Aromatic ring compound, preparation method therefor, and use thereof in medicine

Abstract

The present disclosure relates to an aromatic ring compound, a preparation method therefor, and a use thereof in medicine. Specifically, the present disclosure relates to an aromatic ring compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a therapeutic agent, particularly a use as a Nav inhibitor, and a use thereof in the preparation of a medicament for treating and / or alleviating pain and pain-related disorders. The groups in general formula (I) are as defined in the description.

Description

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

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

[0002] Pain is a complex 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 experience." Pain can serve as a warning signal to alert the body to potential danger, and has an indispensable protective effect on normal life activities. At the same time, pain is also a common clinical symptom. Intense or persistent pain after the disappearance of the external stimulus that triggers pain can cause physiological dysfunction and seriously affect the quality of life of living beings. Statistical data shows that about one-fifth of the world's population suffers from moderate to severe chronic pain.

[0003] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings that are widely distributed in the skin, muscles, joints and internal organs of the whole body, and can convert the heat, mechanical or chemical stimuli they feel into nerve impulses (action potentials) and transmit them to their cell body parts located in the dorsal root ganglia (DRG) via afferent nerve fibers, and ultimately to high-level neural centers, causing pain. The generation and conduction of action potentials in neurons, in turn, depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel is opened, and the inward flow of sodium ions causes the cell membrane to be further depolarized, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

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

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

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

[0007] Patent applications of disclosed Nav1.8 inhibitor compounds include WO2024032774A1, WO2023211990A1, WO2023150201A2, WO2020092667A1, CN116947713A, WO2022121805A1, CN114591293A, and WO2022192487A2, 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 selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0011] Ring B is cycloalkyl or heterocyclyl;

[0012] R B is =CR 15 R 16 ;

[0013] R A is selected from S(O)(NR 4 )R 3 , S(O) v R 3 , C(O)R 3 , C(O)NR 4 R 5 , and a hydrogen atom;

[0014] R 15 and R 16 are the same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyl group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, NR 20 R 21 , C(O)NR 20 R 21 , C(O)R 23 , OR 23 , S(O) v R 23Cycloalkyl, heterocyclic, aryl, and heteroaryl; each of the alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more R * Replaced; or R 15 R 16 Together with the carbon atom attached thereto, they form a cycloalkyl or heterocyclic group, each of which is independently and optionally converted by one or more R... * Replaced;

[0015] R 3 R 4 and R 5 The same or different, and each independently selected from hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 20 R 21 C(O)NR 20 R 21 NR 22 C(O)R 23 C(O)R 23 C(O)OR 23 OC(O)R 23 S(O) v R 23 S(O) v OR 23 OS(O) v R 23 S(O) v NR 20 R 21 OR 23 Cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, alkoxy, alkenyl, alkoxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally converted by one or more R 01 Replaced;

[0016] R a Selected from hydrogen atoms, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, hydroxyl groups, hydroxyalkyl groups, alkoxyalkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, and heterocyclic groups;

[0017] Each R 1 Same or different, and each independently selected from oxo, =S, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 、(CR aa Rbb x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 02

[0018] each R 2 ​​the same or different, and each independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 , (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 02 substituents;

[0019] X 1 is selected from N, N + O - and CR X1 ;

[0020] X 2 is selected from N, N + O - and CR X2 ;

[0021] X 3 is selected from N, N + O - and CR X3 ;

[0022] X 4 is selected from N, N + O - and CR X4 ;

[0023] R X1 , R X2 , R X3 and R X4 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, (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , OS(O) v R 14 , (CR aa R bb ) x C(=NR13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 03 ;

[0024] or, R X1 , R X2 and the carbon atom to which they are attached, or R X2 , R X3 and the carbon atom to which they are attached, or R X3 , R X4 and the carbon atom to which they are attached, form a ring C, which is optionally substituted with one or more R C ;

[0025] ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0026] each R 01 , R 02 , R 03 and R C is the same or different and each is independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, (CR aa R bb ) x NR 11 R 12 , (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14, OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl is independently optionally substituted with one or more R * ;

[0027] each R 20 , R 21 , R 22 , R 23 , R 11 , R 12 , R 13 and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , alkyleneNR 30 R 31 , alkyleneC(O)NR 30 R31 , NR 32 C(O)R 33 , C(O)R 33 , C(O)OR 33 , OR 33 , S(O) v R 33 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is independently optionally substituted with one or more R * ;

