(450mg,3.26mmol)的N，N二甲基甲酰胺(3mL)溶液中加入氘代碘甲烷(440mg,3.26mmol)，将反应液在25℃下搅拌16小时。反应结束后，反应液直接用于下一步。To a solution of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (400 mg, 1.09 mmol) and potassium carbonate (450 mg, 3.26 mmol) in N,N-dimethylformamide (3 mL) was added deuterated iodomethane (440 mg, 3.26 mmol) at room temperature. The reaction mixture was stirred at 25°C for 16 hours. After completion of the reaction, the reaction mixture was used directly in the next step.

LC-MS,M/Z(ESI):386.2(M+H⁺)LC-MS, M/Z (ESI): 386.2 (M+H ⁺ )

第四步:(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸的合成
Step 4: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

在室温下，向乙基-(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸酯(400mg,1.04mmol)的N，N二甲基甲酰胺(3mL)和水溶液(2mL)加入氢氧化钠(124mg,3.11mmol)，将反应液在25℃下搅拌3小时。反应结束后，加水(20mL)稀释和1N稀盐酸(6mL)，调节pH至3，乙酸乙酯(5mL*2)萃取，有机相经过干燥浓缩得到(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(360mg,97.1％收率)。To a solution of ethyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (400 mg, 1.04 mmol) in N,N-dimethylformamide (3 mL) and aqueous solution (2 mL) was added sodium hydroxide (124 mg, 3.11 mmol) at room temperature, and the reaction mixture was stirred at 25°C for 3 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and 1N dilute hydrochloric acid (6 mL), and the pH was adjusted to 3. The mixture was extracted with ethyl acetate (5 mL x 2). The organic phase was dried and concentrated to afford (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (360 mg, 97.1% yield).

LC-MS,M/Z(ESI):356.1(M-H⁺)LC-MS, M/Z (ESI): 356.1 (MH ⁺ )

第五步:(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成
Step 5: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

在室温下，向(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(5)(350mg,979μmol)，氯化铵(157mg,2.94mmol)三乙胺(495mg,4.90mmol)的四氢呋喃(5mL)溶液中加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(409mg,1.08mmol)，将反应液在25℃下搅拌12小时。反应结束后，直接通过柱层析纯化(流动相：石油醚/乙酸乙酯＝3:1)得到(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(160mg,45.8％收率)。To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (5) (350 mg, 979 μmol), ammonium chloride (157 mg, 2.94 mmol) and triethylamine (495 mg, 4.90 mmol) in tetrahydrofuran (5 mL) was added O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (409 mg, 1.08 mmol) at room temperature, and the reaction solution was stirred at 25°C for 12 hours. After the reaction, the product was purified directly by column chromatography (mobile phase: petroleum ether/ethyl acetate = 3:1) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (160 mg, 45.8% yield).

LC-MS,M/Z(ESI):355.1(M+H⁺)LC-MS, M/Z (ESI): 355.1 (M+H ⁺ )

第七步：N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的制备
Step 7: Preparation of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

在室温下，向(2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(6)(160mg,449μmol)和3-乙酰基-N-(叔丁基)-4-氯吡啶酰胺(171mg,673μmol)的二氧六环(4mL)溶液中加入2-二叔丁基膦-2′,4′,6′-三异丙基联苯(42.8mg,89.8μmol)，二亚苄基丙酮钯(51.6mg,89.8μmol)，碳酸铯(439mg,1.35mmol)，并氮气置换三次，在110℃下搅拌24小时。反应结束后，加入乙酸乙酯(15mL)稀释，并用硅藻土过滤浓缩得到粗品，其通过薄层色谱纯化(石油醚/乙酸乙酯＝2:1)得到N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(60.0mg,24.0％收率)。To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (6) (160 mg, 449 μmol) and 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (171 mg, 673 μmol) in dioxane (4 mL) were added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (42.8 mg, 89.8 μmol), dibenzylideneacetonepalladium (51.6 mg, 89.8 μmol) and cesium carbonate (439 mg, 1.35 mmol) at room temperature, and the atmosphere was replaced with nitrogen three times. The mixture was stirred at 110°C for 24 hours. After the reaction, ethyl acetate (15 mL) was added to dilute, and the mixture was filtered and concentrated using celite to give a crude product, which was purified by thin layer chromatography (petroleum ether/ethyl acetate = 2:1) to give N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (60.0 mg, 24.0% yield).

LC-MS,M/Z(ESI):552.2(M+H⁺)LC-MS, M/Z (ESI): 552.2 (M+H ⁺ )

第八步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-20)的合成
Step 8: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-20)

在室温下，向N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(7)(50.0mg,89.8μmol)的甲苯(1.5mL)溶液中加入叔丁基二甲硅基三氟甲磺酸酯(285mg,1.08mmol)，将反应液在60℃下搅拌16小时。反应结束后直接浓缩得到粗品。其经高效液相色谱制备纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:A＝水+0.1％甲酸，B＝乙腈；梯度:38％-68％,15min)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-(甲氧基-d3)苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(18.2mg,39.7％收率)。To a solution of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (7) (50.0 mg, 89.8 μmol) in toluene (1.5 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (285 mg, 1.08 mmol) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the crude product was obtained by direct concentration. It was purified by HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A=water+0.1% formic acid, B=acetonitrile; gradient: 38%-68%, 15min) to obtain 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (18.2 mg, 39.7% yield).

LC-MS,M/Z(ESI):501.2(M+H⁺)LC-MS, M/Z (ESI): 501.2 (M+H ⁺ )

¹H NMR(400MHz,CDCl₃)δ9.03-8.88(m,1H),8.80-8.68(m,1H),8.55-8.31(m,1H),7.34-7.28(m,1H),7.22(s,H),6.95-6.84(m,1H),6.38-6.41(m,1H),5.68(d,J＝10.8,1H),4.26(br t,J＝9.57,1H),2.92(br t,J＝7.75,1H),1.80(s,3H),0.90(d,J＝6.0,3H) ¹ H NMR (400MHz, CDCl ₃ )δ9.03-8.88(m,1H),8.80-8.68(m,1H),8.55-8.31(m,1H),7.34-7.28(m,1H), 7.22(s,H),6.95-6.84(m,1H),6.38-6.41(m,1H),5.68(d,J＝10.8,1H),4.26(br t,J＝9.57,1H),2.92(br t,J＝7.75,1H),1.80(s,3H),0.90(d,J＝6.0,3H)

实施例12：目标化合物I-25的制备Example 12: Preparation of target compound I-25

2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-25)的合成
Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25)

目标化合物I-25的合成路线如下所示：
The synthetic route of target compound I-25 is as follows:

第一步:N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成
Step 1: Synthesis of N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

把3-溴-N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(500mg,790μmol)溶解于二氧六环(5mL)中，然后加入甲磺酸-2-(二叔丁基膦基)-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯(67.6mg,79.1μmol)和氢氧化钾(221mg,3.95nmol)，氮气置换三次。反应于100℃下，搅拌12小时。反应完全后，反应液滴加到稀盐酸中，并调节pH至中性。用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过高效液相色谱分离纯化(柱子：Boston Green ODS 150*30mm*5um；溶剂：A＝水+0.225％甲酸(99％)，B＝乙腈；梯度：50％-80％,11分钟)得到化合物N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(40.0mg,8.90％收率)。3-Bromo-N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (500 mg, 790 μmol) was dissolved in dioxane (5 mL). 2-(di-tert-butylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl methanesulfonate (67.6 mg, 79.1 μmol) and potassium hydroxide (221 mg, 3.95 nmol) were then added. The atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 100°C for 12 hours. After completion of the reaction, the reaction mixture was added dropwise to dilute hydrochloric acid, and the pH was adjusted to neutral. The mixture was extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The crude product was separated and purified by high performance liquid chromatography (column: Boston Green ODS 150*30 mm*5 um; solvent: A = water + 0.225% formic acid (99%), B = acetonitrile; gradient: 50%-80%, 11 minutes) to give the compound N-(tert-butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (40.0 mg, 8.90% yield).

LC-MS,M/Z(ESI):570.3(M+H⁺)LC-MS, M/Z (ESI): 570.3 (M+H ⁺ )

第二步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-25)的合成
Step 2: Synthesis of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25)

把N-(叔丁基)-2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(40mg,70.2μmol)溶解于甲苯(5mL)中，并加入叔丁基二甲基硅基三氟甲基磺酸酯(185mg,702μmol)，反应于70℃下，搅拌1小时。反应完全后，直接浓缩得到粗品，其经高效液相制备(柱子:Waters Xbridge 150*25mm*5um；流动相:溶剂A＝水+10mM碳酸氢铵，B＝乙腈；梯度:33％-63％,10min)纯化之后经超临界流体色谱分离纯化(柱子:DAICEL CHIRALPAK AS(250mm*30mm,10um)；流动相:A＝异丙醇+0.1％氨水，B＝超临界流体二氧化碳；梯度:5％-40％)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-3-羟基-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-25)(10.28mg,25.1％收率)。N-(tert-Butyl)-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (40 mg, 70.2 μmol) was dissolved in toluene (5 mL), and tert-butyldimethylsilyl trifluoromethylsulfonate (185 mg, 702 μmol) was added. The reaction was stirred at 70°C for 1 hour. After the reaction was complete, the crude product was directly concentrated and purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5um; mobile phase: solvent A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 33%-63%, 10min) and then by supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); mobile phase: solvent A = water + 10mM ammonium bicarbonate, B = acetonitrile; gradient: 33%-63%, 10min). Mobile phase: A = isopropanol + 0.1% ammonia, B = supercritical fluid carbon dioxide; gradient: 5%-40%) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-3-hydroxy-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25) (10.28 mg, 25.1% yield).

