Oxyheteroaryl compound, preparation method therefor, and pharmaceutical use thereof

Abstract

The present invention relates to an oxyheteroaryl compound, a preparation method therefor, and a pharmaceutical use thereof. Specifically, the present invention relates to an oxyheteroaryl compound as shown in general formula (I'), a preparation method therefor, a pharmaceutical composition containing the compound, and a use of the oxyheteroaryl compound as a therapeutic agent, especially a use as an 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

Oxoheteroaryl compounds, processes for their preparation and their use in medicine TECHNICAL FIELD

[0001] The present disclosure belongs to the field of medicine, and relates to oxoheteroaryl compounds, processes for their preparation and their use in medicine. In particular, the present disclosure relates to oxoheteroaryl compounds of general formula (I), processes for their preparation and pharmaceutical compositions containing them, as well as their use as Nav inhibitors and their use in the preparation of a medicament for the treatment and / or alleviation of pain and pain-related disorders. BACKGROUND

[0002] Pain is a complex psychophysiological 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 feeling." 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 triggered it 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 perceive 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 Nav1.8 expression. 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, WO2023205465A1, WO2023205468A1, 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] Ring A is aryl or heteroaryl; ring B is cycloalkyl or heterocyclyl;

[0011] R B is =CR 15 R 16 ;

[0012] 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 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 01 ;

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

[0014] G 1 is selected from N, N + O - and CR 9 ; G 2 is selected from N, N + O - and CR1 ;

[0015] G 3 selected from N, N + O - and CR 2 ; G 4 selected from N, N + O - and CR 3 ;

[0016] R, R 1 , R 2 , R 3 and R 9 are the same or different and each 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 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , OR 14 , C(=S)NR 11 R 12 , Si(alkyl)3, 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 ;

[0017] each R A is the same or different and each independently selected from the group consisting of oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 , C(O)NR 11 R 12, NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , C(O)R 14 , C(O)OR 14 , S(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 , OR 14 , Si(alkyl)3, 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 02 ;

[0018] each R 7 is the same or different, and each is independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 , C(O)NR 11 R 12 , NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , C(O)R 14 , C(O)OR 14 , OC(O)R 14 , S(O) v R 14 , S(O) v NR 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , Si(alkyl)3, 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 03 ; or, two R 7together with the atom to which they are attached form a cycloalkyl or heterocyclyl, each independently optionally substituted with one or more R 03 substituted;

[0019] each R 01 , R 02 , and R 03 are 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 , S(O) v R 14 , S(O) v OR 14 , S(O) v NR 11 R 12 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , OR 14 , =CR 15 R 16 , =NR 13 , S(=NR 13 )(O)R 14 , Si(alkyl)3, 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 * ;

[0020] each 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 R31 , C(O)R 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 * ; or R 11 , R 12 and the nitrogen atom to which they are attached together form heterocyclyl, said heterocyclyl being optionally substituted with one or more R * ;

[0021] each R * is the same or different, and each is independently selected from the group consisting of oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, alkylthio, 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 , Si(alkyl)3, 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 the group consisting of a hydrogen atom, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylthio, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl and heterocyclylalkyl;

[0023] m is 0, 1, 2, 3, 4, 5 or 6; n 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 present disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (I’):

[0026] wherein:

[0027] X 1 is N or CR 8 ; X 2 is N or CR 4 ; X 3 is N or CR 5 ; X 4 is N or CR 6 ;

[0028] R 4 , R 5 , R 6 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, 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 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , OR 14 , Si(alkyl)3, 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 02 ; or R 5 , R 6 and the carbon atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R A ;

[0029] Ring B, G 1 to G 4 , R, R B , R 7 , n, R11 to R 14 , R 02 , R A and v are as defined in general formula (I').

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

[0031] wherein,

[0032] ring B, R B , X 1 , G 1 , R, R 1 to R 7 and n are as defined in general formula (I).

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

[0034] wherein: U is N or CR 7a , R 7a is a hydrogen atom or R 7 ;

[0035] s is 0, 1 or 2; r is 0, 1 or 2; t is 0 or 1; q is 0, 1, 2, 3 or 4;

[0036] G 1 , X 1 , R 1 to R 7 , R 11 , R 12 , R 15 and R 16 are as defined in general formula (I).

[0037] In some embodiments of the present disclosure, the compound of general formula (I) to (III) or a pharmaceutically acceptable salt thereof is a compound of general formula (IV) or a pharmaceutically acceptable salt thereof:

[0038] wherein,

[0039] G 1 , X 1 , R 1 to R 7 , R 7a , R 11 , R 12 , R 15R 16 s, r, and q are as defined in general formula (III).

[0040] In some embodiments of the disclosure, the compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof is a compound of general formula (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof:

[0041] wherein,

[0042] R 7a is selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, NR 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , OR 14 , cycloalkyl, and heterocyclyl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is independently optionally substituted with one or more R 03 ;

[0043] G 1 , X 1 , R 1 to R 7 , R 11 , R 12 , R 14 , R 15 , R 16 , s, r, and q are as defined in general formula (IV), and R 03 are as defined in general formula (I’).

[0044] In some embodiments of the disclosure, the compound of general formula (I’) or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; in some embodiments, ring A is phenyl or a 5- or 6-membered heteroaryl; in some embodiments, ring A is phenyl or a 6-membered heteroaryl; in some embodiments, ring A is selected from the group consisting of phenyl, pyridyl, and pyrazolyl; in some embodiments, ring A is phenyl or pyridyl; in some embodiments, ring A is selected from the group consisting of In some embodiments, ring A is In some embodiments, ring A is pyrazolyl; in some embodiments, ring A is * is attached to the ring to which ring B is attached, * is attached to the ring in which NH is located.

[0045] In some embodiments of the disclosure, the compound of general formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein R15 and R 16 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl; in some embodiments, R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or F; in some implementations, R 15 and R 16 They may be the same or different, and each is independently a halogen; in some implementations, R 15 and R 16 All are F.

[0046] In some embodiments of this disclosure, the compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, wherein for In some implementation schemes, for In some implementation schemes, for X 1 X 2 X 3 and X 4 As defined in general formula (I); * the end is connected to ring B.

[0047] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein Selected from X 1 X 2 X 3 X 4 R 4 R 5 and R 6 As defined in general formula (I); in some implementations, for In some implementation schemes, for X 1 X 3 R 4 R 5 R 6 and R 8 As defined in general formula (I).

[0048] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein X1 N or CR 8 R 8 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, X 1 is CR 8 R 8 is as defined in general formula (I); in some embodiments, X 1 is N or CH; in some embodiments, X 1 is N; in some embodiments, X 1 is CH.

[0049] In some embodiments of the disclosure, the compound of general formula (I) is represented by a structure having the formula: 2 N or CR 4 R 4 is selected from 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 a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, X 2 is CR 4 R 4 is as defined in general formula (I); in some embodiments, X 2 is CH or C-methyl; in some embodiments, X 2 is C-methyl.

[0050] In some embodiments of the disclosure, the compound of general formula (I) is represented by a structure having the formula: 3 N or CR 5 R 5 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, X 3 is CR 5 R 5 is as defined in general formula (I); in some embodiments, X 3 is N or CH; in some embodiments, X 3 is CH.

[0051] In some embodiments of the disclosure, the compound of general formula (I) is represented by a structure having the formula: 4 N or CR 6 R 6 is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and 3- to 6-membered cycloalkyl optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 4 is selected from N, CH, C-Cl and C-CF3; in some embodiments, X 4 is C-Cl or C-CF3; in some embodiments, X 4 is C-Cl.

[0052] In some embodiments of the present disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is one wherein X 1 is N or CR 8 , X 2 is N or CR 4 , X 3 is CR 5 , X 4 is CR 6 , or X 1 is N or CR 8 , X 2 is CR 4 , X 3 is N or CR 5 , X 4 is CR 6 , or X 1 is N or CR 8 , X 2 is CR 4 , X 3 is CR 5 , X 4 is N or CR 6 ; in some embodiments, X 1 is N or CR 8 , X 2 is CR 4 , X 3 is CR 5 , X 4 is CR 6 ; in some embodiments, X 1 is CR 8 , X 2 is CR 4 , X 3 is N, X 4 is CR 6 ; in some embodiments, X 1 is CR 8 , X 2 is CR 4, X 3 is CR 5 , X 4 is CR 6 ; R 4 , R 5 , R 6 and R 8 are as defined in general formula (I); in some embodiments, X 1 is N or CH, X 2 is CR 4 , X 3 is CR 5 , X 4 is CR 6 , R 4 , R 5 and R 6 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, and a 3- to 6-membered cycloalkyl group.

