Aromatic ring compounds, preparation method therefor, and pharmaceutical use thereof

Abstract

The present disclosure relates to aromatic ring compounds, a preparation method therefor, and pharmaceutical use thereof. Specifically, the present disclosure relates to an aromatic ring compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof as a therapeutic agent, especially use thereof as a Nav inhibitor and use thereof in the preparation of a drug for treating and / or alleviating pain and pain-related diseases. Each group in general formula (I) is as defined in the specification.

Description

Aromatic cyclic compounds, their preparation methods and their pharmaceutical applications Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to aromatic cyclic compounds, their preparation methods, and their pharmaceutical applications. In particular, this disclosure relates to aromatic cyclic compounds of general formula (I), their preparation methods, pharmaceutical compositions containing such compounds, their use as Nav inhibitors, and their use in the preparation of medicaments for treating and / or alleviating pain and pain-related disorders. Background Technology

[0002] Pain is a complex physiological and psychological activity and one of the most common clinical symptoms. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage; it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers and playing an indispensable protective role in normal bodily functions. At the same time, pain is also a common clinical symptom; after the external stimulus that triggered the pain disappears, intense or persistent pain can cause physiological dysfunction, severely impacting the quality of life. Statistics show that approximately one-fifth of the world's population suffers from moderate to severe chronic pain.

[0003] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings, widely distributed throughout the skin, muscles, joints, and internal organs. They convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane depolarizes, sodium ion channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and alleviate pain.

[0004] Sodium channels (Nav) are a class of transmembrane ion channel proteins. These proteins consist 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 subtypes, Nav1.1 to Nav1.9. Different subtypes exhibit different tissue distributions and electrophysiological and pharmacological characteristics. 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, with their encoding genes located on human chromosome 2q23-24, and they are highly expressed in neurons. Nav1.5, Nav1.8, and Nav1.9 are TTX-R type, with their encoding genes located on human chromosome 3p21-24. Of these, Nav1.5 is mainly found in cardiomyocytes, while Nav1.8 and Nav1.9 are present in the peripheral nervous system. Nav1.4 and Nav1.6 are both TTX-S type, and are abundant in skeletal muscle and the central nervous system, respectively. The local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors, such as lamotrigine, lacocillin, and mexiletine, have been successfully used to treat chronic pain.

[0005] Nav1.8, a TTX-R type gene encoded by SCN10A, is primarily found in trigeminal ganglion neurons and DRG neurons, exhibiting slow inactivation and rapid recovery electrophysiological characteristics. In neurons expressing Nav1.8, the rise in action potentials is mainly driven by Nav1.8 currents. In several models of neuropathic pain, nerve injury increases Nav1.8 expression levels in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides to reduce Nav1.8 expression significantly alleviates pain. Intraplasty of carrageenan in rat paws increased Nav1.8 expression in DRG neurons. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain. Functionally gain mutations in the human Nav1.8 gene lead to peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for treating various pain types, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0006] Clinically used Nav inhibitors, lacking subtype selectivity, inhibit sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application. Nav1.8 is primarily distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, superior pharmacokinetic properties, and fewer side effects.

[0007] Published patent applications for Nav1.8 inhibitor compounds include WO2023205463A1 and WO2023205778A1. Summary of the Invention

[0008] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0009] in:

[0010] R 3 and R 4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 NR 22 C(O)R 23 C(O)R 23 C(O)OR 23 OC(O)R 23 S(O) v R 23 S(O) v NR 20 R 21 OR 23 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0011] Ring A is aryl or heteroaryl;

[0012] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0013] L is selected from bond, O, S(O). v O(CR) 1a R 1b ) x 、(CR 1a R1b ) x O and NR 1c ;

[0014] G 1 Selected from N, N + O - and CR 8 ;

[0015] G 2 Selected from N, N + O - and CR 5 ;

[0016] G 3 Selected from N, N + O - and CR 6 ;

[0017] G 4 Selected from N, N + O - and CR 7 ;

[0018] R 5 R 6 R 7 and R 8 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OS(O) v R 14 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced;

[0019] Each R 1 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 02 Replaced;

[0020] Each R 2 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 03 Replaced; or, two Rs 2 Together with the atoms attached thereto, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally converted by one or more R... 03 Replaced;

[0021] Each R 01 R 02 and R 03 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OC(O)OR 14 S(O) v R 14 S(O) v OR 14OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0022] R 15 and R 16 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 20 R 21 C(O)NR 20 R 21 C(O)R 23 OR 23 Cycloalkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more R * Replaced; or R 15 R 16 Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein each cycloalkyl and heterocyclic group is independently and optionally converted by one or more R... * Replaced;

[0023] Each R 20 R 21 R 22 R 23 R 1c R 11 R 12 R 13 and R 14The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 30 R 31 C(O)NR 30 R 31 C(O)R 33 C(O)OR 33 OR 33 S(O) v R 33 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced;

[0024] Each R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] Each R * The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 30 R 31 C(O)NR 30 R 31 alkylene NR 30 R 31 alkylene C(O)NR 30 R 31 C(O)R 33 C(O)OR 33 OR 33 Nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, and heteroarylalkyl;

[0026] Each R 30 R 31 and R 33 They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl and heterocyclic alkyl;

[0027] m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6;

[0028] Each v may be the same or different, and each is independently 0, 1 or 2;

[0029] Each x is either the same or different, and each x is independently 0, 1, 2, 3 or 4.

[0030] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

[0031] Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;

[0032] X 3 For N or CR X3 ;X 4 For N or CR X4 ;

[0033] R X1 R X2 R X3 and R X4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 02 Replaced;

[0034] Or, R X1 R X2 and the carbon atom or R bonded to it.X2 R X3 and the carbon atom or R bonded to it. X3 R X4 Together with the carbon atom attached to it, they form a ring C, which is optionally bonded by one or more R atoms. 1 Replaced;

[0035] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0036] Rings B and G 1 To G 4 R 1 To R 4 n, R 11 To R 14 R 02 And v is as defined in general formula (I).

[0037] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

[0038] Among them, X 1 For N or CR X1 ;X 2 For N or CR X2 ;

[0039] X 3 For N or CR X3 ;X 4 For N or CR X4 ;

[0040] R X1 R X2 R X3 and R X4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 02 Replaced;

[0041] Or, R X1 R X2 and the carbon atom or R bonded to it. X2 R X3 and the carbon atom or R bonded to it. X3 R X4 Together with the carbon atom attached to it, they form a ring C, which is optionally bonded by one or more R atoms. 1 Replaced;

[0042] The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0043] U is CR 2c Or N, R 2c For hydrogen atoms or R 2 ;

[0044] q is 0, 1, 2, 3 or 4; s is 0, 1 or 2; r is 0, 1 or 2;

[0045] G 1 R 1 To R 7 R 11 To R 14 R 02 And v is as defined in general formula (I).

[0046] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or pharmaceutically acceptable salts thereof are compounds represented by general formulas (IV), (IV-1), or (IV-2) or pharmaceutically acceptable salts thereof:

[0047] Among them, R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or R. 2 ;

[0048] G 1 X 1 R X2 R X3 R X4 R 2 To R 7 U, s, r and q are as defined in general formula (II) or (III).

[0049] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from phenyl, naphthyl, and 5- to 10-membered heteroaryl groups; in some embodiments, ring A is selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyl, quinolinyl, and pyrazolyl; in some embodiments, ring A is selected from phenyl, In some implementations, ring A is In some implementations, ring A is * Connect to L, Terminal and G 4 The ring is connected; in some embodiments, ring A is phenyl or 5 or 6-membered heteroaryl; in some embodiments, ring A is pyridyl or pyrazolyl; in some embodiments, ring A is 6-membered heteroaryl; in some embodiments, ring A is pyridyl.

[0050] In some embodiments of this disclosure, ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and / or L is a bond, and / or ring B is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group, and / or each R 1 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1- 6-Hydroalkoxy, C 1-6 Hydroxyl alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups; and / or each R 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, ring A is phenyl or a 5- or 6-membered heteroaryl, and / or ring B is a 3- to 10-membered heterocyclic group, and / or each R 1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

[0051] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein for In some implementation schemes, for In some implementation schemes, for R 3 and R 4 As defined in general formula (I);

[0052] In some implementation schemes, for In some implementation schemes, for In some implementation schemes, for R 3 and R 4 As defined in general formula (I).

[0053] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R 1 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein each of the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups is independently optionally coupled with one or more R 02 Replaced by, R 02 As defined in general formula (I); in some implementations, each R 1 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, each R 1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; in some embodiments, each R 1 They may be the same or different, and each is independently selected from F, Cl, methyl, trifluoromethyl, and cyclopropyl; in some embodiments, each R... 1 They may be the same or different, and each is independently selected from Cl, methyl and trifluoromethyl.

[0054] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; in some embodiments, m is 0, 1 or 2; in some embodiments, m is 2; in some embodiments, m is 1; in some embodiments, m is 0.

[0055] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein X 1For N or CR X1 R X1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, X 1 For CR X1 R X1 As defined in general formulas (II) to (III); in some implementations, X 1 For N or CH; in some implementations, X 1 Let N be the number of elements in the array.

[0056] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein X 2 For N or CR X2 R X2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, X 2 For CR X2 R X2 As defined in general formula (II) or (III); in some implementations, X 2 For CR X2 R X2 Selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, X 2 It is CH or C-methyl; in some embodiments, X 2 It is C-methyl.

[0057] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein X 3 For N or CR X3 R X3 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, X 3 For CR X3 R X3As defined in general formula (II) or (III); in some implementations, X 3 Selected from N, CH, C-Cl, and C-CF3; in some embodiments, X 3 It is C-Cl or C-CF3; in some implementations, X 3 It is C-Cl.

[0058] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein X 4 For N or CR X4 R X4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, X 4 For N or CH; in some implementations, X 4 For CR X4 R X4 As defined in general formula (II) or (III); in some implementations, X 4 For CH.

[0059] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein X 1 Let N, X 2 For N or CR X2 X 3 For CR X3 X 4 For CR X4 , or X 1 Let N, X 2 For CR X2 X 3 Let N, X 4 For CR X4 , or X 1 For CR X1 X 2 For CR X2 X 3 For N or CR X3 X 4 For N or CR X4 In some implementation schemes, X 1 Let N, X 2 For N or CR X2 X 3 For CR X3 X 4 For CR X4 , or X 1 Let N, X 2 For CR X2 X 3For N or CR X3 X 4 For CR X4 In some implementation schemes, X 1 Let N, X 2 For N or CR X2 X 3 For CR X3 X 4 For CR X4 In some implementation schemes, X 1 For CR X1 X 2 For CR X2 X 3 Let N, X 4 For CR X4 In some implementation schemes, X 1 For CR X1 X 2 Let N, X 3 For CR X3 X 4 For CR X4 In some implementation schemes, X 1 Let N, X 2 For CR X2 X 3 For CR X3 X 4 For CR X4 ;R X1 R X2 R X3 and R X4 As defined in general formula (II) or (III); in some implementations, X 1 Let N, X 2 For CR X2 X 3 For CR X3 X 4 For CR X4 R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, X 1 Let N, X 2 For CR X2 X3 For CR X3 X 4 For CR X4 R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0060] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or their pharmaceutically acceptable salts, wherein R X1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0061] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (IV) or their pharmaceutically acceptable salts, wherein R X2 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, wherein the 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups are each independently selected from halogens, C 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R X2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R X2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R X2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R X2 It is a hydrogen atom or a methyl group; in some embodiments, R X2 For hydrogen atoms; in some implementations, R X2 C 1-6 Alkyl; in some embodiments, R X2 For methyl; in some embodiments, R X2Selected from hydrogen atom, F, Cl, methyl, CF3, cyclopropyl, tert-butyl and

[0062] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (IV) or their pharmaceutically acceptable salts, wherein R X3 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-Hydroalkoxy, C 2-6 rare radical, C 2-6 The alkynyl group, 3- to 6-membered cycloalkyl group, 3- to 6-membered heterocyclic group, phenyl group, and 5- or 6-membered heteroaryl group are each independently selected from halogens, C 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R X3 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R X3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R X3 Selected from hydrogen, F, Cl, methyl, CF3 and cyclopropyl; in some embodiments, R X3 Halogen or C 1-6 Halogenated alkyl; in some embodiments, R X3 C 1-6 Halogenated alkyl; in some embodiments, R X3 It is Cl or CF3; in some implementations, R X3 For Cl; in some implementations, R X3 It is CF3.

[0063] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (IV) or their pharmaceutically acceptable salts, wherein R X4 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups; in some embodiments, R X4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C1-6 Halogenated alkyl; in some embodiments, R X4 It is a hydrogen atom.

