Tetrahydrofuran pyridone compound serving as nav1.8 inhibitor

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

[0001] The present invention claims:

[0002] 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”;

[0003] 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”;

[0004] 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”;

[0005] 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”;

[0006] 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”;

[0007] 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.

[0008] The entire contents of the above-mentioned prior applications are incorporated into the present application by reference. Technical Field

[0009] 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

[0010] 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.

[0011] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They 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 reaching higher nerve centers, causing pain sensation. 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.

[0012] 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.

[0013] 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.

[0014] 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 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 effectiveness, increased metabolic stability, increased solubility and fewer side effects. Summary of the Invention

[0015] 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.

[0016] 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:

[0017] in,

[0018] A is selected from H, C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0019] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0020] Y is selected from O, S or NH;

[0021] Z is N or CR 2 ;

[0022] Ring B is selected from phenyl or 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;

[0023] R 0 Selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 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 R A replaced by;

[0024] R 1Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0025] R A Selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0026] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0027] R B Selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0028] R 3 、R 4 and R5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0029] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0030] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0031] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0032] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0033] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0034] Or, R 5b1 and R 5b2Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0035] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0036] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0037] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0038] X 2c Select N or CR 2c ;

[0039] X 3c Select N or CR 3c ;

[0040] X 4c Select N or CR 4c ;

[0041] X 5c Select N or CR 5c ;

[0042] X 6c Select N or CR 6c ;

[0043] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated alkyl, C1-6 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 C 1-6 Haloalkyl and C 1-6 The hydrogen in the haloalkoxy group is optionally substituted with 0, 1 or more deuteriums;

[0044] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0045] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0046] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0047] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0048] L 1 is a bond or -O-;

[0049] L 2 Is a key or -(C 1-6 alkyl)-;

[0050] 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)

[0051] in,

[0052] A is selected from H, C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0053] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0054] Y is selected from O or S;

[0055] Z is N or CR 2 ;

[0056] Ring B is selected from phenyl or 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;

[0057] R 0 Selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)2R 3 、-S(=O)2NR3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A replaced by;

[0058] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0059] R A Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0060] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more RB replaced by;

[0061] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0062] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0063] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0064] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0065] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0066] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR3 R 4 replaced by;

[0067] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0068] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0069] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0070] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0071] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0072] X 2c Select N or CR 2c ;

[0073] X 3c Select N or CR 3c ;

[0074] X 4c Select N or CR 4c ;

[0075] X5c Select N or CR 5c ;

[0076] X 6c Select N or CR 6c ;

[0077] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated 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 C 1-6 The hydrogen in the haloalkoxy group is optionally substituted with 0, 1 or more deuteriums;

[0078] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0079] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0080] R 5c Selected from H, halogen, C 1-6 Alkyl, or C1-6 haloalkyl; and

[0081] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0082] L 1 is a bond or -O-;

[0083] L 2 Is a key or -(C 1-6 alkyl)-;

[0084] n is selected from 0, 1, 2, 3, 4, 5 and 6.

[0085] 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)

[0086] in,

[0087] A is selected from H, C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0088] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0089] Y is selected from O or S;

[0090] Z is N or CR 2 ;

[0091] Ring B is selected from phenyl or 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;

[0092] R 0 Selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Alkoxy, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0093] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0094] R A Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0095] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0096] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0097] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0098] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0099] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0100] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0101] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0102] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0103] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0104] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0105] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0106] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0107] X 2c Select N or CR 2c ;

[0108] X 3c Select N or CR 3c ;

[0109] X 4c Select N or CR 4c ;

[0110] X 5c Select N or CR 5c ;

[0111] X 6c Select N or CR 6c ;

[0112] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated 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 C 1-6 The hydrogen in the haloalkoxy group is optionally substituted with 0, 1 or more deuteriums;

[0113] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0114] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0115] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0116] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0117] L 1 is a bond or -O-;

[0118] L 2 Is a key or -(C 1-6 alkyl)-;

[0119] n is selected from 0, 1, 2, 3, 4, 5 and 6.

[0120] 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)

[0121] in,

[0122] A is selected from C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0123] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0124] Z is N or CR 2 ;

[0125] Ring B is selected from phenyl or 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;

[0126] R 0 Selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C1-6 Halogenated alkyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0127] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0128] R A Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0129] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0130] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0131] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0132] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0133] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0134] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0135] Or, R 4b1and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0136] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0137] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0138] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0139] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0140] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0141] X 2c Select N or CR 2c ;

[0142] X 3c Select N or CR3c ;

[0143] X 4c Select N or CR 4c ;

[0144] X 5c Select N or CR 5c ;

[0145] X 6c Select N or CR 6c ;

[0146] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated 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 ;

[0147] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0148] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0149] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0150] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0151] L 1 is a bond or -O-;

[0152] L 2 Is a key or -(C 1-6 alkyl)-;

[0153] n is selected from 0, 1, 2, 3, 4, 5 and 6.

[0154] 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)

[0155] in,

[0156] A is selected from C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0157] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0158] Z is N or CR 2 ;

[0159] X 3a N or CR 3a ;

[0160] X 4a N or CR 4a ;

[0161] X 5a N or CR 5a ;

[0162] X6a N, N + -O - or CR 6a ;

[0163] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0164] R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0165] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0166] R A Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 haloalkoxy;

[0167] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0168] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0169] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0170] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0171] R CSelected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0172] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0173] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0174] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0175] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0176] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0177] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0178] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0179] X 2c Select N or CR 2c ;

[0180] X 3c Select N or CR 3c ;

[0181] X 4c Select N or CR 4c ;

[0182] X 5c Select N or CR 5c ;

[0183] X 6c Select N or CR 6c ;

[0184] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated 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 -L2 -R 4 ;

[0185] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0186] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0187] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0188] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0189] L 1 is a bond or -O-;

[0190] L 2 Is a key or -(C 1-6 alkyl)-.

