Aromatic cyclic compound, preparation method therefor, and pharmaceutical use thereof

Abstract

The present disclosure relates to an aromatic cyclic compound, a preparation method therefor, and a pharmaceutical use thereof, and in particular to an aromatic cyclic compound as shown in general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the aromatic cyclic compound as a therapeutic agent, especially a use as a Nav inhibitor and a use in preparation of drugs for treating and / or alleviating pain and pain-related diseases. The groups in general formula (I) are as defined in the description.

Description

Aromatic ring compounds, preparation method thereof and application thereof in medicine TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to aromatic ring compounds, a preparation method thereof and application thereof in medicine. In particular, the present disclosure relates to aromatic ring compounds represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the compounds, and the use of the compounds as Nav inhibitors and the use of the compounds in the preparation of drugs for treating and / or alleviating pain and pain-related diseases. BACKGROUND

[0002] Pain is a complex physiological and psychological activity, and is one of the most common symptoms in clinical practice. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, which is a subjective experience." Pain can serve as a warning signal to alert the body to potential danger, and has an indispensable protective effect on normal life activities. At the same time, pain is also a common clinical symptom. Intense or persistent pain after the disappearance of the external stimulus that triggers pain can cause physiological dysfunction and seriously affect the quality of life of living beings. Statistical data shows that about 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 that are widely distributed in the skin, muscles, joints and internal organs of the whole body, and can convert the heat, mechanical or chemical stimuli they feel into nerve impulses (action potentials) and transmit them to their cell body parts located in the dorsal root ganglia (DRG) via afferent nerve fibers, and ultimately to high-level neural centers, causing pain. The generation and conduction of action potentials in neurons, in turn, depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel is opened, and the influx of sodium ions causes the cell membrane to be further depolarized, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

[0004] Nav is a class of transmembrane ion channel proteins. These proteins are composed of an a subunit with a molecular weight of 260 kD and a β subunit with a molecular weight of 30-40 kD. According to the different a subunits, Nav can be divided into 9 subtypes, Nav1.1-Nav1.9. Different subtypes show different tissue distribution and electrophysiological, pharmacological characteristics. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R). Among them, Nav1.1, Nav1.2, Nav1.3 and Nav1.7 are TTX-S type, and the encoding gene is located on human chromosome 2q23-24, which is highly expressed in neurons. Nav1.5, Nav1.8 and Nav1.9 are TTX-R type, and the encoding gene is located on human chromosome 3p21-24. Among them, Nav1.5 mainly exists in myocardial cells, and Nav1.8 and Nav1.9 exist in the peripheral nervous system. Nav1.4 and Nav1.6 are both TTX-S type, and are highly expressed in skeletal muscle and central nervous system. Local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors, such as lamotrigine, lacosamide, mexiletine, have been successfully used to treat chronic pain.

[0005] Nav1.8 is TTX-R type, and the encoding gene is SCN10A, which mainly exists in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rising of action potential is mainly composed of Nav1.8 current. In some models of studying neuropathic pain, nerve injury can increase the expression level of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Nav1.8. After intracapsular injection of carrageenan in rats, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. After the Nav1.8 gene of humans produces a functional gain-of-function mutation, it can cause peripheral neuropathic pain. According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy, which can be used for the treatment of various types of pain such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0006] The Nav inhibitors used in the clinic have a narrow therapeutic window and limited application due to the lack of subtype selectivity, which can inhibit sodium ion channels expressed in the heart and central nervous system. Nav1.8 is mainly distributed in the peripheral nervous system, so selectively inhibiting Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties, and fewer side effects.

[0007] Patent applications of disclosed Nav1.8 inhibitor compounds include WO2023205463A1, WO2023205778A1, etc. SUMMARY

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

[0009] wherein:

[0010] R 3 and R 4 are the same or different and each is independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an 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 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein the alkyl group, the alkoxy group, the alkoxyalkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently optionally substituted with one or more R 01 ;

[0011] Ring A is an aryl group or a heteroaryl group;

[0012] G 1 is selected from N, N + O - , and CR 8 ;

[0013] G 2 is selected from N, N + O - , and CR5 ;

[0014] G 3 selected from N, N + O - and CR 6 ;

[0015] G 4 selected from N, N + O - and CR 7 ;

[0016] R 5 , R 6 , R 7 and R 8 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an amino group, a 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 , a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein each of said alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more R 01 ;

[0017] each R 1 is the same or different and each is independently selected from the group consisting of an oxo group, =S, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, an amino group, a C(O)NR 11 R 12 , C(O)NR 11 R 12 , NR 13 C(O)R 14 , NR13 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, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 2 ;

[0018] each R 01 and R 2 is the same or different, and each is independently selected from the group consisting of 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, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is independently optionally substituted with one or more R * ;

[0019] R 15 and R 16 are the same or different, and each is independently selected from the group consisting of a 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, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R * ;

[0020] each R 20 , R 21 , R 22 , R 23 , R 11 , R 12 , R 13 , and R 14 are the same or different, and each is independently selected from the group consisting of a 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, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is independently optionally substituted with one or more R * ;

[0021] each R * is the same or different, and each is independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , alkyleneNR 30 R 31 , alkyleneC(O)NR 30 R 31 , C(O)R 33 , C(O)OR 33 , OR 33 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl;

[0022] each R 30 , R 31 , and R 33 are the same or different, and each is independently selected from a hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, and heterocyclylalkyl;

[0023] m is 0, 1, 2, 3, 4, 5, or 6; and

[0024] each v is the same or different, and each is independently 0, 1, or 2.

[0025] In some embodiments of the disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

[0026] wherein X 1 is N or CR X1 ; X 2 is N or CR X2 ;

[0027] X 3 is N or CR X3 ; X 4 is N or CRX4 ; X 5 is N or CR X5 ;

[0028] R X1 , R X2 , R X3 , R X4 and R X5 are the same or different and each is independently selected from the group consisting of a 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, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 2 ;

[0029] G 1 to G 4 , R 2 to R 4 , R 11 to R 14 and v are as defined in general formula (I).

[0030] In some embodiments of the disclosure, the compound of general formula (I) or (II), or a pharmaceutically acceptable salt thereof, is a compound of general formula (III), (III-1) or (III-2), or a pharmaceutically acceptable salt thereof:

[0031] wherein,

[0032] G 1 , X 1 , R X2 , R X3 , R X4 , R X5 , R 3 to R7 as defined in general formula (II).

[0033] In some embodiments of the disclosure, the compound of general formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, is a compound of general formula (IV), or a pharmaceutically acceptable salt thereof:

[0034] wherein U is CR 2c or N, R 2c is a hydrogen atom or R 2 ;

[0035] R 2a and R 2b are the same or different, and each is independently selected from the group consisting of nothing, oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, OR 14 , =CR 15 R 16 , cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R * ;

[0036] q is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4;

[0037] G 1 , X 1 , R X3 , R X4 , R X5 , R 2 to R 7 , R 14 to R 16 and R * are as defined in general formula (II).

[0038] when one of R 2a and R 2b is oxo, =S, or =CR 15 R 16 , the other is nothing.

[0039] In some embodiments of the disclosure, the compound of general formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of phenyl, naphthyl, and 5- to 10-membered heteroaryl; in some embodiments, ring A is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyl, quinolinyl, and pyrazolyl; in some embodiments, ring A is selected from the group consisting of phenyl, terminal and G 4The ring is connected; in some embodiments, ring A is phenyl.

[0040] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein Selected from In some implementation schemes, In some implementation schemes, In some implementation schemes, In some implementation schemes, R 3 and R 4 As defined in general formula (I).

[0041] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, 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 2 Replaced by, R 2 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, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups, wherein the 3- to 6-membered cycloalkyl groups and the 3- to 6-membered heterocyclic groups are each independently selected from halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups 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, each R 1 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are 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, each R 1They may be the same or different, and each is independently selected from F, Cl, methyl, trifluoromethyl, tert-butyl,

[0042] 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 1, 2 or 3; in some embodiments, m is 3.

[0043] In some embodiments of this disclosure, the compounds represented by general formulas (II) to (IV) or their pharmaceutically acceptable salts, wherein X 1 For 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 formula (I); in some implementations, X 1 For N or CH; in some implementations, X 1 For CH.

[0044] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 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, C 1-6 Halogenated alkyl groups 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, X 2 For CR X2 R X2 As defined in general formula (II).

[0045] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, 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 1-6haloalkyl, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 3 is CR X3 , R X3 is as defined in general formula (II); in some embodiments, X 3 is selected from N, CH, C-Cl and C-CF3; in some embodiments, X 3 is C-Cl.

[0046] In some embodiments of the present disclosure, the compound of general formula (II) or a pharmaceutically acceptable salt thereof is described, wherein X 4 is N or CR X4 , R X4 is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 4 is N or CH; in some embodiments, X 4 is CR X4 , R X4 is as defined in general formula (II); in some embodiments, X 4 is CH.

[0047] In some embodiments of the present disclosure, the compound of general formula (II) or a pharmaceutically acceptable salt thereof is described, wherein X 5 is N or CR X5 , R X5 is selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl; in some embodiments, X 5 is CR X5 , R X5 is as defined in general formula (II); in some embodiments, X 5 is selected from N, CH, C-Cl, C-methyl and C-CF3; in some embodiments, X 5 is C-methyl.