[0064] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (IV) or their pharmaceutically acceptable salts, wherein R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 rare radical, C 2-6 Alkyne, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl, wherein C 2-6 rare radical, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl groups are each independently and optionally influenced by one or more R groups. 02 Replaced by, R 02 As defined in general formula (I); in some implementations, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted, or R X2 R X3 Together with the carbon atom attached thereto, it forms a phenyl or pyridyl group; in some embodiments, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1- 6-haloalkoxy and 3 to 6-membered cycloalkyl; in some embodiments, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R X2 RX3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, F, Cl, methyl, and CF. 3、 Cyclopropyl, tert-butyl and In some implementation schemes, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, Cl, methyl groups, and CF3; in some embodiments, R X2 C 1-6 Alkyl, and / or R X3 Halogen or C 1-6 Halogenated alkyl groups, and / or R X4 It is a hydrogen atom.

[0065] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (III) or pharmaceutically acceptable salts thereof are wherein the ring C is phenyl or a 5- or 6-membered heterocyclic group; in some embodiments, the ring C is phenyl or a 6-membered heterocyclic group; in some embodiments, the ring C is phenyl or pyridyl.

[0066] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein L is selected from bond, O, and (CH2). x x is 0, 1, or 2; in some implementations, L is selected from bond, O, and CH2; in some implementations, L is bond.

[0067] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein ring B is a 3- to 12-membered heterocyclic group; in some embodiments, ring B is a 3- to 8-membered heterocyclic group; in some embodiments, ring B is a 3- to 12-membered nitrogen-containing heterocyclic group; in some embodiments, ring B is a 4- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, ring B is a 7-membered nitrogen-containing heterocyclic group; in some embodiments, ring B is selected from... In some implementation schemes, ring B is selected from... In some implementation schemes, ring B is End with L or X 1 The ring it belongs to is connected.

[0068] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein for U, R 2 , s, r and q are as defined in general formula (III); in some implementations, for U, R 2 R 2a R 2b , s, r and q are as defined in general formula (IV).

[0069] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein G 1 For CR 8 R 8 As defined in general formula (I); in some implementations, G 1 For N or CR 8 R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 1 For N or CH; in some implementations, G 1 For N; in some implementations, G 1 For CH.

[0070] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein G 2 For CR 5 R 5 As defined in general formula (I); in some implementations, G 2 For CR 5 R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 2 For N or CH; in some implementations, G 2 For CH.

[0071] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein G 3 For CR 6 R 6 As defined in general formula (I); in some implementations, G 3 For CR 6 R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 3 For N or CH; in some implementations, G 3 For CH.

[0072] In some embodiments of this disclosure, the compounds represented by general formulas (I) and (II) or their pharmaceutically acceptable salts, wherein G4 For CR 7 R 7 As defined in general formula (I); in some implementations, G 4 For CR 7 R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, G 4 For N or CH; in some implementations, G 4 For CH.

[0073] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The alkyl group is selected from halogen, C, alkyl group, 3- to 6-membered cycloalkyl group, and heterocyclic group, wherein the alkyl group and heterocyclic group are each independently selected from halogen, C 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R 7 It is a hydrogen atom or a halogen; in some implementations, R 7 Selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 7 For hydrogen atoms or Cl; in some implementations, R 7 For hydrogen atoms; in some embodiments, R 7 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; in some embodiments, R 7 Halogen or C 1-6 Alkyl; in some embodiments, R 7 It is Cl or methyl; in some embodiments, R 7 C 1-6 Alkyl; in some embodiments, R 7 It is a methyl group.

[0074] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 8 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 8 It is a hydrogen atom.

[0075] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 5 It is a hydrogen atom or a halogen; in some implementations, R 5 Selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 5 For hydrogen atoms; in some implementations, R 5 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0076] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R 6 It is a hydrogen atom or a halogen; in some implementations, R 6 Selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 6 For hydrogen atoms; in some implementations, R 6 Selected from hydrogen atoms, halogens and C 1-6 alkyl.

[0077] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy; in some embodiments, R 5 R 6 and R 7They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 5 R 6 and R 7 For hydrogen atoms; in some implementations, R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen, F, Cl, methyl, methoxy, CF3 and cyclopropyl.

[0078] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently and optionally influenced by one or more R groups. 01 Replaced; R 01 As defined in general formula (I); in some implementations, R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0079] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 4 Selected from hydrogen atom, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and C(O)R 23 ;R 23 As defined in general formula (I); in some implementations, R 4 Selected from hydrogen atom, hydroxyl group, C 1-6 Alkyl, C 1- 6-alkoxy and 3 to 6-membered cycloalkyl; in some embodiments, R 4 It is a hydrogen atom.

[0080] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 3 C 1-6 Alkyl, and / or R4 For hydrogen atoms; in some implementations, R 3 Methyl, and / or R 4 It is a hydrogen atom.

[0081] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, or R 2a and R 2b Together with the carbon atom attached thereto, they form a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally bonded by one or more R... 03 Replaced; R 03 As defined in general formula (I); in some implementations, R 2a and R 2b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl, or R 2a and R 2b Together with the carbon atom attached thereto, they form a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally selected from halogens, C... 1-6 Alkyl and =CR 15 R 16 One or more of them are replaced by R 15 and R 16 As defined in general formula (I); in some implementations, R 2a and R 2b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 2a and R 2b They may be the same or different, and each is independently a halogen; in some implementations, R 2a and R 2b It is F.

[0082] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or their pharmaceutically acceptable salts, wherein each R 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy and =CR 15 R 16 , or two R 2 Together with the carbon atom attached thereto, they form a 3- to 6-membered cycloalkyl group, wherein the 3- to 6-membered cycloalkyl group is optionally selected from halogens and =CR. 15 R 16 One or more of them are replaced; in some implementations, each R 2 They may be the same or different, and each is independently a halogen or =CR 15 R 16 , or two R 2 Together with the same or adjacent carbon atom attached thereto, they form a cyclopropyl, cyclobutyl, or cyclopentyl group, wherein each of the cyclopropyl, cyclobutyl, and cyclopentyl groups is independently selected from halogens and =CR. 15 R 16 One or more of them are replaced; in some implementations, each R 2 They may be the same or different, and each is independently a halogen or =CR 15 R 16 ;R 15 and R 16 As defined in general formula (I); in some implementations, each R 2 Same or different, and each independently selected from F, =CH2, =CHF and =CF2, or two R 2 Together with the same or adjacent carbon atom attached thereto, they form a cyclopropyl, cyclobutyl, or cyclopentyl group, wherein each of the cyclopropyl, cyclobutyl, and cyclopentyl groups is independently and optionally replaced by one or more selected from F, =CH2, =CHF, and =CF2; in some embodiments, each R... 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 2 For halogen; in some implementations, R 2 For F; in some implementations, R 2 C 1-6 Alkyl; F; in some embodiments, R 2 It is a methyl group.

[0083] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or their pharmaceutically acceptable salts, wherein two R... 2 Together with the carbon atoms attached thereto, they form spirocyclic, fused, or bridged rings; in some embodiments, the two R atoms... 2 Together with the carbon atom attached thereto, they form a spirocyclic alkyl, fused cyclic alkyl, or bridged cyclic alkyl; in some embodiments, the two R atoms... 2Together with the carbon atom attached thereto, they form a spirocyclic alkyl or a fused cyclic alkyl; the ring formed thereon may optionally be bonded by one or more R 03 Replaced; R 03 As defined in general formula (I).

[0084] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or F; in some implementations, R 15 and R 16 All are F.

[0085] In some embodiments of this disclosure, the compounds represented by general formulas (III) to (IV) or pharmaceutically acceptable salts thereof, wherein U is CH or N; in some embodiments, U is N.

[0086] In some embodiments of this disclosure, the compounds represented by general formulas (III) to (IV) or their pharmaceutically acceptable salts are used, wherein s is 0 or 1; in some embodiments, s is 1.

[0087] In some embodiments of this disclosure, the compounds represented by general formulas (III) to (IV) or their pharmaceutically acceptable salts are used, wherein r is 1 or 2; in some embodiments, r is 2; and in some embodiments, r is 1.

[0088] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1c It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 1c It is a hydrogen atom.

[0089] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof is used, wherein n is 0, 1 or 2; in some embodiments, n is 2.

[0090] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (III) or pharmaceutically acceptable salts thereof are used, wherein q is 0, 1 or 2; in some embodiments, q is 2; in some embodiments, q is 0; and in some embodiments, q is 1.

[0091] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R 01 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, each R 01 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0092] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R 02 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, each R 02 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0093] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R 03 They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and =CR 15 R 16 In some implementation schemes, each R 03 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and =CR 15 R 16 In some implementation schemes, each R 03 They may be the same or different, and each is independently a halogen or =CR15 R 16 ;R 15 and R 16 As defined in general formula (I); in some implementations, each R 03 They may be the same or different, and each is independently selected from F, =CH2, =CHF and =CF2.

[0094] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R * They may be the same or different, and each is independently selected from oxo groups, halogens, hydroxyl groups, cyano groups, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy C 1-6 Alkyl, 3- to 6-membered cycloalkyl and NR 30 R 31 R 30 and R 31 As defined in general formula (I); in some implementations, each R * They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0095] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 11 and R 12 They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0096] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 It is a hydrogen atom.

[0097] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 14 It is a hydrogen atom or a carbon atom.1-6 Alkyl; in some embodiments, R 14 It is a hydrogen atom or a methyl group; in some embodiments, R 14 It is a hydrogen atom.

[0098] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein each R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 20 and R 21 All are hydrogen atoms.

[0099] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 22 It is a hydrogen atom.

[0100] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 23 Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Alkyl; the C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl groups and 3 to 6-membered heterocyclic C groups 1-6 Each alkyl group is independently and optionally converted by one or more R * Replaced; R * As defined in general formula (I); in some implementations, R 23 Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 23 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 23 It can be a hydrogen atom or a methyl group.

[0101] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 30 and R 31 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 30 and R 31 They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 30 and R 31All are hydrogen atoms.

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 33 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 33 It is a hydrogen atom.

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts are used, wherein v is 2; in some embodiments, v is 1; and in some embodiments, v is 0.

[0104] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts are used, wherein x is 0, 1 or 2; in some embodiments, x is 0.

[0105] In this disclosure, formulas (I) through (III) include formulas (I), (II) and (III); formulas (I) through (IV) include formulas (I), (II), (III), (IV), (IV-1) and (IV-2); and formulas (III) through (IV) include formulas (III), (IV), (IV-1) and (IV-2).

[0106] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N or CH; R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted, or R X2 R X3 Together with the carbon atom attached to it, it forms a phenyl or pyridinyl group; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For N or CH; R 5 R 6 and R 7 They may be the same or different, and each is independently a hydrogen atom or a halogen; s is 0 or 1; r is 0, 1 or 2; R 2a and R2b They may be the same or different, and each is independently a hydrogen atom or a halogen; U is N; q is 0.

[0107] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N or CH; R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For N or CH; R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 alkoxy group; s is 0 or 1; r is 0, 1 or 2; R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or a halogen; U is N; q is 0.

[0108] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N or CH; R X2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R X3 Halogen or C 1-6 Halogenated alkyl; R X4 For hydrogen atoms; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For N or CH; R 5 R 6 and R 7 They may be the same or different, and each is independently a hydrogen atom or a halogen; s is 0 or 1; r is 0, 1 or 2; R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or a halogen; U is N; q is 0.

[0109] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 It is a hydrogen atom or a methyl group; R X3 For Cl or CF3; R X4 For hydrogen atoms; R 3 Methyl; R 4 For hydrogen atoms; G 1 For N or CH; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 7 It represents a hydrogen atom or a halogen; s is 0 or 1; r is 0, 1, or 2; R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or F; U is N; q is 0.

[0110] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; R X3 C 1-6 Halogenated alkyl; R X4 For hydrogen atoms; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For N or CH; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 7 Selected from hydrogen atoms, halogens and C 1-6 Alkyl; s = 1; r = 2; R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or a halogen; U is N; q is 0.

[0111] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 C 1-6 Alkyl; R X3 C 1-6 Halogenated alkyl; R X4 For hydrogen atoms; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For CH; R 5 For hydrogen atoms; R 6For hydrogen atoms; R 7 For hydrogen atoms; s = 1; r = 2; R 2a and R 2b They may be the same or different, and each is an independent halogen; U is N; q is 0.

[0112] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1), or (IV-2), or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 C 1-6 Alkyl; R X3 C 1-6 Halogenated alkyl; R X4 For hydrogen atoms; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; G 1 For CH; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 7 Halogen; s = 1; r = 2; R 2a and R 2b They may be the same or different, and each is an independent halogen; U is N; q is 0.