[0191] 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)

[0192] in,

[0193] A is selected from C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by;

[0194] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0195] X 3a N or CR3a ;

[0196] X 4a N or CR 4a ;

[0197] X 5a N or CR 5a ;

[0198] X 6a N, N + -O - or CR 6a ;

[0199] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0200] R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0201] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0202] R A Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0203] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0204] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0205] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0206] Or, R3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0207] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0208] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0209] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0210] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0211] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0212] Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R4 replaced by;

[0213] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0214] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0215] X 2c Select N or CR 2c ;

[0216] X 3c Select N or CR 3c ;

[0217] X 4c Select N or CR 4c ;

[0218] X 5c Select N or CR 5c ;

[0219] X 6c Select N or CR 6c ;

[0220] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated 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)-NR3 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 ;

[0221] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy);

[0222] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0223] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0224] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0225] L 1 is a bond or -O-;

[0226] L 2 Is a key or -(C 1-6 alkyl)-.

[0227] 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):

[0228] in,

[0229] Z is N or CR 2 ;

[0230] X 3a N or CR 3a ;

[0231] X4a N or CR 4a ;

[0232] X 5a N or CR 5a ;

[0233] X 6a N, N + -O - or CR 6a ;

[0234] R 3a 、R 4a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0235] R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A replaced by;

[0236] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0237] R 1 、R 2 、R 3 、R 4 、R 5 、R 4b1 、R 4b2 、R5b1 、R 5b2 、R 6b 、R 7b 、R A , A are as defined in the present invention. 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):

[0238] in,

[0239] X 3a N or CR 3a ;

[0240] X 4a N or CR 4a ;

[0241] X 5a N or CR 5a ;

[0242] X 6a N, N + -O - or CR 6a ;

[0243] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0244] R 6a H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by one or more hydroxyl groups 1-6 Alkyl, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0245] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0246] R 1 、R 2 、R 3 、R 4 、R 5 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b , A is defined as described in the present invention.

[0247] 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):

[0248] in,

[0249] X 3a N or CR 3a ;

[0250] X 4a N or CR 4a ;

[0251] X 5a N or CR 5a ;

[0252] X 6a N, N + -O - or CR 6a ;

[0253] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0254] R 6a H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0255] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0256] R 1 、R 2 、R 3 、R 4 、R 5 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b , A is defined as described in the present invention.

[0257] 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):

[0258] in,

[0259] X 3a N or CR 3a ;

[0260] X 4a N or CR 4a ;

[0261] X 5a N or CR 5a ;

[0262] X 6a N, N + -O - or CR 6a ;

[0263] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C1-6 haloalkoxy;

[0264] R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0265] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0266] R 1 、R 2 、R 3 、R 4 、R 5 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b , A is defined as described in the present invention.

[0267] 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):

[0268] Among them, X 3a 、X 4a 、X 5a 、X 6a 、R 1 、R 2 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b , A is defined as described in the present invention.

[0269] 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):

[0270] Among them, X 3a 、X 4a 、X 5a 、X 6a 、R 1 、R 2 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b , A is defined as described in the present invention.

[0271] 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):

[0272] Among them, X 3a 、X 4a 、X 5a 、X 6a 、R 1 、R 2 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b 、X 2c 、X 3c 、X 4c 、X 5c and X 6c The definition of is as described in the present invention.

[0273] 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):

[0274] in,

[0275] X 3a N or CR 3a ;

[0276] X 4a N or CR 4a ;

[0277] X 5a N or CR 5a ;

[0278] X 6a N, N + -O - or CR 6a ;

[0279] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0280] R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0281] R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0282] R ASelected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0283] R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0284] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0285] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0286] Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by;

[0287] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0288] R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide;

[0289] Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0290] R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C1-C6 haloalkyl;

[0291] Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by;

[0292] R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0293] R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0294] X 2c Select N or CR 2c ;

[0295] X 3c Select N or CR 3c ;

[0296] X 4c Select N or CR 4c ;

[0297] X 5c Select N or CR 5c ;

[0298] X 6c Select N or CR 6c ;

[0299] R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C2-C6 alkenyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, -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 ;

[0300] R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6alkoxy);

[0301] R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide;

[0302] R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and

[0303] R 6c Selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 alkoxy;

[0304] L 1 is a bond or -O-;

[0305] L 2 Is a key or -(C 1-6 alkyl)-.

[0306] 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):

[0307] in,

[0308] X 3a N or CR 3a ;

[0309] X 4a N or CR 4a ;

[0310] X 5a N or CR 5a ;

[0311] X 6a N, N + -O - or CR 6a ;

[0312] R 3a 、R 4a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0313] R 5a and R6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; The C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A replaced by;

[0314] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0315] 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 The definition of is as described in the present invention.

[0316] 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):

[0317] in,

[0318] X 3a N or CR 3a ;

[0319] X 4a N or CR 4a ;

[0320] X 5a N or CR 5a ;

[0321] X 6a N, N + -O - or CR 6a ;

[0322] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0323] R 6a H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C substituted by one or more hydroxyl groups 1-6 Alkyl, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0324] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0325] 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 X6c The definition of is as described in the present invention.

[0326] 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):

[0327] in,

[0328] X 3a N or CR 3a ;

[0329] X 4a N or CR 4a ;

[0330] X 5a N or CR 5a ;

[0331] X 6a N, N + -O - or CR 6a ;

[0332] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0333] R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0334] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0335] 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 The definition of is as described in the present invention.

[0336] 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):

[0337] in,

[0338] X 3a N or CR 3a ;

[0339] X 4a N or CR 4a ;

[0340] X 5a N or CR 5a ;

[0341] X 6a N, N + -O - or CR 6a ;

[0342] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0343] R 6a H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ;

[0344] W is selected from S, S(=O), S(=O)2, P(=O)2, O or NH;

[0345] 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 The definition of is as described in the present invention.

[0346] 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):

[0347] Among them, X 3a 、X 4a 、X 5a 、X 6a 、R 1 、R 2 、R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b 、R 7b 、X 2c 、X 3c 、X 4c 、X 5c and X 6c The definition of is as described in the present invention.

[0348] In an optional embodiment of the present invention, R 1 H, hydroxyl or C 1-6 Alkoxy; preferably, R 1is H or hydroxyl.

[0349] In an optional embodiment of the present invention, R 1 For H.

[0350] In an optional embodiment of the present invention, Z is N or CR 2 , R 2 The definition of is as described in the present invention.

[0351] In an optional embodiment of the present invention, R 2 independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently optionally substituted with one or more R B Replaced by; R B The definition of is as described in the present invention.