[0048] In some embodiments of the present disclosure, the compound of general formula (II) or a pharmaceutically acceptable salt thereof is described, wherein X 1 is N or CR X1 , X 2 is CR X2 , X 3 is CR X3 , X4 CR X4 ; X 5 is CR X5 ; in some embodiments, X 1 is CR X1 ; X 2 is CR X2 ; X 3 is CR X3 ; X 4 is CR X4 ; X 5 is CR X5 ; R X1 , R X2 , R X3 , R X4 and R X5 are as defined in general formula (II).

[0049] In some embodiments of the disclosure, the compounds of general formulae (II) to (IV), or pharmaceutically acceptable salts thereof, wherein R X1 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; in some embodiments, R X1 is a hydrogen atom.

[0050] In some embodiments of the disclosure, the compounds of general formulae (II) to (III), or pharmaceutically acceptable salts thereof, wherein R X2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1- 6haloalkoxy group, a 3- to 10-membered cycloalkyl group and a 3- to 10-membered heterocyclyl group, each independently optionally substituted with one or more selected from the group consisting of a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group and =CR 15 R 16 ; in some embodiments, R X2 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a 3- to 6-membered cycloalkyl group, optionally substituted with one or more selected from the group consisting of a halogen, a C 1-6 alkyl group and =CR 15 R 16 ; in some embodiments, R X2 is a C 1-6 alkyl group or a 3- to 6-membered cycloalkyl group, optionally substituted with one or more selected from the group consisting of a halogen, a C 1-6 alkyl group and =CR15 R 16 substituted with one or more of R 15 and R 16 are as defined in general formula (I); in some embodiments, R X2 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R X2 is a C 1-6 alkyl group; in some embodiments, R X2 is a t-butyl group; in some embodiments, R X2 is selected from a t-butyl group,

[0051] In some embodiments of the disclosure, the compounds of general formula (II) to (IV) or pharmaceutically acceptable salts thereof, wherein R X3 is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, and a C 1-6 haloalkoxy group; in some embodiments, R X3 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R X3 is selected from a hydrogen atom, F, Cl, a methyl group, a CF3 group, and a cyclopropyl group; in some embodiments, R X3 is a halogen; in some embodiments, R X3 is Cl.

[0052] In some embodiments of the disclosure, the compounds of general formula (II) to (IV) or pharmaceutically acceptable salts thereof, wherein R X4 is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1- 6 haloalkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group; in some embodiments, R X4 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R X4 is a hydrogen atom.

[0053] In some embodiments of the disclosure, the compounds of general formula (II) to (IV) or pharmaceutically acceptable salts thereof, wherein R X1 , R X2 , R X3 , RX4 and R X5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a 3- to 10-membered cycloalkyl group and a 3- to 10-membered heterocyclyl group, each independently optionally substituted with one or more R 2 groups as defined in general formula (I); in some embodiments, R 2 , R X1 , R X2 , R X3 , R X4 and R X5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a 3- to 6-membered cycloalkyl group, optionally substituted with one or more R 1-6 groups selected from the group consisting of a halogen, a C 15 alkyl group and =CR 16 R 15 and R 16 are as defined in general formula (I); in some embodiments, R X1 , R X2 , R X3 , R X4 and R X5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, F, Cl, a methyl group, a tert-butyl group,

[0054] In some embodiments of the present disclosure, the compounds of general formulae (II) to (IV) or pharmaceutically acceptable salts thereof, wherein R X2 , R X3 , R X4 and R X5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1- 6alkyl group, a C 1-6 haloalkyl group and a 3- to 6-membered cycloalkyl group, optionally substituted with one or more R 1-6 groups selected from the group consisting of a halogen, a C 15 alkyl group and =CR 16 R 15 and R 16 are as defined in general formula (I); in some embodiments, R X2 , R X3 , R X4 and R X5the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group; in some embodiments, R X2 is a C 1-6 alkyl group, and / or R X3 is a halogen, and / or R X4 is a hydrogen atom, and / or R X5 is a C 1-6 alkyl group.

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (II) to (IV) or a pharmaceutically acceptable salt thereof, wherein R X3 , R X4 and R X5 are the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (II) to (IV) or a pharmaceutically acceptable salt thereof, wherein X 1 is CH, R X3 , R X4 and R X5 are the same or different, and each independently selected from the group consisting of a hydrogen atom, a halogen and a C 1-6 alkyl group.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (III) or a pharmaceutically acceptable salt thereof, wherein R 1 or R X2 is U, R 2 , R 2a , R 2b , s, r and q are as defined in the general formula (IV).

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR 8 , R 8 are as defined in the general formula (I); in some embodiments, G 1 is N or CR 8 , R 8 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; in some embodiments, G 1 is N or CH; in some embodiments, G 1 is N; in some embodiments, G 1 is CH.

[0059] In some embodiments of the disclosure, the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, wherein G 2 is CR 5 , and R 5 is as defined in Formula (I); in some embodiments, G 2 is CR 5 , and R 5 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, G 2 is N or CH; in some embodiments, G 2 is CH.

[0060] In some embodiments of the disclosure, the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, wherein G 3 is CR 6 , and R 6 is as defined in Formula (I); in some embodiments, G 3 is CR 6 , and R 6 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, G 3 is N or CH; in some embodiments, G 3 is CH.

[0061] In some embodiments of the disclosure, the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, wherein G 4 is CR 7 , and R 7 is as defined in Formula (I); in some embodiments, G 4 is CR 7 , and R 7 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, G 4 is selected from the group consisting of N, CH, and C-Cl; in some embodiments, G 4 is CH.

[0062] In some embodiments of the disclosure, the compound of Formula (I) to (IV), or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6haloalkyl, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 7 selected from a hydrogen atom, a halogen, and C 1-6 alkyl; in some embodiments, R 7 is a hydrogen atom or a halogen; in some embodiments, R 7 selected from a hydrogen atom, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 7 is a hydrogen atom or Cl; in some embodiments, R 7 is a hydrogen atom.

[0063] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof are described, wherein R 8 selected from a hydrogen atom, a halogen, and 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 heterocyclyl; in some embodiments, R 8 is a hydrogen atom.

[0064] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof are described, wherein R 5 selected from a hydrogen atom, a halogen, and 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 heterocyclyl; in some embodiments, R 5 is a hydrogen atom or a halogen; in some embodiments, R 5 selected from a hydrogen atom, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 5 is a hydrogen atom.

[0065] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof are described, wherein R 6 selected from a hydrogen atom, a halogen, and 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 heterocyclyl; in some embodiments, R 6It 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 It is a hydrogen atom.

[0066] 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 and C 1-6 Alkoxy; in some embodiments, 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 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, F, Cl, methyl, methoxy, CF3 and cyclopropyl.

[0067] 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.

[0068] In some embodiments of the disclosure, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 4 selected from the group consisting of a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a 3- to 6-membered cycloalkyl group, and a C(O)R 23 ; R 23 is as defined in Formula (I); in some embodiments, R 4 is a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1- 6alkoxy group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 4 is a hydrogen atom.

[0069] In some embodiments of the disclosure, the compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 3 is a C 1-6 alkyl group, and / or R 4 is a hydrogen atom; in some embodiments, R 3 is a methyl group, and / or R 4 is a hydrogen atom.

[0070] In some embodiments of the disclosure, the compound of Formula (IV), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: 2a and R 2b are the same or different, and each is independently selected from the group consisting of nothing, a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and =CR 15 R 16 , R 15 and R 16 are as defined in Formula (I); in some embodiments, R 2a and R 2b are the same or different, and each is independently selected from the group consisting of nothing, a halogen, and =CR 15 R 16 , R 15 and R 16 are as defined in Formula (I); in some embodiments, R 2a and R 2b are the same or different, and each is independently selected from the group consisting of nothing, F, and =CF2; in some embodiments, R 2a and R 2b are F;

[0071] wherein, when one of R 2a and R 2b is =CR 15 R 16 , the other is nothing.

[0072] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) 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, C 1-6 Haloalkyl, C 1-6 Alkoxy and =CR 15 R 16 In some implementation schemes, each R 2 They may be the same or different, and each is independently selected from halogens, C 1-6 Alkyl and =CR 15 R 16 R 15 and R 16 As defined in general formula (I); in some implementations, each R 2 They may be the same or different, and each is independently selected from F, methyl, 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 groups.

[0073] 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 halogen; in some implementations, 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.

[0074] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein U is CR 2c Or N, R 2c Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, U is CR 2c R 2c Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6haloalkyl; in some embodiments, U is CR 2c 2c 1-6 alkyl; in some embodiments, U is C-methyl.

[0075] In some embodiments of the disclosure, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is described, wherein s is 0 or 1; in some embodiments, s is 0.

[0076] In some embodiments of the disclosure, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is described, wherein r is 1 or 2; in some embodiments, r is 1.

[0077] In some embodiments of the disclosure, the compound of Formula (IV) or a pharmaceutically acceptable salt thereof is described, wherein q is 0, 1, or 2; in some embodiments, q is 2; in some embodiments, q is 0.

[0078] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof is described, wherein each R 01 is the same or different, and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkyl, and 3- to 6-membered cycloalkyl; in some embodiments, each R 01 is the same or different, and each is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.