¹H NMR(400MHz,MeOD)δ8.40(d,J＝6.5Hz,1H),7.67(d,J＝5.9Hz,1H),7.10-7.26(m,1H),6.82-7.00(m,1H),5.99(d,J＝11.8Hz,1H),4.51-4.69(m,1H),4.37-4.48(m,1H),3.97(d,J＝2.5Hz,3H),2.92-3.04(m,1H),1.78(s,3H),0.89(br d,J＝6.6Hz,3H). ^1H NMR (400MHz, MeOD) δ8.40(d,J＝6.5Hz,1H),7.67(d,J＝5.9Hz,1H),7.10-7.26(m,1H),6.82-7.00(m,1H),5.99(d,J＝ 11.8Hz,1H),4.51-4.69(m,1H),4.37-4.48(m,1H),3.97(d,J＝2.5Hz,3H),2.92-3.04(m,1H),1.78(s,3H),0.89(br d,J＝6.6Hz,3H).

LC-MS,M/Z(ESI):514.2(M+H⁺)LC-MS, M/Z (ESI): 514.2 (M+H ⁺ )

实施例13：目标化合物I-63B的制备Example 13: Preparation of target compound I-63B

2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺
2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

目标化合物I-63B的合成路线如下图所示:
The synthetic route of the target compound I-63B is shown below:

第一步：(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-醇的合成Step 1: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

在氮气保护，-78℃条件下，向(4S,5R)-4,5-二甲基-5-三氟甲基二氢呋喃-2(3H)-酮(500mg,2.75mmol)的无水甲苯溶液(14mL)中加入二异丁基氢化铝的正己烷溶液(1.0M，5.5mL)，并在-30℃条件下反应2小时。将反应液温度升至0℃，分批次缓慢加入酒石酸钾钠四水合物(600mg)，然后在室温条件下搅拌1小时，加水(15mL)，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝5：1)，得到(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-醇(360mg，收率：71％)。直接进行下一步反应。Under nitrogen, at -78°C, a solution of (4S,5R)-4,5-dimethyl-5-trifluoromethyldihydrofuran-2(3H)-one (500 mg, 2.75 mmol) in anhydrous toluene (14 mL) was added with a 1.0 M solution of diisobutylaluminum hydride in n-hexane (5.5 mL). The mixture was allowed to react at -30°C for 2 hours. The reaction mixture was then heated to 0°C, and potassium sodium tartrate tetrahydrate (600 mg) was slowly added portionwise. The mixture was stirred at room temperature for 1 hour, and water (15 mL) was added. The mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 5:1) to obtain (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (360 mg, yield: 71%). The product was directly carried to the next step.

第二步：(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯的合成Step 2: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

在氮气保护，室温条件下，向(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-醇(360mg，1.96mmol)和4-二甲氨基吡啶(24mg，0.2mmol)的无水甲苯(10mL)溶液中加入无水乙酸酐(224mg，2.2mmol)和三乙胺(223mg，2.2mmol)。然后在室温条件下反应5小时，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得到(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯(340mg，收率：77％)。直接进行下一步反应。To a solution of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (360 mg, 1.96 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) in anhydrous toluene (10 mL) under nitrogen at room temperature were added anhydrous acetic anhydride (224 mg, 2.2 mmol) and triethylamine (223 mg, 2.2 mmol). The mixture was then allowed to react at room temperature for 5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 10:1) to obtain (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (340 mg, yield: 77%). The product was then directly processed into the next step.

第三步：(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-腈的合成Step 3: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

在氮气保护，-30℃条件下，向(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基乙酸酯(340mg，1.5mmol)的无水甲苯(7.5mL)溶液中依次加入三氟化硼乙醚(213mg,1.5mmol)和三甲基氰硅烷(208mg，2.1mmol)，然后在-20℃反应3小时，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：1)，得到(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-腈(200mg，收率：69％)。Under nitrogen protection, to a solution of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (340 mg, 1.5 mmol) in anhydrous toluene (7.5 mL) were added boron trifluoride etherate (213 mg, 1.5 mmol) and trimethylsilyl cyanide (208 mg, 2.1 mmol) in sequence at -30°C. The mixture was then reacted at -20°C for 3 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The organic phase was concentrated to dryness and then mixed. The product was separated and purified on a silica gel column (mobile phase: petroleum ether:ethyl acetate = 10:1) to give (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (200 mg, yield: 69%).

¹H NMR(400MHz,CDCl₃)δ4.77–4.70(m,1H),2.60–2.48(m,1H),2.35–2.18(m,2H),1.41(s,3H),1.26–1.21(m,3H)ppm ¹ H NMR (400MHz, CDCl ₃ ) δ4.77–4.70(m,1H),2.60–2.48(m,1H),2.35–2.18(m,2H),1.41(s,3H),1.26–1.21(m,3H)ppm

第四步：(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成Step 4: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

在氮气保护条件下，向(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-腈(200mg，1.04mmol)和氢氧化钾(59mg，1.04mmol)的乙醇(4mL)溶液中加入30％的过氧化氢(1mL)，然后在55℃条件下反应1小时。加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝4：1)，得到(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(150mg，收率：70％)。Under nitrogen, 30% hydrogen peroxide (1 mL) was added to a solution of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (200 mg, 1.04 mmol) and potassium hydroxide (59 mg, 1.04 mmol) in ethanol (4 mL). The mixture was then reacted at 55°C for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness, mixed, and purified using a silica gel column (mobile phase: petroleum ether:ethyl acetate = 4:1) to obtain (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (150 mg, yield: 70%).

¹H NMR(400MHz,CDCl₃)δ6.48(brs,1H),5.45(brs,1H),4.54–4.47(m,1H),2.55–2.46(m,1H),2.37–2.25(m,1H),2.05–1.88(m,1H),1.43(s,3H),1.21–1.15(m,3H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ6.48(brs,1H),5.45(brs,1H),4.54–4.47(m,1H),2.55–2.46(m,1H),2.37–2.25(m,1H),2.05–1.88(m,1H),1.43(s,3H),1.21–1.15(m,3H)ppm

第五步：3-乙酰基-N-(叔丁基)-4-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡啶酰胺和N-(叔丁基)-2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成在氮气保护条件下，向(4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(100mg，0.47mmol)、3-乙酰基-N-(叔丁基)-4-氯吡啶酰胺(120mg，0.47mmol)、磷酸三钾(500mg，2.35mmol)、Pd(dba)₂(27mg，0.047mmol)和Xphos(49mg，0.094mmol)的混合物中加入无水甲苯(3mL)，然后在100℃反应16小时。待反应液冷却至室温后过滤除去无机盐，滤液浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝10：3)得到3-乙酰基-N-(叔丁基)-4-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡啶酰胺(30mg，收率：15％)，LC-MS,M/Z(ESI):430.19[M+H]⁺；N-(叔丁基)-2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(65mg，收率：33.6％)，LC-MS,M/Z(ESI):412.43[M+H]⁺ Step 5: Synthesis of 3-acetyl-N-(tert-butyl)-4-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide and N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide Under nitrogen protection, (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (100 mg, 0.47 mmol), 3-acetyl-N-(tert-butyl)-4-chloropicolinamide (120 mg, 0.47 mmol), tripotassium phosphate (500 mg, 2.35 mmol), Pd(dba) ₂ To a mixture of phosphine (27 mg, 0.047 mmol) and Xphos (49 mg, 0.094 mmol) was added anhydrous toluene (3 mL), followed by reaction at 100° C. for 16 hours. After the reaction solution was cooled to room temperature, inorganic salts were removed by filtration. The filtrate was concentrated to dryness and mixed with the sample. The product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:3) to give 3-acetyl-N-(tert-butyl)-4-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (30 mg, yield: 15%), LC-MS, M/Z (ESI): 430.19 [M+H] ⁺ ; N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (65 mg, yield: 33.6%), LC-MS, M/Z (ESI): 412.43 [M+H] ⁺

第六步：2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-63B)的合成Step 6: Synthesis of 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B)

在氮气保护条件下，向N-(叔丁基)-2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(50mg，0.12mmol)的无水甲苯(1.5mL)溶液中加入叔丁基二甲硅基三氟甲磺酸酯(793mg,3mmol)，然后在65℃反应16小时。待反应液冷却至室温后，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得到2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-63B)(15mg，收率：35％)。Under nitrogen protection, to a solution of N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (50 mg, 0.12 mmol) in anhydrous toluene (1.5 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (793 mg, 3 mmol), and then reacted at 65 ° C for 16 hours. After the reaction solution was cooled to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness and mixed, and then separated and purified by silica gel column (mobile phase: petroleum ether: ethyl acetate = 1:5) to obtain 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B) (15 mg, yield: 35%).

