Five-membered heterocyclic compound, pharmaceutical composition, and use

Abstract

Disclosed are a five-membered heterocyclic compound, a pharmaceutical composition, and a use. Specifically provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention has one or more of the following advantages: (1) the compound has a good retarding effect (or inhibiting effect) on the activity of a Nav1.8 channel; (2) the compound has good pharmacokinetic properties; and (3) the compound is expected to be used for the treatment of Nav1.8-related diseases, such as pain.

Description

A five-membered heterocyclic compound, a pharmaceutical composition and its application

[0001] This application claims priority to Chinese Patent Application No. 2024104861037, filed on April 22, 2024; Chinese Patent Application No. 2024109681168, filed on July 18, 2024; Chinese Patent Application No. 2024112492547, filed on September 6, 2024; and Chinese Patent Application No. 2025102437209, filed on March 3, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to a five-membered heterocyclic compound, a pharmaceutical composition, and its application. Background Technology

[0003] Pain is a complex physiological phenomenon, serving both as a warning signal of potential danger and as a symptom of various diseases. Animals use pain to avoid potential tissue damage, playing an indispensable protective role in normal bodily functions. However, many diseases indicate that pain becomes a burden, severely impacting patients' quality of life. Chronic pain not only affects patients' learning, work, and daily living abilities but also increases the incidence of mental illnesses such as depression or anxiety, imposing a heavy psychological and economic burden on patients, their families, and society as a whole.

[0004] Pain can be broadly categorized as follows: nerve injury or injury as a trigger (neurogenic pain); inflammatory response or metabolic disorder that increases pain sensitivity (inflammatory pain); and injury or surgery leading to a short-term increase in pain response (postoperative / motion-related pain). Pain originates from nociceptors in the peripheral nervous system. These receptors convert different stimuli into nerve impulses, which are then transmitted to higher nerve centers to induce pain. Nociceptors are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. They convert various mechanical and chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG), ultimately reaching higher nerve centers and causing pain. Voltage-gated sodium channels (NaV) on the cell membrane play a crucial role in this process. When the cell membrane depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Abnormal activity of these potentials results in pain. Therefore, inhibiting abnormal sodium ion channel activity has been shown to help treat and relieve pain.

[0005] The Nav family of proteins are a class of transmembrane ion channel proteins, composed of an α subunit with a molecular weight of 260 kDa and a β subunit with a molecular weight of 30-40 kDa. Based on the different α subunits, they can be divided into nine isotypes, Nav1.1 to Nav1.9. Different isotypes exhibit different tissue distributions, electrophysiological characteristics, and pharmacological features. Based on their ability to be effectively inhibited by tetrodotoxin (TTX), sodium ion channels are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types. Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are TTX-S type, while Nav1.5, Nav1.8, and Nav1.9 are TTX-R type.

[0006] Nav1.8, a TTX-R type gene, is encoded by SCN10A located in the 3p21-22 region of human chromosome 3. It is primarily found in trigeminal ganglion neurons and DRG neurons, participating in the action potentials and rhythmic firing of sensory neurons. It is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome. Gene knockout and silencing studies have shown that Nav1.8 participates in the regulation of neuropathic and inflammatory pain. Nav1.8 is regulated by inflammatory mediators and is upregulated in a sciatic nerve injury model. Because Nav1.8 is mainly confined to pain-sensing neurons, selective Nav1.8 blockers are likely to avoid inducing the adverse reactions commonly seen with non-selective Nav1.8 blockers. Therefore, research on specific inhibitors targeting Nav1.8 for pain has become a hot topic in the field of pain management. However, known Nav1.8 inhibitors mainly suffer from drawbacks such as a poor therapeutic window, possibly due to a lack of subtype selectivity.

[0007] Currently known Nav1.8 inhibitors include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548, which have been reported and entered clinical trials. However, some of these compounds have been discontinued in the preclinical stage due to insufficient selectivity, poor pharmacokinetic data, low bioavailability, poor solubility, and low absorption rates. Therefore, developing Nv1.8 inhibitors with higher affinity, higher specificity, and better pharmacokinetics has significant social and economic value.

[0008] Published patent applications for Nav1.8 inhibitor compounds include WO2014120808A9, WO2014120815A9, WO2021113627A1, WO2015010065A1, WO2022256622A1, WO2022256676A1, WO2022256679A1, WO2022256842A1, WO2022256702A1 and WO2024041613A1. Summary of the Invention

[0009] The technical problem to be solved by this invention is to overcome the shortcomings of insufficient Nav1.8 channel inhibition in the prior art. To this end, this invention provides a five-membered heterocyclic compound, its pharmaceutical composition, and its application. The compound of this invention has one or more of the following advantages: (1) good blocking effect (or inhibitory effect) on Nav1.8 channel activity; (2) good pharmacokinetic properties; (3) promising for the treatment of Nav1.8 related diseases, such as pain.

[0010] The present invention solves the technical problem of the present invention through the following technical solution:

[0011] This invention provides compounds as shown in formula (I) or pharmaceutically acceptable salts thereof.

[0012] in,

[0013] X is either O or S;

[0014] Q is

[0015] X 1 For N, N + -O - or CR x1 ;

[0016] X 2 For N, N + -O - or CR x2 ;

[0017] R 12a and R 12b Independently hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 aryl, 5-14 heteroaryl; the above C1-C6 alkyl groups optionally bound by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-2 Replaced;

[0018] R 12-1 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 、-C(=NR 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 、-C(=NR 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR)20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); the above C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-3 Replaced;

[0019] R 12-3 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R 26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 -C(=NR) 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 、-S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R 28 -NR 27 C(O)NR25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R 26 、-P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 、-C(=NR 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0020] R 12-2 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 、-C(=NR 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21-S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl);

[0021] R 24 R 25 R 26R 27 R 28 and R 29 It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 30 Replaced;

[0022] And / or, R 25 R 26 R 27 and R 28 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups.

[0023] R 16 R 17 R 18 R 20 and R 21 It is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C1-C6 cycloalkyl, -(C1-C6 alkylene)-Z-3-8 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C6-C 10 aryl or -(C1-C6 alkylene)-Z-5-10 heteroaryl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 23 Replaced;

[0024] And / or, R 16 R 17 R 20 and R 21Any two groups together with the carbon atom they are attached to form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups; Z is independently O, S, NH, S(O) or S(O)2;

[0025] R x1 and R x2 The same or different, independently of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -(C1-C6 alkylene)-(C1-C6 alkoxy) or 5-14 heteroaryl; the above C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl and 5-14 heteroaryl are optionally surrounded by one or more R 24 Replaced;

[0026] And / or, R x1 and R x2 Together with the attached carbon atom or heteroatom, they form a partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl group; wherein the aforementioned 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl group is optionally substituted by one or more of the following substituents: deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 Or -(C1-C6 alkylene)-(C1-C6 alkoxy);

[0027] R aIndependently, it can be a hydrogen atom, deuterium, hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, -COO (C1-C3 alkyl group) or amide group;

[0028] R b It can be independently a hydrogen atom, halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group or C3-C6 cycloalkyl group;

[0029] R 5 and R 6 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl or C1-C6 haloalkyl; the C3-C6 cycloalkyl and 3-6 membered heterocyclic alkyl are optionally substituted with one or more halogens, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0030] R 7 and R 8 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6-membered heterocyclic alkyl, benzene ring, or 5-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, benzene ring, and heteroaryl are optionally represented by one or more R 4 Replaced;

[0031] And / or, R 5 R 6 R 7 and R 8 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups.

[0032] R 11 Independently, it is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl or C2-C6 alkynyl;

[0033] A can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 alkyl. 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 15 Replaced;

[0034] R 4 and R 15 Independently deuterium, halogen, hydroxyl, or oxo group (=O or -O) - ), nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -NR 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 、-C(=NR 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 、-C(=NR 20 )NR 20 -OR 21-C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally separated by one or more R 24 Replaced;

[0035] And / or, adjacent R 15 Together with the carbon atoms attached thereto, they form partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl; said partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl is optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups;

[0036] R 22 Independently hydrogen or C1-C6 alkyl;

[0037] R 23 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 、-C(=NR 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 、-S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R 28 -NR 27 C(O)NR 25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R 26 、-P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 、-C(=NR 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0038] R 30 It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0039] The heteroatoms or groups in the aforementioned heterocyclic alkyl and heteroaryl groups are optionally selected from N, N + -O - ,O,S,S(O),S(O)2,carbonyl,S(O)(=NR 20 ) or P(O)CH3, wherein the number of heteroatoms or groups is 1, 2, 3, 4, 5, 6, 7 or 8.

[0040] In certain preferred embodiments of the present invention, certain groups in the compound represented by formula (I) or its pharmaceutically acceptable salt are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "in some preferred embodiments").

[0041] In some preferred embodiments, wherein,

[0042] X is either O or S;

[0043] Q is

[0044] X 1 For N, N + -O - or CR x1 ;

[0045] X 2 For N, N + -O - or CR x2 ;

[0046] R 12a and R 12b Independently hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 aryl, 5-14 heteroaryl; the above C1-C6 alkyl groups optionally bound by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-2 Replaced;

[0047] R 12-1Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); the above C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-3 Replaced;

[0048] R 12-3 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R 26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 -C(=NR) 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 、-S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R 28 -NR 27 C(O)NR 25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R26 、-P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 -C(=NR) 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0049] R 12-2 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl);

[0050] R 24 R 25 R 26 R 27 R 28 and R 29It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R 30 Replaced;

[0051] And / or, R 25 R 26 R 27 and R 28 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups.

[0052] R 16 R 17 R 18 R 20 and R 21 It is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C1-C6 cycloalkyl, -(C1-C6 alkylene)-Z-3-8 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C6-C 10 aryl or -(C1-C6 alkylene)-Z-5-10 heteroaryl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R 23 Replaced;

[0053] And / or, R 16 R 17 R 20 and R 21 Any two groups together with the carbon atom they are attached to form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups; Z is independently O, S, NH, S(O) or S(O)2;

[0054] Rx1 and R x2 The same or different, independently of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -(C1-C6 alkylene)-(C1-C6 alkoxy) or 5-14 heteroaryl; the above C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl and 5-14 heteroaryl are optionally surrounded by one or more R 24 Replaced;

[0055] And / or, R x1 and R x2 Together with the attached carbon atom or heteroatom, they form a partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein the aforementioned 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by one or more of the following substituents: deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 Or -(C1-C6 alkylene)-(C1-C6 alkoxy);

[0056] R a It can be independently a hydroxyl, halogen, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl halogen, -COO (C1-C3 alkyl) or amide group;

[0057] R b It can be independently a hydrogen atom, halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group or C3-C6 cycloalkyl group;

[0058] R 5and R 6 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl or C1-C6 haloalkyl; the C3-C6 cycloalkyl and 3-6 membered heterocyclic alkyl are optionally substituted with one or more halogens, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0059] R 7 and R 8 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6-membered heterocyclic alkyl, benzene ring, or 5-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, benzene ring, and heteroaryl are optionally represented by one or more R 4 Replaced;

[0060] And / or, R 5 R 6 R 7 and R 8 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups.

[0061] R 11 Independently, it is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl or C2-C6 alkynyl;

[0062] A can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 alkyl. 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 15 Replaced;

[0063] R 4 and R 15 Independently deuterium, halogen, hydroxyl, or oxo group (=O or -O) - ), nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -NR 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 、-P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally separated by one or more R 24 Replaced;

[0064] R 22 Independently hydrogen or C1-C6 alkyl;

[0065] R 23 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R 26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 、-C(=NR 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 、-S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R28 -NR 27 C(O)NR 25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R 26 、-P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 -C(=NR) 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl;

[0066] R 30 It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic alkyl;

[0067] The heteroatoms or groups in the aforementioned heterocyclic alkyl and heteroaryl groups are optionally selected from N, N + -O - ,O,S,S(O),S(O)2,carbonyl,S(O)(=NR 20 ) or P(O)CH3, wherein the number of heteroatoms or groups is 1, 2, 3, 4, 5, 6, 7 or 8.

[0068] In some preferred embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof:

[0069] Among them, A, X, Q, R 5 R 6 R 7 R 8 and R 11 The definition is shown in any embodiment of this application.

[0070] In some preferred embodiments,

[0071] R x1 and R x2 It can be hydrogen, deuterium, or halogen independently;

[0072] R 12a and R 12b Independently C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 Replaced;

[0073] R 12-2 Independently deuterium, halogen, hydroxyl, oxo group, C1-C6 alkyl or -OR 18 ;

[0074] R 12-1 Independently deuterium, halogen, hydroxyl, oxo group, -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-3 Replaced;

[0075] R 12-3 It can be independently deuterium, halogen, hydroxyl, oxo group or C1-C6 alkyl.