[0028] each R aa and R bb is 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, amino, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0029] 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, 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 , S(O) v R 33 , S(O) v OR 33 , S(O) v NR 30 R 31 , C(=NR 32 )R 33 , S(=NR 32 )R 33 , S(=NR 32 )(O)R 33 , P(O)R 30 R 31 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl;

[0030] each R 30 , R 31 , R 32 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 alkenyl group, an alkynyl group, 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; or R 30 , R 31 and the nitrogen atom to which they are attached together form a heterocyclyl group, which is optionally substituted with one or more selected from the group consisting of oxo, halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, and an alkoxyalkyl group;

[0031] m is 0, 1, 2, 3, 4, 5, or 6; n is 0, 1, 2, 3, 4, 5, or 6;

[0032] each v is the same or different and each is independently 0, 1, or 2;

[0033] and x is 0, 1, 2, 3, or 4.

[0034] In some embodiments of the present disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (II) or a pharmaceutically acceptable salt thereof:

[0035] wherein Q is selected from N, N + -O - and CR 1a ;

[0036] R 1a is a hydrogen atom or R 1 ; p is 0, 1, 2, or 3;

[0037] Ring B, R B , X 1 , R X2 , R X3 , R X4 , R 1 to R 4 and n are as defined in Formula (I).

[0038] In some embodiments of the present disclosure, the compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof is a compound of Formula (III), (IV), or (V) or a pharmaceutically acceptable salt thereof:

[0039] wherein R 1b and R 1c are the same or different and each is independently a hydrogen atom or R1 ;

[0040] U is CR 2a or N; R 2a is a hydrogen atom or R 2 ;

[0041] q is 0, 1, 2, 3 or 4; r is 0, 1 or 2, s is 0, 1 or 2;

[0042] r1is 0, 1 or 2, s1is 0, 1 or 2, r2is 0, 1 or 2, s2is 0, 1 or 2;

[0043] t is 0, 1, 2 or 3, t1is 1 or 2; t2is 0, 1, 2 or 3, t3is 1 or 2;

[0044] X 1 , R X2 , R X3 , R X4 , Q, R 1 to R 4 , R 15 and R 16 are as defined in general formula (II).

[0045] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III-1), (IV-1) or (V-1) or a pharmaceutically acceptable salt thereof:

[0046] wherein u is 0, 1, 2, 3, 4, 5 or 6;

[0047] ring C, X 1 , R C , R X4 , Q, R 1b , R 1c , R 3 , R 4 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2and t3are as defined in general formula (III), (IV) or (V).

[0048] In some embodiments of the disclosure, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein ring A is phenyl or 5- to 10-membered heteroaryl; in some embodiments, ring A is phenyl or 5- or 6-membered heteroaryl; in some embodiments, ring A is phenyl or 6-membered heteroaryl; in some embodiments, ring A is selected from pyridyl, pyridine-1-oxide, phenyl, pyridinone, pyrimidinyl, pyrazinyl, and pyridazinyl; in some embodiments, ring A is selected from phenyl, pyridyl, and pyridine-1-oxide; in some embodiments, ring A is phenyl or pyridyl; in some embodiments, ring A is selected from phenyl, In some embodiments, ring A is selected from phenyl, In some embodiments, ring A is phenyl; in some embodiments, ring A is pyridyl; in some embodiments, ring A is selected from

[0049] In some embodiments, ring A is selected from In some embodiments, ring A is wherein the * terminus is attached to NR a , the * terminus is attached to R A .

[0050] In some embodiments of the disclosure, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein R A is S(O)(NR 4 )R 3 ; in some embodiments, R A is selected from In some embodiments, R A is In some embodiments, R A is R 3 and R 4 are as defined in Formula (I).

[0051] In some embodiments of the disclosure, the compound of Formula (I) or pharmaceutically acceptable salt thereof, wherein is selected from In some embodiments, is In some embodiments is In some embodiments is Q, R 1 , R 3 , R 4 , and p are as defined in Formula (II); in some embodiments are Q, R 1bR 1c R 3 R 4 as defined in general formula (III).

[0052] In some embodiments of the disclosure, the compound of general formula (I) to (V-1) or a pharmaceutically acceptable salt thereof, wherein is In some embodiments, is In some embodiments, is R 3 R 4 as defined in general formula (I).