LC-MS,M/Z(ESI):356.32[M+H]⁺ LC-MS, M/Z(ESI):356.32[M+H] ⁺

¹H NMR(400MHz,CDCl₃)δ8.93(brs,1H),8.58(d,J＝5.6Hz,1H),7.99(d,J＝5.6Hz,1H),7.32(s,1H),6.16(brs,1H),5.27–5.19(m,1H),2.68–2.58(m,1H),2.53–2.40(m,1H),1.53(s,3H),1.28–1.19(m,3H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ8.93(brs,1H),8.58(d,J＝5.6Hz,1H),7.99(d,J＝5.6Hz,1H),7.32(s,1H),6.16(brs,1H), 5.27–5.19(m,1H),2.68–2.58(m,1H),2.53–2.40(m,1H),1.53(s,3H),1.28–1.19(m,3H)ppm

第七步：N-(叔丁基)-2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺的合成Step 7: Synthesis of N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

在氮气保护条件下，向3-乙酰基-N-(叔丁基)-4-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺基)吡啶酰胺(30mg，0.07mmol)的1,4-二氧六环溶液中加入叔丁醇钾的四氢呋喃溶液(1.0M，0.15mL)，然后在60℃反应5小时。冷却至室温后，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得到N-(叔丁基)-2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(25mg，收率：87％)LC-MS,M/Z(ESI):412.43[M+H]⁺，Under nitrogen protection, to a solution of 3-acetyl-N-(tert-butyl)-4-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (30 mg, 0.07 mmol) in 1,4-dioxane was added a tetrahydrofuran solution of potassium tert-butoxide (1.0 M, 0.15 mL), and then reacted at 60 ° C for 5 hours. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness and then mixed. The mixture was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 1:5) to obtain N-(tert-butyl)-2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (25 mg, yield: 87%). LC-MS, M/Z (ESI): 412.43 [M+H] ⁺ ,

第八步：2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-63B)的合成Step 8: Synthesis of 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B)

在氮气保护条件下，向N-(叔丁基)-2-((2S,4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(15mg，0.036mmol)的无水甲苯(1mL)溶液中加入叔丁基二甲硅基三氟甲磺酸酯(240mg,0.91mmol)，然后在65℃反应16小时。待反应液冷却至室温后，加水淬灭反应，用乙酸乙酯萃取，有机相浓缩干后拌样，用硅胶柱分离纯化(流动相：石油醚：乙酸乙酯＝1：5)，得到2-((4S,5R)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-4-氧代-1,4-二氢-1,6-萘啶-5-甲酰胺(I-63B)(5mg)。Under nitrogen protection, to a solution of N-(tert-butyl)-2-((2S,4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (15 mg, 0.036 mmol) in anhydrous toluene (1 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (240 mg, 0.91 mmol), and then reacted at 65 ° C for 16 hours. After the reaction solution was cooled to room temperature, water was added to quench the reaction, and the product was extracted with ethyl acetate. The organic phase was concentrated to dryness and mixed, and then separated and purified by silica gel column chromatography (mobile phase: petroleum ether: ethyl acetate = 1:5) to obtain 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-63B) (5 mg).

LC-MS,M/Z(ESI):356.32[M+H]⁺ LC-MS, M/Z(ESI):356.32[M+H] ⁺

¹H NMR(400MHz,CDCl₃)δ8.94(brs,1H),8.59(d,J＝5.6Hz,1H),8.01(d,J＝5.6Hz,1H),7.26(s,1H),6.13(brs,1H),5.37–5.31(m,1H),2.57–2.37(m,2H),2.36–2.50(m,1H),1.60(s,3H),1.21–1.16(m,3H)ppm ¹ H NMR (400MHz, CDCl ₃ )δ8.94(brs,1H),8.59(d,J＝5.6Hz,1H),8.01(d,J＝5.6Hz,1H),7.26(s,1H),6.13(brs,1H), 5.37–5.31(m,1H),2.57–2.37(m,2H),2.36–2.50(m,1H),1.60(s,3H),1.21–1.16(m,3H)ppm

实施例14：目标化合物I-65的制备Example 14: Preparation of target compound I-65

2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,7-萘啶-4-酮(I-65)的合成
Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,7-naphthyridin-4-one (I-65)

目标化合物I-65的合成路线如下所示：
The synthetic route of target compound I-65 is as follows:

第一步:1-(5-氯-2-乙烯基吡啶-4-基)乙烷-1-酮
Step 1: 1-(5-chloro-2-vinylpyridin-4-yl)ethan-1-one

把1-(2,5-二氯吡啶-4-基)乙烷-1-酮(1.2g,6.31mmol)溶解于四氢呋喃/水(15/3mL)中，然后加入碳酸钾(2.62g,18.9mmol)，乙烯基三氟硼酸钾(888mg,6.63mmol)和[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(516mg,631μmol)，氮气保护下，反应于80℃搅拌12小时。反应完全后，反应混合物在0℃下加入水50mL淬灭反应，加入乙酸乙酯(30mL*3)进行萃取。有机层用无水硫酸钠干燥过滤，滤饼用乙酸乙酯洗涤，滤液减压浓缩，得到粗品，经薄层色谱(流动相：石油醚/乙酸乙酯＝15/1，Rfp1＝0.43)得到1-(5-氯-2-乙烯基吡啶-4-基)乙烷-1-酮(0.800g,69.7％收率)。Dissolve 1-(2,5-dichloropyridin-4-yl)ethan-1-one (1.2 g, 6.31 mmol) in tetrahydrofuran/water (15/3 mL). Then add potassium carbonate (2.62 g, 18.9 mmol), potassium vinyl trifluoroborate (888 mg, 6.63 mmol), and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium in dichloromethane (516 mg, 631 μmol). Under nitrogen, stir at 80°C for 12 hours. After the reaction is complete, 50 mL of water is added to quench the reaction mixture at 0°C, and ethyl acetate (30 mL x 3) is added for extraction. The organic layer was dried over anhydrous sodium sulfate and filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether/ethyl acetate = 15/1, Rfp1 = 0.43) to give 1-(5-chloro-2-vinylpyridin-4-yl)ethan-1-one (0.800 g, 69.7% yield).

LC-MS,M/Z(ESI):182.0(M+H⁺)LC-MS, M/Z (ESI): 182.0 (M+H ⁺ )

第二步：2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-6-乙烯基-1,7-萘啶-4(1H)-酮
Step 2: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-vinyl-1,7-naphthyridin-4(1H)-one

把(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(480mg,1.36mmol)和1-(5-氯-2-乙烯基吡啶-4-基)乙烷-1-酮(296mg,1.63mmol)溶解于甲苯(8mL)中，然后加入碳酸铯(85.5mg,421μmol)，2-二环己基磷-2,4,6-三异丙基联苯(259mg,543μmol)，最后加入双(二亚苄基丙酮)钯(156mg,271μmol)，氮气保护下，反应于110℃搅拌12小时。反应完全后，反应混合物经过过滤浓缩得到粗品。其采用薄层色谱纯化(石油醚：乙酸乙酯＝1:1，Rfp1＝0.40)得到2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-6-乙烯基-1,7-萘啶-4(1H)-酮(50mg,7.20％收率)。(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (480 mg, 1.36 mmol) and 1-(5-chloro-2-vinylpyridin-4-yl)ethan-1-one (296 mg, 1.63 mmol) were dissolved in toluene (8 mL). Cesium carbonate (85.5 mg, 421 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (259 mg, 543 μmol) were then added. Finally, bis(dibenzylideneacetone)palladium (156 mg, 271 μmol) was added. The reaction mixture was stirred at 110°C under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was filtered and concentrated to obtain the crude product. It was purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1, Rfp1 = 0.40) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-vinyl-1,7-naphthyridin-4(1H)-one (50 mg, 7.20% yield).

LC-MS,M/Z(ESI):481.3(M+H⁺)LC-MS, M/Z (ESI): 481.3 (M+H ⁺ )

第三步：2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,7-萘啶-4-酮(I-65)的合成
Step 3: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,7-naphthyridin-4-one (I-65)

把铁氰化钾(41.1mg,124μmol)，碳酸钾(17.2mg,124μmol)，三乙烯二胺(9.34mg,83.2μmol)和二水合锇酸钾(15.3mg,41.63μmol)溶解于叔丁醇/水(1/0.3mL)混合溶液中，在0℃下，加入2-((2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基)-6-乙烯基-1,7-萘啶-4(1H)-酮(20.0mg,41.6μmol)，反应于25℃搅拌30分钟。反应完全后，用乙酸乙酯(5ml)稀释溶液，用亚硫酸钠水溶液(5mL)淬灭，搅拌10分钟。混合物用乙酸乙酯(3×10mL)萃取，结合后的有机层用10％稀盐酸(20mL)水溶液，饱和碳酸氢钠水溶液(20mL)洗涤。有机相用无水硫酸钠干燥，过滤，浓缩得到粗品，其经液相制备(柱子:Phenomenex luna C18 150*25mm*10um；流动相:溶剂A＝水+0.2％甲酸，B＝乙腈；梯度:15％-25％,10min)纯化得到2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,7-萘啶-4-酮(I-65)(1.87mg,8.30％收率)。Potassium ferricyanide (41.1 mg, 124 μmol), potassium carbonate (17.2 mg, 124 μmol), triethylenediamine (9.34 mg, 83.2 μmol), and potassium osmate dihydrate (15.3 mg, 41.63 μmol) were dissolved in a mixture of tert-butanol and water (1/0.3 mL). 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-vinyl-1,7-naphthyridin-4(1H)-one (20.0 mg, 41.6 μmol) was added at 0°C and stirred at 25°C for 30 minutes. After the reaction was complete, the solution was diluted with ethyl acetate (5 mL), quenched with aqueous sodium sulfite solution (5 mL), and stirred for 10 minutes. The mixture was extracted with ethyl acetate (3×10 mL), and the combined organic layers were washed with 10% dilute hydrochloric acid (20 mL) and saturated sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by liquid phase preparation (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.2% formic acid, B = acetonitrile; gradient: 15%-25%, 10 min) to give 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,7-naphthyridin-4-one (I-65) (1.87 mg, 8.30% yield).