[0076] In some preferred embodiments,

[0077] X is O;

[0078] R 5 and R 6 They may be the same or different, and each is independently a C1-C6 alkyl or a C1-C6 haloalkyl;

[0079] R 7 and R 8 They may be the same or different, and each is independently hydrogen, deuterium or C1-C6 alkyl;

[0080] R11 Independently hydrogen;

[0081] A is independently C6-C 10 aryl; wherein the aryl group is optionally surrounded by one or more R 15 Replaced;

[0082] R x1 and R x2 Independently deuterium, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, -NR 16 R 17 -C(O)NR 16 R 17 or -OR 18 The alkyl group or haloalkyl group is optionally surrounded by one or more R groups. 24 Replaced;

[0083] R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and alkoxy groups are optionally separated by one or more R 24 replace;

[0084] R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl, said alkyl group optionally being converted by one or more R 23 Replaced;

[0085] R 23 Independently halogen or -OR 29 ;

[0086] R 29 Independently hydrogen or C1-C6 alkyl;

[0087] R 24 Independently halogenated, hydroxyl, or oxo group (=O or -O) - ), C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0088] In some preferred embodiments,

[0089] X is O;

[0090] R 5 and R 6 They may be the same or different, and each is independently a C1-C6 alkyl or a C1-C6 haloalkyl;

[0091] R 7 and R 8They may be the same or different, and each is independently hydrogen, deuterium or C1-C6 alkyl;

[0092] R 11 Independently hydrogen;

[0093] A is independently C6-C 10 aryl; wherein the aryl group is optionally surrounded by one or more R 15 Replaced;

[0094] R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and alkoxy groups are optionally separated by one or more R 24 replace;

[0095] R 24 Halogens are independent of each other;

[0096] R x1 and R x2 It can be hydrogen, deuterium, or halogen independently;

[0097] R 12a and R 12b Independently C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 Replaced;

[0098] R 12-2 Independently hydroxyl or -OC1-C6 alkyl;

[0099] R 12-1 Independently deuterium, halogen, hydroxyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl; the above-mentioned C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-3 Replaced;

[0100] R 12-3 It can be independently deuterium, halogen, hydroxyl, or C1-C6 alkyl.

[0101] In some preferred embodiments,

[0102] Among them, X 1 For N, N + -O - or CR x1 ;

[0103] X 2For N, N + -O - or CR x2 ;

[0104] R x1 and R x2 The same or different, independently of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -(C1-C6 alkylene)-(C1-C6 alkoxy) or 5-14 heteroaryl; the above C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl and 5-14 heteroaryl are optionally surrounded by one or more R 24 Replaced;

[0105] R 24 It is independently a halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0106] R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl; wherein said C1-C6 alkyl is optionally composed of one or more R 23 Replaced;

[0107] R 23 It can be independently a halogen, hydroxyl, or C1-C6 alkoxy group;

[0108] And / or, R x1 and R x2 Together with the attached carbon atoms or heteroatoms, they form partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl groups;

[0109] R aIndependently, it can be a hydrogen atom, deuterium, hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, COO (C1-C3 alkyl group) or amide group; preferably, it can be a hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, COO (C1-C3 alkyl group) or amide group;

[0110] R b It can be independently a hydrogen atom, halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group or C3-C6 cycloalkyl group;

[0111] A, X, R 5 R 6 R 7 R 8 and R 11 The definition is as described in any embodiment of this invention.

[0112] In some preferred embodiments,

[0113] R x1 and R x2 They can be the same or different, independently of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl or -(C1-C6 alkylene)-(C1-C6 alkoxy);

[0114] Or, R x1 and R x2 Together with the attached carbon atoms or heteroatoms, they form partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl groups;

[0115] R a and R b They can be the same or different, independently of hydrogen atoms, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 deuterated alkyl groups, or C3-C6 cycloalkyl groups.

[0116] In some preferred embodiments,

[0117] R x1 and R x2Independently, it can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 -(C1-C6 alkylene)-(C1-C6 alkoxy) or 5-14 heteroaryl; the above C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl and 5-14 heteroaryl are optionally surrounded by one or more R 24 Replaced;

[0118] R 24 It is independently a halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl;

[0119] R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl; wherein said C1-C6 alkyl is optionally composed of one or more R 23 Replaced;

[0120] R 23 It can be independently a halogen, hydroxyl, or C1-C6 alkoxy group;

[0121] And / or, R x1 and R x2 Together with the atoms attached to them, they form partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl groups;

[0122] R a Independently, it can be a hydrogen atom, deuterium, hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, COO (C1-C3 alkyl group) or amide group; preferably, it can be a hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, COO (C1-C3 alkyl group) or amide group;

[0123] R bIt can be independently a hydrogen atom, halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group or C3-C6 cycloalkyl group;

[0124] A, X, R 5 R 6 R 7 R 8 and R 11 The definition is shown in any embodiment of this application.

[0125] In some preferred embodiments,

[0126] X is O;

[0127] R 5 and R 6 They may be the same or different, and each is independently a C1-C6 alkyl or a C1-C6 haloalkyl;

[0128] R 7 and R 8 They may be the same or different, and each is independently hydrogen, deuterium or C1-C6 alkyl;

[0129] R 11 Independently hydrogen;

[0130] A is independently a C3-C8 cycloalkyl, a 3-8 membered heterocycloalkyl, or a C6-C... 10 aryl, 5-10-membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 15 Replaced;

[0131] R x1 and R x2 Independently deuterium, halogen, hydroxyl, or oxo group (=O or -O) - ), cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or -C(O)NR 16 R 17 ;

[0132] R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and alkoxy groups are optionally separated by one or more R 24 replace;

[0133] R 16 and R 17 Independently hydrogen or C1-C6 alkyl;

[0134] R 24 It is a halogen on its own.

[0135] In some preferred embodiments,

[0136] X is O;

[0137] R 5 and R 6 They may be the same or different, and each is independently a C1-C6 alkyl or a C1-C6 haloalkyl;

[0138] R 7 and R 8 They may be the same or different, and each is independently hydrogen, deuterium or C1-C6 alkyl;

[0139] R 11 Independently hydrogen;

[0140] A is independently C6-C 10 aryl; wherein the aryl group is optionally surrounded by one or more R 15 Replaced;

[0141] R x1 and R x2 Independently deuterium, halogen, hydroxyl, or oxo group (=O or -O) - ), cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, -NR 16 R 17 -C(O)NR 16 R 17 -OR 18 、-S(O)2R 21 -S(=NR) 20 )(O)R 21 Or 5-14 heteroaryl groups; the alkyl, haloalkyl, and heteroaryl groups are optionally surrounded by one or more R groups. 24 Replaced;

[0142] R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and alkoxy groups are optionally separated by one or more R 24 replace;

[0143] R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl, said alkyl group optionally being converted by one or more R 23 Replaced;

[0144] R 23 Independently halogen or -OR 29 ;

[0145] R 29 Independently hydrogen or C1-C6 alkyl;

[0146] R 24 Independently halogenated, hydroxyl, or oxo group (=O or -O) - ), C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0147] In some preferred embodiments, the halogen or halogen is F, Cl or Br; preferably F.

[0148] In some preferred embodiments, the C1-C6 alkyl group among the C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl groups is independently a C1-C4 alkyl group; preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, more preferably methyl or ethyl; more preferably methyl.

[0149] In some preferred embodiments, the C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 hydroxyalkoxy groups are independently C1-C4 alkoxy groups; preferably -O-methyl (methoxy), -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl, or -O-tert-butyl, and more preferably methoxy.

[0150] In some preferred embodiments, the C1-C6 alkylene groups are independently C1-C3 alkylene groups; preferably methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2-, -CH2CH(CH3)- or -C(CH3)2-}, and more preferably methylene.

[0151] In some preferred embodiments, the C3-C 10 cycloalkyl and C3-C 10 C3-C in halocycloalkyl groups 10 The cycloalkyl group is independently a C3-C6 cycloalkyl group.

[0152] In some preferred embodiments, the C3-C8 cycloalkyl group and the C3-C8 halocycloalkyl group are independently C3-C6 cycloalkyl groups; preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclopropyl or cyclobutyl.

[0153] In some preferred embodiments, the C3-C6 cycloalkyl group and the C3-C6 halocycloalkyl group are independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl.

[0154] In some preferred embodiments, the 3-10 membered heterocyclic alkyl group is independently a 3-8 membered heterocyclic alkyl group.

[0155] In some preferred embodiments, the 3-8 membered heterocyclic alkyl group is independently a 3-6 membered heterocyclic alkyl group or a 7-8 membered heterocyclic alkyl group.

[0156] In some preferred embodiments, the 3-6 membered heterocyclic alkyl group is independently a nitrogen-containing heterocyclic butyl group (e.g., ...). ), oxetane (e.g.) ), tetrahydrofuranyl (e.g.) ), tetrahydrothiophene group, pyrrolidinyl group (For example ), piperidinyl (e.g.) ), tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl (e.g.) ), piperazine group (e.g.) ).

[0157] In some preferred embodiments, the 7-8 membered heterocyclic alkyl group is independently... Oxyheptanyl,

[0158] In some preferred embodiments, the C3-C 14 The aryl group is independently C6-C 14 Aryl, for example C6-C 10 Aryl; for example, phenyl or naphthyl; and again, phenyl.

[0159] In some preferred embodiments, the C6-C 14 The aryl group can be phenyl or naphthyl independently; for example, phenyl.

[0160] In some preferred embodiments, the C6-C 10 The aryl group is independently a phenyl group.

[0161] In some preferred embodiments, the 5-14-membered heteroaryl group is independently a 5-10-membered heteroaryl group;

[0162] For example, 5-6 membered heteroaryl or 9-10 membered heteroaryl;

[0163] For example, the 5-6 heteroaryl group is independently a 5-heteroaryl or 6-heteroaryl group; the 9-10 heteroaryl group is independently a 9-heteroaryl or 10-heteroaryl group.

[0164] In some preferred embodiments, the 5-membered heteroaryl group is independently an imidazolyl group (e.g. ), oxazolyl (e.g.) ) or pyrazolyl (e.g. ).

[0165] In some preferred embodiments, the 6-membered heteroaryl group is independently pyridyl (e.g. ), pyridazinyl (e.g.) ), pyrimidine (e.g.) ).

[0166] In some preferred embodiments, the 9-membered heteroaryl group is independently...

[0167] In some preferred embodiments, the 10-membered heteroaryl group is independently...

[0168] In some preferred embodiments, the 10-membered heteroaryl group is independently... For example

[0169] In some preferred embodiments, the 13-membered heteroaryl group is independently... For example

[0170] In some preferred embodiments, the 5-14 member heteroaryl or 5-10 member heteroaryl is independently imidazolyl, pyridyl, pyridinyl, pyrimidinyl, oxazolyl, pyrazolyl, etc. Or naphthidyl; for example,

[0171] In some preferred embodiments, when substituted, the number of substituted items is 1, 2, or 3.

[0172] In some preferred embodiments, the haloalkyl group is independently a fluoroalkyl group; for example, -CH2F, -CHF2 or -CF3.

[0173] In some preferred embodiments, the haloalkoxy group is independently a fluoroalkoxy group; for example, -OCH2F, -OCHF2, or -OCF3.

[0174] In some preferred embodiments, X is 0.

[0175] In some preferred embodiments, R 5 and R 6 Each is independently a C1-C6 alkyl or C1-C6 haloalkyl; for example, methyl, -CF3, -CHF2 or -CH2CF3; or, for example, methyl or -CF3.

[0176] In some preferred embodiments, R 5Independently C1-C6 alkyl, R 6 It is independently a C1-C6 haloalkyl group.

[0177] In some preferred embodiments, R 7 and R 8 It is independently hydrogen, deuterium, or a C1-C6 alkyl group; said alkyl group is optionally surrounded by one or more R 4 Replaced;

[0178] For example, one is hydrogen and the other is methyl or isopropyl.

[0179] In some preferred embodiments, R 24 Independently hydrogen, deuterium, =O, -O - Halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0180] In some preferred embodiments, R 24 It is independently hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; for example, deuterium, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0181] In some preferred embodiments, R 24 Halogens can be used independently; for example, F.

[0182] In some preferred embodiments, R 24 Independent of an oxygen group (=O or -O) - ), halogen, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; for example F, =O, methyl, -O-CH3, CF2 or CF3.

[0183] In some preferred embodiments, R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and C1-C6 alkoxy groups are optionally separated by one or more R 24 replace.

[0184] In some preferred embodiments, R 15 It can be F, methyl, -O-methyl, -OCHF2, -OCF3, -CF3, -CHF2, or -CH2CF3 independently.

[0185] In some preferred embodiments, R 15 It can be F, methyl, -O-methyl, -OCF3, -CF3, -CHF2, or -CH2CF3 independently.

[0186] In some preferred embodiments, adjacent R 15Together with the atoms attached to them, they form partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl; for example, partially unsaturated 5-6 membered heterocycloalkyl.

[0187] In some preferred embodiments, adjacent R 15 The atoms between and connected together form

[0188] In some preferred embodiments, adjacent R 15 Together with the atoms attached to them, they form partially unsaturated 3-6 membered cycloalkyl groups or partially unsaturated 5-6 membered heterocycloalkyl groups; for example, partially unsaturated 5-6 membered heterocycloalkyl groups.

[0189] Wherein, the partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl is substituted by one or more of the following substituents: deuterium or halogen.

[0190] In some preferred embodiments, adjacent R 15 The atoms between and connected together form

[0191] In some preferred embodiments, A is independently C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl or 5-10-membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 15 Replaced;

[0192] For example, C3-C8 cycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 15 What it replaced.

[0193] In some preferred embodiments, A is independently C6-C 10 aryl; wherein the aryl group is optionally surrounded by one or more R 15 What it replaced.

[0194] In some preferred embodiments, R 29 It is independently hydrogen or C1-C6 alkyl; for example, hydrogen or methyl.