[0053] In some embodiments of the disclosure, the compound of general formula (II) to (V-1) or a pharmaceutically acceptable salt thereof, wherein Q is selected from N, N + -O - and CR 1a , R 1a is a hydrogen atom or a halogen; in some embodiments, Q is selected from N, N + -O - , CF and CH; in some embodiments, Q is selected from N, N + -O - and CH; in some embodiments, Q is N or CR 1a , R 1a as defined in general formula (I); in some embodiments, Q is N or CR 1a , R 1a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; in some embodiments, Q is N or CH; in some embodiments, Q is N; in some embodiments, Q is CH.

[0054] In some embodiments of the disclosure, the compound of general formula (I) to (V-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different, and each is independently selected from a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, a 3- to 6-membered cycloalkyl group and a 3- to 6-membered heterocyclyl group; in some embodiments, each R 1 is the same or different, and each is independently selected from a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group.

[0055] In some embodiments of the disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, and 3- to 6-membered cycloalkyl, and / or m is 0, 1, or 2; in some embodiments, each R 1 are the same or different and each is independently halogen, and / or m is 0, 1, or 2.

[0056] In some embodiments of the disclosure, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2; in some embodiments, m is 0 or 1; in some embodiments, m is 0.

[0057] In some embodiments of the disclosure, the compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and each is independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy, and / or p is 0 or 1.

[0058] In some embodiments of the disclosure, the compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2; in some embodiments, p is 0 or 1; in some embodiments, p is 0.

[0059] In some embodiments of the disclosure, the compound of Formula (III) to (V-1) or a pharmaceutically acceptable salt thereof, wherein R 1a is selected from hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclyl; in some embodiments, R 1a is selected from hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R 1a is hydrogen atom or halogen; in some embodiments, R 1a is hydrogen atom.

[0060] In some embodiments of the disclosure, the compound represented by the general formula (III) to (V-1) or a pharmaceutically acceptable salt thereof, wherein R 1b 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 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group; in some embodiments, R 1b 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 1b is a hydrogen atom or a halogen; in some embodiments, R 1b is a hydrogen atom.

[0061] In some embodiments of the disclosure, the compound represented by the general formula (III) to (V-1) or a pharmaceutically acceptable salt thereof, wherein R 1c 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 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group; in some embodiments, R 1c 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 1c is a hydrogen atom or a halogen; in some embodiments, R 1c is a hydrogen atom.

[0062] In some embodiments of the disclosure, the compound represented by the general formula (III) to (V-1) or a pharmaceutically acceptable salt thereof, wherein R 1b and R 1c 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; in some embodiments, R 1b and R 1c are the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 1b and R 1c are both hydrogen atoms.

[0063] In some embodiments of the disclosure, the compound represented by the general formula (I) to (V-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N or CR X1 , RX1 selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 1 is CR X1 , R X1 is as defined in general formula (I); in some embodiments, X 1 is N or CH; in some embodiments, X 1 is N.

[0064] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 2 is N or CR X2 , R X2 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 2 is CR X2 , R X2 is as defined in general formula (I); in some embodiments, X 2 is CH or C-methyl.

[0065] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 3 is N or CR X3 , R X3 is selected from hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 haloalkoxy; in some embodiments, X 3 is CR X3 , R X3 is as defined in general formula (I); in some embodiments, X 3 is selected from N, CH, C-Cl and C-CF3; in some embodiments, X 3 is C-Cl or C-CF3.

[0066] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 4 is N or CR X4 , R X4 is selected from hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, X 4 is N or CH; in some embodiments, X 4 is CR X4 , R X4as defined in general formula (I); in some embodiments, X 4 is CH.