[0113] Table A lists typical compounds disclosed herein, including but not limited to:

[0114] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IA) or (Ia).

[0115] Among them, R W It is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0116] Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 m and n are as defined in general formula (I).

[0117] Another aspect of this disclosure relates to compounds of general formulas (IB), (Ib) or salts thereof.

[0118] Among them, R 9 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR11 R 12 OR 14 OR W cycloalkyl, heterocyclic, aryl, and heteroaryl groups; cyclic A, cyclic B, L, and G groups 1 To G 3 R 1 To R 3 R 11 R 12 R 14 R W m and n are as defined in general formula (I).

[0119] In some embodiments disclosed herein, R 9 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 OR 14 cycloalkyl, heterocyclic, aryl, and heteroaryl; in some embodiments, R 9 Halogen or OR W In some implementation schemes, R 9 OR W .

[0120] Another aspect of this disclosure relates to compounds of general formula (IIA) or (IIa) or salts thereof.

[0121] Among them, R W It is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0122] Ring B, X 1 To X 4 G 1 To G 4 R 2 To R 4 And n is as defined in general formula (II).

[0123] Another aspect of this disclosure relates to compounds of general formulas (IIB) and (IIb) or salts thereof.

[0124] Among them, R 9 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 OR 14 OR W cycloalkyl, heterocyclic, aryl, and heteroaryl groups; cyclic B, X1 To X 4 G 1 To G 3 R 2 R 3 And n is as defined in general formula (II).

[0125] Another aspect of this disclosure relates to compounds of general formula (IIIA), (IIIa) or (IIIA-1) or salts thereof.

[0126] Among them, R W X is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is benzyl; X is a halogen, and in some embodiments it is Br;

[0127] X 1 To X 4 U, G 1 R 2 To R 7 , q, r and s are as defined in general formula (III).

[0128] Another aspect of this disclosure relates to compounds of general formulas (IIIB) and (IIIb) or salts thereof.

[0129] Among them, X 1 To X 4 U, G 1 R 2 R 3 R 5 To R 7 , q, r and s are as defined in general formula (III), R 9 As defined in general formula (IIB).

[0130] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IVA), (IVa), (IVA-1), (IV-1A), (IV-1A-1), (IV-2A), and (IV-2A-1).

[0131] Among them, R W X is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is benzyl; X is a halogen, and in some embodiments it is Br;

[0132] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R7 , q, r and s are as defined in general formula (IV), (IV-1) or (IV-2).

[0133] Another aspect of this disclosure relates to compounds of general formulas (IVB), (IVb), or salts thereof.

[0134] Among them, X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 R 3 R 5 To R 7 , q, r and s are as defined in general formula (IV), R 9 As defined in general formula (IIB).

[0135] Another aspect of this disclosure relates to compounds or salts thereof represented by general formulas (IC), (ID), (IE), and (IF).

[0136] Among them, X 1 R X2 R X3 R X4 ,U,R 2a R 2b R 2 R 3 , q, r and s are as defined in general formula (IV), R 9 As defined in general formula (IIB), R W As defined in general formula (IIA).

[0137] In some embodiments disclosed herein, R 9 It is a hydrogen atom or a halogen; in some implementations, R 9 It is a halogen; in some embodiments it is Cl; in some embodiments it is a hydrogen atom.

[0138] Table B lists typical intermediate compounds or salts thereof disclosed herein, including but not limited to:

[0139] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0140] The compound of general formula (IA) or its salt undergoes a deprotection reaction to yield the compound of general formula (I) or its pharmaceutically usable salt, or

[0141] A compound of general formula (Ia) or a salt thereof reacts with ammonia or a salt thereof (in some embodiments, a carbonate) to give a compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0142] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0143] Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 m and n are as defined in general formula (I).

[0144] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0145] The compound of general formula (IIA) or its salt undergoes a deprotection reaction to give the compound of general formula (II) or its pharmaceutically usable salt, or

[0146] The compound of general formula (IIa) or a salt thereof reacts with ammonia or a salt thereof (in some embodiments, a carbonate) to give the compound of general formula (II) or a pharmaceutically acceptable salt thereof, wherein

[0147] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0148] Ring B, X 1 To X 4 G 1 To G 4 R 2 To R 4 And n is as defined in general formula (II).

[0149] Another aspect of this disclosure relates to a method for preparing the compound of the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0150] The compound of general formula (IIIA) or its salt undergoes a deprotection reaction to give the compound of general formula (III) or its pharmaceutically usable salt, or

[0151] A compound of general formula (IIIa) or a salt thereof reacts with ammonia or a salt thereof (in some embodiments, a carbonate) to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof, or

[0152] A compound of general formula (IIIA-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof to yield a compound of general formula (III) or a pharmaceutically acceptable salt thereof, or

[0153] R 7 Compounds of general formula (III) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (III) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0154] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0155] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0156] X 1 To X 4 U, G 1 R 2 To R 7 , q, r and s are as defined in general formula (III).

[0157] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV), (IV-1), and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0158] The compound represented by general formula (IVA) or its salt undergoes a deprotection reaction to yield the compound represented by general formula (IV) or its pharmaceutically usable salt.

[0159] The compound of general formula (IV-1A) or its salt undergoes a deprotection reaction to give the compound of general formula (IV-1) or its pharmaceutically usable salt.

[0160] The compound of general formula (IV-2A) or its salt undergoes a deprotection reaction to give the compound of general formula (IV-2) or its pharmaceutically usable salt, wherein,

[0161] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0162] X1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV), (IV-1) or (IV-2).

[0163] Another aspect of this disclosure relates to a method for preparing a compound of the above general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0164] The compound of general formula (IVa) or a salt thereof reacts with ammonia or a salt thereof (in some embodiments, a carbonate) to give the compound of general formula (IV) or a pharmaceutically acceptable salt thereof, or

[0165] A compound of general formula (IVA-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof to yield a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, or

[0166] R 7 Compounds of general formula (IV) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0167] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0168] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV).

[0169] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0170] A compound of general formula (IV-1A-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof to yield a compound of general formula (IV-1) or a pharmaceutically acceptable salt thereof, or

[0171] R 7 Compounds of the general formula (IV-1) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV-1) for halogens or a pharmaceutically acceptable salt thereof.

[0172] A compound of general formula (IV-2A-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof to yield a compound of general formula (IV-2) or a pharmaceutically acceptable salt thereof, or R. 7 Compounds of the general formula (IV-2) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV-2) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0173] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0174] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV-1) or (IV-2).

[0175] Another aspect of this disclosure relates to a method for preparing compounds of the above general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0176] The compound represented by general formula (IV) or its salts are resolved to yield the compounds represented by general formulas (IV-1) and (IV-2) or their pharmaceutically usable salts, wherein...

[0177] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R2 To R 7 , q, r and s are as defined in general formula (IV-1) or (IV-2).

[0178] In some embodiments of this disclosure, the halogenating agent is selected from elemental iodine, Cl2, Br2, hydrohalic acids (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), thionyl chloride, phosphorus pentachloride, phosphorus trihalides (such as phosphorus trichloride), NBS (N-bromosuccinimide), and NCS; in some embodiments, the halogenating agent is NCS (N-chlorosuccinimide).

[0179] In some embodiments of this disclosure, R' is methyl.

[0180] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I) to (IV) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0181] This disclosure further relates to the use of compounds of general formulas (I) to (IV) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of a medicament for inhibiting a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0182] This disclosure further relates to the use of compounds of general formulas (I) to (IV) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or preventing diseases or conditions mediated by voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0183] This disclosure further relates to the use of compounds of general formulas (I) to (IV) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or alleviating pain and pain-related disorders, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmias; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain, and visceral pain; in some embodiments, the postoperative pain is selected from pain following bunion excision, pain following hernia repair, and pain following abdominoplasty.

[0184] This disclosure further relates to a method of inhibiting voltage-gated sodium channels, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0185] This disclosure further relates to a method of treating and / or preventing diseases or conditions mediated by voltage-gated sodium channels, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0186] This disclosure further relates to a method of treating and / or preventing pain and pain-related disorders, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough, or arrhythmia, comprising administering to a desired patient a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0187] This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a drug; in some embodiments, it is used as a drug for inhibiting the activity of voltage-gated sodium channels; in some embodiments, it is used as a drug for inhibiting Nav1.8 activity.

[0188] This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, for inhibiting voltage-gated sodium channel activity; in some embodiments, it is used to inhibit Nav1.8 activity.

[0189] This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, which acts as a voltage-gated sodium channel inhibitor; in some embodiments, it acts as a Nav1.8 inhibitor.

[0190] This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for treating and / or preventing diseases or conditions mediated by voltage-gated sodium channels; in some embodiments, it is used as a medicament for treating and / or preventing diseases or conditions mediated by Nav1.8.

[0191] This disclosure further relates to a compound of general formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of diseases or conditions mediated by voltage-gated sodium channels.

[0192] This disclosure further relates to a compound of formula (I) to (IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for the treatment and / or prevention of pain and pain-related disorders, multiple sclerosis, Shama-Tutan syndrome, incontinence, pathological cough, or arrhythmia.

[0193] The diseases or conditions described in this disclosure are treated and / or prevented by inhibiting voltage-gated sodium channels.

[0194] In some embodiments, the voltage-gated sodium channel described in this disclosure is Nav1.8.

[0195] In some embodiments, the diseases or conditions mediated by voltage-gated sodium channels described in this disclosure are pain and pain-related diseases, multiple sclerosis, Sharma-Tutus syndrome, incontinence, pathological cough, or arrhythmia; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain, and visceral pain; in some embodiments, the postoperative pain is selected from pain from bunion removal surgery, hernia repair surgery, and abdominoplasty.

[0196] In some embodiments, the diseases or conditions mediated by voltage-gated sodium channels described in this disclosure are selected from painful peripheral neuropathy, painless peripheral neuropathy, anterior cutaneous nerve entrapment syndrome, chronic pain syndrome, nerve entrapment syndrome, trigeminal neuralgia, small fiber neuropathy, diabetic peripheral neuropathy, painful diabetic peripheral neuropathy, painful lumbosacral radiculopathy, postherpetic neuralgia, erythromelalgia, arthralgia, osteoarthritis and fibromyalgia, neuropathic pain, and diabetic neuropathic pain.

[0197] In some implementations, the pain is selected from diabetic pain, osteoarthritis pain, and acute pain after surgical removal of impacted third molars.

[0198] The active compound can be formulated in a form suitable for administration via any appropriate route, either in a unit dose or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition can be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation.

[0199] As a general guideline, a suitable unit dose can be 0.1–1000 mg.

[0200] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0201] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0202] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or isotopic substitution.

[0203] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0204] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0205] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0206] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0207] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0208] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0209] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0210] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. Any blended fixative oil may be used for this purpose. Additionally, fatty acids may also be used to prepare injectable formulations.

[0211] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0212] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the compound, or the type of medicinal salt can be validated based on conventional treatment protocols.

[0213] Terminology Explanation

[0214] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0215] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkyl group). In some embodiments, the alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-10 Alkyl groups, in some embodiments having 1 to 6 carbon atoms (i.e., C164 ... 1-6Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 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, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0216] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C2). 1-20 Alkylene). In some embodiments, the alkylene has 1 to 10 carbon atoms (i.e., C10). 1-10 Alkylenes), in some embodiments having 1 to 8 carbon atoms (i.e., C164-C ... 1-8 Alkylenes), in some embodiments having 2 to 7 carbon atoms (i.e., C164-C ... 2-7 Alkylenes or alkylenes having 1, 2 or 3 carbon atoms (i.e., C14) 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0217] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0218] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0219] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy, etc. Alkoxy groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0220] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered cycloalkyl). In some embodiments, the cycloalkyl group is a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3 to 12-membered cycloalkyl group) or a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3 to 10-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3 to 8-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3 to 6-membered cycloalkyl group), a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4 to 7-membered cycloalkyl group), or a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered cycloalkyl group); in some embodiments, it is a cycloalkyl group having 5 or 6 ring atoms.

[0221] Non-limiting examples of the monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl.

[0222] The polycyclic alkyl groups include: spirocyclic alkyl groups, fused cyclic alkyl groups, and bridged cyclic alkyl groups.