[0195] In some preferred embodiments, R 29 Independently, it is a C1-C6 alkyl group; for example, methyl.

[0196] In some preferred embodiments, R 23 Independently halogen or -OR 29 For example, halogens, hydroxyl groups, or C1-C6 alkoxy groups.

[0197] In some preferred embodiments, R 23 Independently for -OR 29 For example, OH or -O-CH3.

[0198] In some preferred embodiments, R 23 Independently for -OR 29 For example, -O-CH3.

[0199] In some preferred embodiments, R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl, said alkyl group optionally being converted by one or more R 23 What it replaced.

[0200] In some preferred embodiments, R 16 R 17 R 18 R 20 and R 21 It is independently hydrogen or C1-C6 alkyl; for example, H or methyl.

[0201] In some preferred embodiments, R 16 R 17 and R 18 It can be hydrogen, methyl, or (CH2)2-OCH3 independently.

[0202] In some preferred embodiments, R 16 R 17 R 18 R 20 and R 21 Independently hydrogen, methyl, or (CH2)2-OCH3,

[0203] In some preferred embodiments, R 12-3 It can be independently deuterium, halogen, hydroxyl, oxo group or C1-C6 alkyl.

[0204] In some preferred embodiments, R 12-3 It can be independently deuterium, halogen, hydroxyl, or C1-C6 alkyl.

[0205] In some preferred embodiments, R 12-3 It can be independently deuterium, F, hydroxyl, or methyl.

[0206] In some preferred embodiments, R 12-1 Independently deuterium, halogen, hydroxyl, oxo group, -OR18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-3 What it replaced.

[0207] In some preferred embodiments, R 12-1 Independently deuterium, halogen, hydroxyl, -O-C1-C6 alkyl, C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl; the above-mentioned C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-3 What it replaced.

[0208] In some preferred embodiments, R 12-1 Independently, it is deuterium, hydroxyl, -O-methyl, cyclobutyl, oxecyclobutyl, tetrahydrofuranyl, or 1,3-dioxapentyl; the aforementioned cyclobutyl, oxecyclobutyl, tetrahydrofuranyl, or 1,3-dioxapentyl is optionally mixed with one or more R 12-3 What it replaced.

[0209] In some preferred embodiments, R 12-1 Independently, it is deuterium, hydroxyl, -O-methyl, cyclobutyl, Cyclobutyl, Optional by one or more R 12-3 What it replaced.

[0210] In some preferred embodiments, R 12-1 Independently -C(O)NR 16 R 17 .

[0211] In some preferred embodiments, R 12-1 It is independently -C(O)NH2.

[0212] In some preferred embodiments, R 12-2 Independently deuterium, halogen, hydroxyl, oxo group, C1-C6 alkyl or -OR 18 .

[0213] In some preferred embodiments, R 12-2 It can be independently a hydroxyl group or an -OC1-C6 alkyl group.

[0214] In some preferred embodiments, R 12-2 It can be hydroxyl or methoxy on its own.

[0215] In some preferred embodiments, R 12a It is not hydrogen.

[0216] In some preferred embodiments, R 12b It is not hydrogen.

[0217] In some preferred embodiments, R 12a It is hydrogen; R 12b C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 What it replaced.

[0218] In some preferred embodiments, R 12b It is hydrogen; R 12a C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 What it replaced.

[0219] In some preferred embodiments, R 12a and R 12b Independently C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 What it replaced.

[0220] In some preferred embodiments, R 12a and R 12b Independently hydrogen, methyl, n-propyl, cyclobutyl, or tetrahydropyranyl (e.g.) ); methyl and n-propyl are optionally coupled with one or more R 12-1 The cyclobutyl group and tetrahydropyran group are optionally replaced by one or more R groups. 12- 2 What it replaced.

[0221] In some preferred embodiments, R 12a and R 12b Independently hydrogen, methyl,

[0222] In some preferred embodiments, R 12a and R 12bIndependently

[0223] In some preferred embodiments, R a It can be either a deuterium or a hydrogen atom.

[0224] In some preferred embodiments, R x1 and R x2 It can be hydrogen or halogen independently.

[0225] In some preferred embodiments, R x1 and R x2 It can be hydrogen or F independently.

[0226] In some preferred embodiments, X is 0.

[0227] In some preferred embodiments, R 11 Independently hydrogen or methyl; for example, hydrogen.

[0228] In some preferred embodiments, for

[0229] In some preferred embodiments, A is

[0230] In some preferred embodiments, A is

[0231] In some preferred embodiments, A is

[0232] In some preferred embodiments, A is

[0233] In some preferred embodiments,

[0234] Among them, X 1 For N, N + -O - or CR x1 ;

[0235] X 2 For N, N + -O - or CR x2 ;

[0236] R x1 and R x2They can be the same or different, independently of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl or -(C1-C6 alkylene)-(C1-C6 alkoxy);

[0237] R a and R b They can be the same or different, independently of hydrogen atoms, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 deuterated alkyl groups, or C3-C6 cycloalkyl groups.

[0238] In some preferred embodiments, Q is

[0239] In some preferred embodiments, Q is

[0240] In some preferred embodiments, Q is

[0241] In some preferred embodiments, Q is

[0242] In some preferred embodiments, the compound represented by formula (I) is any of the following compounds: Alternatively, its enantiomers, or mixtures thereof with enantiomers (e.g., (exo)racemates).

[0243] This invention provides a pharmaceutical composition comprising:

[0244] (1) The compound shown in formula (I) above, or a pharmaceutically acceptable salt thereof, and

[0245] (2) Pharmaceutically acceptable excipients.

[0246] This invention provides the use of a substance in the preparation of a medicament for treating diseases / symptoms;

[0247] The substance is the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0248] In some preferred embodiments, the drug is a drug for inhibiting voltage-gated sodium channels; the voltage-gated sodium channel is preferably Nav1.8.

[0249] In some preferred embodiments, the drug is a drug for treating and / or alleviating pain and pain-related diseases / conditions, incontinence, or arrhythmias.

[0250] In some preferred embodiments, the pain is one or more of the following: chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0251] This invention provides the application of the above-mentioned substance in the preparation of voltage-gated sodium channel inhibitors; the voltage-gated sodium channel is preferably Nav1.8.

[0252] In some embodiments, the voltage-gated sodium channel inhibitor can be used in mammalian organisms; it can also be used in vitro, primarily for experimental purposes, such as providing a standard or control sample for comparison, or preparing a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting voltage-gated sodium channels.

[0253] Terminology Explanation

[0254] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0255] As used herein, compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. This invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of Formula I contains more than one chiral center, diastereomers may be present. This invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and chiral chromatography.

[0256] The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers. The compounds described in this invention can exist in stereoisomer form, and therefore encompass all possible stereoisomer forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, and transisomers. The compounds described in this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as equal mixtures of meso, racemic, and transisomers, or, for example, a single enantiomer, a single diastereomer or a mixture of more than one, or a single transisomer or a mixture thereof.

[0257] The term "tautomer" refers to a functional group isomer that is produced by the rapid movement of an atom in two positions within a molecule.

[0258] As used herein, in any chemical structure or formula, the bold or scattered wedge-shaped bonds (respectively) attached to the stereoisomer centers of the compound ), such as in

[0259] The absolute stereochemistry of the stereoisomer center, and the relative stereochemistry of the stereoisomer center relative to other stereoisomer centers connected by bold or scattered wedge bonds.

[0260] As used herein, when used in conjunction with chiral compounds, the prefix "rac-" refers to a racemic mixture, which is an equimolar mixture of a chiral molecule with optical activity (optic isomerism) and its enantiomer. It also refers to a single enantiomer with an unknown absolute configuration. In compounds with the "rac-" prefix, the (R) and (S) indicators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily its absolute stereochemistry.

[0261] As used herein, when used in conjunction with chiral compounds, the prefix "rel-" refers to a single enantiomer having an unknown absolute configuration. In compounds with the "rel" prefix, the (R) and (S) indicators in the chemical name reflect the relative stereochemistry of the compound, but not necessarily its absolute stereochemistry. When the compounds described in this invention contain alkene double bonds, unless otherwise specified, they include cis isomers and trans isomers, and any combination thereof.

[0262] In this application, "pharmaceutical composition" refers to a formulation comprising the compounds of the present invention and a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0263] In this application, "pharmaceutical acceptable" means a substance (such as a pharmaceutical excipient) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing an adverse biological reaction or interacting with any component contained in the composition in an undesirable manner.

[0264] In this invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0265] The term "pharmaceutical excipients / carriers" or "pharmaceuticalally acceptable excipients / carriers" refers to the excipients and additives used in the manufacture of pharmaceuticals and the dispensing of prescriptions. These are all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2015 Edition), Volume IV, or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009 Sixth Edition).

[0266] The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art, based on the disclosure. For example, conventional mixing, dissolving, granulation, emulsification, grinding, encapsulation, embedding, or lyophilization processes.

[0267] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0268] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0269] The term "therapeutic effective amount" refers to an amount of compound sufficient to effectively treat the disease or condition described herein when administered to a patient. The "therapeutic effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but may be adjusted as needed by those skilled in the art.

[0270] The term "patient" refers to any animal, preferably a mammal, that is about to receive or has already received administration of the compound or composition according to embodiments of the invention, with humans being the most preferred. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans, with humans being the most preferred.

[0271] Unless otherwise stated, this invention employs traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can be referred to conventional operating procedures and conditions in the field.

[0272] Unless otherwise specified, this invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, organic synthetic chemistry, and optics. In some cases, standard techniques are used in chemical synthesis and chemical analysis.

[0273] Furthermore, it should be noted that, unless otherwise explicitly stated, the descriptive phrase "...independently" used in this invention should be interpreted broadly, meaning that the described entities are independent of each other and can independently be the same or different specific functional groups. More specifically, the descriptive phrase "...independently" can mean either that the specific options expressed by the same symbol in different functional groups do not affect each other, or that the specific options expressed by the same symbol in the same functional group do not affect each other.

[0274] In this specification, groups and their substituents may be selected by those skilled in the art to provide stable structural moieties and compounds. When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left.

[0275] Certain chemical groups defined in this document are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-C4 alkyl or C 1-4 Alkyl refers to an alkyl group having a total of 1, 2, 3, or 4 carbon atoms as defined below. The total number of carbon atoms in the simplified symbol does not include carbons that may be present in substituents of the group.

[0276] In this paper, the numerical ranges defined in the substituents, such as 0 to 10, 1-6, 1-3, etc., indicate the integers within that range. For example, 1-6 means 1, 2, 3, 4, 5, 6.

[0277] The term "optionally by one or more R" a "Replace" indicates that it was not replaced by R a Replaced and by one or more R a Replaces both scenarios.

[0278] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0279] The terms “substituted” or “replaced” refer to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the substituted compound is stable.

[0280] Generally, the terms "substituted" or "substituted" indicate that one or more hydrogen atoms in a given structure are substituted by a specific substituent. Further, when the group is substituted by more than one of the substituents, the substituents are independent of each other; that is, the more than one substituent can be different or the same. Unless otherwise indicated, a substituent group can be substituted at each substituted position of the substituted group. When more than one position in a given structural formula can be substituted by one or more substituents selected from a specific group, the substituents can be substituted at the same or different positions.

[0281] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or scope of the groups. In particular, this invention includes every independent secondary combination of the respective members of these group types and scopes. The term "C" x -C y Alkyl or C x-y "Alkyl" refers to a straight-chain or branched saturated hydrocarbon containing x to y carbon atoms. For example, the terms "C1-C6 alkyl" or "C 1-6 "alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl; "C" 1-4 "Alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl (i.e. propyl, including n-propyl and isopropyl), and C4 alkyl (i.e. butyl, including n-butyl, isobutyl, sec-butyl, and tert-butyl).

[0282] The terms “part,” “structural part,” “chemical part,” “group,” and “chemical group” used in this article refer to specific segments or functional groups within a molecule. A chemical part is generally considered to be a chemical entity embedded in or attached to a molecule.

[0283] When the listed substituents do not specify which atom they are attached to in the general chemical formula (including but not specifically mentioned compounds), such substituents may be bonded to any of their atoms. Combinations of substituents and / or their variants are permitted only if such combinations produce stable compounds.

[0284] When any variable (e.g., R) 1-aWhen a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 1-a Group substitution, meaning that the group can be replaced by up to 3 R groups. 1-a Replacement, where a certain position R 1-a Definition and other positions R 1-a The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0285] When a listed group does not explicitly indicate that it has a substituent, the group refers only to the unsubstituted group. For example, when "C 1-6 When "alkyl" is not specified as "substituted or unsubstituted," it refers only to "C". 1-6 "alkyl" itself or "unsubstituted C" 1-6 alkyl".

[0286] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then it should be understood that "alkyl" represents a linked alkylene group.

[0287] In some specific structures, when the alkyl group is clearly indicated as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halogenated-C". 1-6 C in alkyl- 1-6 Alkyl should be understood as C 1-6 Alkylene.

[0288] In this invention, the structural segments This refers to the structural segment being connected to the rest of the molecule via this bond. For example, It refers to cyclopropyl.

[0289] In this invention, the "-" at the end of a group indicates that the group is connected to the rest of the molecule through that site. For example, -OH refers to a hydroxyl group.

[0290] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... This refers to the corresponding group passing through this It can be linked to other fragments or groups in a compound.