[0067] In some embodiments of the disclosure, the compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein X 1 is N, X 2 is N or CR X2 , X 3 is CR X3 , X 4 is CR X4 , or X 1 is N, X 2 is CR X2 , X 3 is N, X 4 is CR X4 , or X 1 is CR X1 , X 2 is CR X2 , X 3 is N or CR X3 , X 4 is N or CR X4 ; in some embodiments, X 1 is N, X 2 is N or CR X2 , X 3 is CR X3 , X 4 is CR X4 , or X 1 is N, X 2 is CR X2 , X 3 is N or CR X3 , X 4 is CR X4 ; in some embodiments, X 1 is N, X 2 is N or CR X2 , X 3 is CR X3 , X 4 is CR X4 ; in some embodiments, X 1 is N, X 2 is CR X2 , X 3 is CR X3 , X 4 is CR X4 ; R X1 , R X2 , R X3 and R X4 are as defined in general formula (I); in some embodiments, X1 N, X 2 CR X2 , X 3 CR X3 , X 4 CR X4 , R X2 , R X3 and R X4 are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a C 1-6 haloalkoxy group, or R X2 , R X3 and the carbon atom to which they are attached form a heterocyclyl group; in some embodiments, X 1 is N, X 2 is CR X2 , X 3 is CR X3 , X 4 is CR X4 , R X2 , R X3 and R X4 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.

[0068] In some embodiments of the disclosure, the compounds of Formula (I) to (V-1) or pharmaceutically acceptable salts thereof are described, wherein R X1 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group; in some embodiments, R X1 is selected from the group consisting of a hydrogen atom, a halogen, and a C 1-6 alkyl group.

[0069] In some embodiments of the disclosure, the compounds of Formula (I) to (V-1) or pharmaceutically acceptable salts thereof are described, wherein R X2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a 3- to 6-membered cycloalkyl group, and a 3- to 6-membered heterocyclyl group; in some embodiments, R X2 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 X2 is a hydrogen atom or a C 1-6 alkyl group; in some embodiments, R X2is a hydrogen atom or a methyl group; in some embodiments, R X2 is a hydrogen atom; in some embodiments, R X2 is a methyl group; in some embodiments, R X2 is selected from the group consisting of a hydrogen atom, F, Cl, a methyl group, CF3, and a cyclopropyl group.

[0070] In some embodiments of the present disclosure, the compounds of Formula (I) to (V-1) or pharmaceutically acceptable salts thereof, wherein R X3 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 C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, a phenyl group, and a 5- or 6-membered heteroaryl group; in some embodiments, R X3 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; in some embodiments, R X3 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, and a C 1-6 haloalkoxy group; in some embodiments, R X3 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 X3 is a halogen or a C 1-6 haloalkyl group; in some embodiments, R X3 is Cl or CF3; in some embodiments, R X3 is Cl; in some embodiments, R X3 is CF3; in some embodiments, R X3 is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R X3 is selected from the group consisting of a hydrogen atom, F, Cl, a methyl group, CF3, and a cyclopropyl group; in some embodiments, R X3 is a 3- to 6-membered cycloalkyl group; in some embodiments, R X3 is a cyclopropyl group.

[0071] In some embodiments of the disclosure, the compound of Formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) or (I-1) wherein R X4 is selected from the group consisting of 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 X4 is selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R X4 is hydrogen atom or C 1-6 alkyl; in some embodiments, R X4 is hydrogen atom; in some embodiments, R X4 is C 1-6 alkyl; in some embodiments, R X4 is methyl; in some embodiments, R X4 is hydrogen atom or methyl; in some embodiments, R X4 is selected from the group consisting of hydrogen atom, F, Cl, methyl, CF3, and cyclopropyl.

[0072] In some embodiments of the disclosure, the compound of Formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) or (I-1) wherein R X2 , R X3 , and R X4 are the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl, each of which is independently optionally substituted with one or more R 2-6 ; in some embodiments, R 2-6 , R 2-6 , and R 03 together with the carbon atom to which they are attached form a 5- or 6-membered cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted with one or more R X2 ; in some embodiments, R X3 is selected from the group consisting of hydrogen atom, halogen, cyano, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R

[0073] In some implementation schemes, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 2-6 rare radical, C 2-6 Alkyne, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl, wherein C 2-6 rare radical, C 2-6 The alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, phenyl, and 5- or 6-membered heteroaryl groups are each independently and optionally influenced by one or more R groups. 03 Replaced by, R 03 As defined in general formula (I); in some implementations, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, cyano groups, and C atoms. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclic groups; in some embodiments, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, or R X2 R X3 Together with the carbon atom attached thereto, they form a 5- or 6-membered cycloalkyl or phenyl group, wherein the 5- or 6-membered cycloalkyl and phenyl groups are each independently and optionally selected from halogens, C... 1-6 Alkyl and C 1-6 One or more of the haloalkyl groups are substituted; in some embodiments, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; in some embodiments, R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen, F, Cl, methyl, CF3, and cyclopropyl; in some embodiments, R X2 R X3 and R X4the same or different and each independently selected from the group consisting of a hydrogen atom, F, CI, methyl and CF3.