[0079] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof is described, wherein each R * is the same or different, and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy C 1-6 alkyl, 3- to 6-membered cycloalkyl, and NR 30 R 31 , R 30 , and R 31 are as defined in Formula (I); in some embodiments, each R * is the same or different, and each is independently selected from halo, C 1-6 alkyl, and C​​1-6 haloalkyl.

[0080] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 11 and R 12 are the same or different, and each independently is a hydrogen atom or a methyl group; in some embodiments, R 11 and R 12 are both hydrogen atoms.

[0081] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 13 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 13 is a hydrogen atom.

[0082] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 14 is selected from a hydrogen atom, a C 1-6 alkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 14 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 14 is a hydrogen atom or a methyl group; in some embodiments, R 14 is a hydrogen atom.

[0083] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein each R 20 and R 21 are the same or different, and each independently is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R 20 and R 21 are both hydrogen atoms.

[0084] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 22 is a hydrogen atom.

[0085] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 23 is selected from a hydrogen atom, a C 1-6 alkyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a 3- to 6-membered cycloalkyl C 1-6alkyl and 3- to 6-membered heterocyclyl C 1-6 alkyl; the C 1-6 alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered cycloalkyl C 1-6 alkyl and 3- to 6-membered heterocyclyl C 1-6 each R * is independently optionally substituted with one or more R * is as defined in general formula (I); in some embodiments, R 23 is selected from a hydrogen atom, C 1-6 alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 23 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 23 is a hydrogen atom or methyl.

[0086] In some embodiments of the disclosure, the compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 30 and R 31 are the same or different, and each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 30 and R 31 are the same or different, and each independently a hydrogen atom or methyl; in some embodiments, R 30 and R 31 are both hydrogen atoms.

[0087] In some embodiments of the disclosure, the compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R 33 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 33 is a hydrogen atom.

[0088] In some embodiments of the disclosure, the compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein v is 2; in some embodiments, v is 1; in some embodiments, v is 0.

[0089] In the present disclosure, general formula (I) to (III) includes general formula (I), (II), (III), (III-1) and (III-2); general formula (I) to (IV) includes general formula (I), (II), (III), (III-1), (III-2) and (IV).

[0090] In some embodiments of the disclosure, the compound of general formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein X 1 is N or CH; R X2 , RX3 R X4 and R X5 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 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 =CR 15 R 16 One or more of them are replaced by R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or a halogen; 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; R 3 C 1-6 Alkyl; R 4 It is a hydrogen atom.

[0091] In some embodiments of this disclosure, the compound represented by general formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein X 1 For CH; R X3 It is a halogen; R X4 For hydrogen atoms; R X5 C 1-6 Alkyl; R X2 C 1-6 Alkyl or 3- to 6-membered cycloalkyl, 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 They may be the same or different, and each is an independent halogen; G 1 For N or CH; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 7 It can be a hydrogen atom or a halogen.

[0092] In some embodiments of this disclosure, the compound represented by general formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof, wherein X 1 For CH; R X3 It is a halogen; R X4 For hydrogen atoms; R X5 C1-6 Alkyl; R X2 C 1-6 Alkyl; G 1 For CH; R 3 C 1-6 Alkyl; R 4 For hydrogen atoms; R 5 For hydrogen atoms; R 6 For hydrogen atoms; R 7 It is a hydrogen atom.

[0093] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein X 1 For N or CH; R X3 R X4 and R X5 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; 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; U is CR 2c R 2c Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q = 0; s = 0; r = 1; R 2a and R 2b Same or different, and each independently selected from non-existent, halogen, and =CR 15 R 16 ;R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or a halogen.

[0094] In some embodiments of this disclosure, the compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein 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 It is a hydrogen atom or a halogen; X 1 For CH; R X3 It is a halogen; R X4 For hydrogen atoms; R X5 C1-6 Alkyl; U is CR 2c R 2c C 1-6 Alkyl; q = 0; s = 0; r = 1; R 2a and R 2b Same or different, and each independently selected from non-existent, halogen, and =CR 15 R 16 ;R 15 and R 16 They may be the same or different, and each is an independent halogen.

[0095] Table A lists typical compounds disclosed herein, including but not limited to:

[0096] Another aspect of this disclosure relates to compounds or salts thereof represented by general formula (IA) or (Ia).

[0097] Among them, R W R is a hydrogen atom or hydroxyl protecting group. P It is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is a benzyl group.

[0098] Rings A and G 1 To G 4 R 1 R 3 R 4 And m are as defined in general formula (I).

[0099] Another aspect of this disclosure relates to compounds of general formula (IIA) or (IIa) or salts thereof.

[0100] Among them, R W R is a hydrogen atom or hydroxyl protecting group. P It is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is a benzyl group;

[0101] X 1 To X 5 G 1 To G 4 R 3 and R 4 As defined in general formula (II).

[0102] Another aspect of this disclosure relates to compounds of general formulas (IIIA) and (IIIa) or salts thereof.

[0103] Among them, RW is a hydrogen atom or a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0104] X 1 , G 1 , R X2 , R X3 , R X4 , R X5 , R 3 to R 7 as defined in general formula (III).

[0105] Another aspect of the present disclosure relates to a compound represented by general formula (IVA), (IVa), or a salt thereof,

[0106] wherein, R W is a hydrogen atom or a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0107] X 1 , R X3 , R X4 , R X5 , U, R 2a , R 2b , G 1 , R 2 to R 7 , q, r and s are as defined in general formula (IV).

[0108] In some embodiments of the present disclosure, the compound represented by general formula (Ia), (IIa), (IIIa), or a salt thereof, wherein R 3 is not a hydrogen atom.

[0109] Typical intermediate compounds of the present disclosure or a salt thereof include, but are not limited to, those listed in Table B:

[0110] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0111] deprotecting a compound represented by general formula (IA) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or

[0112] The compound represented by General Formula (Ia) or a salt thereof is reacted with ammonia or a salt thereof (in some embodiments, a carbonate salt) in the presence of an oxidizing agent to obtain the compound represented by General Formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0113] R W is a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0114] ring A, G 1 to G 4 , R 1 , R 3 , R 4 and m are as defined in General Formula (I).

[0115] Another aspect of the present disclosure relates to a method for preparing the compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof described above, the method comprising:

[0116] the compound represented by General Formula (IIA) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof, or

[0117] the compound represented by General Formula (IIa) or a salt thereof is reacted with ammonia or a salt thereof (in some embodiments, a carbonate salt) in the presence of an oxidizing agent to obtain the compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof, wherein

[0118] R W is a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0119] X 1 to X 5 , G 1 to G 4 , R 3 and R 4 are as defined in General Formula (II).

[0120] Another aspect of the present disclosure relates to a method for preparing the compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof described above, the method comprising:

[0121] the compound represented by General Formula (IIIA) or a salt thereof is subjected to a deprotection reaction to obtain the compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof, or

[0122] a compound represented by the general formula (III) or a salt thereof, wherein R is a hydrogen atom, is subjected to halogenation with a halogenating agent to give a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R is a halogen atom,

[0123] R 7 a compound represented by the general formula (III) or a salt thereof, wherein R is a hydrogen atom, is subjected to halogenation with a halogenating agent to give a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R is a halogen atom, 7 a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof, wherein R is a halogen atom, wherein

[0124] R W is a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0125] X 1 , G 1 , R X2 , R X3 , R X4 , R X5 , R 3 to R 7 are as defined in the general formula (III).

[0126] Another aspect of the present disclosure relates to a method for producing a compound represented by the above general formula (IV) or a pharmaceutically acceptable salt thereof, the method comprising:

[0127] a compound represented by the general formula (IVA) or a salt thereof is subjected to deprotection to give a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,

[0128] a compound represented by the general formula (IVa) or a salt thereof is reacted with ammonia or a salt thereof (in some embodiments, a carbonate salt) in the presence of an oxidizing agent to give a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, or

[0129] R 7 a compound represented by the general formula (IV) or a salt thereof, wherein R is a hydrogen atom, is subjected to halogenation with a halogenating agent to give a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is a halogen atom, 7 a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is a halogen atom, wherein

[0130] R W is a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; in some embodiments, the hydroxyl protecting group is benzyl;

[0131] X 1 , R X3 , R X4 , R X5 , U, R 2aR 2b R 1 R 2 R 7 q, r and s are as defined in general formula (IV).

[0132] In some embodiments of the present disclosure, the method of preparing a compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, as described above, wherein is selected from R 3 and R 4 are as defined in general formula (I).

[0133] In some embodiments of the present disclosure, the halogenating reagent is selected from the group consisting of iodine, Cl2, Br2, hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), thionyl chloride, phosphorus pentachloride, phosphorus trihalide (such as phosphorus trichloride), NBS (N-bromosuccinimide), and NCS (N-chlorosuccinimide); in some embodiments, the halogenating reagent is NCS (N-chlorosuccinimide).

[0134] In the above synthetic scheme, the deprotection reaction occurs under acidic conditions. Specifically, the reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 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-toluenesulfonic acid, Me3SiCl, TMSOTf, ALC13, BBr3, BF3, and ferric bromide, etc.; in some embodiments, trifluoroacetic acid.