[0291] It should be understood that the singular form used in this invention, such as "a," includes plural references unless otherwise specified.

[0292] The terms "one or more" or "one or two or more" refer to 1, 2, 3, 4, 5, 6, 7, 8, 9 or more. For example, 1, 2 or 3.

[0293] In this invention, the term "B replaced by one or more A" means that when B is replaced by "multiple" A's, the A's are the same or different.

[0294] In this invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine, especially F, Cl or Br.

[0295] In this application, as a group or part of other groups (e.g., used in haloalkyl, deuteralkyl, etc. groups), the term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising branched and straight chains having a specified number of carbon atoms, consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, most preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, wherein propyl is a C3 alkyl group (including isomers, such as n-propyl or isopropyl); butyl is a C4 alkyl group (including isomers, such as n-butyl, sec-butyl, isobutyl, or tert-butyl). Butyl); pentyl is a C5 alkyl group (including isomers, such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tert-pentyl or neopentyl); hexyl is a C6 alkyl group (including isomers, such as n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, n-octyl, nonyl, and decyl, and their similar alkyl groups.

[0296] In this application, as part of a group or other group, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon; that is, one hydrogen atom of the alkyl group is substituted, and the definition of alkyl is as described above. Examples of alkylene groups include methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2-, -CH2CH(CH3)- or -C(CH3)2-}, and so on.

[0297] In this application, as part of a group or other group, the term "alkoxy" refers to -O-alkyl, and the definition of alkyl is as described above.

[0298] In this application, as part of a group or other group, the term "hydroxyalkyl" refers to HO-alkyl-, and the definition of alkyl is as described above.

[0299] In this application, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one double bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to vinyl, 1-propenyl, n-allyl, but-1-enyl, but-2-enyl, pent-1-enyl, or pent-1,4-dienyl.

[0300] In this application, as part of a group or other group, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having at least one triple bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, most preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to ethynyl, 1-propynyl, n-propynyl, but-1-alkynyl, but-2-alkynyl, pent-1-alkynyl, or pent-1,4-dialkynyl.

[0301] In this application, as a group or part of other groups, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic, or more ring-bridged, fused-ring, or spirocyclic) carbocyclic substituent, which may be connected to the rest of the molecule via a single bond through any suitable carbon atom; such as 3- to 15-membered cycloalkyl groups having 3 to 15 carbon atoms, preferably 3- to 12-membered cycloalkyl groups having 3 to 12 carbon atoms, more preferably 3- to 8-membered cycloalkyl groups having 3 to 8 carbon atoms, and most preferably 3- to 6-membered cycloalkyl groups having 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.

[0302] In this application, as part of a group or other group, the term "cycloalkenyl" means a non-aromatic monocyclic or polycyclic (e.g., bicyclic, tricyclic or more bridging rings, fused rings, or spirocyclic systems) carbocyclic substituent containing at least one unsaturated bond, and which may be connected to the rest of the molecule via a single bond through any suitable carbon atom; such as a 3- to 15-membered cycloalkenyl group having 3 to 15 carbon atoms, preferably a 3- to 12-membered cycloalkenyl group having 3 to 12 carbon atoms, more preferably a 3- to 8-membered cycloalkenyl group having 3 to 8 carbon atoms, and most preferably a 3- to 6-membered cycloalkenyl group having 3 to 6 carbon atoms.

[0303] In this application, as part of a group or other group, the term "heterocyclic group" refers to a stable, saturated or partially unsaturated monocyclic or polycyclic (e.g., bicyclic, tricyclic or more ring-bridged, fused-ring, or spirocyclic systems) non-aromatic cyclic group consisting of a carbon atom and 1, 2, 3, 4, 5, 6, 7 or 8 (e.g., 1, 2, 3, 4, 5 or 6) heteroatoms selected from N, O, P and S (e.g., N, O and S); preferably including The heterocyclic groups are 3-14 membered heterocyclic groups containing 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, O, P, and S; preferably 3-12 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; more preferably 3-10 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S; and most preferably 3-8 membered heterocyclic groups containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S. When it is a fused-ring (fused-ring) heterocyclic group of bicyclic, tricyclic, or more rings, it may also include fused-ring (fused-ring) groups with cyclic hydrocarbon groups, aryl groups, or heteroaryl groups as defined herein, provided that the heterocyclic group is connected to the remainder of the molecule via a single bond through any suitable atom in a saturated or partially unsaturated heterocycle. When it is a heterocyclic group of bicyclic, tricyclic, or more spirocyclic forms, it may also include a spirocyclic group formed with a cyclic hydrocarbon group as defined herein, provided that the heterocyclic group is connected to the remainder of the molecule via a single bond through any suitable atom in a saturated or partially unsaturated heterocycle. In one embodiment of the invention, the heterocyclic group includes "heterocyclic alkyl" and "heterocyclic alkenyl," where a heterocyclic alkyl group is a stable, saturated monocyclic or polycyclic (e.g., bridged, fused, or spirocyclic systems of bicyclic, tricyclic, or more cyclic forms) consisting of a carbon atom and 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, O, and S, and a heterocyclic alkenyl group is a stable, partially unsaturated monocyclic or polycyclic (e.g., bridged, fused, or spirocyclic systems of bicyclic, tricyclic, or more cyclic forms) consisting of a carbon atom and 1, 2, 3, 4, 5, or 6 heteroatoms selected from N, O, and S, having at least one double bond. For example, the 3-10 membered heterocyclic groups include 3-10 membered heterocyclic alkyl groups or 3-10 membered heterocyclic alkenyl groups. In some embodiments, "heterocyclic alkyl" is a 3- to 7-membered monocyclic heterocyclic alkyl group, a 4- to 8-membered fused-ring heterocyclic alkyl group, a 4- to 8-membered bridged-ring heterocyclic alkyl group, or a 5- to 10-membered spirocyclic heterocyclic alkyl group. Exemplary 3-membered heterocyclic alkyl groups include, but are not limited to, azirropropyl, ethylene oxide, and thiocyclopropane, or their stereoisomers; exemplary 4-membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl (e.g., ... ), propylene oxide, oxetane (e.g.) ), thioheterocyclic butyl groups, or their isomers and stereoisomers; exemplary 5-membered heterocyclic alkyl groups include, but are not limited to, tetrahydrofuranyl (e.g., ), tetrahydrothiophene (e.g.) ), pyrrolidinyl (For example ), or its isomers and stereoisomers. Exemplary 6-membered heterocyclic alkyl groups include, but are not limited to, piperidinyl (e.g., ), tetrahydropyranyl, sulfide cyclopentyl, morpholinyl (e.g.) ), thiomorpholino, dithiaalkyl, dioxane, piperazine (e.g.) ), triazine alkyl, or its isomers and stereoisomers. Exemplary 7-membered heterocyclic alkyl groups include, but are not limited to, Oxyheptanyl, Or its isomers and stereoisomers. Exemplary 8-membered heterocyclic alkyl groups include, but are not limited to, Or its isomers and stereoisomers. Exemplary heterocyclic alkenyl groups:

[0304] In this application, as a group or part of other groups, the term "aryl" refers to an aromatic group consisting of a conjugated hydrocarbon ring system of carbon atoms that satisfies the 4n+2 rule, where each ring is aromatic. In one embodiment, "aryl" refers to an aromatic group having 6 to 18 (preferably 6 to 14, more preferably 6 to 10) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl groups.

[0305] In this application, as a group or part of other groups, the term "heteroaryl" refers to a conjugated cyclic group having a carbon atom and 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur within the ring. Unless otherwise specifically indicated in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more ring system. When it is a bicyclic, tricyclic, or more ring system, at least one of them is an aromatic ring (e.g., ...). Preferably, the heteroaryl group comprises one, two, three, or four heteroatoms selected from N, O, and S, and more preferably, it comprises one, two, three, or four heteroatoms selected from N, O, and S, and 5-6 or 8-10 heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, thiophene group and imidazolyl group (e.g., ...). ), pyrazolyl (e.g.) ), thiazolyl, oxazolyl (e.g.) ), diazole group, oxadiazole group, isoxazole group, pyridinyl group (For example ), pyrimidine group (For example ), pyrazinyl, pyridazinyl (e.g.) ), benzimidazole group, benzipyrazol group, indole group furanyl, pyrroleyl, triazolyl (e.g.) (e.g., tetrazolyl, triazinyl, indazinyl, isozolyl, thiadiazolyl, isoyndolyl, indazolyl, isoyndazolyl, purinyl, quinolinyl, isoquinolinyl, diazonyl, naphridyl, quinoxalinyl, pteridinyl, carbazole, carbolinyl, phenanthridine, phenanthrolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiopheneyl, oxatriazolyl, cenolinyl, quinazolinyl, indoleyl, o-diaphenanthryl, isoxazolyl, phenoxazinyl, phenthiazinyl, benzoxazolyl, or benzoisothiazolyl. Examples of heteroaryl groups include, but are not limited to, those listed below.)

[0306] Unless otherwise specified, all technical and scientific terms used herein have the standard meaning in the field to which the claimed subject matter pertains. Where multiple definitions exist for a term, the definition herein shall prevail.

[0307] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0308] The reagents and raw materials used in this invention are all commercially available.

[0309] The positive and progressive effects of the present invention are as follows: the compounds of the present invention have one or more of the following advantages: (1) good blocking effect (or inhibitory effect) on Nav1.8 channel activity; (2) good pharmacokinetic properties; (3) promising for the treatment of Nav1.8 related diseases, such as pain. Attached Figure Description

[0310] Figure 1 shows the stimulation parameters recorded by the hNav1.8 / β1 current in Test Example 1 (automated patch-clamp experiment).

[0311] Figure 2 shows the stimulation parameters recorded by the hNav1.8 / β1 current in Test Example 1 (manual patch-clamp experiment).

[0312] Figure 3 shows the stimulation parameters recorded by the hNav1.8 current in Test Example 2 (manual patch-clamp experiment). Detailed Implementation

[0313] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0314] Synthesis technology solution:

[0315] Step (1) involves condensing the compound represented by general formula Ia-1 with the compound represented by general formula Ia-2 to generate the compound represented by general formula Ia-3.

[0316] In step (2), the compound represented by general formula Ia-3 undergoes a ring-closing reaction under acidic or basic conditions to generate the compound represented by general formula Ia-4.

[0317] Among them, X 1 For N, N + -O - or CR x1 ;

[0318] X 2 For N, N + -O - or CR x2 ;

[0319] for

[0320] R x1 and R x2 They can be the same or different, independently of hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl or -(C1-C6 alkylene)-(C1-C6 alkoxy);

[0321] Or, R x1 and R x2 Together with the attached carbon atoms or heteroatoms, they form partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl groups;

[0322] R a and R b They can be the same or different, independently of hydrogen atoms, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 deuterated alkyl groups, or C3-C6 cycloalkyl groups.

[0323] Example 1: Enantiomer 37 of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-methoxy-1,6-naphthidium-4(1H)-one

[0324] Step 1: (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylic acid enantiomer 37a-P1;

[0325] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylic acid enantiomer 37a-P2

[0326] Racemate 37a (8.0 g, prepared using the method disclosed in Example 3 of patent "WO2021113627") was separated by chiral column chromatography to obtain enantiomers 37a-P1 (3.82 g, yield: 47.7%, Rt = 1.045 min, ee purity: 100%) and enantiomers 37a-P2 (3.85 g, yield: 48.1%, Rt = 1.532 min, ee purity: 97.5%), both of which were white oily substances.

[0327] Enantiomer 37a-P1:

[0328] LC-MS m / z (ESI): 355.1 [M+H] + .

[0329] 1 H NMR (400MHz, DMSO-d6) δ7.20–6.96(m,2H),4.54(d,J=10.0Hz,1H),4.00–3.86(m,4H),2.59(t,J=7.5Hz,1H),1.49(s,3H),0.63(dt,J=7.6,2.4Hz,3H).

[0330] Enantiomer 37a-P2:

[0331] LC-MS m / z (ESI): 355.1 [M+H] + .

[0332] 1 H NMR (400MHz, DMSO-d6) δ7.21–6.99(m,2H),4.60(d,J=10.1Hz,1H),3.96(dd,J=10.1,7.6Hz,1H ), 3.90 (d, J = 2.1Hz, 3H), 2.60 (p, J = 7.5Hz, 1H), 1.54–1.42 (m, 3H), 0.63 (dt, J = 7.8, 2.4Hz, 3H).

[0333] Chiral column analysis conditions: Instrument: UPCC (Waters); Column: R,R-Whelk-O1 4.6×100mm, 5um (REGIS); Column temperature: 40℃; Mobile phase: Carbon dioxide / methanol [(0.2% ammonia (7M methanol)] = 90 / 10; Flow rate: 3.0ml / min; Pressure: 2000psi; Injection volume: 2ul.

[0334] Chiral column separation conditions: Instrument: SFC-150 (Waters); Column: R,R-Whelk-O1 25×250mm, 10um (REGIS); Column temperature: room temperature; Mobile phase: carbon dioxide / methanol [(0.2% ammonia (7M methanol)] = 90 / 10; Flow rate: 85ml / min; Pressure: 100bar; Detection wavelength: 214nm; Cycle time: 3.9min; Injection volume: 8g sample dissolved in 280mL methanol; Injection volume: 1.5mL.