[0352] In an optional embodiment of the present invention, R 2 Independently selected from H, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy; the C 1-3 Alkyl, C 1-3 Each alkoxy group is independently optionally substituted with one or more R B Replaced by; R B The definition of is as described in the present invention.

[0353] In an optional embodiment of the present invention, R 2 are independently selected from H, F, Cl, hydroxy, methyl, methoxy; the methyl and methoxy groups are each independently optionally replaced by one or more R B Replaced by; R B The definition of is as described in the present invention.

[0354] In an optional embodiment of the present invention, R B Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy.

[0355] In an optional embodiment of the present invention, R B Selected from H, F, Cl, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy.

[0356] In an optional embodiment of the present invention, R B Selected from H, F, Cl, hydroxy, methyl, methoxy.

[0357] In an optional embodiment of the present invention, R 2H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R 2 It is H, F, Cl, hydroxy, methyl, and methoxy.

[0358] In an optional embodiment of the present invention, R 2 H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy; preferably, R 2 It is H, F, Cl, methyl, or methoxy.

[0359] In an optional embodiment of the present invention, R 2 For H.

[0360] In an optional embodiment of the present invention, Selected from

[0361] X 3a 、X 4a 、X 5a 、X 6a , W are defined as described in the present invention.

[0362] In some embodiments of the present invention, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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)2R 3、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 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 R A Replaced by; wherein R 3 、R 4 、R 5 、R A The definition of is as described 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 、R 5a Each independently selected from cyano, -CH(OH)CH2OH, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C replaced by;

[0363] In some embodiments of the present invention, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ; R 3a 、R 4a are each independently selected from H, halogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A Replaced by; wherein R 3 、R 4 、R 5 、R A The definition of is as described in the present invention.

[0364] In an optional embodiment of the present invention, for X 3a 、X 4a 、X 5a 、X 6a The definition of is as described in the present invention.

[0365] In an optional embodiment of the present invention, for X 4a 、X 5a 、X 6a The definition of is as described in the present invention.

[0366] In an optional embodiment of the present invention, R 6a independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; The C 1-6 Alkyl, C 1- 6 alkoxy groups are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxyl groups; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0367] In an optional embodiment of the present invention, R 6a 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)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0368] In an optional embodiment of the present invention, R 6a 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)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0369] In an optional embodiment of the present invention, R 6a Independently selected from H, hydroxyl, cyano,

[0370] In an optional embodiment of the present invention, R 5a 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; The C 1-6 Alkyl, C 1- 6 alkoxy groups are each independently optionally substituted by 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxyl groups; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0371] In an optional embodiment of the present invention, R 5a 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)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; The C 1-6 Alkyl, independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, hydroxyl; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0372] In an optional embodiment of the present invention, R 5a Independently selected from H, C 1-6Alkyl, -C(=O)NR 3 R 4 、The C 1-6 Alkyl is optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxyl groups independently; R 3 、R 4 、R 5 The definition of is as described in the present invention.

[0373] In an optional embodiment of the present invention, R 5a Independently selected from H, hydroxyl, cyano,

[0374] In an optional embodiment of the present invention, R 3 、R 4 、R 5 Each independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxy.

[0375] In an optional embodiment of the present invention, R 3 、R 4 、R 5 Each independently selected from H, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxy.

[0376] In an optional embodiment of the present invention, R 3 、R 4 、R 5 Each independently selected from H, hydroxyl, C 1-6 Alkyl; the C 1-6 Alkyl groups are independently optionally substituted with 1, 2, 3, 4, 5 or 6 H, halogen, or hydroxy.

[0377] In an optional embodiment of the present invention, R 3 、R 4 、R 5 Each independently selected from H, hydroxy, methyl,

[0378] In an optional embodiment of the present invention, R 4a are each independently selected from H, halogen, C 1-6 alkyl.

[0379] In an optional embodiment of the present invention, R 4a Each is independently selected from H, F, Cl, methyl, ethyl, n-propyl, isopropyl.

[0380] In an optional embodiment of the present invention, R 4a For H.

[0381] In an optional embodiment of the present invention, Selected from Among them, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 6a H, halogen, hydroxyl, 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)2R 3 、-S(=O)2NR 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.

[0382] In an optional embodiment of the present invention, for Among them, R 4a H, halogen, C 1-6 Alkyl, R 6a 、R 5a are each independently selected from H, halogen, C 1-6Alkyl, cyano, -CH(OH)CH2OH, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C As defined in the present invention, R 4 H or C 1-6 Alkyl, the C 1-6 The alkyl group is selected from one or more R C Replaced by R C The definition of is as described in the present invention.

[0383] In an optional embodiment of the present invention, for R 4a 、R 5a 、R 6a Definitions as described in this invention.

[0384] In an optional embodiment of the present invention, for Among them, R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a Cyano, -CH(OH)CH2OH, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by RC As defined in the present invention, R 4 H or C 1-6 Alkyl, the C 1-6 The alkyl group is selected from one or more R C Replaced by R C The definition of is as described in the present invention. In an optional embodiment of the present invention, for Among them, R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a Cyano, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C As defined in the present invention, R 4 H or C 1-6 Alkyl, the C 1-6 The alkyl group is optionally replaced by one or more R C Replaced by R C The definition of is as described in the present invention.

[0385] In an optional embodiment of the present invention, for Among them, R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of is as described in the present invention.

[0386] In an optional embodiment of the present invention, for

[0387] In an optional embodiment of the present invention, for

[0388] In an optional embodiment of the present invention, for

[0389] In an optional embodiment of the present invention, for

[0390] In an optional embodiment of the present invention, Selected from Among them, R 6a is -OCH2CH(OH)CH2OH, -OCH2CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of is as described in the present invention.

[0391] In an optional embodiment of the present invention, Selected from

[0392] In an optional embodiment of the present invention, for where R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition of is as described in the present invention.

[0393] In an optional embodiment of the present invention, for where R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition of is as described in the present invention.

[0394] In an optional embodiment of the present invention, for where R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition of is as described in the present invention.

[0395] In an optional embodiment of the present invention, for where R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition of is as described in the present invention.

[0396] In an optional embodiment of the present invention, for where R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition of is as described in the present invention.

[0397] In an optional embodiment of the present invention, R 5b1 and R 5b2 Each independently selected from C 1-6 Alkyl or C 1-6 preferably, R 5b1 and R 5b2are each independently selected from methyl or trifluoromethyl; more preferably, R 5b1 is methyl, R 5b2 It is trifluoromethyl.