[0074] In some embodiments of the disclosure, the compound of Formula (I), (II), (III-1), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocyclyl, phenyl or a 5- or 6-membered heteroaryl; in some embodiments, ring C is a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclyl; in some embodiments, ring C is a 3- to 10-membered heterocyclyl; in some embodiments, ring C is a 7- to 10-membered heterocyclyl; in some embodiments, ring C is selected from a 5- or 6-membered cycloalkyl, phenyl and a 6-membered heteroaryl; in some embodiments, ring C is a 5- or 6-membered cycloalkyl or phenyl; in some embodiments, ring C is a 3- to 10-membered cycloalkyl; in some embodiments, ring C is a 5- or 6-membered cycloalkyl; in some embodiments, ring C is a cyclohexyl or phenyl; in some embodiments, ring C is a cyclohexyl; in some embodiments, ring C is phenyl.

[0075] In some embodiments of the disclosure, the compound of Formula (I), (II), (III-1), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a 5- or 6-membered cycloalkyl, phenyl and a 6-membered heteroaryl, and / or each R C the same or different and each independently selected from the group consisting of a hydrogen atom, F, CI, methyl and CF3. 1-6 alkyl and C 1-6 haloalkyl, and / or u is 0, 1 or 2; in some embodiments, ring C is a cyclohexyl or phenyl, and / or each R C the same or different and each independently is halogen, and / or u is 0, 1 or 2.

[0076] In some embodiments of the disclosure, the compound of Formula (I), (II), (III-1), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein is selected from cyclohexyl,

[0077] In some embodiments of the disclosure, the compound of Formula (I), (II), (III-1), (IV-1), (V-1) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 12-membered heterocyclyl; in some embodiments, ring B is a nitrogen-containing heterocyclyl; in some embodiments, ring B is a 3- to 12-membered nitrogen-containing heterocyclyl; in some embodiments, ring B is a 3- to 10-membered nitrogen-containing heterocyclyl, and the nitrogen is a point of attachment to X 1 ; in some embodiments, ring B is selected from In some embodiments, ring B is selected from and X 1is connected to the ring, and the *-end is connected to R B is connected to the ring, and the *-end is connected to R

[0078] In some embodiments of the disclosure, the compound of Formula (I), (II), or a pharmaceutically acceptable salt thereof, is: is selected from U, R 2 , q, R 15 , R 16 , r, s, r1, s1, r2, s2, t, t1, t2, and t3 are as defined in Formula (III), (IV), or (V); in some embodiments, is U, R 2 , q, R 15 , R 16 , r, and s are as defined in Formula (III); in some embodiments, is In some embodiments, is U, R 2 , q, R 15 , R 16 , r1, s1, r2, and s2 are as defined in Formula (IV); in some embodiments, is U, R 2 , q, R 15 , R 16 , t, t1, t2, and t3 are as defined in Formula (V).

[0079] In some embodiments of the disclosure, the compound of Formula (IV), (IV-1), or a pharmaceutically acceptable salt thereof, is: is q1 is 0, 1, 2, 3, or 4, U, R 2 , R 15 , R 16 , r1, s1, r2, and s2 are as defined in Formula (IV).

[0080] In some embodiments of the disclosure, the compound of Formula (I) to (V-1), or a pharmaceutically acceptable salt thereof, is: 15 and R 16 are the same or different, and each is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group; in some embodiments, R 15 and R 16 are the same or different, and each is independently a hydrogen atom or a halogen; in some embodiments, R 15 and R 16the same or different, and each independently is a hydrogen atom or F; in some embodiments, R 15 and R 16 are each F.

[0081] In some embodiments of the disclosure, the compounds of the formula (III) to (V-1) or pharmaceutically acceptable salts thereof, wherein U is CH or N; in some embodiments, U is N.

[0082] In some embodiments of the disclosure, the compounds of the formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein s is 0 or 1; in some embodiments, s is 1.

[0083] In some embodiments of the disclosure, the compounds of the formula (I) to (III) or pharmaceutically acceptable salts thereof, wherein r is 1 or 2; in some embodiments, r is 1; in some embodiments, r is 2.