[0335] Step 2: (2R,3S,4S,5R)-N-(3-acetyl-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 37b

[0336] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid enantiomer 37a-P2 (265 mg, 0.75 mmol) was dissolved in anhydrous dichloromethane (5 mL), followed by the addition of 1-(4-amino-2-methoxypyridin-3-yl)ethyl-1-one (137 mg, 0.825 mmol), pyridine (593 mg, 7.5 mmol), and phosphorus oxychloride (575 mg, 3.75 mmol) dropwise under ice bath conditions. After reacting for 1 hour, the reaction solution was poured into a saturated sodium bicarbonate solution, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to give (2R,3S,4S,5R)-N-(3-acetyl-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 37b (250 mg, yield: 64%). LC-MS m / z (ESI): 503 [M+H] + .

[0337] Step 3: Enantiomer 37 of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyridino[3,2-c]pyridin-4-one

[0338] (2R,3S,4S,5R)-N-(3-acetyl-2-methoxypyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 37b (250 mg, 0.48 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and N-methylpyrrolidine (0.5 mL), and potassium tert-butoxide solution (1 M, 7.2 mL, 7.2 mmol) was added dropwise at room temperature. l), after the addition was complete, the mixture was heated to 60°C and reacted for 1 hour. The mixture was then adjusted to acidity with acetic acid, concentrated, and subjected to high performance liquid chromatography to prepare 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one enantiomeric form 37 (150 mg, yield: 64.6%).

[0339] LC-MS m / z (ESI): 485.1 [M+H] + .

[0340] 1 H NMR (400MHz, MeOH-d4) δ8.14(d,J=6.0Hz,1H),7.21(d,J=6.0Hz,1H),7.15(d,J=2.5Hz,1H),7.06-6.96(m,1H),6.33(s,1H),5.47(d, J=11.2Hz,1H),4.26(dd,J=11.2,8.6Hz,1H),4.03(s,3H),3.96(d,J=2.5Hz,3H),2.95-2.83(m,1H),1.72(s,3H),0.94-0.84(m,3H).

[0341] Example 2

[0342] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((S)-2,3-dihydroxypropoxy)-1,6-naphthidium-4(1H)-one enantiomer 56A;

[0343] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((R)-2,3-dihydroxypropoxy)-1,6-naphthidium-4(1H)-one enantiomeric 56B

[0344] Step 1: 2-Fluoro-3-iodopyridin-4-amine 56b

[0345] 4-Amino-2-fluoropyridine 56a (5.0 g, 44.6 mmol) and N,N-dimethylformamide (50 mL) were added sequentially to a reaction flask. The system temperature was adjusted to 0 °C, and N-iodosuccinimide (10.03 g, 44.6 mmol) was added. The temperature was adjusted to 70 °C, and the mixture was stirred for 16 small-scale tests. Samples were taken to detect the reaction until complete. The reaction solution was cooled to room temperature, and water (300 mL) and ethyl acetate (100 mL) were added to the reaction solution. The mixture was stirred, allowed to stand for separation, and the organic phase was collected. The aqueous phase was extracted again with ethyl acetate (100 mL). The combined organic phases were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 2-fluoro-3-iodopyridine-4-amine 56b (7.7 g, yield: 73%). LC-MS m / z (ESI): 239.1 [M+H] + .

[0346] Step 2: 1-(4-amino-2-fluoropyridin-3-yl)ethane-1-one 56c

[0347] In a reaction flask, 2-fluoro-3-iodopyridin-4-amine 56b (3 g, 12.6 mmol), tributyl(1-ethoxyethylene)tin (5.0 g, 13.9 mmol), bis(triphenylphosphine)palladium dichloride (885 mg, 1.26 mmol), and 1,4-dioxane (100 mL) were added sequentially. The mixture was purged with nitrogen three times, the temperature was adjusted to 100 °C, and the mixture was stirred for 16 small-scale tests, with samples taken for testing until the reaction was complete. The reaction solution was cooled to 50 °C, and stirred for another 30 minutes with 13 mL of 1M dilute hydrochloric acid (1 M, 13 mL). The pH of the reaction solution was adjusted to 8-9 with saturated sodium bicarbonate, and the mixture was extracted three times with dichloromethane (100 mL). The organic phases were combined, washed once with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography to give 56c (821 mg, yield: 42%) of 1-(4-amino-2-fluoropyridin-3-yl)ethane-1-one. LC-MS m / z (ESI): 155.0 [M+H] + .

[0348] Step 3: 1-(4-amino-2-{[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl]oxy}pyridin-3-yl)acetoone 56d

[0349] In a reaction flask, 56c of 1-(4-amino-2-fluoropyridin-3-yl)ethane-1-one (700 mg, 4.55 mmol), 2,2-dimethyl-1,3-dioxolane-4-methanol (2.4 g, 18.18 mmol), potassium carbonate (1.26 g, 9.1 mmol), and N-methylpyrrolidone (10 mL) were added sequentially. The temperature was adjusted to 150 °C, and the mixture was stirred for 4 hours. Samples were taken to check for complete reaction. The reaction solution was cooled to room temperature, and ethyl acetate (60 mL) was added to the reaction solution. The mixture was washed three times with water (60 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (HPLC) to give 1-(4-amino-2-{[(2,2-dimethyl-1,3-dioxane-4-yl)methyl]oxy}pyridin-3-yl)acet-1-one 56d (258.9 mg, yield: 21%). Purification method: Boston preparative column C18 10μm 21.2×250mm, mobile phase A: water (10mM ammonium bicarbonate), mobile phase B: acetonitrile; 35%-60%.

[0350] LC-MS m / z(ESI): 267.0 [M+H] + .

[0351] 1 H NMR(400MHz,DMSO-d6)δ7.81(s,2H),7.64(d,J=6.0Hz,1H),6.36(d,J=5.6Hz,1H),4.46-4.41(m,1H) ,4.32(d,J=5.2Hz,2H),4.09-4.05(m,1H),3.81-3.76(m,1H),2.51(s,3H),1.34(s,3H),1.29(s,3H).

[0352] Step 4: (2R,3S,4S,5R)-N-(3-acetyl-2-{[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl]oxy}pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e

[0353] Add (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid enantiomeric 37-P2 (150 mg, 0.423 mmol), 1-(4-amino-2-{[(2,2-dimethyl-1,3-dioxane-4-yl)methyl]oxy}pyridin-3-yl)ethyl-1-one 56d (126 mg, 0.46 mmol) to the reaction flask, dissolve in anhydrous dichloromethane (2 mL), cool to -20 °C in a dry ice bath under argon protection, add pyridine (0.34 mL), and then add phosphorus oxychloride (197 mg, 197 mL) dropwise. The reaction was carried out at -20°C for 0.5 hours with stirring. Water (10 mL) was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was separated, dried, concentrated, and purified by silica gel column chromatography (petroleum ether / tetrahydrofuran) to obtain (2R,3S,4S,5R)-N-(3-acetyl-2-{[(2,2-dimethyl-1,3-dioxanepent-4-yl)methyl]oxy}pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e (202 mg), which was the unpurified crude product.

[0354] LC-MS m / z (ESI): 603.0 [M+H] + .

[0355] Step 5: Obtain 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-dioxacyclopentan-4-yl)methyl]oxy}-1,4-dihydropyrido[3,2-c]pyridin-4-one 56f

[0356] Add (2R,3S,4S,5R)-N-(3-acetyl-2-{[(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methyl]oxy}pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 56e (202 mg, 0.33 mmol), potassium tert-butoxide tetrahydrofuran solution (5 mL, 5 mmol), NMP (0.2 mL), and anhydrous THF (2 mL) to the reaction flask in sequence. The mixture was stirred at room temperature for 6 hours under argon protection. Acetic acid (0.2 mL) was added to quench the reaction, and then the mixture was extracted with dichloromethane (10 mL × 3). The organic phase was separated, dried, and concentrated to obtain 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-dioxacyclopentan-4-yl)methyl]oxy}-1,4-dihydropyrido[3,2-c]pyridin-4-one 56f (208 mg), which was the unpurified crude product.

[0357] Step 6: 56g of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-[(2,3-dihydroxypropyl)oxy]-1,4-dihydropyrido[3,2-c]pyridin-4-one

[0358] 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-dioxacyclopentan-4-yl)methyl]oxy}-1,4-dihydropyrido[3,2-c]pyridin-4-one 56f (208 mg, 0.39 mmol), 1M hydrochloric acid solution (0.4 mmol), and MeOH (1 ml) were added sequentially to the reaction flask. The reaction was allowed to proceed at room temperature for 1 hour. LC-MS analysis confirmed the reaction was complete. Triethylamine (0.1 ml) was then added to the reaction solution to neutralize excess hydrochloric acid. The following product was obtained directly by high performance liquid chromatography: 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-[(2,3-dihydroxypropyl)oxy]-1,4-dihydropyrido[3,2-c]pyridin-4-one 56 g (90 mg, yield: 42.4%).

[0359] LC-MS m / z (ESI): 545.0 [M+H] + .

[0360] Step 7: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((S)-2,3-dihydroxypropoxy)-1,6-naphthidium-4(1H)-one enantiomer 56A;

[0361] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-((R)-2,3-dihydroxypropoxy)-1,6-naphthidium-4(1H)-one enantiomeric 56B

[0362] 56 g (90 mg) of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-[(2,3-dihydroxypropyl)oxy]-1,4-dihydropyrido[3,2-c]pyridin-4-one was resolved by chiral column chromatography to obtain enantiomer 56A (28 mg, yield: 31.1%, RT = 2.156 min, ee purity: 98.74%) and enantiomer 56B (30 mg, yield: 33.3%, RT = 2.914 min, ee purity: 99.84%).

[0363] Enantiomer 56A:

[0364] LC-MS m / z (ESI): 545.0 [M+H] + .

[0365] 1 H NMR(400MHz, Acetonitrile-d3)δ8.06(d,J=6.0Hz,1H),7.19-6.94(m,3H),6.02 (s,1H),5.37(d,J=11.3Hz,1H),4.83(s,1H),4.41(d,J=29.6Hz,2H),4.18(t,J=9 .9Hz,1H),3.88(d,J=2.2Hz,4H),3.71(d,J=12.0Hz,1H),3.61(dd,J=11.5,6.0H z, 1H), 2.84 (p, J = 7.7Hz, 1H), 1.72 (d, J = 1.2Hz, 3H), 0.83 (dt, J = 7.3, 2.3Hz, 3H).

[0366] Enantiomer 56B:

[0367] LC-MS m / z (ESI): 545.0 [M+H] + .

[0368] 1 H NMR(400MHz, Acetonitrile-d3)δ8.06(d,J=6.0Hz,1H),7.13(dd,J=12.2,6.5Hz,2H),7.05-6.9 4(m,1H),6.13(s,1H),5.37(d,J=11.3Hz,1H),4.46(dd,J=11.1,3.9Hz,1H),4.36(dd,J=11.0,4. 4Hz,1H),4.19(dd,J=11.3,8.4Hz,1H),3.88(d,J=2.2Hz,4H),3.71(dd,J=11.5,2.7Hz,1H),3.6 1(dd,J=11.5,6.0Hz,1H),2.85(p,J=7.8Hz,1H),1.74-1.70(m,3H),0.83(dt,J=7.3,2.4Hz,3H).

[0369] Chiral column analysis conditions: Instrument: UPCC (Waters); Column: IK 4.6×100mm, 5um (Daicel); Column temperature: 40℃; Mobile phase: Carbon dioxide / methanol [(0.2% ammonia (7M methanol)] = 80 / 20; Flow rate: 3.0ml / min; Pressure: 2000psi; Injection volume: 7.5ul.

[0370] Chiral column separation conditions: Instrument: SFC-150 (Waters); Column: IK 25×250mm, 10um (Daicel); Column temperature: room temperature; Mobile phase: carbon dioxide / methanol [(0.2% ammonia (7M methanol)] = 80 / 20; Flow rate: 100ml / min; Pressure: 100bar; Detection wavelength: 214nm; Cycle time: 4.56min; Injection volume: 90mg sample dissolved in 72mL methanol; Injection volume: 3.0mL.

[0371] Example 3: Enantiomer 58A of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one;

[0372] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-1,6-naphthidine-4,5(1H,6H)-dione enantiomeric 58B

[0373] Step 1: Dissolve 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one enantiomeric 37 (70 mg, 0.144 mmol) in acetic acid-hydrobromic acid solution (2 mL), and heat to 60 °C to react... The product was concentrated, adjusted to neutral with triethylamine, and purified by high performance liquid chromatography to prepare the enantiomeric product 58A of 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-hydroxy-1,4-dihydropyrido[3,2-c]pyridin-4-one (40 mg, yield: 59%).

[0374] LC-MS m / z(ESI): 471 [M+H] + .

[0375] 1 H NMR (400MHz, MeOH-d4) δ7.63-7.48(m,1H),7.27-7.16(m,1H),7.07-6.91(m,2H),6.78(d,J=7.5Hz,1H),5.59(d,J=11 .1Hz,1H),4.28(dd,J=11.0,8.3Hz,1H),3.95(d,J=2.5Hz,3H),2.90(p,J=7.6Hz,1H),1.74(s,3H),0.97-0.83(m,3H).