[0135] In the above synthetic scheme, the oxidizing agent includes, but is not limited to, iodobenzenediacetic acid, potassium permanganate, m-chloroperbenzoic acid, perbenzoic acid, dibenzoyl peroxide, peroxyacetic acid, hydrogen peroxide, Dess-Martin, sodium hypochlorite, monoperoxyphthalic acid, N-iodosuccinimide, 2-iodoxybenzoic acid, etc.; in some embodiments, iodobenzenediacetic acid.

[0136] In the above synthetic scheme, the ammonia or its salt includes, but is not limited to, ammonia, ammonium chloride, or ammonium carbonate; in some embodiments, ammonium carbonate.

[0137] The halogenation reaction in the above synthetic scheme optionally occurs under acidic or basic conditions; in some embodiments, the halogenation reaction occurs under acidic conditions. Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, formic acid, acetic acid, glacial acetic acid, Ti(i-PrO)3and BF3·Et2O, TiCl4, hydrochloric acid, concentrated sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, titanium tetrachloride, Me3SiCl, TMSOTf, aluminum trichloride, iron trichloride, iron tribromide, tin tetrachloride, zinc chloride, and the like; in some embodiments, the reagent that provides acidic conditions is acetic acid.

[0138] The reactions of the above steps are optionally 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.

[0139] Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound of the present disclosure of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0140] The present disclosure further relates to the use of a compound of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0141] The present disclosure further relates to the use of a compound of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0142] The present disclosure further relates to the use of a compound of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating and / or alleviating pain and pain-related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia; in some embodiments, the pain is selected from the group consisting of chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, idiopathic pain, intestinal pain, idiopathic pain, and visceral pain; in some embodiments, the postoperative pain is selected from the group consisting of bunionectomy pain, hernia repair pain, and abdominal plastic surgery pain.

[0143] The present disclosure further relates to a method of inhibiting voltage-gated sodium channels comprising administering to a patient in need thereof a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0144] The present disclosure further relates to a method of treating and / or preventing a disease or condition mediated by voltage-gated sodium channels comprising administering to a patient in need thereof a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0145] The present disclosure further relates to a method of treating and / or preventing pain and pain-related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias comprising administering to a patient in need thereof a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0146] The present disclosure further relates to a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament; in some embodiments, for use as a medicament for inhibiting voltage-gated sodium channel activity; in some embodiments, for use as a medicament for inhibiting Nav1.8 activity.

[0147] The present disclosure further relates to a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in inhibiting voltage-gated sodium channel activity; in some embodiments, for use in inhibiting Nav1.8 activity.

[0148] The present disclosure further relates to a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a voltage-gated sodium channel inhibitor; in some embodiments, for use as a Nav1.8 inhibitor.

[0149] The present disclosure further relates to a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for treating and / or preventing a disease or condition mediated by voltage-gated sodium channels; in some embodiments, for use as a medicament for treating and / or preventing a disease or condition mediated by Nav1.8.

[0150] The present disclosure further relates to a compound of Formula (I)-(IV) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating and / or preventing a disease or condition mediated by voltage-gated sodium channels.

[0151] The present disclosure further relates to a compound of general formula (I) to (IV) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and / or prevention of pain and pain related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmias.

[0152] The disease or disorder described in the present disclosure is a disease or disorder that is treated and / or prevented by inhibiting a voltage-gated sodium channel.

[0153] In some embodiments, the voltage-gated sodium channel described in the present disclosure is Nav1.8.

[0154] In some embodiments, the disease or disorder mediated by a voltage-gated sodium channel described in the present disclosure is pain and pain related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac 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 bunionectomy pain, herniorrhaphy pain and abdominoplasty pain.

[0155] In some embodiments, the disease or disorder mediated by a voltage-gated sodium channel described in the present disclosure is 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 Neuropathy Peripheral, Painful Diabetic Peripheral Neuropathy, Painful Lumbosacral Radiculopathy, Postherpetic Neuralgia, Rednal Neuropathy, Joint Pain, Osteoarthritis and Fibromyalgia.

[0156] The active compounds can be prepared into various forms for administration, in unit-dosage amounts appropriate for the route of administration, or in unit-dosage amounts appropriate for self-administration by a patient in a single dose. The unit-dosage of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations.

[0157] As a general guide, suitable unit doses can be 0.1 to 1000 mg.

[0158] The pharmaceutical compositions of the present disclosure can contain, in addition to the active compound, one or more adjuvants selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the compositions can contain 0.1 to 99% by weight of the active compound.

[0159] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0160] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or pharmaceutically acceptable salt thereof or isotopically-substituted version thereof, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or pharmaceutically acceptable salt thereof or isotopically-substituted version thereof. In some embodiments, the pharmaceutical composition contains 0.5-99.5% of the aforementioned compound or pharmaceutically acceptable salt thereof or isotopically-substituted version thereof. In some embodiments, the pharmaceutical composition contains 1-99% of the aforementioned compound or pharmaceutically acceptable salt thereof or isotopically-substituted version thereof. In some embodiments, the pharmaceutical composition contains 2-98% of the aforementioned compound or pharmaceutically acceptable salt thereof or isotopically-substituted version thereof.

[0161] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient.

[0162] The pharmaceutical compositions of the present disclosure can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, sachets, cachets, hard or soft capsules, or syrups or elixirs. Such compositions can be prepared as is known in the art of pharmacy, and can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.

[0163] Oral preparations can also be provided as soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with water-soluble carrier or an oil vehicle.

[0164] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension can also include one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

[0165] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil or mineral oil with or without the addition of a fractionated absorbent excipient. Sweetening agents and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an anti-oxidant.

[0166] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. normal sodium chloride solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0167] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. normal sodium chloride solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] Terminology Explanation

[0172] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0173] 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 ... 1-6Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-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 various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more substituents selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0174] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, 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., C 1-20 In some embodiments, the alkylene group has 1 to 10 carbon atoms (i.e., C 1-10 In some embodiments, the alkylene group has 1 to 8 carbon atoms (i.e., C 1-8 In some embodiments, the alkylene group has 2 to 7 carbon atoms (i.e., C 2-7 In some embodiments, the alkylene group has 1, 2, or 3 carbon atoms (i.e., C 1-6"alkylene" refers to a straight or branched divalent saturated aliphatic hydrocarbon group of 1 to 6 carbon atoms (i.e., C1-C6alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. Alkylene groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more D atoms, halo, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0175] The term "alkenyl" refers to an alkyl group, as defined above, that contains at least one carbon-carbon double bond in the molecule, having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 In some embodiments, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 In some embodiments, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more D atoms, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0176] The term "alkynyl" refers to an alkyl group, as defined above, that contains at least one carbon-carbon triple bond in the molecule, having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C 2-12 In some embodiments, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 In some embodiments, the alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more D atoms, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0177] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0178] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or a multicyclic system (i.e., multicyclic 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 has 3 to 12 ring atoms (i.e., 3- to 12-membered cycloalkyl) or 3 to 10 ring atoms (i.e., 3- to 10-membered cycloalkyl), in some embodiments 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), in some embodiments 3 to 6 ring atoms (i.e., 3- to 6-membered cycloalkyl), 4 to 7 ring atoms (i.e., 4- to 7-membered cycloalkyl), or 5 or 6 ring atoms (i.e., 5- or 6-membered cycloalkyl); in some embodiments 5 or 6 ring atoms.

[0179] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0180] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0181] The term "spirocycloalkyl" refers to a polycyclic ring system sharing one carbon atom between rings (referred to as a spiro atom), which can contain one or more double bonds within the rings, or which can contain one or more heteroatoms selected from nitrogen, oxygen, and sulfur within the rings (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one fully carbon ring is present and the point of attachment is on the fully carbon ring, having from 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 has from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), and in some embodiments, from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl includes mono- and polyspirocycloalkyl (such as dispirocycloalkyl and the like), and in some embodiments is a monospriocycloalkyl or dispirocycloalkyl, and in some embodiments is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monospriocycloalkyl. Non-limiting examples include:

[0182] which can be attached at any position; and the like.

[0183] The term "fused cycloalkyl" refers to a polycyclic ring system sharing adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused with one or more monocyclic cycloalkyl groups, or a monocyclic cycloalkyl fused with one or more heterocyclyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic cycloalkyl group, which can contain one or more double bonds within its ring, and 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 fused cycloalkyl). In some embodiments, the fused cycloalkyl has 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic and polycyclic fused cycloalkyl groups (such as tricyclic, tetracyclic, etc.), and in some embodiments, bicyclic or tricyclic fused cycloalkyl groups, and in some embodiments, 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused cycloalkyl groups. Non-limiting examples include:

[0184] which can be attached at any position; and the like.

[0185] The term "bridged cycloalkyl" refers to an all-carbon polycyclic ring system sharing two non-adjacent carbon atoms between the rings, which can contain one or more double bonds within its ring, and which has 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 has 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), and in some embodiments, 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic and polycyclic bridged cycloalkyl groups (such as tricyclic, tetracyclic, etc.), and in some embodiments, bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples include:

[0186] which can be attached at any position.

[0187] The cycloalkyl rings include cycloalkyl groups (including monocyclic, spiro, fused, and bridged) fused to aryl, heteroaryl, or heterocycloalkyl rings as described above, where the ring that is attached to the parent structure is a cycloalkyl group, non-limiting examples of which include and the like.