¹H NMR(400MHz,MeOD)δ9.15(s,1H),8.17(s,1H),7.21(br t,J＝6.56Hz,1H),6.93-7.08(m,1H),6.13-6.44(m,1H),5.55(d,J＝11.12Hz,1H),4.60(br s,1H),4.26(dd,J＝10.94,8.68Hz,1H),3.85-3.97(m,4H),3.74(dd,J＝11.26,6.62Hz,1H),2.88(br t,J＝7.88Hz,1H),1.75(s,3H),0.91(br d,J＝6.12Hz,3H). ¹ H NMR (400MHz, MeOD) δ9.15(s,1H),8.17(s,1H),7.21(br t,J＝6.56Hz,1H),6.93-7.08(m,1H),6.13-6.44(m,1H),5.55(d,J＝11.12Hz,1H),4.60(br s,1H),4.26(dd,J＝10.94,8.68Hz,1H),3.85-3.97(m,4H),3.74(dd,J＝11.26,6.62Hz,1H),2.88(br t,J＝7.88Hz,1H),1.75(s,3H),0.91(br d,J＝6.12Hz,3H).

LC-MS,M/Z(ESI):515.2(M+H⁺)LC-MS, M/Z (ESI): 515.2 (M+H ⁺ )

实施例15：目标化合物I-66的制备Example 15: Preparation of target compound I-66

2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,5-萘啶-4-酮(目标化合物I-66)
2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,5-naphthyridin-4-one (target compound I-66)

目标化合物I-66的合成路线如下所示：
The synthetic route of target compound I-66 is as follows:

第一步：(2R,3S,4S,5R)-N-(6-氯-2-碘吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺的合成
Step 1: Synthesis of (2R,3S,4S,5R)-N-(6-chloro-2-iodopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

将原料(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-羧酸(600mg,1.69mmol)和6-氯-2-碘吡啶-3-胺(431mg,1.69mmol)溶在二氯甲烷(10mL)中，缓慢加入正丁基磷酸酐(2.44g,3.39mmol,50％含量)和N,N-二异丙基乙胺(656mg,5.08mmol)，然后在25℃下，搅拌1小时。反应完毕后，加入水(50mL)淬灭，用二氯甲烷(50mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝3:1，R_fp1＝0.35)，得到化合物(2R,3S,4S,5R)-N-(6-氯-2-碘吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(750mg，74.9％收率)。The raw materials (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (600 mg, 1.69 mmol) and 6-chloro-2-iodopyridin-3-amine (431 mg, 1.69 mmol) were dissolved in dichloromethane (10 mL). N-Butylphosphoric anhydride (2.44 g, 3.39 mmol, 50% content) and N,N-diisopropylethylamine (656 mg, 5.08 mmol) were slowly added to the mixture, and then stirred at 25°C for 1 hour. After completion of the reaction, water (50 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=3:1, R _fp1 =0.35) to give compound (2R,3S,4S,5R)-N-(6-chloro-2-iodopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (750 mg, 74.9% yield).

LC-MS,M/Z(ESI):591.1(M+H⁺)。LC-MS, M/Z(ESI): 591.1(M+H ⁺ ).

第二步：(2R,3S,4S,5R)-N-(2-乙酰基-6-氯吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-甲酰胺的合成
Step 2: Synthesis of (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide

将原料(2R,3S,4S,5R)-N-(6-氯-2-碘吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-甲酰胺(700mg,1.19mmol)和三丁基(1-乙氧基乙烯)锡(856mg,2.37mmol)溶在二氧六环(20mL)中，将反应体系用氮气置换三次，在25℃下，加入双(三苯基膦)二氯化钯(83.2mg,118umol)，然后在100℃下，搅拌8小时。反应完毕后，加入饱和氟化钾水溶液(10mL)淬灭，用乙酸乙酯(50mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用四氢呋喃溶解，然后加入6M盐酸(5mL)，在25℃下搅拌1小时，然后用乙酸乙酯(50mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝3:1，R_fp1＝0.30)，得到化合物(2R,3S,4S,5R)-N-(2-乙酰基-6-氯吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-甲酰胺(550mg，91.5％收率)。The starting material (2R,3S,4S,5R)-N-(6-chloro-2-iodopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (700 mg, 1.19 mmol) and tributyl(1-ethoxyethylene)tin (856 mg, 2.37 mmol) were dissolved in dioxane (20 mL). The reaction system was purged with nitrogen three times. Bis(triphenylphosphine)palladium dichloride (83.2 mg, 118 umol) was added at 25°C, and the mixture was stirred at 100°C for 8 hours. After completion of the reaction, saturated aqueous potassium fluoride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was dissolved in tetrahydrofuran, and then 6M hydrochloric acid (5 mL) was added. The mixture was stirred at 25°C for 1 hour, then extracted with ethyl acetate (50 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was separated and purified by thin-layer chromatography (petroleum ether:ethyl acetate = 3:1, R _fp1 = 0.30) to give the compound (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (550 mg, 91.5% yield).

LC-MS,M/Z(ESI):507.8(M+H⁺)。LC-MS, M/Z(ESI): 507.8(M+H ⁺ ).

第三步：6-氯-2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-1,4-二氢-1,5-萘啶-4-酮的合成
Step 3: Synthesis of 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-1,4-dihydro-1,5-naphthyridin-4-one

将原料(2R,3S,4S,5R)-N-(2-乙酰基-6-氯吡啶-3-基)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-甲酰胺(550mg,1.09mmol)溶在二氧六环(10mL)中，将氢氧化钠(217mg,5.43mmol)缓慢加入到反应液，然后在100℃下搅拌1小时。反应完毕后，加入1M稀盐酸(10mL)淬灭，用二氯甲烷(50mL*3)萃取，合并的有机相，用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝3:1，R_fp1＝0.35)得到化合物6-氯-2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-1,4-二氢-1,5-萘啶-4-酮(240mg，45.2％收率)。The raw material (2R,3S,4S,5R)-N-(2-acetyl-6-chloropyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolane-2-carboxamide (550 mg, 1.09 mmol) was dissolved in dioxane (10 mL). Sodium hydroxide (217 mg, 5.43 mmol) was slowly added to the reaction solution, and then stirred at 100°C for 1 hour. After completion of the reaction, 1M dilute hydrochloric acid (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=3:1, R _fp1 =0.35) to give compound 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-1,4-dihydro-1,5-naphthyridin-4-one (240 mg, 45.2% yield).

LC-MS,M/Z(ESI):489.1(M+H⁺)。LC-MS, M/Z(ESI): 489.1(M+H ⁺ ).

第四步：2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-乙烯基-1,4-二氢-1,5-萘啶-4-酮的合成
Step 4: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-vinyl-1,4-dihydro-1,5-naphthyridin-4-one

将原料6-氯-2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-1,4-二氢-1,5-萘啶-4-酮(200mg,409umol)溶在二氧六环(2mL)和水(1mL)中，在25℃下，缓慢加入碳酸钾(169mg,1.23mmol)，乙烯基硼酸嚬哪醇酯(94.5mg,613umol)和四三苯基膦钯(94.5mg,81.8umol)，然后在100℃下，搅拌3小时。反应完毕后，加入水(10mL)淬灭，用二氯甲烷(40mL*2)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品用薄层色谱分离纯化(石油醚：乙酸乙酯＝1:1，R_fp1＝0.3)，得到化合物2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-乙烯基-1,4-二氢-1,5-萘啶-4-酮(65.0mg，33.1％收率)。The raw material 6-chloro-2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-1,4-dihydro-1,5-naphthyridin-4-one (200 mg, 409 umol) was dissolved in dioxane (2 mL) and water (1 mL). Potassium carbonate (169 mg, 1.23 mmol), vinylboronic acid xanaxol ester (94.5 mg, 613 umol), and tetrakistriphenylphosphine palladium (94.5 mg, 81.8 umol) were slowly added at 25°C. The mixture was then stirred at 100°C for 3 hours. After completion of the reaction, water (10 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (40 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by thin layer chromatography (petroleum ether:ethyl acetate=1:1, R _fp1 =0.3) to give compound 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-vinyl-1,4-dihydro-1,5-naphthyridin-4-one (65.0 mg, 33.1% yield).

LC-MS,M/Z(ESI):481.1(M+H⁺)。LC-MS, M/Z(ESI): 481.1(M+H ⁺ ).

第五步：2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,5-萘啶-4-酮(目标化合物I-66)的合成
Step 5: Synthesis of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,5-naphthyridin-4-one (target compound I-66)

将原料2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-乙烯基-1,4-二氢-1,5-萘啶-4-酮(55.0mg,114umol)溶在甲醇(1mL)和叔丁醇(1mL)中，在25℃下，将AD-mix-α(300mg,114umol)溶在水(2mL)中，然后加入到反应液，然后在25℃下，搅拌1小时。反应完毕后，加入饱和亚硫酸钠溶液(5mL)中淬灭，用乙酸乙酯(10mL*3)萃取，合并的有机相用无水硫酸钠干燥，过滤，浓缩得到粗品。粗品通过高效液相色谱分离纯化(柱子：Waters Xbridge C18 150*25mm*5um；溶剂：A＝水+0.05％氨水(99％)，B＝乙腈；梯度：10％-40％,11分钟)得到黄色固体化合物2-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)氧杂环戊烷-2-基]-6-(1,2-二羟乙基)-1,4-二氢-1,5-萘啶-4-酮(目标化合物I-66)(18.9mg，31.1％收率)。The raw material 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-vinyl-1,4-dihydro-1,5-naphthyridin-4-one (55.0 mg, 114 μmol) was dissolved in methanol (1 mL) and tert-butanol (1 mL). AD-mix-α (300 mg, 114 μmol) was dissolved in water (2 mL) at 25°C and added to the reaction solution. The mixture was then stirred at 25°C for 1 hour. After completion of the reaction, the mixture was quenched by addition of saturated sodium sulfite solution (5 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was separated and purified by HPLC (column: Waters Xbridge C18 150*25mm*5um; solvent: A = water + 0.05% ammonia water (99%), B = acetonitrile; gradient: 10%-40%, 11 minutes) to give a yellow solid compound 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)oxolan-2-yl]-6-(1,2-dihydroxyethyl)-1,4-dihydro-1,5-naphthyridine-4-one (target compound I-66) (18.9 mg, 31.1% yield).