[0223] The term "spirocycloalkyl" refers to a polycyclic system in which rings share a single carbon atom (called a spiro atom), and the ring may contain one or more double bonds, or one or more heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that it contains at least one full carbon ring with a bonding point on that full carbon ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spirocycloalkyl). In some embodiments, the spirocycloalkyl is a spirocycloalkyl having 6 to 14 ring atoms (i.e., 6 to 14-membered spirocycloalkyl), and in some embodiments, it is a spirocycloalkyl having 7 to 10 ring atoms (i.e., 7 to 10-membered spirocycloalkyl). The spirocyclic alkyl group includes monospirocyclic alkyl and polyspirocyclic alkyl (such as bispirocyclic alkyl, etc.), and in some embodiments is a monospirocyclic alkyl or bispirocyclic alkyl group, and in some embodiments is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocyclic alkyl group. Non-limiting examples include:

[0224] Its connection point can be anywhere;

[0225] wait.

[0226] The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between rings. This system is a monocyclic cycloalkyl group fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl group fused with one or more heterocyclic, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic cycloalkyl group, which may contain one or more double bonds and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). In some embodiments, the fused cycloalkyl group is a fused cycloalkyl group having 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and in some embodiments, it is a fused cycloalkyl group having 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The fused cyclic alkyl group includes bicyclic fused cyclic alkyl groups and polycyclic fused cyclic alkyl groups (such as tricyclic fused cyclic alkyl groups, tetracyclic fused cyclic alkyl groups, etc.). In some embodiments, it is a bicyclic fused cyclic alkyl group or a tricyclic fused cyclic alkyl group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cyclic alkyl group. Non-limiting examples include:

[0227] Its connection point can be anywhere; wait.

[0228] The term "bridged cycloalkyl" refers to a fully carbon polycyclic system in which two non-directly connected carbon atoms are shared between rings, and the ring may contain one or more double bonds and have 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). In some embodiments, the bridged cycloalkyl is a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, it is a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, it is a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0229] Its connection point can be anywhere.

[0230] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0231] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; in some implementation schemes, it is

[0232] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., monocyclic heterocyclic group) or polycyclic heterocyclic system (i.e., polycyclic heterocyclic group) containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20 membered heterocyclic groups). In some embodiments, the heterocyclic group has heterocyclic groups with 3 to 12 ring atoms (i.e., 3 to 12-membered heterocyclic groups), heterocyclic groups with 3 to 10 ring atoms (i.e., 3 to 10-membered heterocyclic groups), and heterocyclic groups with 7 to 10 ring atoms (i.e., 7 to 10-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 8 ring atoms (i.e., 3 to 8-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 3 to 6 ring atoms (i.e., 3 to 6-membered heterocyclic groups), 4 to 7 ring atoms (i.e., 4 to 7-membered heterocyclic groups), or 5 or 6 ring atoms (i.e., 5 or 6-membered heterocyclic groups); in some embodiments, it has heterocyclic groups with 5 or 6 ring atoms.

[0233] Non-limiting examples of the monocyclic heterocyclic group include: pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, azacyclic butyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, etc.

[0234] The polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

[0235] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group containing at least one (e.g., 1, 2, 3, or 4) nitrogen atoms within its ring, as defined above. In some embodiments, it is a 3- to 12-membered nitrogen-containing heterocyclic group or a 3- to 10-membered nitrogen-containing heterocyclic group; in some embodiments, it is a 4- to 7-membered nitrogen-containing heterocyclic group; and in some embodiments, it is a 5- or 6-membered nitrogen-containing heterocyclic group.

[0236] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic system in which rings share a single atom (called a spiro atom), which may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), provided that at least one monocyclic heterocyclic group is present and the bonding point is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered spiroheterocyclic groups). In some embodiments, the spiroheterocyclic group is a spiroheterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered spiroheterocyclic group), and in some embodiments, it is a spiroheterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered spiroheterocyclic group). The spiroheterocyclic group includes mono-spiroheterocyclic groups and multi-spiroheterocyclic groups (such as bi-spiroheterocyclic groups), and in some embodiments, it is a mono-spiroheterocyclic group or a bi-spiroheterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered mono-spiroheterocyclic group. Non-limiting examples include:

[0237] wait.

[0238] The term "fused heterocyclic group" refers to a polycyclic heterocyclic system in which two adjacent atoms are shared between rings. The ring may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-). It is a monocyclic heterocyclic group fused with one or more monocyclic heterocyclic groups, or a monocyclic heterocyclic group fused with one or more cycloalkyl, aryl, or heteroaryl groups, wherein the bonding point is on the monocyclic heterocyclic group and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20 membered fused heterocyclic groups). In some embodiments, the fused heterocyclic group is a fused heterocyclic group having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and in some embodiments, it is a fused heterocyclic group having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), and in some embodiments, it is a bicyclic or tricyclic fused heterocyclic group. In some embodiments, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples include:

[0239] wait.

[0240] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic system in which two non-directly bonded atoms are shared between the rings. The rings may contain one or more double bonds and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may optionally be oxidized to form nitrogen oxides; the sulfur may optionally be oxidized to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). In some embodiments, the bridged heterocyclic group has 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and in some embodiments, it has 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). Based on the number of constituent rings, heterocyclic groups can be classified into bicyclic bridged heterocyclic groups and multicyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.). In some embodiments, they are bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

[0241] wait.

[0242] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0243] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0244] wait.

[0245] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 20 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 6 to 20-membered aryl). In some embodiments, the aryl group has 6 to 14 ring atoms (i.e., 6 to 14-membered aryl), and in some embodiments, it has 6 to 10 ring atoms (i.e., 6 to 10-membered aryl). Monocyclic aryl groups include, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthracene, phenanthrene, etc. The polycyclic aryl group further includes fusion of a phenyl group with one or more heterocyclic or cycloalkyl groups, or fusion of a naphthyl group with one or more heterocyclic or cycloalkyl groups, wherein the bonding site is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples including: wait.

[0246] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0247] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0248] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.

[0249] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include: wait.

[0250] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0251] The term "cycloalkyloxy" refers to -O-cycloalkyl, where the cycloalkyl is as defined above.

[0252] The term "heterocyclic oxygen group" refers to an -O-heterocyclic group, wherein the heterocyclic group is as defined above.

[0253] The term "aryloxy group" refers to -O-aryl, where the aryl group is as defined above.

[0254] The term "heteroaryloxy" refers to -O-heteroaryl, where the heteroaryl is as defined above.

[0255] The term "cycloalkylalkyl" refers to an alkyl group that is substituted by one or more cycloalkyl groups, wherein the cycloalkyl and alkyl groups are as defined above.

[0256] The term "heterocyclic alkyl" refers to an alkyl group that is substituted by one or more heterocyclic groups, wherein the heterocyclic group and the alkyl group are as defined above.

[0257] The term "arylalkyl" refers to an alkyl group that is substituted with one or more aryl groups, wherein the aryl and alkyl groups are as defined above.

[0258] The term "heteroarylalkyl" refers to an alkyl group that is substituted by one or more heteroaryl groups, wherein the heteroaryl and alkyl groups are as defined above.

[0259] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0260] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0261] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0262] The term "hydroxyalkoxy" refers to an alkoxy group that is substituted with one or more hydroxyl groups, where the alkoxy group is as defined above.

[0263] The term "alkoxyalkyl" refers to an alkyl group substituted with one or more alkoxy groups, wherein the alkyl and alkoxy groups are as defined above; in some embodiments, they are -alkyl-alkoxy groups; including but not limited to methoxymethyl, ethoxymethyl, and methoxyethyl.

[0264] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0265] The term "hydroxyl group" refers to -OH.

[0266] The term "amino" refers to -NH2.

[0267] The term "cyano" refers to -CN.

[0268] The term "nitro" refers to -NO2.

[0269] The term "oxo" or "oxo group" refers to "=O".

[0270] The term "carbonyl" refers to C=O.

[0271] TBS refers to tert-butyldimethylsilyl.

[0272] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect a hydroxyl group and react on other functional groups of a compound. Non-limiting examples include: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), tert-butyldiphenylsilyl (TBDPS), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, and p-nitrobenzoyl, etc.; in some embodiments, benzyl is used.

[0273] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. Optically active (-)- and (+)- isomers, (R)- and (S)- enantiomers, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0274] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be or Or simultaneously include and Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0275] The supplementary structures a1 and 1-p1 represent the same isomer and can be used interchangeably; the supplementary structures b1 and 1-p2 represent the same isomer and can be used interchangeably.

[0276] The supplementary structures a2 and 2-p1 represent the same isomer and can be used interchangeably; the supplementary structures b2 and 2-p2 represent the same isomer and can be used interchangeably.

[0277] The supplementary structures a3 and 3-p1 represent the same isomer and can be used interchangeably; the supplementary structures b3 and 3-p2 represent the same isomer and can be used interchangeably.

[0278] The supplementary structures a4 and 4-p1 represent the same isomer and are interchangeable; the supplementary structures b4 and 4-p2 represent the same isomer and are interchangeable. 4-p1 and 4-p2 are located below compound 4 in Table A.

[0279] The supplementary structures a5 and 5-p1 represent the same isomer and can be used interchangeably; the supplementary structures b5 and 5-p2 represent the same isomer and can be used interchangeably.

[0280] The supplementary structures a6 and 6-p1 represent the same isomer and can be used interchangeably; the supplementary structures b6 and 6-p2 represent the same isomer and can be used interchangeably.

[0281] The compounds disclosed herein may comprise all of their rotational isomers and conformationally restricted states. They also include transisomers, the term "transisomer" being a stereoisomer resulting from restricted rotation around a single bond, wherein an energy difference attributable to stereostrain or other contributing factors creates a sufficiently high rotational barrier to allow the separation of individual conformational isomers. For example, some of the compounds disclosed herein may exist as mixtures of transisomers (e.g., equal-proportion mixtures, mixtures enriched with one transisomer, etc.) or as a purified transisomer.

[0282] The compounds disclosed herein may exist in various tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to a structural isomer that exists in equilibrium and readily transforms from one isomer to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of said tautomers in any proportion. Non-limiting examples include: keto-enols, imine-enamines, lactam-lactamimides, etc. Examples of lactam-lactamimide equilibrium are shown below:

[0283] An example of keto-enol equilibrium is shown below:

[0284] When referring to the pyrazolyl group, it should be understood to include any one or a mixture of two tautomers of the following two structures:

[0285] All tautomers are within the scope of this disclosure, and the naming of compounds does not exclude any tautomers.

[0286] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 p、 33 p、 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 In some implementations, I is deuterium.

[0287] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0288] When a site is specifically designated as deuterium D, the site should be understood as having a deuterium abundance of at least 1,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compounds in the examples having a natural abundance greater than deuterium can be at least 1000 times abundant deuterium (i.e., at least 15% deuterium doping), at least 2000 times abundant deuterium (i.e., at least 30% deuterium doping), at least 3000 times abundant deuterium (i.e., at least 45% deuterium doping), at least 3340 times abundant deuterium (i.e., at least 50.1% deuterium doping), at least 3500 times abundant deuterium (i.e., at least 52.5% deuterium doping), at least 4000 times abundant deuterium (i.e., at least 60% deuterium doping), or at least 4500 times abundant deuterium (i.e., at least 67.5% deuterium doping). The abundance of deuterium is at least 5000 times (i.e., at least 75% deuterium doping), at least 5500 times (i.e., at least 82.5% deuterium doping), at least 6000 times (i.e., at least 90% deuterium doping), at least 6333.3 times (i.e., at least 95% deuterium doping), at least 6466.7 times (i.e., at least 97% deuterium doping), at least 6600 times (i.e., at least 99% deuterium doping), at least 6633.3 times (i.e., at least 99.5% deuterium doping), or higher.

[0289] "Optional" or "optional" means that the event or situation subsequently described may but is not necessarily to occur; it includes both the possibility that the event or situation will occur or not occur. For example, "C optionally substituted with a halogen or cyano group..." 1- "6-alkyl" includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0290] "Substitution" or "substituted" refers to one or more hydrogen atoms in a group, such as 1, 2, or 3, meaning that 1 to 3 hydrogen atoms are independently replaced by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0291] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0292] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. They can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0293] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0294] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0295] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0296] The method for synthesizing the compounds disclosed herein

[0297] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0298] Option 1

[0299] This disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0300] The compound of general formula (IA) or its salt undergoes a deprotection reaction under acidic conditions or by hydrogenolysis to yield the compound of general formula (I) or its pharmaceutically usable salt, wherein...

[0301] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0302] Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 m and n are as defined in general formula (I).

[0303] Option 1-2

[0304] This disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0305] The compound of general formula (Ia) or a salt thereof undergoes an oxidation reaction with ammonia or a salt thereof (in some embodiments, a carbonate) in the presence of an oxidizing agent to yield the compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0306] Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 m and n are as defined in general formula (I).