[0188] Cycloalkyl groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more substituents selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0189] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocyclic ring (i.e., monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., polycyclic heterocyclyl) having at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-), and having from 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 heterocyclyl). In some embodiments, the heterocyclyl groups are 3- to 12-membered heterocyclyl groups (i.e., 3- to 12-membered heterocyclyl), 3- to 10-membered heterocyclyl groups (i.e., 3- to 10-membered heterocyclyl), and 7- to 10-membered heterocyclyl groups (i.e., 7- to 10-membered heterocyclyl); in some embodiments, 3- to 8-membered heterocyclyl groups (i.e., 3- to 8-membered heterocyclyl); in some embodiments, 3- to 6-membered heterocyclyl groups (i.e., 3- to 6-membered heterocyclyl), 4- to 7-membered heterocyclyl groups (i.e., 4- to 7-membered heterocyclyl), or 5- or 6-membered heterocyclyl groups (i.e., 5- or 6-membered heterocyclyl); in some embodiments, 5- or 6-membered heterocyclyl groups.

[0190] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, among others.

[0191] Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups.

[0192] A "nitrogen-containing heterocyclyl" refers to a heterocyclyl group having at least one (e.g., 1, 2, 3, or 4) nitrogen atom within the heterocyclyl ring, which is as defined above. In some embodiments, 3- to 12-membered nitrogen-containing heterocyclyl groups or 3- to 10-membered nitrogen-containing heterocyclyl groups, in some embodiments, 4- to 7-membered nitrogen-containing heterocyclyl groups, in some embodiments, 5- or 6-membered nitrogen-containing heterocyclyl groups.

[0193] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system that shares one atom (referred to as a spiro atom) between rings, which can contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatom within the ring selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitro oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -0-0-, -0-S-, or -S-S-), provided that at least one monocyclic heterocyclyl is contained and the point of attachment is on the monocyclic heterocyclyl, 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 spiroheterocyclyl). In some embodiments, the spiroheterocyclyl has 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl). The spiroheterocyclyl includes mono- and polyspiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), and in some embodiments, is a monosprioheterocyclyl or dispiroheterocyclyl, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 monosprioheterocyclyl. Non-limiting examples include: etc.

[0194] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system sharing adjacent ring atoms between rings, which rings can contain one or more double bonds, and which rings contain at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., forming a nitro oxide; said sulfur optionally oxidized, i.e., forming a sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-), which is fused to a monocyclic heterocyclyl group or to one or more monocyclic heterocyclyl groups, or to one or more of a cycloalkyl, aryl, or heteroaryl group, with the point of attachment being on the monocyclic heterocyclyl group, and 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 fused heterocyclyl). In some embodiments, the fused heterocyclyl group has 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (such as tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, and the like), and in some embodiments, is a bicyclic fused heterocyclyl group or a tricyclic fused heterocyclyl group, and in some embodiments, is a 3 / 4-, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 3-, 5 / 4-, 5 / 5-, 5 / 6-, 5 / 7-, 6 / 3-, 6 / 4-, 6 / 5-, 6 / 6-, 6 / 7-, 7 / 5-, or 7 / 6 bicyclic fused heterocyclyl group. Non-limiting examples include:

[0195] etc.

[0196] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system sharing two non-adjacent ring atoms between rings, which rings can contain one or more double bonds, and which rings contain at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., forming a nitro oxide; said sulfur optionally oxidized, i.e., forming a sulfoxide or sulfone, but not including -0-0-, -0-S-, or -S-S-), 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 bridged heterocyclyl). In some embodiments, the bridged heterocyclyl group has 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), and in some embodiments, 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). The bridged heterocyclyl group includes bicyclic and polycyclic bridged heterocyclyl groups (such as tricyclic bridged heterocyclyl groups, tetracyclic bridged heterocyclyl groups, and the like), and in some embodiments, is a bicyclic bridged heterocyclyl group or a tricyclic bridged heterocyclyl group. Non-limiting examples include:

[0197] etc.

[0198] The heterocyclyl ring includes heterocyclyl groups (including monocyclic, spirocyclic, fused and bridged heterocyclic rings) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:

[0199] etc.

[0200] The heterocyclyl group can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachment with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0201] The term "aryl" refers to a monocyclic all-carbon aromatic ring having a conjugated pi-electron system (i.e., monocyclic aryl) or a polycyclic aromatic ring system (i.e., polycyclic aryl) 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, 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). The monocyclic aryl group is exemplified by phenyl. The polycyclic aryl group is exemplified by, without limitation, naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused to one or more heterocyclyl or cycloalkyl groups, wherein the point of attachment 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 of which include: etc.

[0202] The aryl group can be substituted or unsubstituted, and when substituted, can be substituted at any available point of attachment with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0203] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having a conjugated pi electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (said nitrogen can optionally be oxidized, i.e., form a nitrogen oxide; said sulfur can optionally be oxidized, i.e., form a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-) within the ring, 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 heteroaryl). In some embodiments, the heteroaryl has 5 to 14 ring atoms (i.e., 5- to 14-membered heteroaryl), in some embodiments 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), and in some embodiments 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl).

[0204] Non-limiting examples of monocyclic heteroaryls include furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridonyl (e.g., pyridazinyl, pyridine-1-oxide, and the like.

[0205] Non-limiting examples of polycyclic heteroaryls include indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryls also include a monocyclic heteroaryl fused to one or more aryl groups, where the point of attachment is on the aromatic ring, and in this case the number of ring atoms continues to designate the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryls also include a monocyclic heteroaryl fused to one or more cycloalkyl or heterocyclyl groups, where the point of attachment is on the monocyclic heteroaromatic ring, and in this case the number of ring atoms continues to designate the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include: and the like.

[0206] A heteroaryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0207] The term "cycloalkyloxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0208] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0209] The term "aryloxy" means -O-aryl, wherein aryl is as defined above.

[0210] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0211] The term "cycloalkylalkyl" means an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0212] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0213] The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0214] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0215] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0216] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0217] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

[0218] The term "hydroxyalkoxy" means an alkoxy group substituted with one or more hydroxyl groups, wherein alkoxy is as defined above.

[0219] The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; in some embodiments -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

[0220] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0221] The term "hydroxyl" means -OH.

[0222] The term "amino" means -NH2.

[0223] The term "cyano" means -CN.

[0224] The term "nitro" means -NO2.

[0225] The term "oxo" or "oxo group" means "=O".

[0226] The term "carbonyl" means C=O.

[0227] TBS refers to tert-butyldimethylsilyl.

[0228] 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.

[0229] 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.

[0230] 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 simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0231] The compounds of the present disclosure can contain all modes of rotation isomers and conformationally restricted states thereof. Also included are atropisomers, the term "atropisomer" is a stereoisomer that results from restricted rotation about a single bond, where the energy difference due to steric strain or other contributing factors is high enough to allow for separation of individual conformers. For example, certain compounds of the present disclosure can exist in the form of a mixture of atropisomers (e.g., an equimolar mixture, a mixture enriched in one atropisomer, etc.) or as a purified atropisomer.

[0232] The compounds of the present disclosure can exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric forms" refers to structural isomers that exist in equilibrium and are readily converted from one isomeric form to another isomeric form. It includes all possible tautomers, in either a single isomeric form or as a mixture of any proportion of said tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of a lactam-lactim equilibrium is shown below:

[0233] An example of a keto-enol equilibrium is shown below:

[0234] As when referring to pyrazolyl, it is understood to include either one or a mixture of both tautomers of the following two structures:

[0235] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0236] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term "isotopic variations" means the compounds having the same atomic numbering but having at least one atom replaced by an atom having the same atomic number but an atomic mass different from the dominant natural isotopic mass. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine, and iodine, such as 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 I, and in some embodiments, deuterium.

[0237] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared to non-deuterated drugs. All isotopic composition variations of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, wherein the replacement of deuterium can be partial or complete, and the partial replacement of deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0238] When a position is specifically designated as deuterium D, the position should be understood as having deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). The compound in the example can have deuterium with an abundance of at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation), at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation), at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium incorporation), or higher.

[0239] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and encompasses the two instances of the event or circumstance occurring and not occurring. For example, “C 1-6 “Alkyl optionally substituted with halogen or cyano” includes both the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.

[0240] "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).

[0241] "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.

[0242] "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.

[0243] 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.

[0244] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0245] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes even more within ±5%. As those skilled in the art will understand, when the parameter is not critical, Detailed Implementation

[0246] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0247] Example

[0248] 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 ohms. -6The NMR measurement is carried out by using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0249] The MS measurement is carried out by using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0250] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0251] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0252] The HPLC analysis is carried out by using an Agilent HPLC 1200 DAD, an Agilent HPLC 1200 VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0253] The chiral HPLC analysis measurement is carried out by using an Agilent 1260 DAD high-performance liquid chromatograph.

[0254] The high-performance liquid preparation is carried out by using a Waters 2545-2767, a Waters 2767-SQ Detector 2, a Shimadzu LC-20AP, and a Gilson GX-281 preparative chromatograph.

[0255] The chiral preparation is carried out by using a Shimadzu LC-20AP preparative chromatograph.

[0256] The CombiFlash rapid preparation instrument is a Combiflash Rf200 (TELEDYNE ISCO).

[0257] The thin layer chromatography silica gel plate is a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the silica gel plate used in the thin layer chromatography (TLC) is 0.15 mm to 0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm to 0.5 mm.