[0398] In an optional embodiment of the present invention, R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl or C 1-6 preferably, R 4b1 and R 4b2 are independently selected from H, methyl, ethyl, n-propyl, isopropyl; more preferably, R 4b1 H, R 4b2 It is a methyl group.

[0399] In an optional embodiment of the present invention, R 6b For H.

[0400] In an optional embodiment of the present invention, R 7b For H.

[0401] In an optional embodiment of the present invention, for

[0402] In an optional embodiment of the present invention, for

[0403] In an optional embodiment of the present invention, for

[0404] In an optional embodiment of the present invention, A is H.

[0405] In an optional embodiment of the present invention, A is where X 2c 、X 3c 、X 4c 、X 5c and X 6c The definition of is as described in the present invention.

[0406] In an optional embodiment of the present invention, for where R 2c 、R 3c and R 4c The definition of is as described in the present invention.

[0407] In an optional embodiment of the present invention, R 2cis a 3-6 membered heterocyclic group substituted by one or more halogens, a C 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, -N(C 1-6 alkyl)2; preferably, R 2c is methyl, ethyl, n-propyl, isopropyl, methoxy, ethyloxy, n-propyloxy, isopropyloxy, -O-CD3, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH3)2, More preferably, R 2c Methyl, methoxy, -O-CD3, -N(CH3)2,

[0408] In an optional embodiment of the present invention, R 2c is a 3-6 membered heterocyclic group substituted by one or more halogens, C 1-6 Alkoxy, -N(C 1-6 alkyl)2; preferably, R 2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH3)2, More preferably, R 2c is methoxy, -N(CH3)2 or

[0409] In an optional embodiment of the present invention, R 2c C 1-6 Alkoxy; preferably, R 2c is methoxy, ethyloxy, n-propyloxy, isopropyloxy, more preferably, R 2c It is a methoxy group.

[0410] 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 H or F.

[0411] In an optional embodiment of the present invention, R 3c is halogen; preferably, R 3c is F or Cl; more preferably, R 3c For F.

[0412] In an optional embodiment of the present invention, R 4c is halogen; preferably, R 4c is F or Cl; more preferably, R 4c For F.

[0413] In an optional embodiment of the present invention, for

[0414] In an optional embodiment of the present invention, for

[0415] In an optional embodiment of the present invention, for

[0416] 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;

[0417] In an optional embodiment of the present invention, A is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; preferably, A is cyclopropyl.

[0418] 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:

[0419] 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:

[0420] 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:

[0421] Solution 1

[0422] 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.

[0423] 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:

[0424] Option 2

[0425] 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.

[0426] The compound of formula (Int5) forms the compound of formula (V) under the action of a strong base (such as NaOH, NaOtBu, Cs2CO3, K3PO4, K2CO3, Na2CO3, KOAc).

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] 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.

[0432] 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.

[0433] 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:

[0434] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0435] 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.

[0436] 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.

[0437] Terms and Definitions

[0438] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0439] 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.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] 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.

[0451] 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 bond Indicates the relative configuration of a stereocenter.

[0452] 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:

[0453] Keto and enol forms interconvert.

[0454] 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:

[0455] Due to resonance, the hydrogen atoms of the tetrazole nitrogen can be on any of the four nitrogen atoms.

[0456] 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"), whether radioactive or not, are encompassed within the scope of the present invention.

[0457] 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.

[0458] 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.

[0459] 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.

[0460] 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.

[0461] 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.

[0462] 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 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. For example, R 1 Be g R a When g is 2, 3 or 4, each R a Are independent options and can be the same or different.

[0463] 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.

[0464] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6Examples of 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.

[0465] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0466] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0467] 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.

[0468] Unless otherwise specified, “C 2-6 "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 of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0469] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer 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 of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0470] Unless otherwise specified, “C 2-6"Alkynyl" is used to represent 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 of the group. 2-6 Alkynyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0471] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent 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 of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0472] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of 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.

[0473] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0474] Unless otherwise specified, the term “C 3-12 Cycloalkyl" or "C 3-12"Saturated ring" means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-12 Cycloalkyl groups include 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, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0475] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0476] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0477] Unless otherwise specified, the term "C 6-12 Aromatic ring" and "C 6-12 Aryl" can be used interchangeably, the term "C 6-12 Aromatic ring" or "C 6-12"Aryl" refers to a cyclic hydrocarbon group composed of 6 to 12 carbon atoms with a conjugated π electron system, which 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 and 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 C6 aryl, etc. 6-12 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0478] 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.

[0479] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one of n to n+m carbons, e.g., C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 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.

[0480] 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.

[0481] 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.

[0482] 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.).

[0483] 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.).

[0484] Unless otherwise specified, the term "5,6-membered ring" refers to a 5-membered ring and a 6-membered ring.

[0485] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0486] 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.

[0487] 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.

[0488] 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.

[0489] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0490] (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;

[0491] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0492] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0493] (iv) Alleviate the symptoms of the disease or condition.

[0494] 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.

[0495] 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. DETAILED DESCRIPTION

[0496] 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.

[0497] 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 The solvents for NMR measurements include deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (MeOD), heavy water (D2O), etc., and tetramethylsilane (TMS) is the internal standard.

[0498] The abbreviations of the present invention are defined as follows:

[0499] PE: Petroleum Ether

[0500] EA: Ethyl Acetate

[0501] brine: saturated salt water (brine)

[0502] DMF: Dimethylformamide

[0503] NBS: N-Bromosuccinimide

[0504] BPO: Benzoyl Peroxide

[0505] NMO: N-Methoxyphthalimide

[0506] THF: Tetrahydrofuran

[0507] DCM: Dichloromethane

[0508] Dioxane:1,4-Dioxane

[0509] Xantphos: 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline

[0510] TLC: Thin layer chromatography

[0511] LC-MS: Liquid chromatography-mass spectrometry

[0512] M: molar concentration, for example, 1M hydrochloric acid means that there is 1 mol of HCl per liter of solution

[0513] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0514] IC50: half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0515] 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.

[0516] Example 1: Preparation of target compound I-1

[0517] 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)

[0518] The route of target compound I-1 is as follows:

[0519] Step 1: Synthesis of N-(tert-butyl)-4-chloro-3-iodopyridineamide

[0520] 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).