[0053] In some embodiments of the disclosure, the compounds of general formula (I) to (IV), or pharmaceutically acceptable salts thereof, wherein 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, R 8 is a hydrogen atom.

[0054] In some embodiments of the disclosure, the compounds of general formula (I) to (IV), or pharmaceutically acceptable salts thereof, wherein R 4 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 1-6 haloalkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group, each of which is independently optionally substituted with one or more selected from the group consisting of a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R 4 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 1-6 haloalkoxy group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 4 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6haloalkyl; in some embodiments, R 4 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 4 is a hydrogen atom or methyl; in some embodiments, R 4 is a hydrogen atom; in some embodiments, R 4 is C 1-6 alkyl; in some embodiments, R 4 is methyl; in some embodiments, R 4 is selected from the group consisting of a hydrogen atom, F, Cl, methyl, CF3, and cyclopropyl.

[0055] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof, wherein R 5 is selected from the group consisting of a hydrogen atom, halogen, cyano, 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 selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 5 is a hydrogen atom.

[0056] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof, wherein R 6 is selected from the group consisting of a hydrogen atom, halogen, cyano, 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, each independently optionally substituted with one or more selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 6 is selected from the group consisting of a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and 3- to 6-membered cycloalkyl; in some embodiments, R 6 is selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 6 is selected from the group consisting of a hydrogen atom, F, Cl, methyl, CF3, and cyclopropyl; in some embodiments, R6 Halogen or C 1-6 Halogenated alkyl; in some embodiments, R 6 It is Cl or CF3; in some implementations, R 6 For Cl; in some implementations, R 6 It is CF3.

[0057] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 4 R 5 R 6 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic groups, each of which is independently optionally converted by one or more R 02 Replaced by, R 02 As defined in general formula (I); in some implementations, R 4 R 5 R 6 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups, wherein the 3- to 6-membered cycloalkyl groups are optionally selected from halogens, C-type alkyl groups, and C-type alkyl groups. 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted, or R 5 R 6 Together with the carbon atom attached thereto, it forms a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclic group; in some embodiments, R 4 R 5 R 6 and R 8 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 4 R 5 R 6 and R 8 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 haloalkyl; in some embodiments, R 4 , R 5 , R 6 and R 8 are the same or different and each is independently selected from the group consisting of a hydrogen atom, F, CI, methyl, CF3, and cyclopropyl.

[0058] In some embodiments of the disclosure, the compounds of Formula (I) to (IV) or pharmaceutically acceptable salts thereof, wherein R 4 , R 5 and R 6 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 4 , R 5 and R 6 are the same or different and each is independently selected from the group consisting of a hydrogen atom, F, CI, methyl, CF3, and cyclopropyl.

[0059] In some embodiments of the disclosure, the compounds of Formula (I’), (I) and (II) or pharmaceutically acceptable salts thereof, wherein ring B is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl; in some embodiments, ring B is a 3- to 10-membered cycloalkyl; in some embodiments, ring B is a 4- to 7-membered cycloalkyl; in some embodiments, ring B is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, is connected to the ring where X 1 is located; in some embodiments, ring B is selected from the group consisting of cyclobutyl, cyclopentyl, and cyclohexyl; in some embodiments, ring B is cyclopentyl.

[0060] In some embodiments of the disclosure, the compounds of Formula (I’), (I) and (II) or pharmaceutically acceptable salts thereof, wherein is U, R 7 , R 15 , R 16 , s, t, r and q are as defined in Formula (III); in some embodiments, is selected from the group consisting of In some embodiments, is In some embodiments, is R 7 , R 7a , R 15 , R16 , s, r, and q are as defined in Formula (IV), (IV-1), or (IV-2); in some embodiments, selected from the group consisting of

[0061] In some embodiments of the disclosure, the compound of Formula (III) or pharmaceutically acceptable salt thereof, wherein selected from the group consisting of In some embodiments, is In some embodiments, is R 7 , R 7a , R 15 , R 16 , s, r, and q are as defined in Formula (IV), (IV-1), or (IV-2).

[0062] In some embodiments of the disclosure, the compound of Formula (I’), (I) to (IV) or pharmaceutically acceptable salt thereof, wherein each R 7 is the same or different and each is independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 alkoxy, or two R 7 and the carbon atoms to which they are attached together form a 3- to 6-membered cycloalkyl group optionally substituted with one or more selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, each R 7 is the same or different and each is independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, each R 7 is the same or different and each is independently selected from the group consisting of C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 7 is C 1-6 alkyl; in some embodiments, R 7 is methyl or CF3; in some embodiments, R 7 is methyl.

[0063] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or pharmaceutically acceptable salt thereof, wherein two R 7 and the carbon atoms to which they are attached together form a spiro, fused, or bridged ring; in some embodiments, two R 7and together with the carbon atom to which they are attached form a spiro cycloalkyl, fused cycloalkyl, or bridged cycloalkyl; in some embodiments, two R 7 and together with the carbon atom to which they are attached form a spiro cycloalkyl or fused cycloalkyl; said formed ring is optionally substituted with one or more R 03 ; R 03 is as defined in general formula (III).

[0064] In some embodiments of the disclosure, the compound of general formula (III) or (IV) or a pharmaceutically acceptable salt thereof is described, wherein q is 0, 1, or 2; in some embodiments, q is 0.

[0065] In some embodiments of the disclosure, the compound of general formula (III) or (IV) or a pharmaceutically acceptable salt thereof is described, wherein s is 0 or 1; in some embodiments, s is 1; in some embodiments, s is 0.

[0066] In some embodiments of the disclosure, the compound of general formula (III) or (IV) or a pharmaceutically acceptable salt thereof is described, wherein r is 0 or 1; in some embodiments, r is 1; in some embodiments, r is 0.

[0067] In some embodiments of the disclosure, the compound of general formula (I’), (I), and (II) or a pharmaceutically acceptable salt thereof is described, wherein n is 0, 1, or 2; in some embodiments, n is 1.

[0068] In some embodiments of the disclosure, the compound of general formula (III) or a pharmaceutically acceptable salt thereof is described, wherein t is 0.

[0069] In some embodiments of the disclosure, the compound of general formula (III) or a pharmaceutically acceptable salt thereof is described, wherein U is CR 7a , R 7a is as defined in general formula (III); in some embodiments, U is N; in some embodiments, U is CR 7a , R 7a 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, U is CR 7a , R 7a is a C 1-6 alkyl group or a C 1-6 haloalkyl group; in some embodiments, U is CR 7a , R 7a is a methyl group or a CF3 group; in some embodiments, U is C-methyl.

[0070] In some embodiments of the disclosure, the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 7a is selected from the group consisting of hydrogen atom, halogen, 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 7a is selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 7a is hydrogen atom or C 1-6 alkyl; in some embodiments, R 7a is hydrogen atom.

[0071] In some embodiments of the disclosure, the compound of Formula (III) or (IV) or a pharmaceutically acceptable salt thereof, wherein R 7a is selected from the group consisting of halogen, 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 7a is selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 7a is C 1-6 alkyl or C 1-6 haloalkyl; in some embodiments, R 7a is C 1-6 alkyl; in some embodiments, R 7a is methyl or CF3; in some embodiments, R 7a is methyl.

[0072] In some embodiments of the disclosure, the compound of Formula (I’) or a pharmaceutically acceptable salt thereof, wherein G is CR, R is as defined in Formula (I’); in some embodiments, G is C-C(O)NH2.

[0073] In some embodiments of the disclosure, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of cyano, C 1-6 hydroxyalkyl, C(O)NR 11 R 12 , S(O)2NR 11 R 12 , and S(=NR 13 )(O)R 14 , R11 , R 12 , R 13 , and R 14 are as defined in general formula (I); in some embodiments, R is C(O)NR 11 R 12 , R 11 , and R 12 are as defined in general formula (I); in some embodiments, R is C(O)NH2.

[0074] In some embodiments of the disclosure, the compounds of general formulae (I) to (IV), or pharmaceutically acceptable salts thereof, wherein G 1 is N or CR 9 ; in some embodiments, G 1 is CR 9 , R 9 are as defined in general formula (I'); in some embodiments, G 1 is N or CR 9 , R 9 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.