[0258] The silica gel column chromatography generally uses 200-300 mesh silica gel of Yantai Huanghai as the carrier.

[0259] The determination of the average inhibition rate of the kinase and IC 50 The NovoStar microplate reader (Germany BMG Company) is used.

[0260] The known starting materials of the present disclosure can be synthesized according to the methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals, etc.

[0261] Unless otherwise specified in the examples, the reactions can be carried out under argon or nitrogen atmosphere.

[0262] The argon or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1 L.

[0263] The hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1 L.

[0264] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation instrument and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenation instrument.

[0265] The hydrogenation reaction is generally vacuumed, filled with hydrogen, and the operation is repeated for 3 times.

[0266] The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

[0267] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0268] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0269] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system used in the column chromatography for purifying the compounds, and the developing agent system of the thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvents is adjusted according to the different polarity of the compounds, and a small amount of triethylamine and basic or acidic reagents such as acetic acid can also be added for adjustment.

[0270] Example 1

[0271] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfonimidoyl)-1,6- naphthyridin-4(1H)-one 1

[0272] First step

[0273] 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-1,6-naphthyridine 6- oxide 1c

[0274] Compound 1c (230 mg, 531.25 μmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was heated to 50 °C for 0.5 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was cooled in an ice bath and made basic with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (15 mL x 3), and the organic layers were combined and concentrated under reduced pressure to give the crude title compound 1d (239 mg). The product was used directly in the next step without purification.

[0275] MS m / z (ESI): 451.4 [M+1].

[0276] Second step

[0277] 4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-chloro-1,6-naphthyridine 1d

[0278] Compound 1c (230 mg, 531.25 μmol) was dissolved in phosphorus oxychloride (3 mL), and the reaction was heated to 50 °C for 0.5 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was cooled in an ice bath and made basic with saturated sodium bicarbonate. The solution was extracted with ethyl acetate (15 mL x 3), and the organic layers were combined and concentrated under reduced pressure to give the crude title compound 1d (239 mg). The product was used directly in the next step without purification.

[0279] MS m / z (ESI): 451.4 [M+1].

[0280] Third step

[0281] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(methylthio)-1,6-naphthyridin-4-ol 1e

[0282] The crude compound 1d (265 mg, 587.08 pmol) was dissolved in N,N- dimethylformamide (3 mL), sodium thiomethoxide (1.03 g, 2.93 mmol, 20% in water) was added, the reaction was stirred for 16 hours, the reaction solution was added saturated ammonium chloride solution, extracted with ethyl acetate (15 mL x 2), the organic phase was combined, concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1e (57 mg, yield: 26%).

[0283] MS m / z (ESI): 373.3 [M+1].

[0284] Fourth step

[0285] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfonimidoyl)-1,6- naphthyridin-4(1 H)-one 1

[0286] The compound 1e (57 mg, 152.8 pmol) was dissolved in methanol (15 mL), ammonium carbonate (88 mg, 917.1 pmol) and iodobenzenedicarboxylic acid (103.9 mg, 305.7 pmol) were added, the reaction was stirred for 1 hour, the reaction solution was added saturated sodium sulfite solution and concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Boston phlex prep C18, 30*150 mm, 5 pm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to obtain the title compound 1 (5 mg, yield: 8.1%).

[0287] MS m / z (ESI): 404.4 [M+1].

[0288] 1 H NMR (500 MHz, CD3OD): d 8.60 (d, 1 H), 7.69 (d, 1 H), 7.53 (d, 2H), 6.46 (s, 1 H), 3.50 (s, 3H), 2.38 (s, 3H), 1.55 (s, 9H).

[0289] Example 2

[0290] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfonimidoyl)quinolin-4(1 H)- one 2

[0291] First Step

[0292] 2,4-Dichloro-5-(methylthio)quinoline 2b

[0293] Dissolve 3-(methylthio)aniline 2a (13.5 g, 96.97 mmol, Shanghai Titan) in phosphorus oxychloride (80 mL), add malonic acid (10.11 g, 97.15 mmol), heat to 105 °C for 6 hours, concentrate the reaction solution under reduced pressure, dissolve the residue in dichloromethane, adjust to alkaline with saturated sodium bicarbonate in ice bath, extract with dichloromethane (50 mL x 3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 2b (5.4 g). The product is used directly in the next step without purification.

[0294] MS m / z (ESI): 244.2 [M+1].

[0295] Second Step

[0296] 4-(Benzyl oxy)-2-chloro-5-(methylthio)quinoline 2c

[0297] Dissolve the crude compound 2b (5.4 g, 22.11 mmol) and benzyl alcohol (2.4 g, 22.19 mmol) in N,N-dimethylformamide (80 ml) and tetrahydrofuran (80 mL), add sodium hydride (929 mg, 23.22 mmol, 60% purity) in ice bath, keep the temperature for 1 hour, then naturally raise the temperature to room temperature for 16 hours, add water to the reaction solution in ice bath, extract with ethyl acetate (50 mL x 2), combine the organic phases, concentrate under reduced pressure, and purify the residue with silica gel column chromatography with eluent system B to obtain the title compound 2c (6 g, yield: 85.9%).

[0298] MS m / z (ESI): 316.3 [M+1].

[0299] Third Step

[0300] 4-(Benzyl oxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(methylthio)quinoline 2d

[0301] Compound 1a (147 mg, 476.2675 pmol), compound 2c (100 mg, 316.6 pmol) were dissolved in 1,4-dioxane (5 mL) and water (1 mL), 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride (42 mg, 63.4 pmol) and potassium phosphate (168 mg, 791.4587 pmol) were added, and the reaction was carried out under a nitrogen atmosphere at 50 °C for 1 hour. After the reaction solution was cooled to room temperature, water was added, and extraction was performed with dichloromethane (10 mL x 3). The combined organic phases were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 2d (87 mg, yield: 59.4%). MS m / z (ESI): 462.5 [M+1].

[0302] Fourth step

[0303] (4-(benzyloxy)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)quinolin-5-yl)(imino)(methyl)-lambda 6 - thione 2e

[0304] Compound 2d (87 mg, 188.3 pmol) was dissolved in methanol (3 mL), ammonium carbonate (73 mg, 759.7 pmol) and iodo benzene diacetic acid (123 mg, 381.9 pmol) were added, and the reaction was stirred for 16 hours. The reaction solution was diluted with ethyl acetate, and washing was performed sequentially with saturated sodium chloride solution and saturated sodium sulfite solution. The organic phase was concentrated under reduced pressure to obtain the crude title compound 2e (92 mg). The product was used directly in the next reaction without purification.

[0305] MS m / z (ESI): 493.5 [M+1].

[0306] Fifth step

[0307] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfonimidoyl)quinolin-4(lH)-one 2

[0308] The crude title compound 2e (92 mg, 186.6 pmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. After the reaction was stirred for 30 minutes and heated to 40 °C for 16 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Waters-2545, column: Boston phlex prep C18, 30*150 mm, 5 pm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-60%, flow rate: 30 mL / min) to obtain the title compound (35 mg, yield: 46.5%).

[0309] MS m / z (ESI): 403.4 [M+1].

[0310] 1 H NMR (500 MHz, DMSO-d6): δ 12.34 (s, 1H), 8.08 (d, 1H), 7.89-7.82 (m, 2H), 7.53 (s, 1H), 7.49 (s, 1H), 6.28 (s, 1H), 4.44 (s, 1H), 3.38 (s, 3H), 2.32 (s, 3H), 1.49 (s, 9H).

[0311] Example 2 - p1, 2-p2

[0312] (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfmoyl)quinolin-4(lH)-one 2-p1

[0313] (S)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-5-(S-methanesulfmoyl)quinolin-4(lH)-one 2-p2

[0314] The compound 2 (250 mg) was resolved by chiral column (Gilson 281, Column: CHIRALPAK IG, 20*250 mm, 5 pm; mobile phase A: n-hexane, mobile phase B: ethanol (0.5% 7M ammonium methanol solution), gradient ratio: A:B: 85:15, flow rate: 20 mL / min) to give the title compound (60 mg, yield: 48%) and (60 mg, yield: 48%).

[0315] Single configuration compound (shorter retention time): (60 mg, yield: 48%).

[0316] MS m / z (ESI): 402.9 [M+1].

[0317] Chiral HPLC analysis: Retention time 10.270 min, purity: 99% (Column: CHIRALPAK IK 250*4.6 mm, 5 pm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine + 0.1% trifluoroacetic acid), gradient ratio: A:B: 80:20, flow rate: 1.0 mL / min).

[0318] 1 H NMR (500 MHz, CD3OD): δ 8.27 (dd, 1H), 7.92-7.84 (m, 2H), 7.50 (s, 1H), 7.47 (s, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 2.34 (s, 3H), 1.53 (s, 9H).

[0319] Single configuration compound (longer retention time): (60 mg, yield: 48%).

[0320] MS m / z (ESI): 402.9 [M+1].

[0321] Chiral HPLC analysis: Retention time 14.084 min, purity: 99% (column: CHIRALPAK IK 250*4.6 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine + 0.1% trifluoroacetic acid), gradient ratio: A:B: 80:20, flow rate: 1.0 mL / min).