¹H NMR(400MHz,MeOD)δ8.22(d,J＝8.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.15-7.24(m,1H),6.91-7.02(m,1H),6.57(s,1H),5.52(d,J＝11.3Hz,1H),4.85-4.87(m,1H),4.21-4.31(m,1H),3.91(d,J＝2.1Hz,3H),3.82-3.88(m,1H),3.74-3.80(m,1H),2.81-2.94(m,1H),1.72(s,3H),0.89(br d,J＝5.9Hz,3H) ^1H NMR (400MHz, MeOD) δ8.22(d,J＝8.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.15-7.24(m,1H),6.91-7.02(m,1H),6.57(s,1H),5.52(d,J＝11.3Hz,1H) ,4.85-4.87(m,1H),4.21-4.31(m,1H),3.91(d,J=2.1Hz,3H),3.82-3. 88(m,1H),3.74-3.80(m,1H),2.81-2.94(m,1H),1.72(s,3H),0.89(br d,J＝5.9Hz,3H)

LC-MS,M/Z(ESI):515.1(M+H⁺)。LC-MS, M/Z(ESI): 515.1(M+H ⁺ ).

实施例16：目标化合物I-67的制备Example 16: Preparation of target compound I-67

6-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]-8-氧亚基-5H-吡啶并[3,2-b]吡啶-2-甲酰胺(I-67)
6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxamide (I-67)

化合物I-67的合成路线如下所示：

The synthetic route of compound I-67 is as follows:

第一步：5-氨基-6-碘吡啶-2-甲酸甲酯的合成
Step 1: Synthesis of methyl 5-amino-6-iodopyridine-2-carboxylate

冰浴条件下，将5-氨基-2-(甲酯基)吡啶(5.0g,32.86mmol)溶于无水DMF(50mL)中，再加入I₂(9.20g,36.15mmol)和NaIO₄(16.80g,78.86mmol)，加完后，反应液在室温条件下反应16小时。TLC(PE:EA＝5:1)显示反应完全。向反应液中加入H₂O(50mL)，再用EtOAc(50mL*3)萃取，分液，合并有机相。有机相再分别用H₂O(50mL*2)和brine(50mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品通过正相硅胶柱层析分离(EtOAc/PE＝0％-30％)得到55-氨基-6-碘吡啶-2-甲酸甲酯(2)(5.80g；产率:63.46％)。5-Amino-2-(carbomethoxy)pyridine (5.0 g, 32.86 mmol) was dissolved in anhydrous DMF (50 mL) under ice-cooling conditions. _I₂ (9.20 g, 36.15 mmol) and _NaIO₄ (16.80 g, 78.86 mmol) were then added. After complete addition, the reaction mixture was allowed to react at room temperature for 16 hours. TLC (PE:EA = 5:1) indicated completion of the reaction. _H₂O (50 mL) was added to the reaction mixture, which was then extracted with EtOAc (50 mL x 3). The organic phases were separated and combined. The organic phase was washed with _H2O (50 mL*2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by normal phase silica gel column chromatography (EtOAc/PE=0%-30%) to obtain 5,5-amino-6-iodopyridine-2-carboxylic acid methyl ester (2) (5.80 g; yield: 63.46%).

第二步：5-氯-6-碘吡啶-2-甲酸甲酯(3)的合成
Step 2: Synthesis of methyl 5-chloro-6-iodopyridine-2-carboxylate (3)

室温下，分别称取化合物2(0.50g,1.80mmol)和CuCl₂(0.36g,2.70mmol)于ACN(5mL)中，然后加入t-BuNO(0.37g,3.60mmol)，加完后，反应液加热到60℃,并在该条件反应2小时。TLC(PE:EA＝3:1)显示反应完全。反应液冷却至室温，反应液过滤，减压浓缩得到粗品，粗品通过正相硅胶柱层析分离(EtOAc/PE＝0％-50％)得到5-氯-6-碘吡啶-2-甲酸甲酯(3)(0.26g；产率:48.15％)。At room temperature, compound 2 (0.50 g, 1.80 mmol) and _CuCl₂ (0.36 g, 2.70 mmol) were weighed separately in ACN (5 mL), followed by the addition of t-BuNO₂ (0.37 g, 3.60 mmol). After the addition was complete, the reaction solution was heated to 60°C and allowed to react for 2 hours. TLC (PE:EA = 3:1) indicated the reaction was complete. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc/PE = 0%-50%) to give methyl 5-chloro-6-iodopyridine-2-carboxylate (3) (0.26 g; yield: 48.15%).

第三步：6-乙酰基-5-氯吡啶-2-甲酸甲酯(5)的合成
Step 3: Synthesis of methyl 6-acetyl-5-chloropyridine-2-carboxylate (5)

室温下，分别称取化合物3(0.26g,0.84mmol)和化合物4(0.32g,1.01mmol)于无水甲苯(5mL)，然后加入Pd(dppf)Cl₂(0.94g,0.08mmol)，加完后，反应液抽真空，并用氮气置换三次,最后反应液升温至100℃,并在氮气保护下反应16小时。TLC(PE:EA＝3:1)显示反应完全。反应液冷却至室温，向反应液中加入6N HCl(10mL)，在室温下搅拌2小时。向反应液中加入饱和KF水溶液(20mL)，搅拌30min,再加入饱和碳酸氢钠水溶液调pH至8，反应液用EtOAc(10mL*2)萃取，分液,合并有机相。有机相再用brine(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品通过正相硅胶柱层析分离(EtOAc/PE＝0％-50％)得到6-乙酰基-5-氯吡啶-2-甲酸甲酯(5)(0.09g；产率:50.28％)。At room temperature, compound 3 (0.26 g, 0.84 mmol) and compound 4 (0.32 g, 1.01 mmol) were weighed separately in anhydrous toluene (5 mL), followed by the addition of Pd(dppf) _Cl₂ (0.94 g, 0.08 mmol). After complete addition, the reaction mixture was evacuated and replaced with nitrogen three times. Finally, the reaction mixture was heated to 100°C and allowed to react under nitrogen for 16 hours. TLC (PE:EA = 3:1) indicated the reaction was complete. The reaction mixture was cooled to room temperature, and 6N HCl (10 mL) was added, followed by stirring at room temperature for 2 hours. Saturated aqueous KF solution (20 mL) was added to the reaction mixture, stirred for 30 minutes, and then saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8. The reaction mixture was extracted with EtOAc (10 mL x 2), separated, and the organic phases combined. The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by normal phase silica gel column chromatography (EtOAc/PE = 0%-50%) to give methyl 6-acetyl-5-chloropyridine-2-carboxylate (5) (0.09 g; yield: 50.28%).

第四步：5-({[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)-6-乙酰基吡啶-2-甲酸甲酯(7)的合成
Step 4: Synthesis of methyl 5-({[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)-6-acetylpyridine-2-carboxylate (7)

室温下，分别称取化合物6(0.14g,0.40mmol)和化合物5(0.09g,0.40mmol)于无水Toluene(2mL)中，再分别加入K₃PO₄(0.27g,1.2mmol)；Pd(dba)₂(23.90mg,0.04mmol)和Xphos(40.20mg,0.08mmol)，加完后，反应液抽真空，并用氮气置换三次,反应液升温至100℃,并在氮气保护下反应16小时。TLC(PE:EA＝3:1)显示反应完全。向反应液中加入H₂O(5mL)稀释，再用EtOAc(10mL*2)萃取，分液,合并有机相,有机相再用brine(50mL)洗涤,无水硫酸钠干燥，过滤，减压浓缩得到粗品，粗品通过正相硅胶柱层析分离(EtOAc/PE＝0％-50％)得到5-({[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]羰基}氨基)-6-乙酰基吡啶-2-甲酸甲酯(7)(92.0mg；产率:43.39％)。At room temperature, compound 6 (0.14 g, 0.40 mmol) and compound 5 (0.09 g, 0.40 mmol) were weighed into anhydrous toluene (2 mL). K ₃ PO ₄ (0.27 g, 1.2 mmol), Pd(dba) ₂ (23.90 mg, 0.04 mmol), and Xphos (40.20 mg, 0.08 mmol) were added, respectively. After complete addition, the reaction solution was evacuated and replaced with nitrogen three times. The reaction solution was heated to 100°C and reacted under nitrogen for 16 hours. TLC (PE:EA = 3:1) indicated the reaction was complete. The reaction solution was diluted with _H2O (5 mL), and then extracted with EtOAc (10 mL*2). The organic phases were separated, and the organic phases were combined. The organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by normal phase silica gel column chromatography (EtOAc/PE=0%-50%) to give 5-({[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)-6-acetylpyridine-2-carboxylic acid methyl ester (7) (92.0 mg; yield: 43.39%).