[0307] Option 2

[0308] This disclosure provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0309] The compound of general formula (IIA) or its salt undergoes a deprotection reaction under acidic conditions or by hydrogenolysis to yield the compound of general formula (II) or its pharmaceutically usable salt, wherein...

[0310] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0311] Ring B, X 1 To X 4 G 1 To G 4 R 2 To R 4 And n is as defined in general formula (II).

[0312] Option 2-2

[0313] This disclosure provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0314] The compound of general formula (IIa) or a salt thereof undergoes an oxidation reaction with ammonia or a salt thereof (in some embodiments, a carbonate) in the presence of an oxidizing agent to give the compound of general formula (II) or a pharmaceutically acceptable salt thereof, wherein

[0315] Ring B, X 1 To X 4 G 1 To G 4 R 2 To R 4 And n is as defined in general formula (II).

[0316] Option 3

[0317] This disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0318] The compound of general formula (IIIA) or its salt undergoes a deprotection reaction under acidic conditions or by hydrogenolysis to yield the compound of general formula (III) or its pharmaceutically usable salt, wherein...

[0319] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0320] X 1 To X 4 U, G 1 R 2 To R 7 , q, r and s are as defined in general formula (III).

[0321] Option 3-2

[0322] This disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0323] The compound of general formula (IIIa) or a salt thereof undergoes an oxidation reaction with ammonia or a salt thereof (in some embodiments, a carbonate) in the presence of an oxidizing agent to give the compound of general formula (III) or a pharmaceutically acceptable salt thereof, or

[0324] A compound of general formula (IIIA-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (III) or a pharmaceutically acceptable salt thereof, or, R 7 Compounds of general formula (III) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (III) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0325] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0326] X 1 To X 4 U, G 1 R 2 To R 7 , q, r and s are as defined in general formula (III).

[0327] Option 4

[0328] This disclosure provides a method for preparing compounds of general formulas (IV), (IV-1), and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0329] Compounds of general formula (IVA) or their salts undergo deprotection reactions under acidic conditions or via hydrogenolysis to yield compounds of general formula (IV) or their pharmaceutically usable salts.

[0330] The compound represented by general formula (IV-1A) or its salt undergoes a deprotection reaction under acidic conditions or by hydrogenolysis to yield the compound represented by general formula (IV-1) or its pharmaceutically usable salt.

[0331] The compound represented by general formula (IV-2A) or its salt undergoes a deprotection reaction under acidic conditions or by hydrogenolysis to yield the compound represented by general formula (IV-2) or its pharmaceutically usable salt.

[0332] R W It is a hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0333] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV), (IV-1) or (IV-2).

[0334] Option 4-2

[0335] This disclosure provides a method for preparing a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0336] The compound of general formula (IVa) or a salt thereof undergoes an oxidation reaction with ammonia or a salt thereof (in some embodiments, a carbonate) in the presence of an oxidizing agent to yield the compound of general formula (IV) or a pharmaceutically acceptable salt thereof, or

[0337] A compound of general formula (IVA-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (IV) or a pharmaceutically acceptable salt thereof, or, R 7Compounds of general formula (IV) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0338] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0339] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV).

[0340] Option 5

[0341] This disclosure provides a method for preparing compounds of general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0342] A compound of general formula (IV-1A-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (IV-1) or a pharmaceutically acceptable salt thereof, or R. 7 Compounds of the general formula (IV-1) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV-1) for halogens or a pharmaceutically acceptable salt thereof.

[0343] A compound of general formula (IV-2A-1) or a salt thereof undergoes a coupling reaction with a compound of general formula (IIIB), (IIIB-1) and / or (IIIB-2) or a salt thereof under basic conditions in the presence of a catalyst to give a compound of general formula (IV-2) or a pharmaceutically acceptable salt thereof, or, R 7 Compounds of the general formula (IV-2) containing hydrogen atoms or their salts undergo halogenation reactions with halogenating reagents to yield R. 7 A compound of the general formula (IV-2) for halogens or a pharmaceutically acceptable salt thereof, wherein

[0344] X is a halogen, and in some embodiments it is Br; R' may be the same or different, and each is independently C. 1-6 alkyl;

[0345] X1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV-1) or (IV-2).

[0346] Option 5-2

[0347] This disclosure provides a method for preparing compounds of general formulas (IV-1) and (IV-2) or pharmaceutically acceptable salts thereof, the method comprising:

[0348] Compounds of general formula (IV) or their salts were resolved by chiral column chromatography to give compounds of general formulas (IV-1) and (IV-2) or their pharmaceutically usable salts, wherein...

[0349] X 1 R X2 R X3 R X4 ,U,R 2a R 2b G 1 R 2 To R 7 , q, r and s are as defined in general formula (IV-1) or (IV-2).

[0350] In some implementation schemes, the above-mentioned synthesis schemes one to four involve a deprotection reaction under acidic conditions.

[0351] The reagents providing acidic conditions in the above schemes include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, 1,4-dioxane solution of hydrochloric acid, trifluoroacetic acid, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me3SiCl, TMSOTf, ALCl3, BBr3, BF3, and ferric bromide, etc.; in some embodiments, trifluoroacetic acid is used.

[0352] The oxidizing agents in the above synthesis schemes include, but are not limited to, iodophenyldiacetic acid, potassium permanganate, m-chloroperoxybenzoic acid, peroxybenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide, Dess-Martin, sodium hypochlorite, monoperoxyphthalic acid, N-iodosuccinimide, 2-iodobenzoic acid, etc.; in some embodiments, iodophenyldiacetic acid is used.

[0353] The ammonia or its salts in the above synthesis schemes include, but are not limited to, ammonia, ammonium chloride or ammonium carbonate; in some embodiments, it is ammonium carbonate.

[0354] The reagents providing alkaline conditions in the above synthesis schemes include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrahydrofuran solution of tetrabutylammonium fluoride, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride, and potassium hydroxide; in some embodiments, potassium carbonate is used.

[0355] The catalysts in the above synthesis schemes include metal catalysts, and more specifically palladium catalysts; these include palladium acetate, ferrocene diphenylphosphine palladium dichloride, tetraphenylphosphine palladium, dichlorotriphenylphosphine palladium, palladium on carbon, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, etc.; in some embodiments, it is 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride.

[0356] The reactions described above can be carried out in a solvent, including but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof. Detailed Implementation

[0357] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0358] Example

[0359] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰. -6 The unit (ppm) is given. NMR determination was performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0360] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0361] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0362] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

[0363] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0364] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0365] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0366] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0367] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0368] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0369] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0370] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0371] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0372] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0373] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0374] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0375] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0376] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0377] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0378] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0379] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0380] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for column chromatography to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0381] Example 1

[0382] 2-(5-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-6-methylpyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one

[0383] first step

[0384] 1-(2-amino-6-(methylthio)phenyl)ethyl-1-one 1b

[0385] 1-(2-amino-6-bromophenyl)ethyl-1-one 1a (1.25 g, 5.84 mmol, Shanghai Bide) was dissolved in N,N-dimethylformamide (15 mL), and 20% sodium methanethiol aqueous solution (5.73 g, 16.35 mmol) was added. The mixture was sealed and heated to 80 °C for 3 days. After the reaction solution was cooled to room temperature, saturated sodium chloride solution and ethyl acetate were added. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 1b (520 mg, yield: 49.1%).

[0386] MS m / z(ESI): 182.3 [M+1].

[0387] Step 2

[0388] 2-(4,4-Difluoroazacycloheptan-1-yl)-6-methylnicotinate methyl ester 1e

[0389] 2-Chloro-6-methylnicotinic acid methyl ester 1d (5 g, 26.93 mmol, Shanghai Leyan) and 4,4-difluorozazepine heptane hydrochloride 1c (4.62 g, 26.92 mmol, Shanghai Bide) were dissolved in 1,4-dioxane (100 mL), and N,N-diisopropylethylamine (6.96 g, 53.85 mmol) was added. The mixture was reacted at 80 °C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1e (3.2 g, yield: 41.7%).

[0390] MS m / z(ESI):285.1[M+1].

[0391] Step 3

[0392] 5-Chloro-2-(4,4-difluoroazacycloheptan-1-yl)-6-methylnicotinate methyl ester 1f

[0393] Compound 1e (2 g, 7.03 mmol) was dissolved in N,N-dimethylformamide (30 mL), and N-chlorosuccinimide (1.22 g, 9.13 mmol) was added. The mixture was stirred for 16 hours. Water and ethyl acetate were added to the reaction solution, and the mixture was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 1f (1.6 g, yield: 71.3%).

[0394] MS m / z(ESI): 319.1 [M+1].

[0395] Step 4

[0396] 1g of 5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylnicotinic acid

[0397] Compound 1f (680 mg, 2.13 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (5 mL), and water (1 mL). Lithium hydroxide (358 mg, 8.53 mmol) was added, and the mixture was stirred at 50 °C for 16 hours. After the reaction solution was cooled to room temperature, the pH was adjusted to <7 with saturated citric acid solution. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 1 g (640 mg). The product was used directly in the next reaction without purification.

[0398] MS m / z(ESI): 305.3 [M+1].

[0399] Step 5

[0400] N-(2-acetyl-3-(methylthio)phenyl)-5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylnicotinamide 1h

[0401] 1 g (650 mg, 2.13 mmol) of the crude compound was dissolved in dichloromethane (10 mL), and compound 1b (232 mg, 1.28 mmol), N,N-diisopropylethylamine (208 mg, 1.6 mmol), and tripyrrolylphosphonium hexafluorophosphate bromide (1.1 g, 2.34 mmol, Shanghai Titan) were added. The mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 1h (620 mg, yield: 62.1%).

[0402] MS m / z(ESI):468.4[M+1].

[0403] Step 6

[0404] 2-(5-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-6-methylpyridin-3-yl)-5-(methylthio)quinoline-4(1H)-one

[0405] Compound 1h (610 mg, 1.3 mmol) was dissolved in 1,4-dioxane (20 mL), sodium hydroxide (417.1 mg, 10.42 mmol) was added, and the mixture was reacted at 90 °C for 16 hours. After the reaction solution was cooled to room temperature, saturated ammonium chloride aqueous solution was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to give the title compound 1i (130 mg, yield: 22.1%).

[0406] MS m / z(ESI): 450.4 [M+1].

[0407] Step 7

[0408] 4-Chloro-2-(5-Chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylpyridin-3-yl)-5-(methylthio)quinoline

[0409] Compound 1i (130 mg, 288.92 μmol) was dissolved in phosphine oxychloride (5 mL), heated to 100 °C and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The solution was adjusted to alkalinity with saturated sodium bicarbonate under ice bath conditions and extracted with dichloromethane (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1j (100 mg, yield: 73.9%).

[0410] MS m / z(ESI):468.3[M+1].

[0411] Step 8

[0412] 4-(benzyloxy)-2-(5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylpyridin-3-yl)-5-(methylthio)quinoline 1k

[0413] Compound 1j (100 mg, 213.5 μmol) and benzyl alcohol (46 mg, 425.38 μmol) were dissolved in N,N-dimethylformamide (5 mL). Sodium hydroxide (17 mg, 425 μmol, 60% purity) was added under ice bath conditions, and the mixture was stirred for 16 hours. Saturated sodium chloride solution and ethyl acetate were added to the reaction solution. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1k (70 mg, yield: 60.7%).

[0414] MS m / z(ESI): 540.3 [M+1].

[0415] Step 9

[0416] (4-(benzyloxy)-2-(5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylpyridin-3-yl)quinoline-5-yl)(imino)(methyl)-λ 6 - Thione 1l

[0417] Compound 1k (70 mg, 129.6 μmol) was dissolved in methanol (10 mL), and ammonium carbonate (49.77 mg, 518.4 μmol) and iodophenyl diacetic acid (132.2 mg, 388.8 μmol) were added. The mixture was stirred for 3 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium chloride solution, and the organic phase was separated. The product was concentrated under reduced pressure to obtain crude title compound 1l (74 mg). The product was used directly in the next reaction without purification.

[0418] MS m / z(ESI): 571.4 [M+1].

[0419] Step 10

[0420] 2-(5-chloro-2-(4,4-difluoroazacycloheptan-1-yl)-6-methylpyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one

[0421] The crude compound 1 (74 mg, 129.5 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The mixture was heated at 40 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give title compound 1 (35 mg, yield: 56.1%).

[0422] MS m / z(ESI):481.4[M+1].

[0423] 1 H NMR (500MHz, CDCl3): δ8.19-8.17(d,1H),8.05(d,1H),7.60(s,1H),7.56(t,1H),6.42(s,1H),3.65-3.54(m ,2H),3.52(s,3H),3.23-3.16(m,2H),2.45(s,3H),2.37-2.27(m,2H),2.01-1.93(m,2H),1.78-1.71(m,2H).