[0075] In some embodiments of the disclosure, the compounds of general formulae (I') and (I), or pharmaceutically acceptable salts thereof, wherein G 2 is N or CR 1 ; in some embodiments, G 2 is CR 1 , R 1 are as defined in general formula (I'); in some embodiments, G 2 is CR 1 , R 1 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.

[0076] In some embodiments of the disclosure, the compounds of general formulae (I') and (I), or pharmaceutically acceptable salts thereof, wherein G 3 is N or CR 2 ; in some embodiments, G 3 is CR 2 , R 2as defined in general formula (I'); in some embodiments, G 3 is CR 2 ; in some embodiments, G 2 is N or CH; in some embodiments, G 1-6 is CH. 1-6 ; in some embodiments, G 3 is N or CH; in some embodiments, G 3 is CH.

[0077] In some embodiments of the disclosure, the compounds of general formula (I) and (I), or pharmaceutically acceptable salts thereof, wherein G 4 is N or CR 3 ; in some embodiments, G 4 is CR 3 ; in some embodiments, G 3 is N or CH; in some embodiments, G 4 is CH. 3 ; in some embodiments, G 3 is N or CH; in some embodiments, G 1-6 is CH. 1-6 ; in some embodiments, G 4 is N or CH; in some embodiments, G 4 is CH.

[0078] In some embodiments of the disclosure, the compounds of general formula (I) to (IV), or pharmaceutically acceptable salts thereof, wherein R 9 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, and a C 1-6 haloalkoxy group; in some embodiments, R 9 is a hydrogen atom.

[0079] In some embodiments of the disclosure, the compounds of general formula (I) to (IV), or pharmaceutically acceptable salts thereof, wherein R 1 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 1-6 haloalkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-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, and a C 1-6 haloalkyl group; in some embodiments, R 1 is a hydrogen atom. 1-6 ; in some embodiments, R 1-6haloalkyl; in some embodiments, R 1 is a hydrogen atom or halo; in some embodiments, R 1 is selected from the group consisting of a hydrogen atom, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 1 is a hydrogen atom or F; in some embodiments, R 1 is a hydrogen atom.

[0080] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or pharmaceutically acceptable salt thereof is one wherein R 2 is selected from the group consisting of a hydrogen atom, halo, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 2 is a hydrogen atom or halo; in some embodiments, R 2 is selected from the group consisting of a hydrogen atom, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 2 is a hydrogen atom.

[0081] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or pharmaceutically acceptable salt thereof is one wherein R 3 is selected from the group consisting of a hydrogen atom, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, each independently optionally substituted with one or more selected from the group consisting of halo, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 3 is selected from the group consisting of a hydrogen atom, halo, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 3 is a hydrogen atom or halo; in some embodiments, R 3 is selected from the group consisting of a hydrogen atom, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 3 is selected from the group consisting of a hydrogen atom, F, and Cl; in some embodiments, R 3 is a hydrogen atom; in some embodiments, R 3 is halo.

[0082] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or pharmaceutically acceptable salt thereof is one wherein R 1 , R 2 , and R 3They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Haloalkoxy; in some embodiments, R 1 R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 1 R 2 and R 3 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 1 R 2 and R 3 They may be the same or different, and each is independently selected from hydrogen, F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R 1 R 2 and R 3 It is a hydrogen atom.

[0083] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (IV) or their pharmaceutically acceptable salts, wherein R 1 R 2 R 3 and R 9 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R 1 R 2 R 3 and R 9 They may be the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 1 R 2 R 3 and R 9 It is a hydrogen atom.

[0084] In some embodiments of this disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3 or 4; in some embodiments, m is 0, 1 or 2; in some embodiments, m is 2; in some embodiments, m is 1; in some embodiments, m is 0.

[0085] In some embodiments of this disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein each R Athe same or different, and each independently selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is independently optionally substituted with one or more of halogen, C 1-6 alkyl, C 1-6 alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl, each of which is independently optionally substituted with one or more of halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; in some embodiments, each R A the same or different, and each independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, each R A the same or different, and each independently selected from the group consisting of F, Cl, methyl, methoxy, CF3, and cyclopropyl; in some embodiments, R A is Cl or methyl.

[0086] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof, wherein each R 01 the same or different, and each independently selected from the group consisting of oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6 alkyl, and 3- to 6-membered cycloalkyl; in some embodiments, each R 01 the same or different, and each independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

[0087] In some embodiments of the disclosure, the compounds of Formula (I)-(IV) or pharmaceutically acceptable salts thereof, wherein each R 02 the same or different, and each independently selected from the group consisting of oxo, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyC 1-6alkyl and 3- to 6-membered cycloalkyl; in some embodiments, each R 02 the same or different, and each independently selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl.

[0088] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein each R 03 the same or different, and each independently selected from the group consisting of oxo, halo, hydroxy, cyano, C 1-6 alkyl and 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 03 the same or different, and each independently selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl.

[0089] In some embodiments of the disclosure, the compound of Formula (I) to (IV) or a pharmaceutically acceptable salt thereof, wherein each R * the same or different, and each independently selected from the group consisting of oxo, halo, hydroxy, cyano, C 1-6 alkyl and 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 * the same or different, and each independently selected from the group consisting of halo, C 1-6 alkyl and C 1-6 haloalkyl.

[0090] 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 the same or different, and each independently selected from the group consisting of a hydrogen atom, C 1-6 alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 11 and R 12 the same or different, and each independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 11 and R 12 the same or different, and each independently a hydrogen atom or methyl; in some embodiments, R 11 and R12 each is a hydrogen atom.

[0091] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 11 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 11 is a hydrogen atom or methyl; in some embodiments, R 11 is a hydrogen atom.

[0092] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 12 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 12 is a hydrogen atom or methyl; in some embodiments, R 12 is a hydrogen atom.

[0093] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 13 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 13 is a hydrogen atom.

[0094] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 14 is selected from a hydrogen atom, C 1-6 alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 14 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 14 is a hydrogen atom or methyl; in some embodiments, R 14 is a hydrogen atom.

[0095] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 30 and R 31 are the same or different, and each is independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 30 and R 31 are the same or different, and each is independently a hydrogen atom or methyl; in some embodiments, R 30 and R 31 are each a hydrogen atom.

[0096] In some embodiments of the disclosure, the compound of Formula (I)-(IV) or a pharmaceutically acceptable salt thereof, wherein R 33is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 33 is a hydrogen atom.

[0097] In some embodiments of the disclosure, the compound of 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.

[0098] In the present disclosure, Formula (I) to (IV) includes Formula (I), (I'), (II), (III), (IV), (IV-1) and (IV-2); Formula (I) to (III) includes Formula (I), (I'), (II) and (III).

[0099] In some embodiments of the disclosure, the compound of Formula (III) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 is a hydrogen atom; G 1 is N or CH; R 1 , R 2 and R 3 are the same or different, and each is independently selected from a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; X 1 is N or CH; R 4 , R 5 and R 6 are the same or different, and each is independently selected from a hydrogen atom, a halogen, C 1-6 alkyl and C 1-6 haloalkyl; U is CR 7a , R 7a is a hydrogen atom or C 1-6 alkyl; q is 0; s is 0 or 1; r is 0 or 1; t is 0 or 1; R 15 and R 16 are the same or different, and each is independently a hydrogen atom or a halogen.

[0100] In some embodiments of the disclosure, the compound of Formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 is a hydrogen atom; G 1 is N or CH; R 1 , R 2 and R 3 are the same or different, and each is independently a hydrogen atom or a halogen; X 1 is N or CH; R 4 , R 5 and R 6They 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 7a C 1-6 Alkyl; q is 0; s is 0 or 1; r is 0 or 1; R 15 and R 16 They may be the same or different, and each is an independent halogen.

[0101] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 For hydrogen atoms; G 1 For N; R 1 R 2 and R 3 For hydrogen atoms; X 1 For N or CH; R 4 C 1-6 Alkyl; R 5 For hydrogen atoms; R 6 It is a halogen; R 7a C 1-6 Alkyl; q = 0; s = 1; r = 0; R 15 and R 16 They may be the same or different, and each is an independent halogen.

[0102] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 For hydrogen atoms; G 1 For N; R 1 R 2 and R 3 For hydrogen atoms; X 1 For CH; R 4 C 1-6 Alkyl; R 5 For hydrogen atoms; R 6 It is a halogen; R 7a C 1-6 Alkyl; q = 0; s = 1; r = 0; R 15 and R 16 They may be the same or different, and each is an independent halogen.