[0322] 1 H NMR (500 MHz, CD3OD): δ 8.27 (dd, 1H), 7.92-7.84 (m, 2H), 7.50 (s, 1H), 7.47 (s, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 2.34 (s, 3H), 1.53 (s, 9H).

[0323] Example 3

[0324] 2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-3-chloro-5-(S-methanesulfonimidoyl)quinolin-4(lH)-one 3

[0325] Compound 2 (20 mg, 51.4 μmol) was dissolved in N,N-dimethylformamide (2 mL), acetic acid (0.1 mL) and N-chlorosuccinimide (7 mg, 52.4 μmol) were added, the reaction was stirred for 16 hours, water was added to the reaction solution, extracted with ethyl acetate (15 mL x 3), the organic phase was combined, concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 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 obtain the title compound 3 (4 mg, yield: 17.8%).

[0326] MS m / z (ESI): 437.4 [M+1].

[0327] 1H NMR (500 MHz, DMSO-d6): δ 12.84 (s, 1H), 8.16 (d, 1H), 7.89-7.84 (m, 2H), 7.55 (s, 1H), 7.53 (s, 1H), 4.35 (s, 1H), 3.42 (s, 3H), 2.20 (s, 3H), 1.50 (s, 9H).

[0328] Example 3 - p1, 3-p2 (R)-2-(4-(tert-butyl)-5-chloro-2-methylphenyl)-3-chloro-5-(S- methanesulfonimidoyl)quinolin-4(lH)-one 3-p1 or (S)-2-(4-(tert-butyl)-5-chloro-2- methylphenyl)-3-chloro-5-(S-methanesulfonimidoyl)quinolin-4(lH)-one 3-p2

[0329] One of the compounds 2-p1, 2-p2 with longer retention time (retention time 14.084 min) (40 mg, 99 μmol) was dissolved in N,N-dimethylformamide (4 mL), acetic acid (0.2 mL) and N-chlorosuccinimide (30 mg, 225 μmol) were added, the reaction was stirred for 16 hours, water was added to the reaction solution, the pH was adjusted to >7 with sodium bicarbonate, and ethyl acetate (5 mL x 3) was extracted, the organic phase was combined, concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: Welch Xtimate C18, 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 obtain the title compound 3-p1 or 3-p2 (14 mg, yield: 32.2%).

[0330] MS m / z (ESI): 437.4 [M+1].

[0331] 1 H NMR (500 MHz, CD3OD): δ 8.35 (dd, 1H), 7.92-7.87 (m, 2H), 7.54 (s, 1H), 7.45 (d, 1H), 3.58 (s, 3H), 2.25 (s, 3H), 1.55 (s, 9H).

[0332] Example 4

[0333] 2-(5-chloro-4-(3,3-difluoro-l-methylcyclopentyl)-2-methylphenyl)-5-(S- methanesulfonimidoyl)quinolin-4(lH)-one 4

[0334] Using the synthetic route in Example 2, replacing the compound 1a in the third step with 2-(5-chloro-4-(3,3-difluoro-1-methylcyclopentyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (prepared using the method disclosed in Intermediate B-99 of the specification of patent application “WO2023205778”) to obtain the title compound 4 (75 mg, yield: 60%).

[0335] MS m / z (ESI): 465.5 [M+1].

[0336] 1 H NMR (500 MHz, CD3OD): δ 8.30 (dd, 1H), 7.92-7.87 (m, 2H), 7.54 (s, 1H), 7.43 (s, 1H), 6.41 (s, 1H), 3.54 (s, 3H), 2.85-2.77 (m, 2H), 2.62-2.52 (m, 2H), 2.40-2.27 (m, 2H), 2.36 (s, 3H), 1.53 (s, 3H).

[0337] Example 5

[0338] 3-chloro-2-(5-chloro-4-(3,3-difluoro-1-methylcyclopentyl)-2-methylphenyl)-5-(S- methanesulfonimidoyl)quinolin-4(1H)-one 5

[0339] Using the synthetic route in Example 3, replacing the compound 2 with compound 4 to obtain the title compound 5 (70 mg, yield: 40.7%).

[0340] MS m / z (ESI): 499.5 [M+1].

[0341] 1 H NMR (500 MHz, DMSO-d6): δ 12.85 (s, 1H), 8.16 (dd, 1H), 7.90-7.85 (m, 2H), 7.60 (s, 1H), 7.49 (s, 1H), 4.35 (s, 1H), 3.42 (s, 3H), 2.82-2.72 (m, 1H), 2.63-2.50 (m, 1H), 2.41-2.25 (m, 4H), 2.20 (s, 3H), 1.48 (s, 3H).

[0342] Example 6

[0343] 2-(5-chloro-4-(3-(difluoromethylidene)-1-methylcyclopentyl)-2-methylphenyl)-5-(S- methanesulfonimidoyl)quinolin-4(1H)-one 6

[0344] First step

[0345] 1 -Bromo-5-chloro-4-(3-(difluoromethyl)-1 -methylcyclopentyl)-2-methylbenzene 6b

[0346] Compound 6b (350 mg, 1.04 mmol), pinacol diborane (529.6 mg, 2.08 mmol) were dissolved in 1.4-dioxane (10 mL), [1,1 '-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (85 mg, 104.3 pmol) and potassium acetate (204.5 mg, 2.08 mmol) were added, the reaction was carried out at 90 °C for 16 hours under nitrogen atmosphere, the reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (399 mg, yield: 99%).

[0347] Second step

[0348] 2-(5-Chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane 6c

[0349] Compound 6b (350 mg, 1.04 mmol), pinacol diborane (529.6 mg, 2.08 mmol) were dissolved in 1.4-dioxane (10 mL), [1,1 '-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (85 mg, 104.3 pmol) and potassium acetate (204.5 mg, 2.08 mmol) were added, the reaction was carried out at 90 °C for 16 hours under nitrogen atmosphere, the reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (399 mg, yield: 99%).

[0350] Third step

[0351] 2-(5-Chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-5-(S- methanesulfonimidoyl)quinolin-4(1 H)-one 6

[0352] Using the synthetic route in Example 2, the third step compound 1a was replaced by compound 6c to obtain the title compound 6 (200 mg, yield: 60.9%).

[0353] MS m / z (ESI): 477.5 [M+1].

[0354] 1 H NMR (500 MHz, CD3OD): δ 8.31 (dd, 1H), 7.96 - 7.86 (m, 2H), 7.55 (s, 1H), 7.47 (s, 1H), 6.43 (s, 1H), 3.56 (s, 3H), 3.03 (d, 1H), 2.68 (d, 1H), 2.57 - 2.46 (m, 2H), 2.38 (s, 4H), 2.26 - 2.16 (m, 1H), 1.43 (s, 3H).

[0355] Example 7

[0356] 3-chloro-2-(5-chloro-4-(3-(difluoromethylidene)-1-methylcyclopentyl)-2- methylphenyl)-5-(S-methanesulfonimidoyl)quinolin-4(1H)-one 7

[0357] Using the synthetic route in Example 3, replacing compound 2 with compound 6 to obtain the title compound 7 (10 mg, yield: 33.3%).

[0358] MS m / z (ESI): 511.4 [M+1].

[0359] 1 H NMR (500 MHz, CD3OD): δ 8.36 (dd, 1H), 7.93 - 7.88 (m, 2H), 7.52 - 7.47 (m, 2H), 3.60 (d, 3H), 3.05 (dd, 1H), 2.70 (dt, 1H), 2.51 (d, 2H), 2.38 (d, 1H), 2.27 (s, 3H), 2.23 - 2.17 (m, 1H), 1.45 (d, 3H).

[0360] Biological evaluation

[0361] Test 1, determination of the Nav1.8 inhibitory activity of the compounds of the present disclosure

[0362] The purpose of the experiment is to detect the effect of the compound on Nav1.8 ion channel in vitro. Nav1.8 ion channel is stably expressed on HEK293 cells. After the Nav1.8 current is stabilized, the size of the Nav1.8 current before and after the compound treatment can be compared to obtain the effect of the compound on the Nav1.8 ion channel.

[0363] 1 Experimental materials and instruments

[0364] 1) Patch Clamp PC-505B (WARNER instruments)

[0365] 2) Digital to Analog Converter: Digidata 1440A (Axon instruments)

[0366] 3) Micro Manipulator: MP-225 (SUTTER instrument)

[0367] 4) Inverted Microscope: TL4 (Olympus)

[0368] 5) Glass Microelectrode Puller: PC-10 (NARISHIGE)

[0369] 6) Microelectrode Glass Capillary: B12024F (Wuhan Micro- Probe Scientific Instrument Co., Ltd.)

[0370] 7) Dimethyl Sulfoxide (DMSO) (Sigma-Aldrich, D2650)

[0371] 8) TTX (Affix Scientific, AF3014)

[0372] 2 Experimental Procedure

[0373] 2.1 Compound Preparation

[0374] All compounds used for preparation of intracellular and extracellular solutions were purchased from Sigma, except NaOH and KOH for pH titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). The intracellular solution (mM) was: aspartate, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound solutions contained 1 mM TTX.

[0375] Test compounds were stored at 9 mM in dimethyl sulfoxide (DMSO). On the day of testing, they were dissolved in extracellular solution to the desired concentration.

[0376] 2.2 Manual Patch Clamp Test Procedure

[0377] 1) After the compound was prepared into a solution of the specified concentration, the drug solution was added to each of the channels in order of concentration from low to high, and each channel was labeled.