[0424] Example 1-p1, 1-p2

[0425] (R)-2-(5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylpyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 1-p1

[0426] (S)-2-(5-chloro-2-(4,4-difluoroazacycloheptane-1-yl)-6-methylpyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 1-p2

[0427] Compound 1 (25 mg) was purified by chiral column resolution (Gilson-281, column: ChromegaChiral CC4 (ES Industries), 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.5% 7M ammonia methanol solution), gradient ratio: A:B = 65:35, flow rate: 20 mL / min) to give the title compound (8 mg, yield: 32%).

[0428] Chiral HPLC analysis of compound 1: retention time 8.629 min (49.8%), 15.932 min (50.1%) (Column: CHIRALPAK OX-H, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 70:30, flow rate: 1 mL / min).

[0429] Single configuration compound (shorter retention time) (8.629 min, 8 mg, yield: 32%)

[0430] MS m / z(ESI):481.4[M+1].

[0431] 1 H NMR (500MHz, CDCl3): δ8.13-8.11(d,1H),8.06(d,1H),7.60-7.57(m,2H),6.40(s,1H),3.65-3.51(m,2H) ),3.48(s,3H),3.27-3.15(m,2H),2.44(s,3H),2.36-2.29(m,2H),2.01-1.95(m,2H),1.80-1.74(m,2H).

[0432] Single configuration compound (longer retention time) (15.932 min, 8 mg, yield: 32%)

[0433] MS m / z(ESI):481.4[M+1].

[0434] 1H NMR (500MHz, CDCl3): δ8.10-8.06(m,2H),7.60(t,1H),7.54(s,1H),6.37(s,1H),3.64-3.52(m,2H),3 .44(s,3H),3.27-3.16(m,2H),2.44(s,3H),2.36-2.26(m,2H),2.02-1.94(m,2H),1.79-1.72(m,2H).

[0435] Example 2

[0436] 2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2

[0437] first step

[0438] 1-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane 2b

[0439] 2,6-Dichloro-3-(trifluoromethyl)pyridine 2a (11.5 g, 53.24 mmol, Shanghai Leyan) and compound 1c (10.05 g, 58.56 mmol) were dissolved in 1,4-dioxane (100 mL), and N,N-diisopropylethylamine (13.76 g, 106.47 mmol) was added. The mixture was reacted at 80 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to give title compound 2b (16 g, yield: 95.3%).

[0440] MS m / z(ESI): 315.2 [M+1].

[0441] Step 2

[0442] 4,4-Difluoro-1-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)azacycloheptane 2c

[0443] Compound 2b (16 g, 50.8 mmol), a 50% tetrahydrofuran solution of trimethylboroxane (127 g, 505.8 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (3.71 g, 5.07 μmol), and potassium carbonate (21.02 g, 152.3 mmol) were mixed with 1,4-dioxane (200 mL) and water (40 mL), purged with nitrogen, and heated to 100 °C for 16 hours. After the reaction solution cooled to room temperature, it was filtered, the filtrate was diluted with water, and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 2c (12.9 g, yield: 86.3%).

[0444] MS m / z(ESI):295.2[M+1].

[0445] Step 3

[0446] 1-(3-bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-4,4-difluoroazacycloheptane 2d

[0447] Compound 2c (6.9 g, 23.4 mmol) was dissolved in dichloromethane (100 mL), and N-bromosuccinimide (4.59 g, 25.8 mmol) was added. The mixture was stirred for 2 hours, and the reaction solution was quenched with saturated sodium sulfite solution. The mixture was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2d (8.4 g, yield: 96%).

[0448] MS m / z(ESI): 373.2 [M+1].

[0449] Step 4

[0450] 2-(4,4-Difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid methyl ester 2e

[0451] Compound 2d (4 g, 10.7 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (1.57 g, 2.14 mmol), and triethylamine (3.25 g, 32.1 mmol) were dissolved in methanol (20 mL) and N,N-dimethylacetamide (20 mL), substituted with carbon monoxide, and heated to 85 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2e (3.7 g, yield: 98.1%).

[0452] MS m / z(ESI): 353.4 [M+1].

[0453] Step 5

[0454] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(methylthio)quinoline-4(1H)-one 2f

[0455] Using steps four through six of the synthetic route in Example 1, the starting compound 1f in step four was replaced with compound 2e to obtain the title compound 2f (1.24 g, yield: 61.2%).

[0456] MS m / z(ESI):484.5[M+1].

[0457] Step 6

[0458] 2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2

[0459] Compound 2f (50 mg, 103.4 μmol) was dissolved in methanol (6 mL), and ammonium carbonate (39.74 mg, 413.59 μmol) and iodophenyl diacetic acid (105.51 mg, 310.2 μmol) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give title compound 2 (5 mg, yield: 9.4%).

[0460] MS m / z(ESI): 515.4 [M+1].

[0461] 1 H NMR (500MHz, CDCl3): δ8.26(d,1H),8.05(s,1H),7.89(s,1H),7.68(s,1H),6.78(s,2H),3.7 6–3.71(m,2H),3.49(s,3H),3.20(d,1H),2.60(s,3H),2.39–2.33(m,2H),2.09–1.86(m,4H).

[0462] Example 2A

[0463] 2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2

[0464] first step

[0465] 2g of methyl 2-(4,4-difluorozacycloheptan-1-yl)-5-iodo-6-methylnicotinate

[0466] Compound 1e (61 g, 214.56 mmol) was dissolved in N,N-dimethylacetamide (200 mL), and N-iodosuccinimide (90.08 g, 400.39 mmol) was added. The mixture was stirred at 80 °C for 16 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2 g (70 g, yield: 79.5%).

[0467] MS m / z(ESI):411.2[M+1].

[0468] Step 2

[0469] 2-(4,4-Difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid methyl ester 2e

[0470] 2 g (70 g, 170.65 mmol) of compound was dissolved in N,N-dimethylformamide (250 mL), and methyl fluorosulfonyl difluoroacetate (82 g, 426.83 mmol, Shanghai Titan) and cuprous iodide (35 g, 183.77 mmol) were added. The mixture was purged with nitrogen and stirred at 100 °C for 20 h. After the reaction solution was cooled to room temperature, it was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with water and saturated sodium chloride, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 2e (53 g, yield: 88.1%). MS m / z (ESI): 353.2 [M+1].

[0471] Step 3

[0472] 2-(4,4-Difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid 2h

[0473] Compound 2e (53 g, 150.44 mmol) was dissolved in tetrahydrofuran (100 mL), methanol (100 mL), and water (100 mL). Potassium hydroxide (20 g, 356.47 mmol) was added, and the mixture was stirred at 75 °C for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove the organic solvent. The pH was adjusted to <6 with saturated citric acid solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was slurried with petroleum ether / ethyl acetate (V / V = 5:1), filtered, and dried to obtain the crude title compound 2h (48 g). The product was used directly in the next reaction without purification.

[0474] MS m / z(ESI): 339.3 [M+1].

[0475] Step 4

[0476] N-(2-acetyl-3-(methylthio)phenyl)-2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)nicotinamide 2i

[0477] The crude compound 2h (7 g, 20.69 mmol) was dissolved in dichloromethane (150 mL), and compound 1b (4.50 g, 24.82 mmol), N,N-diisopropylethylamine (8.02 g, 62.05 mmol), and tripyrrolylphosphonium hexafluorophosphate bromide (19.29 g, 41.38 mmol) were added. The mixture was stirred for 16 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 2i (6.5 g, yield: 62.6%).

[0478] MS m / z(ESI): 502.4 [M+1].

[0479] Step 5

[0480] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(methylthio)quinoline-4(1H)-one 2f

[0481] Compound 2i (20 g, 39.88 mmol) was dissolved in 1,4-dioxane (150 mL), sodium hydroxide (4.78 g, 119.51 mmol) was added, nitrogen was purged, and the reaction was carried out at 110 °C for 5 hours. After the reaction solution was cooled to room temperature, water was added, and the pH was adjusted to ≈6 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to give the title compound 2f (4.2 g, yield: 22.7%).

[0482] MS m / z(ESI):484.4[M+1].

[0483] Step 6

[0484] 2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2

[0485] Compound 2f (50 mg, 103.4 μmol) was dissolved in methanol (6 mL), and ammonium carbonate (39.74 mg, 413.59 μmol) and iodophenyl diacetic acid (105.51 mg, 310.2 μmol) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give title compound 2 (5 mg, yield: 9.4%).

[0486] MS m / z(ESI): 515.4 [M+1].

[0487] Example 2-p1, 2-p2

[0488] (R)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2-p1

[0489] (S)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 2-p2

[0490] Compound 2 (40 mg) was purified by chiral column resolution (Shimadzu LC-20AP, column: Enantiocel C9, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.5% 7M ammonia methanol solution, gradient ratio: A:B = 90:10, flow rate: 30 mL / min) to give title compounds 2-p2 (11 mg, yield: 27.5%) and 2-p1 (14 mg, yield: 35%).

[0491] Single configuration compound (shorter retention time) 2-p2 (11 mg, yield: 27.5%)

[0492] MS m / z(ESI): 515.4 [M+1].

[0493] Chiral HPLC analysis: retention time 10.045 min, purity: 99% (column: CHIRALPAK IK, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0494] 1 H NMR (500MHz, CDCl3): δ12.75(brs,1H),8.08(d,2H),7.72(s,1H),7.59(t,1H),6.30(s,1H),3.80–3.61( m,2H),3.39(s,3H),3.34–3.17(m,2H),2.51(d,3H),2.43–2.26(m,2H),1.95(q,2H),1.86–1.69(m,2H).

[0495] Single-configuration compound (longer retention time) 2-p1 (14 mg, yield: 35%)

[0496] MS m / z(ESI): 515.4 [M+1].

[0497] Chiral HPLC analysis: retention time 16.422 min, purity: 99% (column: CHIRALPAK IK, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0498] 1H NMR (500MHz, CDCl3): δ12.66(brs,1H),8.09(d,2H),7.73(s,1H),7.60(d,1H),6.32(s,1H),3.79–3.60(m, 2H),3.40(s,3H),3.23-3.20(m,2H),2.57–2.47(m,3H),2.41–2.23(m,2H),1.95(d,2H),1.91-1.75(m,2H).

[0499] Example 3

[0500] 3-Chloro-2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one

[0501] Compound 2 (60 mg, 116.61 μmol) was dissolved in tetrahydrofuran (10 mL), and N-chlorosuccinimide (17.1 mg, 128.2 μmol) was added. The mixture was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, Boston Phlex Prep C18 column, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40-60%, flow rate: 30 mL / min) to give title compound 3 (5 mg, yield: 7.8%).

[0502] MS m / z(ESI): 549.5 [M+1].

[0503] 1 H NMR (500MHz, CDCl3): δ8.16(s,2H),7.76(s,1H),7.66(d,1H),3.78–3.73(m,4H),3.53(s,3H),3.10(s,3H),2.58(d,2H),1.99(dd,4H).

[0504] Examples 3-p1, 3-p2

[0505] (R)-3-chloro-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 3-p1

[0506] (S)-3-chloro-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 3-p2

[0507] Compound 3 (60 mg) was first resolved by a chiral column (Shimadzu LC-20AP, column: Enantiocel C9, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid), gradient ratio: A:B = 90:10, flow rate: 30 mL / min), then alkalized with ammonia, and purified by silica gel column chromatography with elution system A to obtain the title compound (18 mg, yield: 30%) and (23 mg, yield: 38.3%).

[0508] Single configuration compound (shorter retention time) (18 mg, yield: 30%)

[0509] MS m / z(ESI): 549.5 [M+1].

[0510] Chiral HPLC analysis: retention time 6.757 min, purity: 99% (column: CHIRALPAK IK, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0511] 1 H NMR (500MHz, CDCl3): δ8.13(s,2H),7.70(s,1H),7.66(s,1H),3.74(d,2H),3.47(s,3H),3.11(s,2H),2.54(s,3H),2.34(t,,2H),2.00(d,4H).

[0512] Single configuration compound (longer retention time) (23 mg, yield: 38.3%)

[0513] MS m / z(ESI): 549.5 [M+1].

[0514] Chiral HPLC analysis: retention time 8.358 min, purity: 98.6% (column: CHIRALPAK IK, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0515] 1H NMR (500MHz, CDCl3): δ8.15–7.96(m,2H),7.70(s,1H),7.58(s,1H),3.74(d,2H),3.50 (s,3H),3.17–3.04(m,2H),2.54(s,3H),2.34(s,2H),2.05–1.89(m,2H),1.79(t,2H).