[0376] Step 2: Enantiomer 58B of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-1,6-naphthidium-4,5(1H,6H)-dione

[0377] In a dry 10 mL three-necked flask, 2-[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one enantiomer 58A (10 mg, 0.02 mmol) and dry tetrahydrofuran (3 mL) were added and stirred at room temperature until a clear solution was obtained. Then, 60% sodium hydride (4 mg, 1 mmol) was slowly added at 0 °C, and the reaction mixture was stirred at 0 °C for 10 min. Iodomethane (3 mg, 0.02 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was complete, the reaction mixture was poured into a 10 mL aqueous solution and extracted with ethyl acetate (2 × 10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then separated by high-performance liquid chromatography (HPLC). Acidic preparation (BOSTON Phlex ODS-C18 (21.2mm×250mm×10um), 35% acetonitrile, elution time 3 min; 35% to 80% acetonitrile, elution time 15 min; jump to 100% acetonitrile, elution time 7 min; mobile phase preparation: mobile phase A: 0.05% trifluoroacetic acid / water, mobile phase B: acetonitrile, peak time: RT = 11.9 min), freeze-dried to obtain ((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-methyl-1,6-naphthidium-4,5(1H,6H)-dione enantiomeric form 58B (4 mg, yield: 41%).

[0378] LC-MS: m / z 485.1 [M+H] + .

[0379] 1 HNMR(400MHz,CD3CN)δ7.56(d,J=7.6Hz,1H),7.30–7.17(m,1H),6.95(dd,J=18.4,8.2Hz,2H),6.79(d,J=7.6Hz,1H),5.59(d,J=11.2H z,1H),4.27(dd,J=11.2,8.0Hz,1H),3.89(d,J=2.2Hz,3H),3.53(s,3H),2.87(dt,J=15.4,7.8Hz,2H),1.71(s,3H),0.93–0.79(m,3H).

[0380] Example 4: Enantiomer 79 of 2-[(2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one

[0381] Following the synthesis method described in step 1 of Example 3, (2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant to obtain the target product enantiomer 79 (15.21 mg).

[0382] LC-MS m / z (ESI): 519.1 [M+H] + .

[0383] 1 H NMR (400MHz, MeOH-d4) δ7.63-7.48(m,1H),7.27-7.16(m,1H),7.07-6.91(m,2H),6.78(d,J=7.5Hz,1H),5.59(d,J=11 .1Hz,1H),4.28(dd,J=11.0,8.3Hz,1H),3.95(d,J=2.5Hz,3H),2.90(p,J=7.6Hz,1H),1.74(s,3H),0.97-0.83(m,3H).

[0384] Example 5: Enantiomer 100 of 6-(difluoromethyl)-2-((2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5(1H,6H)-dione

[0385] Following the synthesis method described in Example 3, (2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant, and diethyl bromodifluoromethyl phosphate was used instead of iodomethane as the reagent to obtain enantiomeric 100 (1.1 mg) of the target product.

[0386] LCMS: RT=2.18, m / z=569.3[M+1] + .

[0387] 1 H NMR(400MHz, Methanol-d4):7.92-7.47(m,2H),7.48-7.46(m,1H),6.84-6.78(m,3H),5.56(d,J=11Hz,1H ),5.37-5.31(m,1H),4.24-4.20(m,1H),3.84(s,3H),2.97-2.91(m,1H),1.69(s,3H),0.82-0.81(m,3H).

[0388] Example 6: Enantiomer 101 of 2-(2-((2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dione-1,5-dihydro-1,6-naphthidium-6(4H)-yl)acetamide

[0389] Following the synthesis method described in Example 3, (2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant, and 2-bromoacetamide was used instead of iodomethane as the reagent to obtain the target product enantiomer 101 (8.46 mg).

[0390] LCMS: RT=1.96, m / z=576.3[M+1] + .

[0391] 1 H NMR (400MHz, Methanol-d4): 7.57(d,J=7.5Hz,1H),7.47(d,J=8.5Hz,1H),6.97(s,1H),6.83-6.81(m,2H),6.73(d,J=8Hz, 1H), 5.57 (d, J = 11Hz, 1H), 4.70 (s, 2H), 4.24-4.20 (m, 1H), 3.84 (s, 3H), 2.96-2.93 (m, 1H), 1.71 (s, 3H), 0.83-0.81 (m, 3H).

[0392] Example 7: Enantiomer 102 of 6-(2,2-difluoroethyl)-2-((2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5(1H,6H)-dione

[0393] Following the synthesis method described in Example 3, (2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant, and 1,1-difluoro-2-iodoethane was used instead of iodomethane as the reagent to obtain the target product enantiomer 102 (10.17 mg).

[0394] LCMS: RT=2.19, m / z=583.2[M+1] + .

[0395] 1 H NMR(400MHz, Methanol-d4):7.69(d,J=7.5Hz,1H),7.47(d,J=8Hz,1H),7.02(s,1H),6.85-6.79(m,3H),5.62(d,J=11Hz, 1H),4.86(s,1H),4.47-4.40(m,2H),4.27-4.23(m,1H),3.84(s,3H),2.97-2.94(m,1H),1.71(s,3H),0.83-0.82(m,3H).

[0396] Example 8: Enantiomer 103 of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(difluoromethyl)-1,6-naphthidine-4,5(1H,6H)-dione

[0397] Following the synthesis method described in Example 3, diethyl bromodifluoromethyl phosphate was used instead of iodomethane as a reagent to obtain the target product enantiomer 103 (2.21 mg).

[0398] LCMS: RT=2.10, m / z=521.3[M+1] + .

[0399] 1H NMR(400MHz, Methanol-d4):7.93-7.67(m,2H),7.23(s,1H),7.12-7.02(m,1H),6.96-6.91(m,1H),6.74(d,J=7.5Hz, 1H), 5.50 (d, J = 11.5Hz, 1H), 4.26-4.22 (m, 1H), 3.91-3.90 (m, 3H), 2.87-2.81 (m, 1H), 1.70 (s, 3H), 0.88-0.86 (m, 3H).

[0400] Example 9: Enantiomer 104 of 2-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-4,5-dione-1,5-dihydro-1,6-naphthidium-6(4H)-yl)acetamide

[0401] Following the synthesis method described in Example 3, 2-bromoacetamide was used instead of iodomethane as a reagent to obtain the target product enantiomer 104 (9.35 mg).

[0402] LCMS: RT=1.89, m / z=528.3[M+1] + .

[0403] 1 H NMR (400MHz, Methanol-d4): 7.67 (d, J=7.5Hz, 1H), 7.23-7.20 (m, 1H), 6.99-6.96 (m, 2H), 6.79 (d, J=7.5Hz, 1H), 5.56 (d ,J=11.5Hz,1H),4.73(s,1H),4.27-4.24(m,1H),3.92(d,J=2Hz,3H),2.89-2.86(m,1H),1.72(s,3H),0.90-0.88(m,3H).

[0404] Example 10: Enantiomer 105 of 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(2,2-difluoroethyl)-1,6-naphthidine-4,5(1H,6H)-dione

[0405] Following the synthesis method described in Example 3, 1,1-difluoro-2-iodoethane was used instead of iodomethane as a reagent to obtain the target product enantiomer 105 (8.47 mg).

[0406] LCMS: RT=2.08, m / z=535.3[M+1] + .

[0407] 1 H NMR(400MHz, Methanol-d4):7.58(d,J=8Hz,1H),7.23-7.20(m,1H),6.98-6.91 (m,2H),6.69(d,J=7.5Hz,1H),6.32-6.08(m,1H),5.49(d,J=11.5Hz,1H),4.44 4.37(m,2H),4.25-4.21(m,1H),3.91(d,J=2Hz,3H),2.86-2.82(m,1H),1.71(s,3H),0.88-0.86(m,3H).

[0408] Example 11: Enantiomer 106 of 2-[(2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]-5-methoxy-1,4-dihydropyrido[3,2-c]pyridin-4-one

[0409] Following the synthesis method described in step 1 of Example 3, (2R,3S,4S,5R)-3-(3-(difluoromethyl)-4-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant to obtain the target product enantiomer 106. LC-MS m / z (ESI): 503.1 [M+H] + .

[0410] 1 H NMR(400MHz, Methanol-d4):7.70-7-68(m,1H),7.34(d,J=7.0Hz,1H),7.06-6.85(m,3H),6.58(d,J=7.0Hz,1H ), 5.48 (d, J = 11.0Hz, 1H), 4.29-4.25 (m, 1H), 3.70 (s, 3H), 2.88-2.85 (m, 1H), 1.72 (s, 3H), 0.89-0.88 (m, 3H).

[0411] Example 12: 6-(2,3-dihydroxypropyl)-2-((2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1,6-naphthidine-4,5(1H,6H)-dione enantiomeric 107

[0412] Following the synthesis method described in Example 3, (2R,3S,4S,5R)-3-(2-methoxy-4-(trifluoromethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was used instead of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as the reactant, and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane was used instead of iodomethane as the reagent to obtain the target product enantiomer 107.

[0413] LCMS: m / z = 593.2 [M+1] + .

[0414] 1 H NMR (400MHz, Methanol-d4): 7.55(d,J=8.0Hz,1H),7.49(d,J=8.0Hz,1H),7.01(s.1H),6.89-6.79(m,2H),6.67(d,J=7.6Hz,1H),5.53(d,J=11.2Hz,1H) ,4.33-4.28(m,1H),4.22-4.17(m,1H),3.99-3.94(m,1H),3.83-3.78(m,4H ), 3.55 (d, J = 5.2Hz, 2H), 2.98-2.91 (m, 1H), 1.71 (s, 3H), 0.82-0.80 (m, 3H).

[0415] Biological evaluation

[0416] Test Example 1: Evaluation of the inhibitory activity of the disclosed compounds against Nav1.8

[0417] 1. Experimental Objective

[0418] This study used HEK-293 cells stably expressing hNav1.8 / β1 channels and employed a fully automated patch-clamp method to investigate the effects of compounds at different concentrations on hNav1.8 / β1 currents and their dose-response relationship.

[0419] 2. Experimental Methods

[0420] 2.1. Cell Culture

[0421] HEK-293 cells, which stably express the hNav1.8 / β1 channel, were cultured in an incubator at 37°C and 5% CO2. Tetracycline at a final concentration of 1 μg / mL was added to the incubator (37°C, 5% CO2) for induction for 12–24 hours before the experiment.

[0422] Table 1. HEK-293hNav1.8 / β1 culture medium

[0423] 2.2. Cell Preparation

[0424] HEK-293 cells used in the experiment were cultured for at least two days and the cell density reached at least 75%. Before the experiment, the cells were digested with TrypLE until they became round, then gently pipetted and resuspended in physiological solution to collect the cells.

[0425] 2.3. Solution Preparation

[0426] The composition of the solutions required for the experiment is shown in Table 2, and all solutions were stored in a refrigerator at 4°C after filtration.

[0427] Table 2. Composition of physiological solutions, extracellular fluid and intracellular fluid

[0428] 2.4. Preparation of the test compound

[0429] The test compound was dissolved in 100% DMSO to prepare a 10.00 mM stock solution. The 10.00 mM solution was then stepwise diluted with 100% DMSO to obtain intermediate concentration stock solutions of 33.33 μM, 3.33 μM, 0.33 μM, 0.033 μM, and 0.0033 μM. Finally, the intermediate concentration stock solutions were further diluted in extracellular fluid to obtain final concentrations of 100.00, 10.00, 1.00, 0.10, and 0.01 nM. Each concentration was replicated at least twice per cell. The precipitate was visually inspected before testing. The final DMSO solution concentration of the test compound should not exceed 0.3%.

[0430] The control compound 1 is compound 7 in WO2021113627A1, and the synthesis method in WO2021113627A1 is followed.

[0431] 2.5.A SyncroPatch Whole-Cell Patch-Clamp Recording (Automated Patch-Clamp Experiment)

[0432] The hNav1.8 / β1 experiment was conducted at room temperature. Various programs were created on Biomek software (Nanion), including basic information settings, chip loading, cell capture formation sealing, amplifier settings, voltage pulse programs, and compound applications, to run the experiment.

[0433] Voltage pulse program: After establishing whole-cell recording mode, maintain the clamp potential at -120mV, apply a -50mV pulse voltage for 8000ms to inactivate the channel, then return to the clamp potential of -120mV and hold for 20ms. Next, depolarize to -10mV for 20ms to activate the hNav1.8 / β1 channel (Figure 2). The peak current generated under the -10mV pulse is used for data analysis. Finally, return to the clamp potential of -120mV. During recording, the above voltage pulse program is repeated every 15 seconds until the end of the detection (hNav1.8 / β1 current recording stimulation parameters are shown in Figure 1).

[0434] Compound Application: After recording begins, add 40 μL of extracellular fluid and monitor the peak current for 300 seconds; this period serves as the baseline for subsequent analysis. Then, add 40 μL of each concentration of the test compound, incubating for at least 300 seconds for each concentration. Throughout the recording process, all QC indicators must meet the data analysis acceptance criteria. If the acceptance criteria are not met, the cell / well will not be included in the data analysis, and the corresponding concentration will be retested. The entire recording process is automated using PatchControl analysis software.