[0378] 2) The cell is transferred to the perfusion chamber, a positive pressure is applied to the electrode, the electrode tip is brought into contact with the cell, the three-way valve of the suction device is set to the three-way state, and then a negative pressure is applied to the electrode, so that the electrode forms a high-resistance seal with the cell. The negative pressure is continuously applied so that the cell membrane is ruptured and an electrical current path is formed.

[0379] 3) After the membrane-rupturing current is stable, perfusion is performed in different concentrations in turn. If the current is stable for at least one minute, the next concentration can be used for perfusion. The perfusion time for each concentration is not more than five minutes.

[0380] 4) The perfusion chamber is washed. The washing is performed from high to low concentration of the drug solution, and each concentration of the drug solution is washed for 20 s. Finally, the extracellular solution is washed for 1 min.

[0381] 2.3 Test voltage equation

[0382] The cell is clamped at -80 mV, and then depolarized to 10 mV by a 10-millisecond square wave to obtain Nav1.8 current. This procedure is repeated every 5 seconds. The maximum current induced by the square wave is detected, and after it is stable, the test compound is perfused, and when the response is stable, the strength of the inhibition is calculated.

[0383] 3. Data analysis

[0384] The data will be stored in a computer system for analysis. The data acquisition and analysis use pCLAMP 10 (Molecular Devices, Union City, CA).

[0385] The inhibitory activity of the compounds of the present disclosure on Nav1.8 is determined by the above experiment, and the IC 50 values measured are shown in Table 1.

[0386] Table 1, IC 50

[0387] Conclusion: The compounds in the present disclosure have obvious inhibitory effect on Nav1.8 channel activity.

[0388] Test Example 2, Pharmacokinetics

[0389] I. Mouse Pharmacokinetics

[0390] 1. Abstract

[0391] C57 mice were used as test animals, and the drug concentration in the plasma of the mice at different times after oral administration (i.g.) of the compound of the example was determined by LC-MS / MS method, the pharmacokinetic behavior of the compound of the present disclosure in mice was studied, and the pharmacokinetic characteristics were evaluated.

[0392] 2. Test scheme

[0393] 2.1, Test drug

[0394] The compound with a retention time of 14.084 minutes in 2-p1 and 2-p2.

[0395] 2.2, Test animals

[0396] Nine mice (female) were provided by Vantianlihua Experimental Animal Technology Co., Ltd. and the production license was SCXK (Zhe) 2024-0001.

[0397] 2.3, Drug preparation

[0398] A certain amount of test compound was weighed, 5% DMSO + 5% Tween 80 + 90% physiological saline was added, and a 0.1 mg / mL colorless and transparent solution was prepared.

[0399] 2.4, Drug administration

[0400] Dose: 2.0 mg / kg; Volume: 20 mL / kg.

[0401] 3, Operation

[0402] Before and after administration, 0.1 mL of blood was taken from the eye socket, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing. The blood collection to centrifugation process was operated under ice bath conditions.

[0403] Take 25 μL of mouse plasma sample at each time point after administration, add 200 μL of internal standard acetonitrile solution, vortex mix, and centrifuge at 4000 rpm for 15 minutes. Mix 70 μL of water with 70 μL of supernatant and vortex mix for 5 minutes. Take the solution for LC-MS / MS analysis.

[0404] 4, Pharmacokinetic parameter results

[0405] Table 2, Pharmacokinetic parameters of the compound of the present disclosure in mice

[0406] Conclusion: The compound of the present disclosure has high blood drug concentration and high exposure in mice, and has pharmacokinetic advantages.

[0407] Two, rat pharmacokinetics

[0408] 1, Abstract

[0409] Rats were used as test animals, and LC-MS / MS was used to determine the drug concentration in the plasma of rats at different times after intragastrically (i.g.) administering the compound of the example, to study the pharmacokinetic behavior of the compound of the present disclosure in dogs, and to evaluate its pharmacokinetic characteristics.

[0410] 2. Test plan

[0411] 2.1. Test drug

[0412] The compound with a retention time of 14.084 minutes in 2-p1 and 2-p2.

[0413] 2.2. Test animals

[0414] Four rats, half male and half female, were provided by Vantoll Experimental Animal Technology Co., Ltd., with a production license SCXK(Zhe)2024-0001.

[0415] 2.3. Drug preparation

[0416] A certain amount of the test compound was weighed, and 5% DMSO + 5% Tween 80 + 90% physiological saline was added to prepare a 0.2 mg / mL colorless and transparent solution.

[0417] 2.4. Drug administration

[0418] Dose: 2.0 mg / kg; volume: 10 mL / kg.

[0419] 3. Operation

[0420] Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the eye orbit, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process were operated under ice bath conditions.

[0421] 20 μL of the plasma sample at each time point after administration was taken, 200 μL of acetonitrile solution (containing an internal standard) was added, vortex mixed, and centrifuged at 4000 rpm for 15 minutes. 90 μL of water was mixed with 90 μL of supernatant, vortex mixed for 5 minutes, and finally 0.2 μL of the solution was taken for LC-MS / MS analysis.

[0422] 4. Pharmacokinetic parameter results

[0423] Table 3. Pharmacokinetic parameters of the compound of the present disclosure in rats

[0424] Conclusion: The compound of the present disclosure has a high blood drug concentration and high exposure in rats, and has pharmacokinetic advantages.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof: wherein: R 3 and R 4 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, 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 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more R 01 ; Ring A is aryl or heteroaryl; 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 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, 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, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 01 ; each R 1 are the same or different and each is independently selected from oxo, =S, halo, 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, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 2 ; each R 01 and R 2 are the same or different and each is independently selected from oxo, =S, halo, 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, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is independently optionally substituted with one or more R * ; each R 15 and R 16 are the same or different and each is independently selected from the group consisting of a 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, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R * ; each R 20 , R 21 , R 22 , R 23 , R 11 , R 12 , R 13 , and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, 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 , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl groups is independently optionally substituted with one or more R * groups; each R * are the same or different and each is independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , alkyleneNR 30 R 31 , alkyleneC(O)NR 30 R 31 , C(O)R 33 , C(O)OR 33 , OR 33 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each R 30 , R 31 , and R 33 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, and a heterocyclylalkyl group; m is 0, 1, 2, 3, 4, 5, or 6; and Each v is the same or different, and each is independently 0, 1, or 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof: wherein X 1 is N or CR X1 ; X 2 is N or CR X2 ; X 3 is N or CR X3 ; X 4 is N or CR X4 ; X 5 is N or CR X5 ; R X1 R X2 R X3 R X4 R X5 are the same or different and each is independently selected from the group consisting of a 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, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 2 ; G 1 to G 4 , R 2 to R 4 , R 11 to R 14 and v are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound represented by General Formula (III), (III-1) or (III-2) or a pharmaceutically acceptable salt thereof: wherein, G 1 , X 1 , R X2 , R X3 , R X4 , R X5 , R 3 to R 7 as defined in claim 2. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by General Formula (IV) or a pharmaceutically acceptable salt thereof: wherein U is CR 2c or N, R 2c is a hydrogen atom or R 2 ; R 2a and R 2b are the same or different and each is independently selected from the group consisting of absent, oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, OR 14 , =CR 15 R 16 , cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R * ; q is 0, 1, 2, 3, or 4; s is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; G 1 , X 1 , R X3 , R X4 , R X5 , R 2 to R 7 , R 14 to R 16 and R * as defined in claim 2. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein X 1 is CH, R X3 , R X4 and R X5 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein G 1 is N or CH; preferably, G 1 is CH. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 , R 6 and R 7 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group; preferably, R 5 , R 6 and R 7 are each a hydrogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 3 is a C 1-6 alkyl group, and / or R 4 is a hydrogen atom. The compound or pharmaceutically acceptable salt thereof according to any one of claims 4 to 8, wherein R 2a and R 2b are the same or different, and each is independently selected from the group consisting of absent, halogen, and =CR 15 R 16 , R 15 and R 16 are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof according to any one of claims 2, 3 and 6 to 9, wherein R X2 , R X3 , R X4 and R X5 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, a halogen and a C 1-6 alkyl group; preferably, R X2 is a C 1-6 alkyl group, and / or R X3 is a halogen, and / or R X4 is a hydrogen atom, and / or R X5 is a C 1- 6 alkyl group. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from the following compounds: A compound of the formula (IA) or (Ia) or a salt thereof: wherein R W is a hydrogen atom or a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; preferably, the hydroxyl protecting group is benzyl; Ring A, G 1 to G 4 , R 1 , R 3 , R 4 and m are as defined in claim 1. The compound according to claim 12 or a salt thereof, which is selected from the following compounds: A process for the preparation of a compound of general formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: The compound represented by General Formula (IA) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (I) or a pharmaceutically acceptable salt thereof, or a compound of Formula (I) or a salt thereof, wherein R W is a hydroxyl protecting group, R P is a hydrogen atom or a hydroxyl protecting group; preferably, the hydroxyl protecting group is benzyl; Ring A, G 1 to G 4 , R 1 , R 3 , R 4 and m are as defined in claim 1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channels are Nav1.

8. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment and / or alleviation of pain and pain-related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmias; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, idiopathic pain, intestinal pain, idiopathic pain, and visceral pain.

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