[0521] LC-MS, M / Z: 339.0 (M+H + )

[0522] Step 2: Synthesis of 3-acetyl-N-(tert-butyl)-4-chloropyridineamide

[0523] 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).

[0524] LC-MS, M / Z: 255.0 (M+H + )

[0525] Step 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0526] (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).

[0527] LC-MS, M / Z: 354.0 (M+H + )

[0528] 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

[0529] (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).

[0530] LC-MS, M / Z: 554.2 (M+H + )

[0531] 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)

[0532] 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 completion of the reaction, the reaction solution was concentrated to obtain a crude product, which was separated and purified by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18150*25mm*10μm; mobile phase: solvent A=water+0.1% formic acid, B=acetonitrile; gradient: 38%-68%, 11 min) 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).

[0533] LC-MS, M / Z: 498.3 (M+H + )

[0534] 1 H 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)

[0535] Example 2: Preparation of target compound I-4

[0536] 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)

[0537] The synthetic route of target compound I-4 is as follows:

[0538] 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

[0539] 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).

[0540] LC-MS, M / Z (ESI): 680.1 (M+H + ).

[0541] 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

[0542] 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).

[0543] LC-MS, M / Z (ESI): 568.2 (M+H + ).

[0544] 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)

[0545] 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 complete, the reaction solution was concentrated to dryness, and the crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 35%-65%, 9 min) to give 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).

[0546] LC-MS, M / Z (ESI): 512.3 (M+H + ).

[0547] 1 H 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)

[0548] Example 3: Preparation of target compound I-6

[0549] 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)

[0550] The synthetic route of target compound I-6 is as follows:

[0551] 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

[0552] 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).

[0553] LC-MS, M / Z (ESI): 588.1 (M+H + ).

[0554] 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)

[0555] 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 complete, the reaction solution was concentrated to dryness, and the crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 38%-68%, 9 min) to give 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).

[0556] LC-MS, M / Z (ESI): 532.2 (M+H + ).

[0557] 1 H 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),6.4 1-6.51(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)

[0558] Example 4: Preparation of target compound I-7

[0559] 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)

[0560] The synthetic route of target compound I-7 is as follows:

[0561] 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)

[0562] 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 complete, 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%, 9 min) 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).

[0563] LC-MS, M / Z (ESI): 516.2 (M+H + )

[0564] 1 H 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).

[0565] Example 5: Preparation of target compound I-8

[0566] 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)

[0567] The synthetic route of target compound I-8 is as follows:

[0568] 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

[0569] 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).

[0570] LC-MS, M / Z (ESI): 533.1 (M+H + ).

[0571] 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

[0572] 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).

[0573] LC-MS, M / Z (ESI): 585.3 (M+H + ).

[0574] 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)

[0575] 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 give 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) (8.00 mg, 17% yield).

[0576] LC-MS, M / Z (ESI): 545.3 (M+H + ).

[0577] 1 H 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=5.1 4Hz,2H),4.25(dd,J=11.00,8.50Hz,1H),4.00-4.08(m,1H),3.96(d,J=2.50 Hz,3H),3.71(d,J=5.26Hz,2H),2.88(m,1H),1.72(s,3H),0.82-0.94(m,3H).

[0578] Example 6: Preparation of target compound I-9

[0579] 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)

[0580] The synthetic route of target compound I-9 is as follows:

[0581] Step 1: Synthesis of 2-(benzylthio)-3-bromo-4-chloropyridine

[0582] 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 obtain 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)

[0583] LC-MS, M / Z (ESI): 315.8 (M+H + ).

[0584] Step 2: Synthesis of 3-bromo-4-chloropyridine-2-sulfonyl chloride

[0585] 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.

[0586] Step 3: Synthesis of 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide

[0587] 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%, 15 min) to give 3-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (2.50 g, 30.7% yield).

[0588] LC-MS, M / Z (ESI): 512.9 (M+H + ).

[0589] Step 4: Synthesis of 3-acetyl-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide

[0590] The raw 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 then stirred at 110°C for 12 hours. After the reaction was complete, it was concentrated directly to obtain a crude product. The crude product was diluted in tetrahydrofuran (20 mL), and hydrochloric acid (1 M, 8.21 mL) was slowly added dropwise to it. Finally, it was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was adjusted to a pH of approximately 12 with sodium hydroxide solution (1 N), 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), affording 3-acetyl-4-chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (650 mg, 50% yield).

[0591] LC-MS, M / Z (ESI): 475.2 (M+H + ).

[0592] 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

[0593] 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), giving 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).

[0594] LC-MS, M / Z (ESI): 774.0 (M+H + ).

[0595] 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)

[0596] 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%, 15 min) 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).

[0597] 1 H 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).

[0598] LC-MS, M / Z (ESI): 534.2 (M+H + ).

[0599] Example 7: Preparation of target compound I-10

[0600] 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)

[0601] The synthetic route of target compound I-10 is as follows:

[0602] Step 1: Synthesis of 3-iodo-2-methylthiopyridin-4-amine

[0603] 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.

[0604] LC-MS, M / Z (ESI): 266.9 (M+H + ).

[0605] 1 H 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).

[0606] Step 2: Synthesis of 1-(4-amino-2-(methylthio)pyridin-3-yl)ethan-1-one

[0607] 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).

[0608] LC-MS, M / Z (ESI): 183.2 (M+H + ).

[0609] 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

[0610] 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).

[0611] LC-MS, M / Z (ESI): 519.1 (M+H + ).

[0612] 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

[0613] 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).

[0614] LC-MS, M / Z (ESI): 501.1 (M+H + ).

[0615] 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)

[0616] 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).

[0617] LC-MS, M / Z (ESI): 532.1 (M+H + ).

[0618] 1 H 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).

[0619] Example 8: Preparation of target compounds I-14 and I-14A

[0620] 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)

[0621] 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)

[0622] The synthetic routes of target compounds I-14 and I-14A are shown below:

[0623] Step 1: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0624] 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%).

[0625] 1 H 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

[0626] Step 2: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0627] 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.

[0628] Step 3: Synthesis of (4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0629] 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.

[0630] 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

[0631] 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%).