[0103] In some embodiments of this disclosure, the compound represented by general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 For hydrogen atoms; G 1 For N or CH; R 1R 2 and R 3 are hydrogen atoms; X 1 is N or CH; R 4 is methyl; R 5 is hydrogen atom; R 6 is Cl or CF3; R 7a is methyl; q is 0; s is 1; r is 0; R 15 and R 16 are F.

[0104] In some embodiments of the disclosure, the compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are hydrogen atoms; G 1 is N; R 1 is hydrogen atom; R 2 is hydrogen atom; R 3 is hydrogen atom or halogen; X 1 is CH; R 4 is C 1-6 alkyl; R 5 is hydrogen atom; R 6 is halogen; R 7a is C 1-6 alkyl; q is 0; s is 1; r is 0; R 15 and R 16 are the same or different, and each independently halogen.

[0105] In some embodiments of the disclosure, the compound represented by the general formula (IV), (IV-1) or (IV-2) or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are hydrogen atoms; G 1 is N; R 1 is hydrogen atom; R 2 is hydrogen atom; R 3 is halogen; X 1 is CH; R 4 is C 1-6 alkyl; R 5 is hydrogen atom; R 6 is halogen; R 7a is C 1-6 alkyl; q is 0; s is 1; r is 0; R 15 and R 16 are the same or different, and each independently halogen.

[0106] Table A representative compounds of the disclosure include, but are not limited to:

[0107] Another aspect of this disclosure relates to compounds of general formula (I'A) or salts thereof.

[0108] Among them, R W It is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0109] Rings A and R A m, ring B, G to G 4 R B R 7 And n is as defined in the general formula (I').

[0110] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0111] Among them, R W R is a hydrogen atom or a hydroxyl protecting group, and in some embodiments it is a benzyl group; in some embodiments it is a cyano group.

[0112] Ring B, X 1 To X 4 G 1 To G 4 , R, R B R 7 And n is as defined in general formula (I).

[0113] Another aspect of this disclosure relates to compounds of general formulas (IIA) and (IIa) or salts thereof.

[0114] Among them, R W R is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is a benzyl group; in some embodiments, R is a cyano group; X is selected from halogen, boric acid or borate ester group; in some embodiments, X is Br or

[0115] Ring B, R B X 1 G 1 , R, R 1 To R 7 And n is as defined in general formula (II).

[0116] Another aspect of this disclosure relates to compounds of general formulas (IIIA) and (IIIa) or salts thereof.

[0117] Among them, R W It is a hydrogen atom or hydroxyl protecting group, and in some embodiments it is a benzyl group;

[0118] X is selected from halogen, boronic acid or boronic ester group; in some embodiments, X is Br or

[0119] U, X 1 , G 1 , R 1 to R 7 , R 15 , R 16 , q, t, r and s are as defined in general formula (III).

[0120] Another aspect of the present disclosure relates to a compound represented by general formula (IVA), (IV-1A) or (IV-2A), or a salt thereof,

[0121] wherein R W is a hydrogen atom or a hydroxyl protecting group, in some embodiments, a benzyl group;

[0122] G 1 , X 1 , R 1 to R 7 , R 7a , R 15 , R 16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).

[0123] In some embodiments of the present disclosure, R is cyano.

[0124] Table B Exemplary intermediate compounds of the present disclosure, or a salt thereof, include, but are not limited to:

[0125] 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, as described above, the method comprising:

[0126] A compound represented by general formula (I’A), or a salt thereof, is subjected to a hydrolysis reaction to obtain a compound represented by general formula (I’), or a pharmaceutically acceptable salt thereof, wherein

[0127] R W is a hydroxyl protecting group, in some embodiments, a benzyl group;

[0128] Ring A, R A , m, ring B, G to G 4 , R B , R 7 and n are as defined in general formula (I’);

[0129] In some embodiments, G is CR in Formula (I'A) and R is cyano, and G is CR in Formula (I) and R is C(O)NH2.

[0130] Another aspect of the present disclosure relates to a method of preparing a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0131] The compound represented by Formula (IA) or a salt thereof is subjected to a hydrolysis reaction to obtain a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein

[0132] R W is a hydroxyl protecting group, in some embodiments, benzyl;

[0133] ring B, X 1 to X 4 , G 1 to G 4 , R, R B , R 7 and n are as defined in Formula (I);

[0134] In some embodiments, R is cyano in Formula (IA) and R is C(O)NH2in Formula (I);

[0135] In some embodiments, the compound represented by Formula (IA) or a salt thereof, wherein R is cyano, is subjected to a hydrolysis reaction to obtain a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R is C(O)NH2.

[0136] Another aspect of the present disclosure relates to a method of preparing a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0137] The compound represented by Formula (IIA) or a salt thereof is subjected to a hydrolysis reaction to obtain a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof, or R 3 is subjected to a halogenation reaction with a halogenating agent to obtain a compound represented by Formula (II) or a pharmaceutically acceptable salt thereof, wherein R 3 is halogen, wherein

[0138] R W is a hydroxyl protecting group, in some embodiments, benzyl;

[0139] ring B, R B , X 1 , G 1 , R, R 1 to R 7and n is as defined in general formula (II); in some embodiments, R in general formula (IIA) is cyano and R in general formula (II) is C(O)NH2;

[0140] In some embodiments, a compound represented by general formula (IIA) or a salt thereof, wherein R is cyano, is hydrolyzed to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein R is C(O)NH2.

[0141] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0142] hydrolysis of a compound represented by general formula (IIIA) or a salt thereof to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, or R 3 halogenation of a compound represented by general formula (III) or a salt thereof, wherein R 3 is a hydrogen atom, with a halogenating agent to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein R

[0143] R W is a hydroxyl protecting group, in some embodiments, benzyl; R 11 and R 12 is a hydrogen atom;

[0144] U, X 1 , G 1 , R 1 to R 7 , R 15 , R 16 , q, t, r and s are as defined in general formula (III).

[0145] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IV), (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0146] hydrolysis of a compound represented by general formula (IVA) or a salt thereof to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, or R 3 halogenation of a compound represented by general formula (IV) or a salt thereof, wherein R 3 is a hydrogen atom, with a halogenating agent to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof, wherein R

[0147] reaction of a compound represented by general formula (IV-1A) or a salt thereof to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof, or R 3halogenation of a compound represented by General Formula (IV-1) or a salt thereof, wherein R 3 halogenation of a compound represented by General Formula (IV-1) or a salt thereof, wherein R

[0148] hydrolysis of a compound represented by General Formula (IV-2A) or a salt thereof to obtain a compound represented by General Formula (IV-2) or a pharmaceutically acceptable salt thereof, or R 3 halogenation of a compound represented by General Formula (IV-2) or a salt thereof, wherein R 3 halogenation of a compound represented by General Formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R

[0149] R W is a hydroxyl protecting group, in some embodiments, benzyl; R 11 and R 12 is a hydrogen atom;

[0150] G 1 , X 1 , R 1 to R 7 , R 7a , R 15 , R 16 , s, r, and q are as defined in General Formula (IV), (IV-1), or (IV-2).

[0151] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formulae (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof described above, the method comprising:

[0152] resolution of a compound represented by General Formula (IV) or a salt thereof to obtain a compound represented by General Formulae (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, wherein,

[0153] G 1 , X 1 , R 1 to R 7 , R 7a , R 11 , R 12 , R 15 , R 16 , s, r, and q are as defined in General Formula (IV-1) or (IV-2).

[0154] In some embodiments of the disclosure, the halogenating reagent is selected from the group consisting of iodine monomer, Cl2, Br2, hydrohalic acid (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), thionyl chloride, phosphorus pentachloride, phosphorus trihalide (such as phosphorus trichloride), N-bromosuccinimide, N-chlorosuccinimide, and l-chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane ditetrafluoroborate; in some embodiments, the halogenating reagent is N-chlorosuccinimide or l-chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane ditetrafluoroborate.

[0155] Another aspect of the disclosure relates to a pharmaceutical composition comprising a compound 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.

[0156] The 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 Navl.8.

[0157] The 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 Navl.8.

[0158] The 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.

[0159] The disclosure further relates to a method of inhibiting a voltage-gated sodium channel comprising administering to a patient in need thereof a compound of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0160] The disclosure further relates to a method of treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel comprising administering to a patient in need thereof a compound of Formula (I)-(IV) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0161] 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 arrhythmia 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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 a voltage-gated sodium channel; in some embodiments, for use as a medicament for treating and / or preventing a disease or condition mediated by Nav1.8.