[0516] Example 4

[0517] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-5-(S-methanesulfonyl)quinoline-4(1H)-one

[0518] first step

[0519] 3-Bromo-2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 4a

[0520] Compound 2 (150 mg, 291.5 μmol) was dissolved in tetrahydrofuran (10 mL), and N-bromosuccinimide (51.88 mg, 291.5 μmol) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 4a (130 mg, yield: 75.1%).

[0521] MS m / z(ESI): 593.4 [M+1].

[0522] Step 2

[0523] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-3-methyl-5-(S-methanesulfonyl)quinoline-4(1H)-one

[0524] Compound 4a (30 mg, 50.5 μmol), a 50% tetrahydrofuran solution of trimethylboroxane (12.69 mg, 101.1 μmol), methylboronic acid (6.1 mg, 101.1 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (7.39 mg, 10.1 μmol), and potassium carbonate (17.5 mg, 126.3 μmol) were mixed with 1,4-dioxane (16 mL) and water (4 mL), purged with nitrogen, and heated to 90 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, Boston Phlex Prep column). C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 45-60%, flow rate: 30mL / min) to obtain title compound 4 (2mg, yield: 7.5%).

[0525] MS m / z(ESI): 529.5 [M+1].

[0526] 1 H NMR (500MHz, CDCl3): δ8.10(d,1H),7.94(s,1H),7.64(s,1H),7.59(t,1H),3.69(s,2H) ,3.45(s,3H),3.13(t,2H),2.57(d,3H),2.33(dd,3H),2.21(t,2H),2.09–1.86(m,4H).

[0527] Example 5

[0528] (R)-3-bromo-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 5-p1

[0529] (S)-3-bromo-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 5-p2

[0530] first step

[0531] 3-Bromo-2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(methylthio)quinoline-4(1H)-one 5a

[0532] Compound 2f (330 mg, 682.5 μmol) was dissolved in tetrahydrofuran (20 mL), and N-bromosuccinimide (121.4 mg, 682.1 μmol) was added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 5a (300 mg, yield: 78.1%).

[0533] MS m / z(ESI): 562.4 [M+1].

[0534] Step 2

[0535] 3-Bromo-2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 4a

[0536] (R)-3-bromo-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 5-p1

[0537] (S)-3-bromo-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one 5-p2

[0538] Compound 5a (260 mg, 462.3 μmol) was dissolved in methanol (20 mL), and ammonium carbonate (177.7 mg, 1.85 mmol) and iodophenyl diacetic acid (471.7 mg, 1.39 mmol) were added. The mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: Boston Phlex Prep C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to give title compound 4a (60 mg, yield: 21.8%).

[0539] Compound 4a (60 mg) was resolved by a chiral column (Shimadzu LC-20AP, column: ColumnTek Enantiocel C9, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid + 0.1% 7M ammonia-methanol solution), gradient ratio: A:B = 90:10, flow rate: 30 mL / min) to give the title compound (25 mg, yield: 41.6%).

[0540] Single configuration compound (shorter retention time) (25 mg, yield: 41.6%)

[0541] MS m / z(ESI): 593.2 [M+1].

[0542] Chiral HPLC analysis: retention time 9.485 min, purity: 99% (column: CHIRALPAK IK, 5 μm, 4.6*250 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid and 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0543] 1 H NMR (500MHz, CDCl3): δ8.23(d,1H),8.01(s,1H),7.63(d,2H),3.71(d,2H),3 .44(s,3H),3.16(s,2H),2.50(s,3H),2.45–2.28(m,2H),2.045–1.81(m,4H).

[0544] Single configuration compound (longer retention time) (25 mg, yield: 41.6%)

[0545] MS m / z(ESI): 593.2 [M+1].

[0546] Chiral HPLC analysis: retention time 15.347 min, purity: 99% (column: CHIRALPAK IK, 5 μm, 4.6*250 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid and 0.1% diethylamine), gradient ratio: A:B = 80:20, flow rate: 1 mL / min).

[0547] 1 H NMR (500MHz, CDCl3): δ8.23(d,1H),8.01(s,1H),7.69–7.57(m,2H),3.69(d,2H) ),3.48(s,3H),3.14(s,2H),2.51(s,3H),2.46–2.23(m,2H),2.00–1.81(m,4H).

[0548] Example 6

[0549] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidium-4(1H)-one6

[0550] (R)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidin-4(1H)-one 6-p1

[0551] (S)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidin-4(1H)-one 6-p2

[0552] first step

[0553] (2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid 6a

[0554] Compound 2d (17.4 g, 46.63 mmol) was dissolved in tetrahydrofuran (180 mL), purged with nitrogen, and 2.5 M n-butyllithium in n-hexane solution (19.6 mL) was added dropwise at -78 °C. The reaction was maintained at this temperature for 1 hour. Trimethyl borate (14.5 g, 139.89 mmol) in tetrahydrofuran solution was added at -78 °C, and the reaction was allowed to proceed naturally to room temperature for 1 hour. Saturated ammonium chloride solution was added under ice bath conditions, and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give title compound 6a (2.5 g, yield: 15.8%).

[0555] MS m / z(ESI): 339.3 [M+1].

[0556] Step 2

[0557] 4-(benzyloxy)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-1,6-naphthidine 6-oxide 6c

[0558] Compound 6a (2.9 g, 8.72 mmol), 4-(benzyloxy)-2-chloro-1,6-naphthylpyridine 6-oxide 6b (2.5 g, 8.72 mmol, prepared by the method disclosed in intermediate A-1 on page 189 of patent application "WO2023205463") were dissolved in 1,4-dioxane (30 mL) and water (5 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (712.1 mg, 872 μmol) and potassium carbonate (2.41 g, 17.44 mmol) were added. The reaction was carried out at 90 °C for 5 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to give title compound 6c (4.2 g, yield: 88.4%). MS m / z (ESI): 545.5 [M+1].

[0559] Step 3

[0560] 4-(benzyloxy)-5-chloro-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-1,6-naphthidine 6d

[0561] Compound 6c (4.2 g, 7.71 mmol) was dissolved in phosphine oxychloride (30 mL), and the mixture was heated to 90 °C and reacted for 0.5 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was adjusted to alkalinity with saturated sodium bicarbonate in an ice bath and extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 6d (1.25 g, yield: 28.8%).

[0562] MS m / z(ESI): 563.5 [M+1].

[0563] Step 4

[0564] 4-(benzyloxy)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(methylthio)-1,6-naphthylidine 6e

[0565] Compound 6d (1.25 g, 2.22 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium methanethiol (466.9 mg, 6.66 mmol) was added, and the mixture was stirred for 1 hour. The reaction solution was quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 6e (700 mg, yield: 54.8%).

[0566] MS m / z(ESI): 575.5 [M+1].

[0567] Step 5

[0568] (4-(benzyloxy)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-1,6-naphthidin-5-yl)(imino)(methyl)-λ 6 -Thione 6f

[0569] Compound 6e (140 mg, 243.6 μmol) was dissolved in methanol (10 mL), and ammonium carbonate (187.2 mg, 1.95 mmol) and iodophenyl diacetic acid (497 mg, 1.46 mmol) were added. The mixture was stirred for 16 hours. The reaction solution was quenched with saturated ammonium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 6f (130 mg, yield: 88.1%).

[0570] MS m / z(ESI): 606.4 [M+1].

[0571] Step 6

[0572] 2-(2-(4,4-difluoroazacycloheptan-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidium-4(1H)-one6

[0573] (R)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidin-4(1H)-one 6-p1

[0574] (S)-2-(2-(4,4-difluoroazacycloheptane-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)-1,6-naphthidin-4(1H)-one 6-p2

[0575] Compound 6f (130 mg, 214.6 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoromethanesulfonic acid (0.25 mL) was added. The mixture was stirred for 15 minutes. The reaction solution was adjusted to alkalinity with saturated sodium bicarbonate solution under ice bath conditions. The mixture was extracted with dichloromethane (15 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give title compound 6 (80 mg, yield: 72%).

[0576] Compound 6 (80 mg) was resolved by a chiral column (Gilson-281, column: Regis Whelk-O1, 250*20 mm, 10 μm (Regis Technologies), in-house packed; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid), gradient ratio: A:B = 50:50, flow rate: 30 mL / min) to give the title compound (26 mg, yield: 32.5%).

[0577] Chiral HPLC analysis of compound 6: retention time 7.358 min (48.8%), 14.806 min (51.1%) (column: ReGIS(S,S)-Whelk-01, 150*4.6mm, 5μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% trifluoroacetic acid), gradient ratio: A:B = 50:50, flow rate: 1.0 mL / min).

[0578] Single configuration compound (shorter retention time): (retention time 7.358 min, 26 mg, yield: 32.5%).

[0579] MS m / z(ESI): 516.4 [M+1].

[0580] HPLC analysis: retention time 1.21 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0581] 1 H NMR (500MHz, DMSO-d6): δ12.48(s,1H),8.56(d,,1H),7.95(s,1H),7.67(d,1H),6.42(s,1H),4.93( s,1H),3.66(q,2H),3.32(s,3H),3.27(s,2H),2.56(s,3H),2.35(d,2H),1.95(q,2H),1.77(t,2H).

[0582] Single configuration compound (longer retention time): (retention time 14.806 min, 26 mg, yield: 32.5%).

[0583] MS m / z(ESI): 516.4 [M+1].

[0584] HPLC analysis: retention time 1.21 min, purity: 99% (column: Xtimate, C18, 1.8 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0585] 1 H NMR (500MHz, DMSO-d6): δ12.47(s,1H),8.56(d,1H),7.95(s,1H),7.67(d,1H),6.42(d,1H),4.93(s,1 H),3.66(q,2H),3.32(s,3H),3.25(s,2H),2.56(s,3H),2.40–2.26(m,2H),1.97(dd,2H),1.77(p,2H).

[0586] Example 7

[0587] 2-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one7

[0588] first step

[0589] 2,4-Dichloro-5-(methylthio)quinoline 7b

[0590] 3-Methylthioaniline 7a (13.50 g, 96.97 mmol, Shanghai Titan) was dissolved in phosphorus oxychloride (80 mL), and malonic acid (10.11 g, 97.15 mmol, Shanghai Titan) was added. The mixture was heated to 105 °C and reacted for 6 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) under ice bath conditions. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 7b (5.4 g, yield: 22.8%).

[0591] MS m / z(ESI):244.2[M+1].

[0592] Step 2

[0593] 4-(benzyloxy)-2-chloro-5-(methylthio)quinoline 7c

[0594] Compound 7b (5.4 g, 22.12 mmol) and benzyl alcohol (2.40 g, 22.19 mmol) were dissolved in N,N-dimethylformamide (80 mL) and tetrahydrofuran (80 mL). Sodium hydride (929 mg, 23.22 mmol, 60% purity) was added under ice bath conditions. The reaction was maintained at this temperature for 1 hour, then allowed to return to room temperature for 16 hours. Water and ethyl acetate were added to the reaction mixture under ice bath conditions. The mixture was separated, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give the title compound 7c (6.0 g, yield: 85.9%).

[0595] MS m / z(ESI): 316.8 [M+1].

[0596] Step 3

[0597] 3-Bromo-2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridine 7e

[0598] Using the first to third steps of the synthetic route in Example 2, the starting compound 1c in the first step was replaced with 4,4-difluoro-3-methylpiperidine hydrochloride 7d (Shanghai Bide) to obtain the title compound 7e (5.5 g, yield: 85%).

[0599] Step 4

[0600] (2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid 7f

[0601] Compound 7e (6.30 g, 16.88 mmol) was dissolved in tetrahydrofuran (100 mL), purged with nitrogen, and 2.5 M n-butyllithium in n-hexane solution (8.1 mL) was added dropwise at -78 °C. The reaction was maintained at this temperature for 1 hour. Then, trimethyl borate (2.63 g, 25.3 mmol) in tetrahydrofuran solution (20 mL) was added at -78 °C. The mixture was allowed to return to room temperature naturally with stirring for 1 hour. Saturated ammonium chloride solution was added under ice bath conditions, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title compound 7f (2.5 g, yield: 43.8%).

[0602] MS m / z(ESI): 339.3 [M+1].

[0603] Step 5

[0604] 4-(benzyloxy)-2-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(methylthio)quinoline 7g

[0605] Compound 7f (1.98 g, 5.85 mmol) and compound 7c (1.0 g, 3.16 mmol) were dissolved in 1,4-dioxane (40 mL) and water (5 mL). Anhydrous potassium carbonate (875 mg, 6.33 mmol) and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (259 mg, 317 μmol) were added, and the mixture was purged with nitrogen. The mixture was heated to 90 °C for 16 hours. After the reaction solution was cooled to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system B to give the title compound 7 g (1.05 g, yield: 57.8%).