第五步：6-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]-8-氧亚基-5H-吡啶并[3,2-b]吡啶-2-甲酸(8)的合成
Step 5: Synthesis of 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxylic acid (8)

室温下，称取化合物7(82.0mg,0.15mmol)于Dioxane(21mL)中，然后加入氢氧化钠(18.86mg,0.45mmol),加完后，反应液升温至110℃,并在该条件下反应3小时。LCMS显示反应完全。反应液直接减压浓缩得到粗品6-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]-8-氧亚基-5H-吡啶并[3,2-b]吡啶-2-甲酸(8)(0.10g；粗品)。At room temperature, compound 7 (82.0 mg, 0.15 mmol) was weighed into dioxane (21 mL), and sodium hydroxide (18.86 mg, 0.45 mmol) was added. After the addition was complete, the reaction solution was heated to 110°C and reacted under these conditions for 3 hours. LCMS showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain the crude product 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxylic acid (8) (0.10 g; crude).

第六步：6-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]-8-氧亚基-5H-吡啶并[3,2-b]吡啶-2-甲酰胺(I-67)
Step 6: 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxyylidene-5H-pyrido[3,2-b]pyridine-2-carboxamide (I-67)

室温下，称取化合物8(50.0mg,0.10mmol)和HATU(68.8mg,0.45mmol)于无水DMF(1mL)中，再分别加入DIPEA(51.7mg,0.40mmol)和NH₄Cl(21.40mg,0.40mmol)，加完后，反应液在该条件下反应16小时。LCMS显示反应完全。反应液通过高效液相(Column:SunFire^TM Prep C18 OBD^TM 5μm,30X 150mm,Phase:ACN/H₂O(0.5％FA)40％ACN)分离得到6-[(2R,3S,4S,5R)-3-(3,4-二氟-2-甲氧基苯基)-4,5-二甲基-5-(三氟甲基)四氢呋喃-2-基]-8-氧亚基-5H-吡啶并[3,2-b]吡啶-2-甲酰胺(I-67)(3.1mg，产率：6.23％)。At room temperature, compound 8 (50.0 mg, 0.10 mmol) and HATU (68.8 mg, 0.45 mmol) were weighed into anhydrous DMF (1 mL), and DIPEA (51.7 mg, 0.40 mmol) and NH ₄ Cl (21.40 mg, 0.40 mmol) were added, respectively. After the addition was complete, the reaction mixture was reacted under the same conditions for 16 hours. LCMS showed that the reaction was complete. The reaction mixture was separated by HPLC (Column: SunFire ^™ Prep C18 OBD ^™ 5μm, 30X 150mm, Phase: ACN/ _H2O (0.5% FA) 40% ACN) to give 6-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-8-oxylidene-5H-pyrido[3,2-b]pyridine-2-carboxamide (I-67) (3.1 mg, yield: 6.23%).

¹H NMR(400MHz,DMSO_-d₆)：δ8.96(s,1H),8.36(d,1H,J＝8.0Hz),8.28(d,1H,J＝8.0Hz),7.76(s,1H),7.36-7.32(m,2H),7.14-7.08(m,1H),5.64-5.61(m,1H),4.36-4.31(m,1H),3.89(s,3H),3.51(s,1H),2.89-2.83(m,1H),1.71(s,3H),0.81(d,3H,J＝8.0Hz)。 ¹ H NMR (400MHz, DMSO _- d ₆ ): δ8.96(s,1H),8.36(d,1H,J＝8.0Hz),8.28(d,1H,J＝8.0Hz),7.76(s,1H),7.36-7.32(m,2H),7.14-7.08(m,1H),5. 64-5.61(m,1H),4.36-4.31(m,1H),3.89(s,3H),3.51(s,1H),2.89-2.83(m,1H),1.71(s,3H),0.81(d,3H,J＝8.0Hz).

LC-MS,M/Z(ESI):498.21[M+H]⁺ LC-MS, M/Z(ESI):498.21[M+H] ⁺

测试例1：化合物对Nav1.8离子通道抑制活性检测Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

试剂除用于酸碱滴定的NaOH和KOH外，均从Sigma(St.Louis,MO)公司购买。测试化合物的最终浓度均在当天配制，再溶于细胞外液。细胞外液(mM)为:NaCl,137；KCl,4；CaCl₂,1.8；MgCl₂,1；HEPES,10；glucose 10；pH 7.4(NaOH滴定)。所有测试化合物和对照化合物溶液均含1μM TTX。细胞内液(mM)为：天冬氨酸，140；氯化镁，2；乙二醇四乙酸(EGTA)，11；N-2-羟乙基哌嗪-N’-2-乙磺酸(HEPES)，10。用氢氧化铯调整pH到7.4。All reagents, except NaOH and KOH for acid-base titration, were purchased from Sigma (St. Louis, MO). Final concentrations of test compounds were prepared on the day of the experiment and dissolved in extracellular fluid. The extracellular fluid (mM) consisted of: NaCl, 137; KCl, 4; _CaCl₂ , 1.8; MgCl₂ _, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). All test and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) consisted of: aspartic acid, 140; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11; and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. The pH was adjusted to 7.4 with cesium hydroxide.

测试化合物溶于二甲基亚砜(DMSO)，浓度为9mM。测试当天再溶于细胞外液，配制成要求浓度。The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM and redissolved in the extracellular fluid on the day of the test to prepare the required concentration.

电生理实验步骤：Electrophysiological experimental steps:

将细胞转移到灌流槽中，用细胞外液进行灌流。细胞内液实验当天融化。电极用PC–10(Narishige，Japan)拉制。全细胞膜片钳记录，噪音用采样频率的五分之一进行过滤。电极内加入1/4电极管长的细胞内液，将电极安装在探针上。设置好所需要的Protocol，将界面调成Membrane test，Stage调成Bath。电极内施加正压，将电极尖端接触到细胞，抽气装置三通阀调成三通状态，然后对电极施加负压，使得电极与细胞形成高阻封接。Stage调成Patch，leak控制在-200pA内，继续施加负压，使得细胞膜破裂，形成电流通路。打开抽滤装置和细胞外液阀门进行灌流，观察细胞电流，待细胞电流稳定开始加药(至少3个sweep的电流曲线重叠)。从低浓度往高浓度加药，每个浓度加药时间不少于2min且等到电流稳定再更换浓度加药。Transfer the cells to a perfusion tank and perfuse with extracellular solution. Thaw the intracellular solution on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, and noise was filtered at one-fifth of the sampling frequency. 1/4 of the length of the electrode tube was filled with intracellular solution and the electrode was mounted on the probe. Set the required protocol, adjust the interface to Membrane test, and adjust the Stage to Bath. Apply positive pressure to the electrode, touch the electrode tip to the cell, adjust the three-way valve of the vacuum device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the Stage to Patch, control the leak within -200pA, and continue to apply negative pressure to rupture the cell membrane, forming a current path. Open the vacuum device and the extracellular solution valve to perfuse, observe the cell current, and start adding drugs when the cell current stabilizes (the current curves of at least 3 sweeps overlap). Add medicine from low concentration to high concentration, the adding time for each concentration should be no less than 2 minutes and wait until the current is stable before changing the concentration.

供试品给药采用利用自身重力的灌流系统进行灌流。在初始记录期间，观察峰值电流幅度至少1分钟直到其稳定。在此期间，所有峰值电流幅度的CV％应小于10％以排除初始电流的上下波动。初始记录期间最后10次记录的峰值电流幅度的平均值作为阴性对照的电流峰值。待初始电流稳定后，试验样品从低浓度开始给药直到10次记录的峰值电流再次稳定或者持续给药5min后，给药后和给药前峰值电流“不变”。我们将下面两种情况定义为“稳定”或者“不变”：1)如果连续10次扫描的峰值电流的绝对平均值超过200pA而CV值小于10％，2)或者连续10次扫描的峰值电流的平均值在200pA和50pA之间而且CV值小于30％。然后给予下一个更高浓度的检测。The test article is administered using a gravity-fed perfusion system. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude fluctuations in the initial current. The average of the peak current amplitudes recorded during the last 10 recordings during the initial recording period is used as the peak current of the negative control. After the initial current stabilizes, the test article is administered starting at a low concentration until the peak currents of the 10 recordings stabilize again or, after 5 minutes of continuous administration, the peak current remains unchanged after administration. "Stable" or "unchanged" is defined as follows: 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA with a CV value of less than 10%, or 2) if the average of the peak current for 10 consecutive scans is between 200pA and 50pA with a CV value of less than 30%. The next higher concentration is then administered.

每个浓度最后10次扫描的峰值电流平均值作为该浓度的峰值电流，用于数据分析。如果5分钟内不能达到稳定状态，那么此时的最后10次扫描的峰值电流平均值作为该浓度的峰值电流用于数据分析。同时该细胞要丢弃，不再用于更高浓度的检测。化合物每个浓度至少测试两个细胞。The average peak current of the last 10 scans for each concentration was used as the peak current for that concentration and was used for data analysis. If steady state was not achieved within 5 minutes, the average peak current of the last 10 scans at that time was used as the peak current for that concentration and was used for data analysis. The cell was discarded and not used for testing at higher concentrations. At least two cells were tested for each compound concentration.