[0166] 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 a voltage-gated sodium channel.

[0167] 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 pain and pain-related disorders, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough, or cardiac arrhythmia.

[0168] The disease or condition described in the present disclosure is a disease or condition that is treated and / or prevented by inhibiting a voltage-gated sodium channel.

[0169] In some embodiments, the voltage-gated sodium channel described in the present disclosure is Nav1.8.

[0170] In some embodiments, the disease or disorder mediated by voltage-gated sodium channels described herein 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, idiopathic pain, intestinal pain, idiopathic pain, and visceral pain; in some embodiments, the postoperative pain is selected from bunionectomy pain, hernia repair pain, and abdominal plastic surgery pain.

[0171] In some embodiments, the disease or disorder mediated by voltage-gated sodium channels described herein 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 Limb Pain, Joint Pain, Osteoarthritis and Fibromyalgia, Neuropathic Pain, Diabetic Neuropathic Pain.

[0172] In some embodiments, the pain is selected from diabetic pain, osteoarthritic pain, and acute pain after surgical removal of impacted third molars.

[0173] The active compounds can be prepared in dosage unit form appropriate for the route of administration selected, in some embodiments the active compounds are in unit dosage form, or in a form that the patient can self-administer in a single dose. Expressions of unit dose of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials of solution or suspension, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations.

[0174] As a general guide, suitable unit doses can be 0.1 to 1000 mg.

[0175] The pharmaceutical composition of the present disclosure can contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. in addition to the active compound. Depending on the method of administration, the composition can contain 0.1 to 99% by weight of the active compound.

[0176] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0177] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 1-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof. In certain embodiments, the pharmaceutical composition contains 2-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-substituted version thereof.

[0178] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5-99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1-99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2-98% of a pharmaceutically acceptable excipient.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. This suspension can be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. 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.

[0186] The compounds of the present disclosure can be administered in a form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are

[0187] The dosage of the drug to be administered depends on various factors, as is well known to those skilled in the art, including but not limited to the following: the activity of the particular compound used, the age of the patient, the body weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal therapeutic regime such as the mode of treatment, the daily amount of the compound or the kind of the pharmaceutically acceptable salt can be verified according to the conventional therapeutic regime.

[0188] Terminology

[0189] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0190] The term "alkyl" refers to saturated straight-chain or branched-chain aliphatic hydrocarbon groups having from 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 alkyl group has from 1 to 12 carbon atoms (i.e., C 1-10 In some embodiments, the alkyl group has from 1 to 6 carbon atoms (i.e., C 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, in some embodiments 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.

[0191] 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 1-6Alkylenes. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point. Substituents are selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0192] The term "alkenyl" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C atoms). 2-12 Alkenyl group). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (i.e., C16). 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linker. Substituents are selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0193] The term "alkynyl" refers to an alkyl group in a molecule that contains at least one carbon-carbon triple bond, wherein the alkyl group is defined as described above and has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) carbon atoms (i.e., C64, C74, C84, C9 ... 2-12 (Alynyl group). In some embodiments, the alkynyl group has 2 to 6 carbon atoms (i.e., C12). 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any usable linker. The substituent is selected from one or more of the following: D atom, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0194] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is as 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.

[0195] The term "alkylthio" refers to -S-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methylthio, ethylthio, propylthio, and butylthio, and the like. The alkylthio 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.

[0196] 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.

[0197] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0198] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0199] 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 groups have 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 groups include mono- and polyspirocycloalkyl groups (such as dispirocycloalkyl groups and the like), and in some embodiments, are a monospriocycloalkyl or dispirocycloalkyl group, and in some embodiments, are 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 group. Non-limiting examples include:

[0200] which can be attached at any position;

[0201] and the like.

[0202] The term "fused cycloalkyl" refers to a polycyclic ring system sharing two 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 of heterocyclyl, aryl, or heteroaryl, 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 group 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 group includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), and in some embodiments, is bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, 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 cycloalkyl. Non-limiting examples include:

[0203] which can have the point of attachment at any position; and the like.

[0204] 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 group 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 group includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, is bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0205] which can have the point of attachment at any position.

[0206] 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.

[0207] 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 the group consisting of 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.

[0208] Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, azetidinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl, and the like.

[0209] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0210] 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:

[0211] etc.

[0212] 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:

[0213] etc.

[0214] 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:

[0215] etc.

[0216] Heterocyclyl can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0217] 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 with one or more heterocyclyl or cycloalkyl groups, where 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, which is exemplified by, without limitation:

[0218] etc.

[0219] Aryl can be substituted or unsubstituted, and when substituted can be substituted at any available attachment point with one or more D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0220] The term "heteroaryl" refers to a monocyclic heteroaryl ring (i.e., monocyclic heteroaryl) or a polycyclic heteroaryl ring system (i.e., polycyclic heteroaryl) having a conjugated π-electron system, containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form nitrogen oxides; the sulfur may optionally be oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20 membered heteroaryl). In some embodiments, the heteroaryl group is a heteroaryl group having 5 to 14 ring atoms (i.e., a 5 to 14-membered heteroaryl group), in some embodiments it is a heteroaryl group having 5 to 10 ring atoms (i.e., a 5 to 10-membered heteroaryl group), and in some embodiments it is a heteroaryl group having 5 or 6 ring atoms (i.e., a 5 or 6-membered heteroaryl group).

[0221] Non-limiting examples of the aforementioned monocyclic heteroaryl groups include: furanyl, thiopheneyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazonyl, pyrroleyl, N-alkylpyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, N-alkylpyridone (e.g.) (etc.), pyrazinyl, pyridazinyl, pyridine-1-oxide, etc.

[0222] Non-limiting examples of the polycyclic heteroaryl groups include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, quinazolinyl, benzothiazolyl, carbazole, etc. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more aryl groups, wherein the connecting point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused with one or more cycloalkyl or heterocyclic groups, wherein the connecting point is on the monocyclic heteroaryl ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaryl ring system. Non-limiting examples include:

[0223] wait.

[0224] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is selected from one or more of the following: D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0225] The term "cycloalkyloxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0226] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0227] The term "aryloxy" means -O-aryl, wherein aryl is as defined above.

[0228] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0229] The term "cycloalkylalkyl" means alkyl substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0230] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0231] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0232] The term "heteroarylalkyl" means alkyl substituted by one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

[0233] The term "haloalkyl" means alkyl substituted by one or more halogen, wherein alkyl is as defined above.

[0234] The term "haloalkoxy" means alkoxy substituted by one or more halogen, wherein alkoxy is as defined above.

[0235] The term "hydroxyalkyl" means alkyl substituted by one or more hydroxyl groups, wherein alkyl is as defined above.

[0236] The term "hydroxyalkoxy" means alkoxy substituted by one or more hydroxyl groups, wherein alkoxy is as defined above.

[0237] The term "alkoxyalkyl" means alkyl substituted by 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.

[0238] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0239] The term "hydroxyl" means -OH.

[0240] The term "amino" means -NH2.

[0241] The term "cyano" means -CN.

[0242] The term "nitro" means -NO2.

[0243] The term "oxo" or "oxo group" means "=0".

[0244] The term "carbonyl" means C=0.

[0245] TBS means tert-butyldimethylsilyl group.

[0246] The term "hydroxyl protecting group" means a hydroxyl derivative typically used to block or protect a hydroxyl group while reactions are carried out 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, among others; in some embodiments, benzyl.

[0247] The compounds of the present disclosure can exist in particular stereoisomeric forms. The term "stereoisomers" refers to isomers having the same structure except they have non-identical arrangements of atoms in space. It includes cis- and trans- (or Z- and E-) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomeres, diastereomers, (D)- and (L)- isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure can present additional asymmetric atoms. All such stereoisomers, as well as mixtures thereof, are included in the scope of the present disclosure. The optically active (-)- and (+)- isomers, (R)- and (S)- enantiomeres, and (D)- and (L)- isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or chiral auxiliary, 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 diastereomeric salt with an appropriate optically active acid or base, followed by separation of the diastereomeric salt by conventional means and then recovering the pure enantiomer by conventional means. Additionally, separation of the enantiomers and diastereomers is typically accomplished by chromatography.

[0248] In the chemical structures of the compounds of the present disclosure, the bond indicates unspecified configuration, i.e., if chiral isomers exist in the chemical structure, the bond may be or both configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.