[0632] (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile:

[0633] 1 H 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

[0634] (2S,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile:

[0635] 1 H 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

[0636] Step 5: Synthesis of (2R,3R,4S,5R)-3,4,5-trimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0637] 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%).

[0638] 1 H NMR(400MHz, CDCl3)δ6.44(brs,1H),5.37(brs,1H),3.99(d,J=9.6Hz,1H),2.18–2.0 4(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

[0639] 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

[0640] 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%).

[0641] LC-MS, M / Z(ESI):426.19[M+H] +

[0642] 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)

[0643] 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%).

[0644] LC-MS, M / Z(ESI):370.13[M+H] +

[0645] 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(b rs,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

[0646] 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)

[0647] 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.

[0648] LC-MS, M / Z(ESI):370.13[M+H] +

[0649] 1 H 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),5.3 8(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

[0650] Example 9: Preparation of target compound I-15

[0651] The synthetic route of target compound I-15 is as follows:

[0652] Step 1: Synthesis of ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0653] 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%).

[0654] LC-MS, M / Z (ESI): 279.1 (M+H + ).

[0655] Step 2: Synthesis of ethyl 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0656] 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.

[0657] LC-MS, M / Z (ESI): 281.0 (M+H + ).

[0658] Step 3: Synthesis of 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0659] 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.

[0660] LC-MS, M / Z (ESI): 251.1 (MH + ).

[0661] Step 4: Synthesis of 3-cyclopropyl-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0662] 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).

[0663] LC-MS, M / Z (ESI): 252.0 (M+H + ).

[0664] 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

[0665] 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).

[0666] LC-MS, M / Z (ESI): 452.3 (M+H + ).

[0667] 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)

[0668] 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 ID, 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 is from 5% to 40%; flow rate: 3mL / min; detector: PDA; column temperature: 35℃; column pressure: 100bar) 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 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-15P1) (4.90 mg, 5.30% yield) Furan-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 Amine (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).

[0669] LC-MS, M / Z (ESI): 396.1 (M+H + ).

[0670] I-15P1

[0671] 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)

[0672] I-15P2

[0673] 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)

[0674] I-15P3

[0675] 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)

[0676] I-15P4

[0677] 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)

[0678] Example 10: Preparation of target compound I-16

[0679] 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)

[0680] The synthetic route of target compound I-16 is as follows:

[0681] 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)

[0682] 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 give 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(2-hydroxyethoxy)-1,6-naphthyridin-4(1H)-one (target compound I-16) (150 mg, 26.6% yield).

[0683] LC-MS, M / Z (ESI): 471.1 (M+H + ).

[0684] 1 H 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).

[0685] Example 11: Preparation of target compound I-20

[0686] 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)

[0687] The synthetic route of target compound I-20 is as follows:

[0688] Step 1: Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0689] 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. The reaction mixture was stirred at 80°C for 3 hours. After completion of the reaction, the reaction mixture was neutralized with 80 mL of cold 3% sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to afford 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).

[0690] LC-MS, M / Z (ESI): 383.2 (M+H + )

[0691] Step 2: Synthesis of ethyl-(2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0692] 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).

[0693] LC-MS, M / Z (ESI): 369.1 (M+H + )

[0694] 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

[0695] 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.

[0696] LC-MS, M / Z (ESI): 386.2 (M+H + )

[0697] 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

[0698] 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).

[0699] LC-MS, M / Z (ESI): 356.1 (MH + )

[0700] Step 5: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0701] 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).

[0702] LC-MS, M / Z (ESI): 355.1 (M+H + )

[0703] 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

[0704] 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).

[0705] LC-MS, M / Z (ESI): 552.2 (M+H + )

[0706] 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)

[0707] 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. The product was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A=water+0.1% formic acid, B=acetonitrile; gradient: 38%-68%, 15min) to give 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).

[0708] LC-MS, M / Z (ESI): 501.2 (M+H + )

[0709] 1 H NMR (400MHz, CDCl3) δ9.03-8.88(m,1H),8.80-8.68(m,1H),8.55-8.31(m,1H),7.34-7.2 8(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)

[0710] Example 12: Preparation of target compound I-25

[0711] 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)

[0712] The synthetic route of target compound I-25 is as follows:

[0713] 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

[0714] 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 x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. The crude product was separated and purified by HPLC (column: Boston Green ODS 150 x 30 mm x 5 μm; solvent: A = water + 0.225% formic acid (99%), B = acetonitrile; gradient: 50%-80% over 11 minutes) to afford 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).

[0715] LC-MS, M / Z (ESI): 570.3 (M+H + )

[0716] 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)

[0717] 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: A=isopropanol+0.1% ammonia water, B=supercritical fluid carbon dioxide; gradient: 5%-40%) to obtain 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).

[0718] 1 H 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).

[0719] LC-MS, M / Z (ESI): 514.2 (M+H + )

[0720] Example 13: Preparation of target compound I-63B

[0721] 2-((4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

[0722] The synthetic route of the target compound I-63B is shown below:

[0723] Step 1: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0724] 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.

[0725] Step 2: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0726] 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.

[0727] Step 3: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

[0728] 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%).

[0729] 1 H 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

[0730] Step 4: Synthesis of (4S,5R)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0731] 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%).

[0732] 1 H NMR(400MHz, CDCl3)δ6.48(brs,1H),5.45(brs,1H),4.54–4.47(m,1H),2.55–2.4 6(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

[0733] 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-yl)picolinamide was added. To a mixture of 4-(methyl)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 (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 then mixed. The product was separated and purified by silica gel column chromatography (mobile phase: petroleum ether:ethyl acetate = 10:3) to obtain 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] +

[0734] 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)

[0735] 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%).

[0736] LC-MS, M / Z(ESI):356.32[M+H] +

[0737] 1 H 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

[0738] 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

[0739] 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] + ,

[0740] 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)

[0741] 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).

[0742] LC-MS, M / Z(ESI):356.32[M+H] +

[0743] 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

[0744] Example 14: Preparation of target compound I-65

[0745] 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)

[0746] The synthetic route of target compound I-65 is as follows:

[0747] Step 1: 1-(5-chloro-2-vinylpyridin-4-yl)ethan-1-one

[0748] 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).

[0749] LC-MS, M / Z (ESI): 182.0 (M+H + )

[0750] 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

[0751] (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).