电压脉冲程序：Voltage pulse program:

将细胞钳制在–80mV，然后用持续10毫秒方波去极化到10mV，以得到NaV1.8电流。这一程序每5秒重复一次。检测方波引发的最大电流，待其稳定后，灌流测试化合物，当反应稳定后，计算阻断的强度。The cell is clamped at –80 mV and then depolarized to 10 mV with a 10-ms square wave to elicit a NaV1.8 current. This procedure is repeated every 5 seconds. The maximum current evoked by the square wave is measured and, after stabilization, the test compound is perfused. Once the response stabilizes, the magnitude of the blockade is calculated.

数据处理和拟合Data processing and fitting

资料采集和分析将用pCLAMP 10(Molecular Devices,Union City,CA)。电流稳定指的是电流随时间变化在有限的范围内。通过绘制药物的梯度稀释系列浓度和其作用在HEK293/Nav1.8上产生的稳定电流值之间的量效关系，Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the fact that the current changes within a limited range over time. The dose-response relationship between the drug concentration series and the stable current values produced by its action on HEK293/Nav1.8 cells was plotted.

进而计算该药物对Nav1.8离子通道的抑制活性(IC₅₀)。The inhibitory activity (IC ₅₀ ) of the drug on Nav1.8 ion channel was then calculated.

表1：本发明化合物Nav1.8离子通道抑制活性

Table 1: Nav1.8 ion channel inhibitory activity of the compounds of the present invention

试验结果表明，本发明化合物具有较强的对Nav1.8离子通道抑制活性。The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

测试例2：小鼠药代动力学试验Test Example 2: Pharmacokinetics test in mice

小鼠药代动力学试验，采用雄性ICR鼠3只，20-30g，禁食过夜，口服灌胃给药10mg/kg。在给药前和在给药后5、15、30分钟以及1、2、4、6、8、24小时采血。血液样品6000g下2-8℃离心3分钟，收集血浆，于-20℃保存。取各时间点血浆，加入10倍量含内标的50％甲醇乙腈溶液混合，涡旋混合5分钟，4000转/分钟4℃离心10分钟，取上清液加入1倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。For the pharmacokinetic study in mice, three male ICR mice weighing 20-30 g were fasted overnight and orally administered with 10 mg/kg. Blood was collected before administration and at 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and the plasma was collected and stored at -20°C. The plasma at each time point was taken, 10 times the amount of 50% methanol-acetonitrile solution containing the internal standard was added and mixed, vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, the supernatant was taken and 1 times the amount of water was added and mixed, and an appropriate amount of the mixture was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

表2：本发明化合物小鼠药代动力学参数
Table 2: Pharmacokinetic parameters of the compounds of the present invention in mice

实验结果表明，本发明化合物在小鼠上具有良好的药代动力学特性。The experimental results show that the compound of the present invention has good pharmacokinetic properties in mice.

测试例3：大鼠药代动力学试验Test Example 3: Pharmacokinetics test in rats

大鼠药代动力学试验，采用雄性SD大鼠3只，180-240g，禁食过夜，口服灌胃给药10mg/kg。在给药前和在给药后5、15、30分钟以及1、2、4、6、8、24小时采血。血液样品6000g下2-8℃离心3分钟，收集血浆，于-20℃保存。取各时间点血浆，加入10倍量含内标的50％甲醇乙腈溶液混合，涡旋混合5分钟，4000转/分钟4℃离心10分钟，取上清液加入1倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。For the pharmacokinetic study in rats, three male SD rats weighing 180-240 g were fasted overnight and orally administered with 10 mg/kg. Blood was collected before administration and at 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and the plasma was collected and stored at -20°C. The plasma at each time point was taken, 10 times the amount of 50% methanol-acetonitrile solution containing the internal standard was added and mixed, vortexed for 5 minutes, centrifuged at 4000 rpm and 4°C for 10 minutes, the supernatant was taken and 1 times the amount of water was added and mixed, and an appropriate amount of the mixture was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

表3：本发明化合物大鼠药代动力学参数
Table 3: Pharmacokinetic parameters of the compounds of the present invention in rats

实验结果表明，本发明化合物在大鼠上具有良好的药代动力学特性。The experimental results show that the compound of the present invention has good pharmacokinetic properties in rats.

测试例4：犬药代动力学试验Test Example 4: Dog Pharmacokinetics Study

犬药代动力学试验，采用雄性Beagle犬3只，7-11kg，禁食过夜，口服灌胃给药5mg/kg。在给药前和在给药后5、15、30分钟以及1、2、4、6、8、24小时采血。血液样品6000g下2-8℃离心3分钟，收集血浆，于-20℃保存。取各时间点血浆，加入10倍量含内标的50％甲醇乙腈溶液混合，涡旋混合5分钟，4000转/分钟4℃离心10分钟，取上清液加入1倍量水混合，取适量混合液进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 7.0软件非房室模型分析。Canine pharmacokinetic study was conducted using 3 male Beagle dogs weighing 7-11 kg, fasted overnight, and orally administered with 5 mg/kg. Blood was collected before administration and 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. Blood samples were centrifuged at 6000g for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point, added with 10 times the amount of 50% methanol-acetonitrile solution containing internal standard, mixed, vortexed for 5 minutes, centrifuged at 4000 rpm at 4°C for 10 minutes, and the supernatant was added with 1 times the amount of water and mixed. An appropriate amount of the mixture was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

表4：本发明化合物犬药代动力学参数
Table 4: Pharmacokinetic parameters of the compounds of the present invention in dogs

实验结果表明，本发明化合物在犬上具有良好的药代动力学特性。The experimental results show that the compound of the present invention has good pharmacokinetic properties in dogs.

尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

A compound, wherein the compound is a compound represented by formula (V), or a tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (V):

Wherein, A is selected from H, C _1-6 alkyl or C _3-12 cycloalkyl; wherein the C _1-6 alkyl and C _3-12 cycloalkyl are each independently optionally substituted by one or more R ^D ;

R ^D is selected from H, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy;

Y is selected from O, S or NH;

Z is N or CR ² ;

Ring B is selected from phenyl or a 5-6 membered heteroaromatic ring, wherein the heteroatom or heteroatom group in the 5-6 membered heteroaromatic ring is selected from S, S(=O), S(=O) ₂ , P(=O) ₂ , O, N ⁺ —O ⁻ , N or NH;

R ⁰ is selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, 5-12 membered heteroaryl, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, 4-12-membered heterocycloalkenyl, C _6-12 aryl, 5-12-membered heteroaryl are each independently optionally substituted with one or more ^RA ;

^R1 is selected from H, hydroxyl, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl, 5-12 membered heteroaryl; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted with one or more ^RA ;

^RA is selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy;

^R2 is independently selected from H, halogen, hydroxyl, cyano, nitro, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, C3-12 cycloalkyl, _3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl, 5-12 membered heteroaryl; wherein the _C1-6 alkyl, _C2-6 alkenyl, _C2-6 _alkynyl , _C1-6 alkoxy, C3-12 cycloalkyl, _3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, _C6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R ^B ;

^RB is selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), _C1-6 alkyl, _C1-6 alkoxy, _C1-6 haloalkyl, _C1-6 haloalkoxy;

R ³ , R ⁴ and R ⁵ are each independently selected from H, halogen, hydroxyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, 5-12 membered heteroaryl; wherein the C _1-6 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl and 5-12 membered heteroaryl are each independently optionally substituted by one or more R ^C ;

Alternatively, R ³ , R ^{4 ,} together with the atoms to which they are attached, form a C _3-12 cycloalkyl group or a 3-12 membered heterocyclyl group, wherein the C _3-12 cycloalkyl group and the 3-12 membered heterocyclyl group are optionally substituted with one or more R ^C ;

R ^C is selected from H, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy;

R ^4b1 and R ^4b2 are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

Alternatively, R ^4b1 and R ^4b2 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

R ^5b1 and R ^5b2 are each independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl or C _1-6 haloalkyl;

Alternatively, R ^5b1 and R ^5b2 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

Alternatively, R ^4b1 and R ^5b1 together with the atoms to which they are attached form a C _3-6 saturated ring, which is optionally substituted with one or more halogen, -OR ⁴ , -CN or -NR ³ R ⁴ _;

R ^6b is selected from H, -OH, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy;

R ^7b is selected from H, -OH, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy;

X ^2c is selected from N or CR ^2c ;

X ^3c is selected from N or CR ^3c ;

X ^4c is selected from N or CR ^4c ;

X ^5c is selected from N or CR ^5c ;

X ^6c is selected from N or CR ^6c ;

R ^2c is selected from H, -OH, halogen, C _1-6 alkyl, C _2-6 alkenyl, C _1-6 haloalkyl, C _1-6 deuterated alkyl, C _1-6 alkoxy, C _1-6 deuterated alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -L ¹ -(C _1-6 alkyl)-OR ⁴ , -L ¹ -(C _1-6 haloalkyl)-OR ⁴ , -L ₁ -(C ₂ - ₆ alkenyl)-OR ⁴ , -L ¹ -(C _1-6 alkyl)-NR ³ ^{R 4} ^, -L ₁ ^- (C _1-6 alkyl)-N＝S(O)(C _1-3 alkyl) ₂ , -L ¹ -(C _1-6 alkyl)-S(O) ₂ (C _1-6 alkyl) or -L ¹ -L ² -R ⁴ ; wherein the hydrogen in the C _1-6 haloalkyl and C _1-6 haloalkoxy is optionally replaced by 0, one or more deuterium;

R ^3c is selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, or -(C _1-6 alkylene)-(C _1-6 alkoxy);

R ^4c is selected from H, halogen, C _1-6 alkyl, or C _1-6 haloalkyl;

R ^5c is selected from H, halogen, C _1-6 alkyl, or C _1-6 haloalkyl; and

R ^6c is selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, or C _1-6 alkoxy;

L ¹ is a bond or -O-;

L ² is a bond or -(C _1-6 alkyl)-;

n is selected from 0, 1, 2, 3, 4, 5 and 6.