[0249] 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 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.

[0250] 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 the single isomeric form or in mixtures of any proportion of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of a lactam-lactim equilibrium is shown below:

[0251] As when referring to pyrazolyl, it is understood to include either one or a mixture of both tautomers of the following two structures:

[0252] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0253] 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, phosphorus, sulfur, 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.

[0254] 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.

[0255] 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 deuterium of the example compound can have 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.

[0256] “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, “optionally substituted with halo or cyano” means that the C 1-6 “Alkyl” includes instances where alkyl is substituted with halo or cyano and instances where alkyl is not substituted with halo or cyano.

[0257] "Substituted" or "substitution" means that one or more hydrogen atoms, in some embodiments 1, 2, or 3, in some embodiments 1 to 3 hydrogen atoms, independently of one another, are replaced by a corresponding number of substituents. The skilled person is able to determine, without undue effort (by experiment or theory), what substitutions are possible or not possible. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated bond, such as an alkene.

[0258] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or pharmaceutically acceptable salts thereof with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism, to facilitate absorption, and thereby facilitate biological utilization of the active ingredient.

[0259] "Pharmaceutically acceptable salt" means a salt of a compound of the disclosure that is safe and effective for use in a mammal, and that possesses the desired biological activity. The salts can be prepared from the final isolated and purified compound, or by reacting a suitable precursor with the appropriate base or acid. Alkali bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium and potassium hydroxides, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids, as well as organic acids.

[0260] The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0261] As used herein, the singular forms "a", "an" and "the" include plural reference unless the context clearly dictates otherwise.

[0262] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As will be understood by those skilled in the art, numbers are often given only to the nearest whole number for the sake of readability and convenience, not limitation, when the parameter is not critical.

[0263] Synthetic methods for compounds of the disclosure

[0264] To achieve the purposes of the present disclosure, the present disclosure adopts the following technical solutions:

[0265] Scheme One

[0266] The present disclosure provides a method for preparing a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:

[0267] The compound of Formula (I') or a pharmaceutically acceptable salt thereof, is prepared by reacting a compound of Formula (I'A) or a salt thereof, under acidic conditions, wherein

[0268] R W is a hydroxyl protecting group, in some embodiments benzyl;

[0269] G in Formula (I'A) is CR, R is cyano, and G in Formula (I') is CR, R is C(O)NH2;

[0270] ring A, R A , m, ring B, G to G 4 , R B , R 7 and n are as defined in Formula (I').

[0271] Scheme II

[0272] The present disclosure provides a method of preparing a compound of Formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0273] The compound of Formula (I) or a pharmaceutically acceptable salt thereof, is prepared by reacting a compound of Formula (IA) or a salt thereof, under acidic conditions, wherein

[0274] R W is a hydroxyl protecting group, in some embodiments benzyl;

[0275] R in Formula (IA) is cyano, and R in Formula (I) is C(O)NH2;

[0276] ring B, X 1 to X 4 , G 1 to G 4 , R, R B , R 7 and n are as defined in Formula (I).

[0277] Scheme III

[0278] The present disclosure provides a method of preparing a compound of Formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0279] The compound of Formula (II) or a pharmaceutically acceptable salt thereof, is prepared by reacting a compound of Formula (IIA) or a salt thereof, under acidic conditions, wherein

[0280] R W is a hydroxyl protecting group, in some embodiments benzyl;

[0281] R in general formula (IIA) is cyano, and R in general formula (II) is C(O)NH2;

[0282] ring B, R B , X 1 , G 1 , R, R 1 to R 7 and n are as defined in general formula (II).

[0283] Scheme IV

[0284] The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0285] reacting a compound represented by general formula (IIIA) or a salt thereof under acidic conditions to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein

[0286] R W is a hydroxyl protecting group, in some embodiments, benzyl; R 11 and R 12 are hydrogen atoms;

[0287] U, X 1 , G 1 , R 1 to R 7 , R 15 , R 16 , q, t, r and s are as defined in general formula (III).

[0288] Scheme V

[0289] The present disclosure provides a method for preparing a compound represented by general formula (IV), (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0290] reacting a compound represented by general formula (IVA) or a salt thereof under acidic conditions to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0291] reacting a compound represented by general formula (IV-1A) or a salt thereof under acidic conditions to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0292] reacting a compound represented by general formula (IV-2A) or a salt thereof to obtain a compound represented by general formula (IV-2) or a pharmaceutically acceptable salt thereof,

[0293] R W is a hydroxyl protecting group, in some embodiments, benzyl; R 11and R 12 is a hydrogen atom;

[0294] G 1 , X 1 , R 1 to R 7 , R 7a , R 15 , R 16 , s, r and q are as defined in general formula (IV), (IV-1) or (IV-2).

[0295] Scheme five-2

[0296] The present disclosure provides a method for preparing a compound represented by general formula (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0297] chirally resolving a compound represented by general formula (IV) or a salt thereof into a compound represented by general formula (IV-1) and (IV-2) or a pharmaceutically acceptable salt thereof,

[0298] G 1 , X 1 , R 1 to R 7 , R 7a , R 11 , R 12 , R 15 , R 16 , s, r and q are as defined in general formula (IV-1) or (IV-2).

[0299] The reagent providing acidic conditions in the above-mentioned schemes includes, but is not limited to, hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a 1,4-dioxane solution of hydrochloric 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 iron bromide, etc.; in some embodiments, it is trifluoroacetic acid.

[0300] The reaction of the above-mentioned step is optionally carried out in a solvent, and the solvent used includes, but is 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 a mixture thereof. DETAILED DESCRIPTION

[0301] The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0302] EXAMPLES

[0303] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is measured by Bruker AVANCE-400 NMR or Bruker AVANCE NEO 500M, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0304] The determination of MS is measured by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0305] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0306] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0307] High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0308] The determination of chiral HPLC analysis uses Agilent 1260DAD high performance liquid chromatograph.

[0309] High performance liquid preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

[0310] Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.

[0311] CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0312] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) is 0.15mm-0.2mm, the specification of product used in thin layer chromatography separation and purification is 0.4mm-0.5mm.

[0313] Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as carrier.

[0314] Determination of average inhibition rate and IC 50 of kinase uses NovoStar microplate reader (Germany BMG company).

[0315] Known starting materials of the present disclosure can be synthesized according to methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals and the like.

[0316] Unless otherwise specified in the examples, the reactions can be carried out under argon or nitrogen atmosphere.

[0317] Argon or nitrogen atmosphere refers to connecting a reaction bottle to an argon or nitrogen balloon with a volume of about 1L.

[0318] Hydrogen atmosphere refers to connecting a reaction bottle to a hydrogen balloon with a volume of about 1L.

[0319] Packed hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0320] Hydrogenation reaction is usually vacuumed, filled with hydrogen, and repeated 3 times.

[0321] Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

[0322] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0323] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0324] The reaction progress in the examples is monitored by thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system of column chromatography used for purification of compounds and the developing agent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of solvents is adjusted according to the polarity of the compound, and a small amount of triethylamine and acetic acid and other basic or acidic reagents can also be added for adjustment.

[0325] Example 1

[0326] 2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1

[0327] (S)-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1-p1

[0328] (R)-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1-p2

[0329] First step

[0330] 1-bromo-5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylbenzene 1b

[0331] 3-(4-bromo-2-chloro-5-methylphenyl)-3-methylcyclopentan-1-one 1a (300 mg, 994.67 µmol, prepared using the method disclosed in the patent application “WO2023205778” in the description page 375, intermediate B-99) and 2-((difluoromethyl)sulfonyl)pyridine (230 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (9 mL), 1M potassium tert-butoxide solution in tetrahydrofuran (1.5 mL) was added at -40 °C, the temperature was maintained and the reaction was stirred for 3.5 hours, saturated ammonium chloride solution was added to the reaction, it was extracted with ethyl acetate (10 mL x 3), the organic phases were combined and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1b (90 mg, yield: 27%).

[0332] Second step

[0333] 2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1c

[0334] Compound 1b (90 mg, 268.16 μmol), potassium acetate (52.6 mg, 536.32 μmol), bis(pinacolato)diboron (204.3 mg, 804.5 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (21.9 mg, 26.8 μmol) were dissolved in 1,4 dioxane (1 mL), replaced by nitrogen, warmed to 90 °C for 16 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (100 mg, yield: 97.4%).