[0752] LC-MS, M / Z (ESI): 481.3 (M+H + )

[0753] 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)

[0754] 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 preparative chromatography (column: Phenomenex luna C18 150*25mm*10um; mobile phase: solvent A = water + 0.2% formic acid, B = acetonitrile; gradient: 15%-25% over 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).

[0755] 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).

[0756] LC-MS, M / Z (ESI): 515.2 (M+H + )

[0757] Example 15: Preparation of target compound I-66

[0758] 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)

[0759] The synthetic route of target compound I-66 is as follows:

[0760] 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

[0761] 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), and n-butylphosphonic anhydride (2.44 g, 3.39 mmol, 50% content) and N,N-diisopropylethylamine (656 mg, 5.08 mmol) were slowly added, and then stirred at 25°C for 1 hour. After the reaction was completed, 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 the 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).

[0762] LC-MS, M / Z (ESI): 591.1 (M+H + ).

[0763] 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

[0764] 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, stirred at 25 ° C for 1 hour, and then extracted with ethyl acetate (50 mL * 3). The combined organic phase was 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 =0.30), 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).

[0765] LC-MS, M / Z (ESI): 507.8 (M+H + ).

[0766] 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

[0767] 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), and sodium hydroxide (217 mg, 5.43 mmol) was slowly added to the reaction solution, and then stirred at 100 ° C for 1 hour. After the reaction was completed, 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 phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a 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 the 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).

[0768] LC-MS, M / Z (ESI): 489.1 (M+H + ).

[0769] 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

[0770] 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 the 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).

[0771] LC-MS, M / Z (ESI): 481.1 (M+H + ).

[0772] 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)

[0773] 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 high performance liquid chromatography (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-naphthyridin-4-one (target compound I-66) (18.9 mg, 31.1% yield).

[0774] 1 H 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)

[0775] LC-MS, M / Z (ESI): 515.1 (M+H + ).

[0776] Example 16: Preparation of target compound I-67

[0777] 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)

[0778] The synthetic route of compound I-67 is as follows:

[0779] Step 1: Synthesis of methyl 5-amino-6-iodopyridine-2-carboxylate

[0780] 5-Amino-2-(carbomethoxy)pyridine (5.0 g, 32.86 mmol) was dissolved in anhydrous DMF (50 mL) under an ice bath. I2 (9.20 g, 36.15 mmol) and NaIO4 (16.80 g, 78.86 mmol) were 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 layers were separated and the organic phases were 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%).

[0781] Step 2: Synthesis of methyl 5-chloro-6-iodopyridine-2-carboxylate (3)

[0782] 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), and t-BuNO (0.37 g, 3.60 mmol) was added. After the addition was complete, the reaction solution was heated to 60°C and reacted under this condition for 2 hours. TLC (PE:EA=3:1) showed that 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 obtain methyl 5-chloro-6-iodopyridine-2-carboxylate (3) (0.26 g; yield: 48.15%).

[0783] Step 3: Synthesis of methyl 6-acetyl-5-chloropyridine-2-carboxylate (5)

[0784] 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%).

[0785] 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)

[0786] 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). K₃PO₄ (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 combined, and 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 obtain 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%).

[0787] 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)

[0788] 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).

[0789] 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)

[0790] At room temperature, compound 8 (50.0 mg, 0.10 mmol) and HATU (68.8 mg, 0.45 mmol) were weighed and dissolved in anhydrous DMF (1 mL). DIPEA (51.7 mg, 0.40 mmol) and NH4Cl (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 purified by high performance liquid chromatography (HPLC) (Column: SunFire TM Prep C18 OBD TM 5μm, 30X 150mm, Phase: ACN / H2O (0.5% FA) 40% ACN) was separated to give 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) (3.1 mg, yield: 6.23%).

[0791] 1 H NMR (400 MHz, 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).

[0792] LC-MS, M / Z(ESI):498.21[M+H] +

[0793] Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

[0794] 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.

[0795] 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.

[0796] Electrophysiological experimental steps:

[0797] 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, with noise filtered at one-fifth the sampling frequency. Fill the electrode with intracellular solution to a quarter of the length of the electrode tube and install the electrode on the probe. Set the desired protocol, adjust the interface to Membrane test, and the Stage to Bath. Apply positive pressure to the electrode, touch the electrode tip to the cell, adjust the three-way valve of the aspirator to the three-way position, 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 to -200pA, and continue to apply negative pressure to rupture the cell membrane, establishing a current path. Open the aspirator and extracellular solution valves to allow perfusion, observe the cell current, and begin drug addition after the cell current stabilizes (at least three sweeps of overlapping current curves). Add drug from low to high concentrations, with each dose lasting at least 2 minutes. Wait until the current stabilizes before changing concentrations.

[0798] 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.

[0799] 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.

[0800] Voltage pulse program:

[0801] 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.

[0802] Data processing and fitting

[0803] 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's serial dilution concentration and the stable current value generated by its action on HEK293 / Nav1.8 cells was plotted.

[0804] Then the inhibitory activity of the drug on Nav1.8 ion channel (IC 50 ).

[0805] Table 1: Nav1.8 ion channel inhibitory activity of the compounds of the present invention

[0806] The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

[0807] Test Example 2: Pharmacokinetics test in mice

[0808] For a pharmacokinetic study in mice, three male ICR mice weighing 20-30 g were fasted overnight and administered 10 mg / kg orally by gavage. Blood was collected before dosing and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 10-fold volume of 50% methanol-acetonitrile solution containing an internal standard. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes. The supernatant was then mixed with 1-fold volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0809] Table 2: Pharmacokinetic parameters of the compounds of the present invention in mice

[0810] The experimental results show that the compound of the present invention has good pharmacokinetic properties in mice.

[0811] Test Example 3: Pharmacokinetics test in rats

[0812] For a pharmacokinetic study in rats, three male Sprague-Dawley rats (180-240 g) were fasted overnight and administered 10 mg / kg orally by gavage. Blood was collected before dosing and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 10-fold volume of 50% methanol-acetonitrile solution containing an internal standard. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes. The supernatant was then mixed with 1-fold volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0813] Table 3: Pharmacokinetic parameters of the compounds of the present invention in rats

[0814] The experimental results show that the compound of the present invention has good pharmacokinetic properties in rats.