The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it is a compound represented by formula (II-D), formula (II-E), formula (II-F) or (II-G):

in,

Z is N or CR ² ;

X ^3a is N or CR ^3a ;

X ^4a is N or CR ^4a ;

X ^5a is N or CR ^5a ;

X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R ^3a and R ^4a are each independently selected from H, halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 haloalkoxy;

R ^5a and R ^6a are each independently selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ;

W is selected from S, S(═O), S(═O) ₂ , P(═O) ₂ , O or RH;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , ^R7b , RA and ^A are as defined in claim 1.

The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that it is a compound represented by formula (IC), formula (ID), formula (IF) or formula (IG):

in,

X ^3a is N or CR ^3a ;

X ^4a is N or CR ^4a ;

X ^5a is N or CR ^5a ;

X ^6a is N, N ⁺ —O ^— , or CR ^6a ;

R ^5a and R ^6a are each independently selected from H, halogen, hydroxyl, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -NR ³ R ⁴ , -C(＝O)NR ³ R ⁴ , -C(＝NR ⁵ )NR ³ R ⁴ , -OR ⁴ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NR ³ R ⁴ or -S(＝O)(＝NR ⁵ )R ³ ; said _C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy and C _1-6 haloalkoxy are each independently optionally substituted by one or more ^RA ;

W is selected from S, S(=O), S(=O) ₂ , P(=O) ₂ , O or NH;

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b , R ^7b , X ^2c , X ^3c , X ^4c , X ^5c and X ^6c are as defined in the present invention.

The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that:

R ¹ is H, hydroxy or C _1-6 alkoxy; or, R ¹ is H or hydroxy;

and/or, R ² is H, halogen, hydroxy, C _1-6 alkyl, C _1-6 alkoxy, wherein the C _1-6 alkyl and C _1-6 alkoxy are each independently optionally substituted by one or more ^RB ; or, R ² is H, F, Cl, hydroxy, methyl, methoxy, wherein the methyl and methoxy are each independently optionally substituted by one or more ^RB ;

And/or, ^RB is selected from H, F, Cl, hydroxy, methyl, methoxy.

^R2 is H, halogen, hydroxy, _C1-6 alkyl, _C1-6 alkoxy; or, ^R2 is H, F, Cl, hydroxy, methyl, methoxy;

Selected from wherein X ^3a is N or CR ^3a ; X ^4a is N or CR ^4a ; X ^5a is N or CR ^5a ; X ^6a is N, N ⁺ —O ^— , or CR ^6a ; and R ^3a , R ^4a , R ^5a , and R ^6a are each independently selected from H, halogen, hydroxy, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl, —NR ³ R ⁴ , —C(═O)NR ³ R ⁴ , —C(═NR ⁵ )NR ³ R ⁴ , —OR ⁴ , —S(═O) ₂ R ³ , —S(═O) ₂ NR ³ R ⁴ or -S(=O)(=NR ⁵ )R ³ ; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C _6-12 aryl, and 5-12 membered heteroaryl are each independently optionally substituted by one or more ^RA ;

and/or, R ^3a , R ^4a , R ^5a and R ^6a are each independently selected from H, halogen, C _1-6 alkyl, R ^6a and R ^5a are each independently selected from cyano, -CH(OH)CH ₂ OH, -OCH ₂ CH(OH)CH ₂ OH, -C(═O)NHR ³ , -C(═NH)NHR ³ , -S(═O) ₂ R ³ , -S(═O) ₂ NHR ³ , -S(═O)(═NH)R ³ or -OR ⁴ , R ³ is H, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, and the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted by one or more R ^C ;

and/or, for wherein R ^4a is H, halogen, or C _1-6 alkyl; R ^6a and R ^5a are each independently selected from H, halogen, C _1-6 alkyl, cyano, -CH(OH)CH ₂ OH, -OCH ₂ CH(OH)CH ₂ OH, -C(═O)NHR ³ , -C(═NH)NHR ³ , -S(═O) ₂ R ³ , -S(═O) ₂ NHR ³ , -S(═O)(═NH)R ³ or -OR ⁴ ; R ³ is H, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, wherein the C _1-6 alkyl and C _1-6 alkoxy are optionally substituted by one or more ^RC ; and R ⁴ is H or C _1-6 alkyl, wherein _the C _1-6 alkyl is optionally substituted by one or more ^RC ;

and/or, R ³ and R ⁴ are each independently selected from H, hydroxyl, methyl,

and/or, for

and/or, Selected from wherein R ^6a is -OCH ₂ CH(OH)CH ₂ OH, -OCH ₂ CH ₂ OH, -C(＝O)NHR ³ , -C(＝NH)NHR ³ , -S(＝O) ₂ R ³ , -S(＝O) ₂ NHR ³ or -S(＝O)(＝NH)R ³ , and R ³ is H, hydroxy, C _1-6 alkyl or C _1-6 alkoxy, and the C _1-6 alkyl and C _1-6 alkoxy groups are optionally substituted with one or more R ^C ;

and/or, Selected from

for

or, for

and/or, R ^5b1 and R ^5b2 are each independently selected from C _1-6 alkyl or C _1-6 haloalkyl; or, R ^5b1 and R ^5b2 are each independently selected from methyl or trifluoromethyl; more preferably, R ^5b1 is methyl and R ^5b2 is trifluoromethyl;

and/or, R ^4b1 and R ^4b2 are each independently selected from H, C _1-6 alkyl or C _1-6 haloalkyl; or, R ^4b1 and R ^4b2 are each independently selected from H, methyl, ethyl, n-propyl, isopropyl; or, R ^4b1 is H, and R ^4b2 is methyl;

and/or, R ^6b is H;

and/or, R ^7b is H;

and/or, for

A is H;

And/or, A is wherein X ^2c , X ^3c , X ^4c , X ^5c and X ^6c are as defined in claim 1;

and/or, for wherein R ^2c , R ^3c and R ^4c are as defined in claim 1;

and/or, R ^2c is a 3-6 membered heterocyclyl substituted by one or more halogens, a C _3-6 cycloalkyl substituted by one or more halogens, a C _1-6 alkyl, a C _1-6 alkoxy, a C _1-6 deuterated alkoxy, or -N(C _1-6 alkyl) ₂ ; or, R ^2c is methyl, ethyl, n-propyl, isopropyl, methoxy, ethyloxy, n-propyloxy, isopropyloxy, -O-CD ₃ , -N(CH ₂ CH ₃ ) ₂ , -N(CH ₃ )(CH ₂ CH ₃ ), -N(CH ₃ ) ₂ , More preferably, R ^2c is methyl, methoxy, -O-CD ₃ , -N(CH ₃ ) ₂ ,

and/or, R ^3c is H or halogen; or, R ^3c is H, F or Cl; more preferably, R ^3c is H or F;

and/or, R ^4c is halogen; or, R ^4c is F or Cl; more preferably, R ^4c is F;

and/or, for

and/or, A is C _1-6 alkyl; or, A is methyl, ethyl, n-propyl or isopropyl; or, A is methyl;

And/or, A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; or, A is cyclopropyl.

The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that the compound is selected from the following compounds:

The compound is selected from the following compounds:

A method for preparing the compound according to any one of claims 1 to 8, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug,

The method is selected from solution 1, comprising the following steps:

Formula (Int1) and Formula (Int2) are reacted in the presence of a palladium catalyst (e.g., Pd2(dba)3, Pd(dba)2), a phosphine ligand (e.g., Xphos or Xantphos), and a strong base (e.g., one or more _of NaOH, _NaOtBu , _Cs2CO3 , _K3PO4 , _K2CO3 , _Na2CO3 , KOAc) in a non-polar organic solvent (e.g., dioxane, toluene) to obtain _a compound of Formula ( _V ); wherein the reaction is carried out in an oxygen-free environment; and/or the reaction temperature is 90°C to 110°C; and/or the reaction time is 8-30 hours.

Or the method is selected from Scheme 2, comprising the steps of:

reacting the compound of formula (Int3) and formula (Int4) in the presence of an acylating agent (e.g., an acid anhydride (e.g., acetic anhydride) or an acid chloride (e.g., oxalyl chloride)) and an organic base (e.g., N,N-dimethylformamide) to obtain a compound of formula (Int5); wherein the reaction is carried out in an anaerobic environment; and/or the reaction temperature is 20° C. to 30° C.; and/or the reaction time is 1-4 hours;

The compound of formula (Int5) forms the compound of formula (V) under the action of a strong base (eg, NaOH, NaOtBu, Cs ₂ CO ₃ , K ₃ PO 4 , K ₂ CO ₃ , Na ₂ CO ₃ , KOAc).

A compound as follows:

wherein, ring B, R ⁰ , n, Y, A, R ^4b1 , R ^4b2 , R ^5b1 , R ^5b2 , R ^6b and R ^7b are as defined in claim 1.

A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 10, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable excipient.

The use of a compound according to any one of claims 1 to 10, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition according to claim 11 in the preparation of a drug for inhibiting voltage-gated sodium ion channels; and/or, in the preparation of a drug for treating, relieving or preventing pain; and/or, wherein the voltage-gated sodium ion channel is Nav1.8; and/or, wherein the pain includes acute pain, especially postoperative pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, intestinal pain, idiopathic pain, primary pain such as fibromyalgia, primary pain such as headache and maxillofacial pain.