[0606] MS m / z(ESI): 574.6 [M+1].

[0607] Step 6

[0608] (4-(benzyloxy)-2-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)quinoline-5-yl)(imino)(methyl)-λ 6 -Thion 7h

[0609] 7 g (530 mg, 924 μmol) of the compound, ammonium carbonate (355 mg, 3.69 mmol), and iodophenyl diacetic acid (942 mg, 2.77 mmol) were dissolved in methanol (10 mL) and tetrahydrofuran (10 mL), and stirred for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the mixture was separated. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give the title compound 7h (540 mg, yield: 96.6%).

[0610] MS m / z(ESI): 605.6 [M+1].

[0611] Step 7

[0612] 2-(2-(4,4-difluoro-3-methylpiperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridin-3-yl)-5-(S-methanesulfonyl)quinoline-4(1H)-one7

[0613] Compound 7h (540 mg, 893 μmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The mixture was stirred for 30 minutes and then heated to 40 °C for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-42%, flow rate: 30 mL / min) to give title compound 7 (330 mg, yield: 71.8%).

[0614] MS m / z(ESI): 515.6 [M+1].

[0615] 1 H NMR (500MHz, CDCl3): δ8.16-8.12(m,2H),7.98(s,1H),7.62-7.59(m,1H),6.81(s,1H),3.74-3.66(m,2H) ,3.49(s,3H),3.19(q,1H),2.91(t,1H),2.61(s,3H),2.19–2.06(m,1H),2.03-1.84(m,2H),0.93(d,3H).

[0616] Example 8

[0617] Compound 8 was prepared according to the method disclosed in WO2023205463A1 and was used as a control compound.

[0618] Biological evaluation

[0619] Test Example 1: Determination of the inhibitory activity of the disclosed compound against Nav1.8

[0620] The purpose of this experiment was to investigate the effect of a compound on the Nav1.8 ion channel in vitro. The Nav1.8 ion channel is stably expressed in HEK293 cells. By comparing the magnitude of the Nav1.8 current before and after compound treatment after the Nav1.8 current stabilized, the effect of the compound on the Nav1.8 ion channel can be determined.

[0621] 1. Experimental Materials and Instruments

[0622] 1) Patch clamp amplifier: PC-505B (WARNER instruments)

[0623] 2) Digital-to-analog converter: Digidata 1440A (Axon Instruments)

[0624] 3) Microcontroller: MP-225 (SUTTER instrument)

[0625] 4) Inverted microscope: TL4 (Olympus)

[0626] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0627] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0628] 7) Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, D2650)

[0629] 8)TTX(Affix Scientific,AF3014)

[0630] 2 Experimental Procedure

[0631] 2.1 Compound Preparation

[0632] Except for NaOH and KOH used in acid-base titrations, all compounds used to prepare intracellular and extracellular solutions were purchased from Sigma-Aldrich. The extracellular solution (mM) consisted of: NaCl, 137 g; KCl, 4 g; CaCl₂, 1.8 g; MgCl₂, 1 g; HEPES, 10 g; glucose, 10 g; pH 7.4 (NaOH titration). The intracellular solution (mM) consisted of: aspartic acid, 140 g; MgCl₂, 2 g; EGTA, 11 g; HEPES, 10 g; pH 7.2 (CsOH titration). All test compound solutions contained 1 μM TTX.

[0633] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.

[0634] 2.2 Manual Patch Clamp Test Procedure

[0635] 1) After the compound is prepared into a solution of a specified concentration, add the solution to each pipe in order of increasing concentration and label each pipe.

[0636] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and bring the electrode tip into contact with the cell. Adjust the three-way valve of the suction device to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current pathway.

[0637] 3) After the cell membrane rupture current stabilizes, perform perfusion at different concentrations sequentially. If the current stabilizes for at least one minute, proceed to the next concentration. The perfusion time for each concentration should not exceed five minutes.

[0638] 4) Clean the perfusion tank. Rinse with the drug solution from high to low concentration, rinsing for 20 seconds for each concentration. Finally, rinse with extracellular fluid for 1 minute.

[0639] 2.3 Test Voltage Equation

[0640] Cells were clamped at -80 mV and then depolarized to 10 mV using a square wave for 10 milliseconds to obtain the Nav1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. Once the reaction stabilized, the strength of the inhibition was calculated.

[0641] 3. Data Analysis

[0642] The data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA).

[0643] The inhibitory activity of the disclosed compound against Nav1.8 was determined through the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 1.

[0644] Table 1. IC50 of the compounds disclosed herein on the inhibition of Nav1.8 channel activity 50

[0645] Conclusion: The compounds disclosed herein have a significant inhibitory effect on Nav1.8 channel activity.

[0646] Test Example 2: Pharmacokinetic Evaluation

[0647] I. Rat Experiment

[0648] 1. Abstract

[0649] Using SD rats as test animals, the drug concentration in plasma at different time points after gavage (ig) administration of the compound of the present invention to rats was determined by LC-MS / MS to study the pharmacokinetic behavior of the compound in rats and evaluate its pharmacokinetic characteristics.

[0650] 2. Test Plan

[0651] 2.1 Test Drugs

[0652] Compounds 2-p1 and 8.

[0653] 2.2 Experimental Animals

[0654] Four female rats were provided by Vital River Laboratory Animal Technology Co., Ltd., with the production license SCXK(Beijing) 2021-0006.

[0655] 2.3. Drug preparation

[0656] Weighed a certain amount of the test compound respectively, added 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.2 mg / mL light yellow or colorless clear solution.

[0657] 2.4. Drug administration

[0658] Drug administration dose: 2.0 mg / kg, drug administration volume: 10 mL / kg.

[0659] 3. Operation

[0660] Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 2 minutes (4 °C), plasma was separated within 1 hour, and stored at -²0 °C or -80 °C for further measurement. The blood collection to centrifugation process was carried out under ice bath conditions.

[0661] Determine the content of the test compound in the plasma of rats after drug administration: Take 50 μL of the plasma samples of rats at each time point after drug administration, add 450 μL of acetonitrile and 25 μL of tolbutamide (or camptothecin), vortex mix, and centrifuge at 3700 rpm for 15 minutes. Take the supernatant for LC-MS / MS analysis.

[0662] 4. Results of pharmacokinetic parameters <00…​​​​​

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof: in: R 3 and R 4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 NR 22 C(O)R 23 C(O)R 23 C(O)OR 23 OC(O)R 23 S(O) v R 23 S(O) v NR 20 R 21 OR 23 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced; Ring A is aryl or heteroaryl; Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; L is selected from bond, O, S(O). v O(CR) 1a R 1b ) x 、(CR 1a R 1b ) x O and NR 1c ; G 1 Selected from N, N + O - and CR 8 ; G 2 Selected from N, N + O - and CR 5 ; G 3 Selected from N, N + O - and CR 6 ; G 4 Selected from N, N + O - and CR 7 ; R 5 R 6 R 7 and R 8 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OS(O) v R 14 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 01 Replaced; Each R 1 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 02 Replaced; Each R 2 The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 03 Replaced; or, two Rs 2 Together with the atoms attached thereto, they form cycloalkyl or heterocyclic groups, each of which is independently and optionally converted by one or more R... 03 Replaced; Each R 01 R 02 and R 03 The same or different, and each independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 OC(O)R 14 OC(O)OR 14 S(O) v R 14 S(O) v OR 14 OS(O) v R 14 S(O) v NR 11 R 12 C(=NR) 13 )R 14 S(=NR) 13 )R 14 S(=NR) 13 )(O)R 14 P(O)R 11 R 12 OR 14 =CR 15 R 16 =NR 13 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced; R 15 and R 16 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 20 R 21 C(O)NR 20 R 21 C(O)R 23 OR 23 Cycloalkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more R * Replaced; or R 15 R 16 Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, wherein each cycloalkyl and heterocyclic group is independently and optionally converted by one or more R... * Replaced; Each R 20 R 21 R 22 R 23 R 1c R 11 R 12 R 13 and R 14 The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 30 R 31 C(O)NR 30 R 31 C(O)R 33 C(O)OR 33 OR 33 S(O) v R 33 Cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl; wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, ynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclic alkyl, arylalkyl, and heteroarylalkyl are each independently optionally selected by one or more R * Replaced; Each R 1a and R 1b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; Each R * The same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 30 R 31 C(O)NR 30 R 31 alkylene NR 30 R 31 alkylene C(O)NR 30 R 31 C(O)R 33 C(O)OR 33 OR 33 Nitro, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl, heterocyclicalkyl, arylalkyl, and heteroarylalkyl; Each R 30 R 31 and R 33 They may be the same or different, and each is independently selected from hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylalkyl and heterocyclic alkyl; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6; Each v may be the same or different, and each is independently 0, 1 or 2; Each x is either the same or different, and each x is independently 0, 1, 2, 3 or 4.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl, and / or L is a bond, and / or ring B is a 3- to 12-membered cycloalkyl or a 3- to 12-membered heterocyclic group, and / or each R 1 They may be the same or different, and each is independently selected from halogens, cyano groups, and C. 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyl alkyl, 3- to 6-membered cycloalkyl and 3- to 6-membered heterocyclic groups; and / or each R 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, ring A is phenyl or a 5- or 6-membered heteroaryl, and / or ring B is a 3- to 10-membered heterocyclic group, and / or each R 1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy group; more preferably, ring A is pyridinyl group.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by general formula (III) or a pharmaceutically acceptable salt thereof: in, X 1 For N or CR X1 ;X 2 For N or CR X2 ; X 3 For N or CR X3 ;X 4 For N or CR X4 ; R X1 R X2 R X3 and R X4 The same or different, and each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 C(O)NR 11 R 12 NR 13 C(O)R 14 NR 13 C(O)NR 11 R 12 C(O)R 14 C(O)OR 14 S(O) v R 14 S(O) v NR 11 R 12 OR 14 Cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally selected by one or more R groups. 02 Replaced; Or, R X1 R X2 and the carbon atom or R bonded to it. X2 R X3 and the carbon atom or R bonded to it. X3 R X4 Together with the carbon atom attached to it, they form a ring C, which is optionally bonded by one or more R atoms. 1 Replaced; The ring C is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups; U is CR 2c Or N, R 2c For hydrogen atoms or R 2 ; q is 0, 1, 2, 3 or 4; s is 0, 1 or 2; r is 0, 1 or 2; G 1 R 1 To R 7 R 11 To R 14 R 02 and v as defined in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 3, wherein the compound is a compound or a pharmaceutically acceptable salt thereof represented by general formula (IV), (IV-1) or (IV-2): in: R 2a and R 2b They may be the same or different, and each is independently a hydrogen atom or R. 2 ; G 1 X 1 R X2 R X3 R X4 R 2 To R 7 U, s, r and q are as defined in claim 3.

5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements in the array.

6. The compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, wherein R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; preferably, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R X2 C 1-6 Alkyl, and / or R X3 Halogen or C 1-6 Halogenated alkyl groups, and / or R X4 It is a hydrogen atom.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein G 1 It is N or CH; preferably, G 1 For CH.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkoxy; preferably, R 5 R 6 and R 7 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; more preferably, R 5 R 6 and R 7 It is a hydrogen atom.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 C 1-6 Alkyl, and / or R 4 It is a hydrogen atom.

10. The compound according to any one of claims 4 to 9, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; preferably, R 2a and R 2b They may be the same or different, and each is an independent halogen.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

12. A compound or a salt thereof represented by general formulas (IA), (Ia), (IB), or (Ib): in, R W R is a hydrogen atom or hydroxyl protecting group. W Preferably benzyl; R 9 Selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, C(O)NR 11 R 12 OR 14 OR W cycloalkyl, heterocyclic, aryl, and heteroaryl; preferably, R 9 Halogen or OR W ; Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 R 11 R 12 R 14 m and n are as defined in claim 1.

13. A compound or a salt thereof, selected from the following compounds:

14. A method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of general formula (IA) or its salt undergoes a deprotection reaction to yield the compound of general formula (I) or its pharmaceutically usable salt, or A compound of general formula (Ia) or a salt thereof reacts with ammonia or a salt thereof (preferably a carbonate) to give a compound of general formula (I) or a pharmaceutically usable salt thereof, wherein R W It is a hydroxyl protecting group, preferably benzyl; Ring A, Ring B, L, G 1 To G 4 R 1 To R 4 m and n are as defined in claim 1.

15. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and one or more pharmaceutically acceptable carriers, diluents or excipients.

16. Use of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 15 in the preparation of a medicament for inhibiting a voltage-gated sodium channel; preferably, the voltage-gated sodium channel is Nav1.

8.

17. Use of the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 15 in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain and visceral pain.

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