[0435] 2.6.A Data Analysis (Automated Patch Clamp Experiment)

[0436] Data analysis was performed using DataControl, Excel 2013 (Microsoft), and GraphPad Prism 5.0 software. For each cell / well, the mean of its last five current peaks during the monitoring period (when no test compound was administered) was used as the current peak for the blank control. Similarly, at each concentration assay, the mean of its last five current peaks was used as the current peak for that concentration for statistical data analysis. The percentage inhibition of hNav1.8 / β current at each assay concentration was calculated using the following formula:

[0437] (1 - Peak tail current recorded after compound perfusion / Peak tail current recorded before compound perfusion) × 100%

[0438] The mean value of the percentage inhibition of hNav1.8 / β1 current by all recorded cells / wells at the same detection concentration was calculated, and the data are expressed as mean ± standard deviation.

[0439] The results show that the compound of this application has inhibitory activity against Nav1.8.

[0440] 2.5.B SyncroPatch whole-cell patch-clamp recording (manual patch-clamp experiment)

[0441] 2.5.1. The glass microelectrode (model GC150tF-10, Harvard Apparatus CO.UK) is drawn in two steps using a microelectrode drawing instrument. The resistance value of the drawn microelectrode tip is required to be between 2 and 5 MΩ when it enters the test system.

[0442] 2.5.2 Whole-cell patch-clamp recording of hNav1.8 / β1 current at room temperature. Cell suspension was added to a 35 mm culture dish and placed on an inverted microscope stage. After cell adhesion, whole-cell hNav1.8 / β1 current recording was established, requiring a sealing resistance of at least 500 MΩ. Simultaneously, extracellular fluid was used for perfusion at a flow rate of 1–2 mL / min. During the initial recording period, the peak current amplitude was continuously monitored until it stabilized (CV < 10% for 10 consecutive current acquisitions). After the peak current stabilized, the sample to be tested was perfused, starting with a low concentration, and the current was continuously monitored until the peak current stabilized again (CV < 5% for 5 consecutive current acquisitions). If the peak current remained unchanged, perfusion was maintained at that concentration for approximately 5 minutes before perfusing the next concentration. This process should be performed under good cell condition. Two cells were analyzed for each concentration.

[0443] 2.5.3 After establishing whole-cell recordings, the clamp potential was maintained at -120mV. The channel was inactivated by applying a half-inactivation voltage for 8000ms, then the clamp potential was returned to -120mV and held for 20ms. Next, the channel was depolarized to 0mV and held for 20ms to activate the hNav1.8 / β1 channel (Figure 2). The peak current generated at the 0mV pulse was used for data analysis. Finally, the clamp potential was returned to -120mV. During recording, the above voltage pulse program was repeated every 15 seconds until the detection was completed.

[0444] 2.6.B Data Analysis (Manual Patch Clamp Experiment)

[0445] The signal was amplified using a Multiclamp 700B patch-clamp amplifier (Molecular Devices, USA), and data was acquired using a DigiData 1440A / DD / A board (Molecular Devices, USA). Data statistics were compiled using Clampfit (V10, Molecular Devices, USA) software, or data was acquired using an EPC 10USB amplifier and recorded using Patchmaster v2×90 software. Further data analysis and curve fitting were performed using Excel 2013 (Microsoft) and GraphPad Prism 7.0. The percentage of inhibition of hNav1.8 / β current at each detected concentration was calculated using the following formula:

[0446] (1 - Peak tail current recorded after compound perfusion / Peak tail current recorded before compound perfusion) × 100%

[0447] The mean value of the percentage inhibition of hNav1.8 / β1 current by cells at the same detection concentration was calculated, and the data are expressed as mean ± standard deviation.

[0448] Final half-maximal inhibitory concentration (IC50) 50 The value is obtained by fitting the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope))

[0449] Where Y = inhibition%; Top = 100%; Bottom = 0%; X = compound concentration; IC50 = half-maximal inhibitory concentration; HillSlope = slope.

[0450] Curve fitting and IC 50 All calculations were performed using GraphPad Prism 7.0. If the inhibition rate at the lowest concentration exceeds half-inhibition or the inhibition rate at the highest concentration does not reach half-inhibition, the IC50 of the compound is shown as less than the lowest concentration or greater than the highest concentration.

[0451] Test Example 2: Inhibitory activity (IC50) of the disclosed compound against Nav1.8 50 Evaluation of (manual patch-clamp experiment)

[0452] 1. Materials and Methods

[0453] 1.1 Reagent and Instrument Information

[0454] 1.1.1 Reagent Information

[0455] Table 1 Reagent Information

[0456] 1.1.2 Instrument Information

[0457] Table 2 Patch Clamp Systems

[0458] 1.2 Compound Preparation

[0459] 1.2.1 Preparation of blank control standard

[0460] DMSO was used as the blank control stock solution. An appropriate amount of DMSO was added to the extracellular fluid to obtain an extracellular fluid containing 0.1% DMSO, which was used as the blank control working solution.

[0461] 1.2.2 Preparation of test substance

[0462] The test substance was serially diluted with DMSO from high to low concentration to prepare intermediate dilutions, which were then further diluted with extracellular fluid to the working solution concentration. The concentration of DMSO in each working solution did not exceed 0.3%. The extracellular fluid used for Nav1.8 detection contained 100 nM TTX to block the endogenous TTX-S (tetrodotoxin-sensitive) Na+ current present in cells. The test substance working solution was sonicated for 20 min before patch-clamp assays.

[0463] 1.2.3 Basis for Concentration Selection

[0464] For Nav1.8, the maximum test concentration is 100 nM, with 10-fold dilutions and 5 concentrations. Storage conditions.

[0465] 1.3 Cell Culture

[0466] In this patent, we used a CHO cell line expressing the Nav1.8 channel. The gene information is as follows:

[0467] Nav1.8 (SCN10A, NM_006514; SCN1B, NM_199037; SCN3B, NM_018400)

[0468] ●Maintenance medium: CHO cells were cultured in Ham's F-12 medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin S, 200 μg / mL Hygromycin B, 0.8 mg / mL G418, and 100 μg / mL Zeocin at 37°C and 5% carbon dioxide.

[0469] ● Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at 37°C for approximately 1.5 min. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed the cells into 6 cm cell culture dishes, with a seeding density of 2.5 × 10⁵ cells per dish (final volume: 5 mL).

[0470] ● To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0471] ● Patch clamp assay: Before the assay, cells were separated with 0.25% Trypsin-EDTA, and 6.5 × 10³ cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). After induction with tetracycline for 24-72 hours, the assay was performed.

[0472] 1.4 Electrophysiological Recording

[0473] 1.4.1 Record the liquids used

[0474] ●Extracellular fluid: K-007-1

[0475] 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, with NaOH adjusted to pH 7.4.

[0476] ●Intracellular fluid: Nav-001-2

[0477] Adjust pH to 7.2 with 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, and CsOH.

[0478] Extracellular fluid should be stored at 4°C and used within 2 weeks. Intracellular fluid should be prepared, aliquoted into 1 mL tubes, and stored at -20°C. Freshly thawed intracellular fluid should be used daily for experiments. All intracellular fluid should be used within three months; otherwise, it should be discarded and reprepared.

[0479] 1.4.2 Patch clamp testing

[0480] The voltage stimulation protocol for whole-cell patch-clamp recording of sodium currents is as follows: After whole-cell sealing, the cell voltage is clamped at -120 mV. The voltage is first stepped from -130 mV to -10 mV in 10 mV increments and held for 5 s, followed by a 0 mV depolarization pulse to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of sodium currents are detected using a dual-pulse mode. First, a depolarization pulse (TP1) to 0 mV is applied for 50 ms to detect the resting sodium current. Then, the voltage is adjusted to Vhalf and held for 5 s, followed by restoring the voltage to -120 mV and holding for 20 ms to restore unbound and inactivated channels. A second depolarization pulse (TP2) to 0 mV is then applied for 50 ms to detect the half-inactivated sodium current. Finally, the voltage was restored to the clamping voltage of -120mV, and data were collected repeatedly at 20s intervals to observe the effect of the drug on the peak sodium current in two different states (the stimulation parameters of the hNav1.8 current recording are shown in Figure 3).

[0481] Experimental data were acquired using an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software. The patch-clamp procedure began by using a microelectrode puller to draw a glass capillary into a recording electrode. The electrode, filled with intracellular fluid, was then placed into a microelectrode holder. Next, a coverslip containing cells was placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator was used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) was recorded. The electrode was then slowly brought into contact with the cell surface, and negative pressure was applied to create a GΩ high-resistance seal. Fast capacitance compensation was then performed, and negative pressure was continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was applied.

[0482] Once the current amplitude stabilized in the control extracellular solution, drug administration began. After each drug concentration reached equilibrium (approximately 5 minutes), the next concentration was measured. Blank control extracellular solution and the working solution of the test compound were administered sequentially from low to high concentration through the recording bath using gravity perfusion, while a peristaltic pump was used for fluid replacement during recording. The current detected in each cell in extracellular solution without the compound served as its control group. All electrophysiological experiments were performed at room temperature.

[0483] 1.4.3 Data Quality Control Standards

[0484] The following criteria are used to determine whether data is acceptable:

[0485] (1) Electrode resistance <5MΩ

[0486] (2) Sealing resistance > 1 GΩ

[0487] (3) Initial connection resistance <15MΩ

[0488] (4) Connection resistor ends <15MΩ

[0489] (5) Peak starting current > 300pA

[0490] (6) The current does not show obvious spontaneous decay.

[0491] (7) At the same concentration, the difference in inhibition rate between repeated data is ≤15%.

[0492] 2. Data Analysis

[0493] First, the peak sodium current (Peak current compound) and peak control current (Peak current control) after each drug concentration were normalized. Then, the inhibition rate corresponding to each drug concentration under different conditions was calculated. For each concentration inhibition rate, the mean (Mean), standard deviation (SD), and standard error (SE) were calculated, and the data are expressed as Mean ± SE. Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope))

[0494] Calculate the IC of the compound using the above equation. 50 The value was calculated, and a nonlinear fit was performed on the concentration-effect curve, where IC50 was the concentration-effect value. 50 This is the half-inhibitory concentration (IC50). 50 The calculations and curve fitting were performed using GraphPad Prism software.

[0495] Table 4: IC50 results of the disclosed compounds for Nav1.8 (manual patch clamp)

[0496] Experimental data show that some compounds of the present invention have better inhibitory activity against Nav1.8 than control compound 1, and have the potential to have better pain treatment effects.

[0497] Test Example 3: Pharmacokinetic Test of the Compounds Disclosed

[0498] 1. Drug preparation

[0499] Weigh a certain amount of the drug and prepare a formulation for gavage and intravenous injection. The solvent for both gavage and intravenous injection is 10% DMA + 10% Solutol HS15 + 80% Saline.

[0500] 2. Administration

[0501] ICR mice were fasted for 12 hours before administration, but had free access to water. The intravenous dose was 1 mg / kg, and the gavage dose was 2 mg / kg. Mice were allowed to resume eating 4 hours after administration.

[0502] 3. Sampling

[0503] At 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 h after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 8 and 24 h after gavage administration, 30 mL of whole blood was collected from the submandibular vein of mice and placed in anticoagulant centrifuge tubes containing EDTA-K2. The centrifuge tubes were centrifuged at 5000 rpm and 4℃ for 5 min, and the separated plasma was stored at -80℃ for analysis.

[0504] 4. Measurement

[0505] Take 10 mL of plasma sample and add 200 mL of MeOH / Acetonitrile (1:1, v / v) containing internal standards (50 nM terfenadine and 500 nM tolbutamide) for protein precipitation (vortex for 10 min, then centrifuge at 4000 rpm for 10 min). Transfer 100 mL of the supernatant to a 96-well plate and perform LC-MS / MS analysis.

[0506] 5. Pharmacokinetic Parameter Results

[0507] The compound of this invention exhibits a longer half-life and better oral bioavailability in mice compared to control compound 1, demonstrating significantly different pharmacokinetic characteristics. The pharmacokinetic parameters of the disclosed compound and its control compound 1 are shown in Table 5 below.