[0815] Test Example 4: Dog Pharmacokinetics Study

[0816] Canine pharmacokinetic studies were conducted using three male Beagle dogs weighing 7-11 kg, fasted overnight, and administered 5 mg / kg orally by gavage. Blood was collected before dosing and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 6000 g for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 10-fold volume of 50% methanol-acetonitrile solution containing an internal standard. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes. The supernatant was then mixed with 1-fold volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0817] Table 4: Pharmacokinetic parameters of the compounds of the present invention in dogs

[0818] The experimental results show that the compound of the present invention has good pharmacokinetic properties in dogs.

[0819] 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): in, A is selected from H, C 1-6 Alkyl or C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R D replaced by; R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, 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 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 Selected from H, halogen, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 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 R A replaced by; R 1 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by; R A Selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 2 are independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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 2-6 Alkenyl, C 2- 6 alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by; R B Selected from H, halogen, hydroxy, cyano, nitro, oxo (C=O), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, 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 heteroaryl are each independently optionally substituted by one or more R C replaced by; Or, R 3 、R 4 Together with the atoms to which they are attached, they form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups are optionally substituted by one or more R C replaced by; R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide; Or, R 4b1 and R 4b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by; R 5b1 and R 5b2 Each independently selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 alkyl halide; Or, R 5b1 and R 5b2 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by; Or, R 4b1 and R 5b1 Together with the atoms to which they are attached, they form C 3-6 Saturated ring, the C 3-6 The saturated ring is optionally substituted with one or more halogen, -OR 4 , -CN or -NR 3 R 4 replaced by; R 6b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy; R 7b Selected from H, -OH, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy; X 2c Select N or CR 2c ; X 3c Select N or CR 3c ; X 4c Select N or CR 4c ; X 5c Select N or CR 5c ; X 6c Select N or CR 6c ; R 2c Selected from H, -OH, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Halogenated alkyl, 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 -(C1-6 haloalkyl)-OR 4 、-L 1 -(C2-6 alkenyl)-OR 4 、-L 1 -(C1-6 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 1-6 Haloalkyl and C 1-6 The hydrogen in the haloalkoxy group is optionally substituted with 0, 1 or more deuteriums; R 3c Selected from H, halogen, C 1-6 Alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-(C 1-6 alkoxy); R 4c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 alkyl halide; R 5c Selected from H, halogen, C 1-6 Alkyl, or C 1-6 haloalkyl; and R 6c 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 key 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 N or CR 3a ; X 4a N or CR 4a ; X 5a N or CR 5a ; X 6a N, N + -O - or CR 6a ; R 3a 、R 4a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A replaced by; 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 、R7 b 、R A , A is defined as 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 N or CR 3a ; X 4a N or CR 4a ; X 5a N or CR 5a ; X 6a N, N + -O - or CR 6a ; R 3a 、R 4a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; The C 1-6 Alkyl, C 1- 6 haloalkyl, C 1-6 Alkoxy, C 1-6 Each haloalkoxy group is independently optionally substituted with one or more R A replaced by; 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 The definition of is as described 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 H, hydroxyl or C 1-6 Alkoxy; or, R 1 is H or hydroxyl; and / or, R 2 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, wherein the C 1-6 Alkyl, C 1-6 Each alkoxy group is independently optionally substituted with one or more R B or, R 2 is H, F, Cl, hydroxy, methyl, methoxy, wherein the methyl and methoxy groups are each independently optionally replaced by one or more R B replaced by; and / or, R B Selected from H, F, Cl, hydroxy, methyl, methoxy. The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: R 2 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy; or, R 2 H, F, Cl, hydroxyl, methyl, methoxy; Selected from Among them, X 3a N or CR 3a ;X 4a N or CR 4a ;X 5a N or CR 5a ;X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a and R 6a Each independently selected from H, halogen, hydroxy, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, 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)2R 3 、-S(=O)2NR 3 R 4 or -S(=O)(=NR 5 )R 3 ; wherein, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-12 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 R A replaced by; and / or, R 3a 、R 4a 、R 5a and R 6a are each independently selected from H, halogen, C 1-6 Alkyl, R 6a 、R 5a Each independently selected from cyano, -CH(OH)CH2OH, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C replaced by; and / or, for Among them, R 4a H, halogen, C 1-6 Alkyl, R 6a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, cyano, -CH(OH)CH2OH, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 、-S(=O)(=NH)R 3 OR 4 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R 4 H or C 1-6 Alkyl, the C 1- 6 alkyl is selected from one or more R C replaced by; and / or, R 3 、R 4 Each independently selected from H, hydroxy, methyl, and / or, for and / or, Selected from Among them, R 6a is -OCH2CH(OH)CH2OH, -OCH2CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)2NHR 3 or -S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C replaced by; and / or, Selected from The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: for or, for and / or, R 5b1 and R 5b2 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, R 5b2 is trifluoromethyl; and / or, R 4b1 and R 4b2 Each independently selected from H, C 1-6 Alkyl or C 1-6 haloalkyl; or, R 4b1 and R 4b2 Each independently selected from H, methyl, ethyl, n-propyl, isopropyl; or, R 4b1 H, R 4b2 is methyl; and / or, R 6b is H; and / or, R 7b is H; and / or, for The compound according to claim 1, its tautomer, stereoisomer, nitrogen oxide, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: A is H; And / or, A is where X 2c 、X 3c 、X 4c 、X 5c and X 6c The definition of as claimed in claim 1; and / or, for where R 2c 、R 3c and R 4c The definition of as claimed in claim 1; and / or, R 2c is a 3-6 membered heterocyclic group substituted by one or more halogens, a C 3-6 Cycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, -N(C 1-6 alkyl)2; or, R 2c is methyl, ethyl, n-propyl, isopropyl, methoxy, ethyloxy, n-propyloxy, isopropyloxy, -O-CD3, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH3)2, More preferably, R 2c Methyl, methoxy, -O-CD3, -N(CH3)2, and / or, R 3c is H or halogen; or, R 3c is H, F or Cl; more preferably, R 3c 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 (such as NaOH, NaOtBu, Cs2CO3, K3PO4, K2CO3, Na2CO3, KOAc). A compound as follows: in, Ring B, R 0 ,n,Y,A,R 4b1 、R 4b2 、R 5b1 、R 5b2 、R 6b and R 7b The definition as in claim 1. A pharmaceutical composition, characterized in that The invention 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.

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