[0335] Third step

[0336] 4-(benzyloxy)-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2- methylphenyl)-1,6-naphthyridine-5-carbonitrile 1e

[0337] Compound 1c (155.28 mg, 405.78 μmol), 4-(benzyloxy)-2-chloro-1,6-naphthyridine-5- carbonitrile 1d (100 mg, 338.18 μmol, prepared by the method disclosed in the patent application “WO2023205778” in the description page 212, intermediate A-1A), [1,1'-bis(ditert- butylphosphino)ferrocene]palladium(II) dichloride (44 mg, 67.6 μmol), potassium phosphate (149.4 mg, 845.3 μmol) were dissolved in 1,4 dioxane (1 mL), under nitrogen atmosphere, 50 °C for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1e (90 mg, yield: 51.5%).

[0338] MS m / z (ESI): 516.5 [M+1].

[0339] Fourth step

[0340] 2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1

[0341] (S)-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1-p1

[0342] (R)-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-4-oxo-1,4- dihydro-1,6-naphthyridine-5-carboxamide 1-p2

[0343] Compound 1e (90 mg, 174.4 μmol) was dissolved in toluene (3 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at 70 °C for 6 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid 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 give title compound 1 (35 mg, yield: 45.2%).

[0344] MS m / z(ESI):444.3[M+1].

[0345] 1 H NMR (500MHz, DMSO-d6): δ11.99(s,1H),8.50(d,1H),7.53(s,2H),7.46(s,1H),7.44(d,1H),7.31(s,1H),6.13( s,1H),2.97(d,1H),2.67–2.58(m,1H),2.31(s,4H),2.08(q,1H),2.02–1.96(m,1H),1.46(t,1H),1.34(s,3H).

[0346] Compound 1 (50 mg) was resolved by a chiral column (Waters SFC 150, column: 30*250mm, 10μm; Mobile phase A: Supercritical CO2, Mobile phase B: Ethanol (containing 0.1% 7M ammonia methanol solution), Gradient ratio: A:B = 85:15, Flow rate: 140mL / min) to purify and obtain the title compound (15mg, yield: 33.8%).

[0347] Single configuration compound (shorter retention time) (15 mg, yield: 33.8%)

[0348] MS m / z(ESI):444.3[M+1].

[0349] Chiral HPLC analysis: Retention time 5.471 min, purity: 99% (column: 3*100mm, 3μm; Mobile phase A: Supercritical CO2, Mobile phase B: Ethanol (containing 0.1% diethylamine), Gradient ratio: A:B = 85:15, Flow rate: 1.5mL / min).

[0350] 1H NMR (500 MHz, DMSO-d6): δ 12.18 (s, 1H), 8.69 (d, 1H), 7.72 (s, 2H), 7.67 - 7.57 (m, 2H), 7.50 (s, 1H), 6.32 (s, 1H), 3.16 (d, 1H), 2.86 - 2.77 (m, 1H), 2.66 (s, 1H), 2.57 - 2.52 (m, 1H), 2.50 (s, 3H), 2.31 - 2.23 (m, 1H), 2.22 - 2.14 (m, 1H), 1.53 (s, 3H).

[0351] Single configuration compound (longer retention time) (15 mg, yield: 33.8%)

[0352] MS m / z (ESI): 444.3 [M+1].

[0353] Chiral HPLC analysis: Retention time 7.049 min, purity: 96.9% (Chromatography column: Chiralpak IC-3*100 mm, 3 pm; mobile phase A: Supercritical CO2, mobile phase B: Ethanol (containing 0.1% diethylamine), gradient ratio: A:B 85:15, flow rate: 1.5 mL / min). 3*100 mm, 3 pm; mobile phase A: Supercritical CO2, mobile phase B: Ethanol (containing 0.1% diethylamine), gradient ratio: A:B 85:15, flow rate: 1.5 mL / min).

[0354] 1 H NMR (500 MHz, DMSO-d6): δ 11.99 (s, 1H), 8.50 (d, 1H), 7.52 (s, 2H), 7.48 - 7.41 (m, 2H), 7.31 (s, 1H), 6.12 (s, 1H), 2.96 (d, 1H), 2.68 - 2.57 (m, 1H), 2.45 (d, 1H), 2.37 - 2.32 (m, 1H), 2.30 (s, 3H), 2.13 - 2.06 (m, 1H), 2.05 - 1.89 (m, 1H), 1.33 (s, 3H).

[0355] Example 2-1

[0356] (S)-3-chloro-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2- methylphenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2-1 or

[0357] (R)-3-chloro-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2- methylphenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2-2

[0358] Compound 1-p1, 1-p2 with shorter retention time (50 mg, 112.6 μmol) was dissolved in N,N-dimethylformamide (5 mL), acetic acid (15 mg, 249.8 μmol) and N-chlorosuccinimide (30 mg, 224.6636 μmol) were added, the reaction was stirred for 48 hours, a few drops of methanol were added to the reaction solution, and purified by high performance liquid chromatography preparation (Waters-2545, chromatographic 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 (22 mg, yield: 40.8%).

[0359] MS m / z (ESI): 478.1 [M+1].

[0360] 1 H NMR (500 MHz, DMSO-d6): δ 12.53 (s, 1H), 8.52 (d, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.44 (d, 1H), 7.37 (s, 1H), 3.00-2.92 (m, 1H), 2.65-2.58 (m, 1H), 2.50-2.41 (m, 2H), 2.39-2.30 (m, 1H), 2.18 (s, 3H), 2.11-2.04 (m, 1H), 1.33 (s, 3H).

[0361] Example 2-2

[0362] (R)-3-chloro-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2- methylphenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2-2 or

[0363] (S)-3-chloro-2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2- methylphenyl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 2-1

[0364] The longer retention time (600 mg, 1.35 mmol) of compound 1-p1, 1-p2 was dissolved in N, N-dimethylformamide (60 mL), acetic acid (363 mg, 6.04 mmol) and N-chlorosuccinimide (271 mg, 2.03 mmol) 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 combined organic phase was concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5um; mobile phase: water phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-60%, flow rate: 30 mL / min) to obtain the title compound (340 mg, yield: 52.5%).

[0365] MS m / z (ESI): 478.1 [M+1].

[0366] 1 H NMR (500 MHz, DMSO-d6): δ 12.53 (s, 1H), 8.52 (d, 1H), 7.57 (s, 1H), 7.54 (s, 1H), 7.48 (s, 1H), 7.44 (d, 1H), 7.37 (s, 1H), 3.00-2.92 (m, 1H), 2.65-2.58 (m, 1H), 2.50-2.41 (m, 2H), 2.39-2.30 (m, 1H), 2.18 (s, 3H), 2.11-2.04 (m, 1H), 1.33 (s, 3H).

[0367] Example 3

[0368] 2-(5-chloro-4-(3-(difluoromethyl)-1-methylcyclopentyl)-2-methylphenyl)-3-fluoro-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide 3

[0369] Compound 1 (30 mg, 67.6 μmol) was dissolved in acetonitrile (9 mL), 1-chloromethyl-4-fluoro-1,4-diazidobicyclo[2.2.2]octane bis-tetrafluoroborate (26 mg, 73.4 μmol) was added, replaced by nitrogen, and the reaction was stirred for 16 hours. Water was added to the reaction solution, and the organic phase was extracted with ethyl acetate (5 mL x 3), combined, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Waters-2545, column: Welch Xtimate C18, 30*150mm, 5μm; mobile phase: water 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: 12.8%).

[0370] MS m / z (ESI): 462.1 [M+1].

[0371] 1 H NMR (500 MHz, DMSO-d6): δ 12.27 (s, 1H), 8.49 (d, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.49 (s, 1H), 7.45 (d, 1H), 7.38 (s, 1H), 2.97 (d, 1H), 2.67-2.59 (m, 1H), 2.50-2.42 (m, 2H), 2.38-2.31 (m, 1H), 2.24 (s, 3H), 2.12-2.05 (m, 1H), 1.34 (s, 3H).

[0372] Example 4 (control)

[0373] Compounds 4-1 and 4-2 were prepared as control compounds according to WO2023205778A1 Examples 4 and 84.

[0374] Biological evaluation

[0375] Test Example 1, determination of the Nav1.8 inhibitory activity of the compounds of the present disclosure

[0376] 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 is compared, and the effect of the compound on the Nav1.8 ion channel can be obtained.