[0508] Table 5: Pharmacokinetic parameters of enantiomers 101 and 104 of the present invention and control compound 1

[0509] The compounds of this invention exhibit high area under the curve and high blood concentration in mice, as well as ideal oral bioavailability, demonstrating favorable pharmacokinetic characteristics.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in, X is either O or S; Q is X 1 For N, N + -O - or CR x1 ; X 2 For N, N + -O - or CR x2 ; R 12a and R 12b Independently hydrogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 aryl, 5-14 heteroaryl; the above C1-C6 alkyl groups optionally bound by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-2 Replaced; R 12-1 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 -S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 -P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); the above C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, optionally substituted with one or more R 12-3 Replaced; R 12-3 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R 26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 -C(=NR) 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 -S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R 28 -NR 27 C(O)NR 25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R 26 -P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 -C(=NR) 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; R 12-2 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 -S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 -P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 Cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); R 24 R 25 R 26 R 27 R 28 and R 29 It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 30 Replaced; And / or, R 25 R 26 R 27 and R 28 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups. R 16 R 17 R 18 R 20 and R 21 It is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C1-C6 cycloalkyl, -(C1-C6 alkylene)-Z-3-8 membered heterocycloalkyl, -(C1-C6 alkylene)-Z-C6-C 10 aryl or -(C1-C6 alkylene)-Z-5-10 heteroaryl, C6-C 14 Aryl or 5-14-membered heteroaryl; wherein the alkyl, alkylene, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally surrounded by one or more R groups. 23 Replaced; And / or, R 16 R 17 R 20 and R 21 Any two groups together with the carbon atom they are attached to form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups; Z is independently O, S, NH, S(O) or S(O)2; R x1 and R x2 The same or different, independently of hydrogen, deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 -S(O)2R 21 -S(=NR) 20 )(O)R 21 -(C1-C6 alkylene)-(C1-C6 alkoxy) or 5-14 heteroaryl; the above C1-C6 alkyl, C1-C6 deuterated alkyl, C3-C6 cycloalkyl and 5-14 heteroaryl are optionally surrounded by one or more R 24 Replaced; And / or, R x1 and R x2 Together with the attached carbon atom or heteroatom, they form a partially unsaturated 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl; wherein the aforementioned 3-6 membered cycloalkyl, phenyl, partially unsaturated 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by one or more of the following substituents: deuterium, halogen, cyano, amino, nitro, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C1-C6 haloalkyl, -C(O)NR 16 R1 7 -OR 18 -S(O)2R 21 -S(=NR) 20 )(O)R 21 Or -(C1-C6 alkylene)-(C1-C6 alkoxy); R a Independently, it can be a hydrogen atom, deuterium, hydroxyl group, halogen, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group, C3-C6 cycloalkyl halogen group, -COO (C1-C3 alkyl group) or amide group; R b It can be independently a hydrogen atom, halogen, hydroxyl group, cyano group, amino group, C1-C6 alkyl group, C1-C6 alkoxy group, C1-C6 deuterated alkyl group or C3-C6 cycloalkyl group; R 5 and R 6 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl or C1-C6 haloalkyl; the C3-C6 cycloalkyl and 3-6 membered heterocyclic alkyl are optionally substituted with one or more halogens, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 7 and R 8 The same or different, and each independently being hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkoxy, C3-C6 cycloalkyl, 3-6-membered heterocyclic alkyl, benzene ring, or 5-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, benzene ring, and heteroaryl are optionally represented by one or more R 4 Replaced; And / or, R 5 R 6 R 7 and R 8 Any two groups together with the carbon atom attached to them form a C3-C6 cycloalkyl or a 3-6 membered heterocycloalkyl; the C3-C6 cycloalkyl and the 3-6 membered heterocycloalkyl are optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups. R 11 Independently, it is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C2-C6 alkenyl or C2-C6 alkynyl; A can be independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, amide, nitro, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 alkyl. 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, 5-10-membered heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R groups. 15 Replaced; R 4 and R 15 Independently deuterium, halogen, hydroxyl, or oxo group (=O or -O) - ), nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -NR 16 R 17 -(C1-C6 alkylene)-NR 16 R 17 -O-(C1-C6 alkylene)-NR 16 R 17 -C(=NR) 20 )R 21 -S(O)NR 16 R 17 -S(O)2NR 16 R 17 -NR 20 S(O)R 21 -NR 20 S(O)2R 21 -SR 21 -S(O)R 21 -S(O)2R 21 -S(=NR) 20 )(O)R 21 -NR 20 C(O)R 21 -NR 20 C(O)NR 16 R 17 -C(O)NR 20 -OR 21 -C(O)NR 16 R 17 -P(O)R 24 R 24 -C(O)NR 20 -NR 16 R 17 -C(=NR) 20 )NR 20 -OR 21 -C(O)NR 20 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 20 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 20 )NR 16 R 17 -C(O)-C(O)-NR 16 R 17 -S(=NR) 20 )NR 16 R 17 -S(=NR) 20 )R 21 、-Si(R 22 3. -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 14 Aryl, 5-14 heteroaryl, -(C3-C 10 Cycloalkyl)-(C1-C6 alkyl), -(3-10 member heterocyclic alkyl)-(C1-C6 alkyl), -C(O)-(C3-C 10 cycloalkyl), -C(O)-(3-10 membered heterocycloalkyl), -(C1-C6 alkylene)-O-(C1-C6 alkylene)-(C3-C 10 cycloalkyl), -(C1-C6 alkylene)-O-(C3-C 10 cycloalkyl), -O-(C1-C6 alkylene)-(5-14-membered heteroaryl), -O-(C1-C6 alkylene)-(3-10-membered heterocycloalkyl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally separated by one or more R 24 Replaced; And / or, adjacent R 15 Together with the carbon atoms attached thereto, they form partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl; said partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl is optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups or C1-C6 haloalkoxy groups; R 22 Independently hydrogen or C1-C6 alkyl; R 23 Independently, it can be deuterium, halogen, hydroxyl, oxo, nitro, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -NR. 25 R 26 -(C1-C6 alkylene)-NR 25 R 26 -O-(C1-C6 alkylene)-NR 25 R 26 -C(=NR) 27 )R 28 -S(O)NR 25 R 26 -S(O)2NR 25 R 26 -NR 27 S(O)R 28 -NR 27 S(O)2R 28 -SR 28 -S(O)R 28 -S(O)2R 28 -S(=NR) 27 )(O)R 28 -NR 27 C(O)R 28 -NR 27 C(O)NR 25 R 26 -C(O)NR 27 -OR 28 -C(O)NR 25 R 26 -P(O)R 24 R 24 -C(O)NR 27 -NR 25 R 26 -C(=NR) 27 )NR 27 -OR 28 -C(O)NR 27 -(C1-C6 alkylene)-C3-C8 cycloalkyl, -C(O)NR 27 -(C1-C6 alkylene)-3-10 membered heterocyclic alkyl, -C(=NR) 27 )NR 25 R 26 -C(O)-C(O)-NR 25 R 26 -S(=NR) 27 )NR 25 R 26 -S(=NR) 27 )R 28 、-Si(R 22 3. -OR 29 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; R 30 It can be hydrogen, halogen, hydroxyl, oxo group, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkoxy, C3-C 10 Cycloalkyl or 3-10 membered heterocyclic alkyl; The heteroatoms or groups in the aforementioned heterocyclic alkyl and heteroaryl groups are optionally selected from N, N + -O - ,O,S,S(O),S(O)2,carbonyl,S(O)(=NR 20 ) or P(O)CH3, wherein the number of heteroatoms or groups is 1, 2, 3, 4, 5, 6, 7 or 8.

2. The compound of formula (I) as claimed in claim 1, characterized in that, It can be any of the following schemes: Option 1 The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt thereof: Among them, A, X, Q, R 5 R 6 R 7 R 8 and R 11 The definition is as described in claim 1.

3. The compound of formula (I) as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The halogen or halogen is F, Cl or Br; preferably F; (2) The C1-C6 alkyl group in the C1-C6 alkyl group, C1-C6 deuterated alkyl group, C1-C6 haloalkyl group and C1-C6 hydroxyalkyl group is independently a C1-C4 alkyl group; preferably it is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, preferably methyl or ethyl; more preferably methyl; (3) The C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 hydroxyalkoxy in the C1-C6 alkoxy group are independently C1-C4 alkoxy groups; preferably -O-methyl, -O-ethyl, -O-n-propyl, -O-isopropyl, -O-n-butyl, -O-isobutyl or -O-tert-butyl, preferably methoxy; (4) The C1-C6 alkylene group is independently a C1-C3 alkylene group; preferably a methylene group, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)- or -C(CH3)2-, preferably a methylene group; (5) The C3-C 10 cycloalkyl, the aforementioned C3-C 10 C3-C in halocycloalkyl groups 10 The cycloalkyl group, the C3-C8 cycloalkyl group, and the C3-C8 halocycloalkyl group are all C3-C6 cycloalkyl groups; preferably cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, more preferably cyclopropyl or cyclobutyl. (6) The C3-C6 cycloalkyl group and the C3-C6 halocycloalkyl group are independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl or cyclobutyl; (7) The 3-10 membered heterocyclic alkyl group is independently a 3-8 membered heterocyclic alkyl group; (8) The 3-8 membered heterocyclic alkyl group is independently azahexacyclic butylene, oxacyclobutylene, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, morpholinyl, piperazineyl, Oxyheptanyl, Preferably (8) The 3-6 membered heterocyclic alkyl group is independently azahexacyclic butylene, oxacyclobutylene, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiophenyl, morpholinyl, or piperazineyl; preferably it is... (9) The C3-C 14 Aryl, C6-C 14 Aryl or C6-C 10 The aryl group is independently a phenyl group; (10) The 5-14-membered heteroaryl or 5-10-membered heteroaryl group is independently imidazolyl, pyridinyl, pyridinyl, pyrimidinyl, oxazolyl, pyrazolyl, Preferably (11) The 5-6 membered heteroaryl group is independently pyridyl or pyrazolyl; preferably it is... (12) When replaced, the number of replacements is 1, 2 or 3; (13) The haloalkyl group is independently a fluoroalkyl group; preferably -CH2F, -CHF2 or -CF3; (14) In the 5-14 heteroaryl group, the 13 heteroaryl group is independently... Preferably 4. The compound of formula (I) as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) X is O; (2)R 5 and R 6 Each is independently a C1-C6 alkyl or C1-C6 haloalkyl; preferably methyl, -CF3, -CHF2 or -CH2CF3; (3)R 5 Independently C1-C6 alkyl, preferably methyl, R 6 It is independently a C1-C6 haloalkyl group, preferably -CF3; (4)R 7 and R 8 It is independently hydrogen, deuterium, or a C1-C6 alkyl group; said alkyl group is optionally surrounded by one or more R 4 Replaced; preferably R 7 and R 8 One of them is hydrogen, and the other is a C1-C6 alkyl group; (5) A is independently C3-C 10 Cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl or 5-10-membered heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 15 The substituted substance is preferably a C3-C8 cycloalkyl group or a C6-C4 cycloalkyl group. 10 aryl, 5-10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl group is optionally surrounded by one or more R 15 Replaced; (6)R 15 Independently halogen, C1-C6 alkyl, or C1-C6 alkoxy, wherein the alkyl and C1-C6 alkoxy groups are optionally separated by one or more R 24 replace; (7)R 24 Independently hydrogen, deuterium, =O, -O - Halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; preferably hydrogen, deuterium, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; preferably deuterium, halogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; preferably halogen; (8)R 11 Independently hydrogen or methyl; (9)R 12-3 Independently, it is deuterium, halogen, hydroxyl, oxo group or C1-C6 alkyl; preferably deuterium, F, hydroxyl or methyl; (10)R 12-1 Independently deuterium, halogen, hydroxyl, oxo group, -OR 18 C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl or -C(O)NR 16 R 17 The aforementioned C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-3 The substituted substance is preferably deuterium, hydroxyl, -O-methyl, cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, or 1,3-dioxapentylcycloyl; the aforementioned cyclobutyl, oxacyclobutyl, tetrahydrofuranyl, or 1,3-dioxapentylcycloyl is optionally replaced by one or more R 12-3 Replaced; (11)R 12-2 Independently deuterium, halogen, hydroxyl, oxo group, C1-C6 alkyl or -OR 18 Preferably, it is hydroxyl or methoxy; (12)R 12a and R 12b Independently C1-C6 alkyl, C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl; the above C1-C6 alkyl groups may optionally be converted by one or more R 12-1 Replaced; the above C3-C 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, optionally with one or more R 12-2 The substituted group is preferably methyl, n-propyl, cyclobutyl, or tetrahydropyranyl; methyl or n-propyl may optionally be replaced by one or more R 12-1 The cyclobutyl group and tetrahydropyran group are optionally replaced by one or more R groups. 12-2 Replaced; (13)R x1 and R x2 Independently hydrogen or halogen; (14)R 16 R 17 R 18 R 20 and R 21 Independently hydrogen or C1-C6 alkyl, said alkyl group optionally being converted by one or more R 23 The alkyl group is optionally replaced by one or more R 23 The substitute is preferably hydrogen, methyl, or (CH2)2-OCH3. (15)R 29 Independently hydrogen or C1-C6 alkyl; preferably hydrogen or methyl; (16)R 23 Independently for -OR 29 Preferably, it is -O-CH3; (17) Adjacent R 15 Together with the atoms attached to it, they form partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl; preferably partially unsaturated 5-6 membered heterocycloalkyl. The partially unsaturated 3-6 membered cycloalkyl or partially unsaturated 5-6 membered heterocycloalkyl is substituted with one or more of the following substituents: deuterium or halogen; Preferably 5. The compound of formula (I) as claimed in claim 1, characterized in that, It satisfies one or more of the following conditions: (1)R 12a and R 12b Independently hydrogen, methyl, (2)R 15 It can be F, methyl, -O-methyl, -OCHF2, -OCF3, -CF3, -CHF2 or -CH2CF3; (3)R 11 For H; (4)R 24 Independently, it can be F, =O, methyl, -O-CH3, CF2, or CF3; (4) for (5) A is (6) Q is (7)R x1 and R x2 It can be hydrogen or F independently.

6. The compound of formula (I) as claimed in claim 1, characterized in that, It is any of the following compounds: Alternatively, its enantiomers, or mixtures thereof with enantiomers.

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) The compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

8. The use of a substance in the preparation of a medicament for treating a disease / symptom; characterized in that, The substance is a compound of formula (I) as described in any one of claims 1-6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 7.

9. The application as described in claim 8, characterized in that, The drug is used to inhibit voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.8; And / or, the medicine is a medicine for treating and / or relieving pain and pain-related diseases / conditions, incontinence or arrhythmia; Preferably, the pain is one or more of the following: chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

10. The application of a substance in the preparation of a voltage-gated sodium channel inhibitor; characterized in that, The substance is a compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof; Preferably, the voltage-gated sodium channel is Nav1.8.

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