[0377] 1Experimental materials and instruments

[0378] 1) Patch clamp: patch clamp PC-505B (WARNER instruments)

[0379] 2) Digital to analog converter: Digidata 1440A (Axon instruments)

[0380] 3) Micro manipulator: MP-225 (SUTTER instrument)

[0381] 4) Inverted microscope: TL4 (Olympus)

[0382] 5) Glass microelectrode puller: PC-10 (NARISHIGE)

[0383] 6) Microelectrode glass capillary: B12024F (Wuhan Micro Probe Scientific Instrument Co., Ltd.)

[0384] 7) Dimethyl sulfoxide (DMSO) (Sigma-Aldrich, D2650)

[0385] 8) TTX (Affix Scientific, AF3014)

[0386] 2 Experimental procedures

[0387] 2.1 Compound preparation

[0388] The compounds used to prepare the intracellular and extracellular solutions were purchased from Sigma, except for NaOH and KOH used for acid-base titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (titrated with NaOH). The intracellular solution (mM) was: aspartic acid, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (titrated with CsOH). All test compound solutions contained 1 μM TTX.

[0389] The test compounds were stored at a concentration of 9 mM in dimethyl sulfoxide (DMSO). On the day of testing, they were dissolved in extracellular solution to the desired concentration.

[0390] 2.2 Manual patch clamp test procedure

[0391] 1) After the compounds were prepared into solutions of the specified concentrations, the drug solutions were added to the respective channels in order of concentration from low to high, and each channel was labeled.

[0392] 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 ruptures and an electrical current path is formed.

[0393] 3) After the membrane of the cell is ruptured and the current is stable, perfusion is performed in different concentrations in sequence. If the current is stable for at least one minute, the next concentration can be used for perfusion. The perfusion time of each concentration is not more than five minutes.

[0394] 4) The perfusion chamber is washed. The drug solution is washed in sequence from high to low concentration, and each concentration of drug solution is washed for 20 s. Finally, the extracellular solution is washed for 1 min.

[0395] 2.3 Test voltage equation

[0396] 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 inhibition is calculated.

[0397] 3. Data analysis

[0398] The data will be stored in a computer system for analysis. Data collection and analysis use pCLAMP 10 (Molecular Devices, Union City, CA).

[0399] 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.

[0400] Table 1, IC 50

[0401] Conclusion: The compounds in the present disclosure have obvious inhibitory effect on Nav1.8 channel activity.

[0402] Test Example 2, Rat Pharmacokinetic Evaluation

[0403] 1, Abstract

[0404] SD rats were used as test animals, and LC-MS / MS method was used to determine the drug concentration in the plasma of rats at different time points after i.g. administration of the compound of the example, to study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

[0405] 2, Test Scheme

[0406] 2.1, Test drug

[0407] Compound 2-1 and 2-2.

[0408] 2.2, Test animals

[0409] Eight rats were provided by Vantianlihua Experimental Animal Technology Co., Ltd. with production license SCXK (Jing) 2021-0006.

[0410] 2.3, Drug preparation

[0411] A certain amount of 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.

[0412] 2.4, Drug administration

[0413] Dose: 2.0 mg / kg, volume: 10 mL / kg.

[0414] 3, Operation

[0415] Before and after administration, 0.2 mL of blood was taken from the orbit, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 2 minutes (4°C), and the plasma was separated within 1 hour and stored at -20°C or -80°C for testing. The blood collection to centrifugation process was operated under ice bath conditions.

[0416] Determination of the content of the test compound in the plasma of rats after administration: 50 μL of rat plasma sample at each time point after administration was taken, 450 μL of acetonitrile and 25 μL of camptothecin, tolbutamide were added, vortex mixed for 5 min, and centrifuged at 3700 rpm for 10 min. The supernatant was analyzed by LC-MS / MS.

[0417] 4, Pharmacokinetic parameter results

[0418] Table 2, Pharmacokinetic parameters of the compound of the present disclosure in rats

[0419] Conclusion: The compound of the present disclosure has high blood drug concentration and high exposure in rats, and has pharmacokinetic advantages.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: ###00001### (I) wherein: Ring A is aryl or heteroaryl; Ring B is cycloalkyl or heterocyclyl; R B R 15 R 16 ; 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 11 R 12 , C(O)NR 11 R 12 , C(O)R 14 , OR 14 , 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 01 ; G is selected from N, N + O - and CR; G 1 selected from N, N + O - and CR 9 ; G 2 selected from N, N + O - and CR 1 ; G 3 selected from N, N + O - and CR 2 ; G 4 selected from N, N + O - and CR 3 ; R, R 1 , R 2 , R 3 and R 9 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 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , OR 14 , C(=S)NR 11 R 12 , Si(alkyl)3, 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 A 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 , S(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 , OR 14 , Si(alkyl)3, 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 02 ; each R 7 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 NR 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , Si(alkyl)3, 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 03 ; or, two R 7 and the atom to which they are attached together form a cycloalkyl or heterocyclyl, each of which is independently optionally substituted with one or more R 03 ; each R 01 , 02 and R 03 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 , S(O) v R 14 , S(O) v OR 14 , S(O) v NR 11 R 12 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , OR 14 , =CR 15 R 16 , =NR 13 , S(=NR 13 )(O)R 14 , Si(alkyl)3, 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 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, a NR 30 R 31 , a C(O)NR 30 R 31 , a C(O)R 33 , an OR 33 , a 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 group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, cycloalkylalkyl group, heterocyclylalkyl group, arylalkyl group, and heteroarylalkyl group is independently optionally substituted with one or more R * ; or R 11 , R 12 and the nitrogen atom to which they are attached together form a heterocyclyl group, said heterocyclyl group is optionally substituted with one or more R * ; each R * the same or different, and each independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, alkylthio, 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 , Si(alkyl)3, 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, an alkylthio 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; n 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.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof: ###00002### (I) wherein, X 1 is N or CR 8 ; X 2 is N or CR 4 ; X 3 is N or CR 5 ; X 4 is N or CR 6 ; R 4 R 5 R 6 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, 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 , C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , OR 14 , Si(alkyl)3, 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 02 ; or R 5 , R 6 and the carbon atom to which they are attached together form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R A ; Ring B, G 1 to G 4 , R, R B , R 7 , n, R 11 to R 14 , R 02 , R A and v are as defined in claim 1.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III) or a pharmaceutically acceptable salt thereof: ###00003### (III) wherein: U is N or CR 7a , R 7a is a hydrogen atom or R 7 ; s is 0, 1 or 2; r is 0, 1 or 2; t is 0 or 1; q is 0, 1, 2, 3 or 4; G 1 , X 1 , R 1 to R 7 , R 11 , R 12 , R 15 and R 16 are as defined in claim 2.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 15 and R 16 are the same or different and each independently a hydrogen atom or a halogen; preferably, R 15 and R 16 are the same or different and each independently a halogen.

5. The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 and R 8 are the same or different and each is independently selected from 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 and a 3- to 6-membered cycloalkyl group; preferably, R 4 , R 5 , R 6 and R 8 are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein G 1 is N or CH.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 and R 3 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 and a C 1-6 haloalkyl group; preferably, R 1 , R 2 and R 3 are the same or different and each is independently a hydrogen atom or a halogen.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, 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; preferably, R 11 and R 12 are hydrogen atoms.

9. A compound according to any one of claims 3 to 8, or a pharmaceutically acceptable salt thereof, wherein R 7a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; preferably, R 7a is a C 1-6 alkyl group.

10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

11. A compound of the formula (IA) or a salt thereof: ###00006### (IA) wherein, R W is a hydrogen atom or a hydroxyl protecting group, preferably a benzyl group; ring B, X 1 to X 4 , G 1 to G 4 , R, R B , R 7 and n are as defined in claim 2; R is preferably cyano.

12. A compound or salt thereof selected from the following compounds:

13. A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: The compound represented by General Formula (IIIA) or a salt thereof is subjected to a hydrolysis reaction to obtain a compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof, or R 3 The compound represented by General Formula (III) or a salt thereof, wherein R is hydrogen, is subjected to a halogenation reaction with a halogenating agent to obtain a compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof, wherein R is halogen. 3 The compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof, wherein R is halogen, is subjected to a reaction with a compound represented by General Formula (IV) or a salt thereof to obtain a compound represented by General Formula (I) or a pharmaceutically acceptable salt thereof. R W is a hydroxyl protecting group, preferably benzyl; R 11 and R 12 is a hydrogen atom; U, X 1 , G 1 , R 1 to R 7 , R 15 , R 16 , q, t, r and s are as defined in claim 3.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

15. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channels are Navl.

8.

16. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, 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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