[0084] In some embodiments of the disclosure, the compounds of the formula (I) or pharmaceutically acceptable salts thereof, wherein R a is a hydrogen atom or C 1-6 alkyl; in some embodiments, R a is a hydrogen atom.

[0085] In some embodiments of the disclosure, the compounds of the formula (I), (II), (IV), (IV-1) or pharmaceutically acceptable salts thereof, wherein r1 is 1, s1 is 1, r2 is 1, and s2 is 1.

[0086] In some embodiments of the disclosure, the compounds of the formula (I), (II), (V), (V-1) or pharmaceutically acceptable salts thereof, wherein t is 0, 1 or 2, t2 is 0, 1 or 2; in some embodiments, t is 1 or 2, t2 is 1 or 2; in some embodiments, t is 1, t2 is 1.

[0087] In some embodiments of the disclosure, the compounds of the formula (I), (II), (V), (V-1) or pharmaceutically acceptable salts thereof, wherein t1 is 1, t3 is 1.

[0088] In some embodiments of the disclosure, the compounds of the formula (I) to (V-1) or pharmaceutically acceptable salts thereof, wherein each R 2 is the same or different, and each independently is selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 2 is halogen; in some embodiments, R 2 is F.

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

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

[0091] In some embodiments of this disclosure, q1 is 0, 1, or 2; in other embodiments, q1 is 0.

[0092] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, and / or R 4 For hydrogen atoms; in some implementations, R 3 C 1-6 Alkyl, and / or R 4 For hydrogen atoms; in some implementations, R 3 Methyl, and / or R 4 It is a hydrogen atom.

[0093] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 3 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, wherein the C 1-6 Alkyl groups and 3- to 6-membered cycloalkyl groups are each independently and optionally influenced by one or more R groups. 01 Replaced; R 01 As defined in general formula (I); in some implementations, R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; in some embodiments, R 3 C 1-6 Alkyl; in some embodiments, R 3 It is a methyl group.

[0094] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 4 Selected from hydrogen atom, hydroxyl group, C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl and C(O)R 23 ;R 23as defined in general formula (I); in some embodiments, R 4 is selected from the group consisting of a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a 3- to 6-membered cycloalkyl group; in some embodiments, R 4 is a hydrogen atom.

[0095] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein each R 01 is the same or different, and each is independently selected from the group consisting of an oxo group, a halogen, a hydroxyl group, 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 C 1-6 alkoxyalkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, each R 01 is the same or different, and each is independently selected from the group consisting of a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group.

[0096] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein each R 02 is the same or different, and each is independently selected from the group consisting of an oxo group, a halogen, a hydroxyl group, 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 C 1-6 alkoxyalkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, each R 02 is the same or different, and each is independently selected from the group consisting of a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group.

[0097] In some embodiments of the present disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein each R 03 is the same or different, and each is independently selected from the group consisting of an oxo group, a halogen, a hydroxyl group, 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 C 1-6 alkoxyalkyl group, and a 3- to 6-membered cycloalkyl group; in some embodiments, each R 03 is the same or different, and each is independently selected from the group consisting of a halogen, a C 1-6 alkyl group, and a C 1-6 haloalkyl group.

[0098] In some embodiments of the disclosure, the compounds of Formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, are those wherein each R C are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyalkyl, and 3- to 6-membered cycloalkyl; in some embodiments, each R C are the same or different and each is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, each R C are the same or different and each is independently halo; in some embodiments, R C is F.

[0099] In some embodiments of the disclosure, the compounds of Formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, are those wherein u is 0, 1, or 2; in some embodiments, u is 0; in some embodiments, u is 2.

[0100] In some embodiments of the disclosure, the compounds of Formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, are those wherein each R * are the same or different and each is independently selected from oxo, halo, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxyalkyl, 3- to 6-membered cycloalkyl, and NR 30 R 31 , R 30 , and R 31 are as defined in Formula (I); in some embodiments, each R * are the same or different and each is independently selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl.

[0101] In some embodiments of the disclosure, the compounds of Formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, are those wherein R 11 and R 12 are the same or different and each is independently a hydrogen atom or C 1-6 alkyl; in some embodiments, R 11 and R 12They may be the same or different, and each is independently a hydrogen atom or a methyl group; in some embodiments, R 11 and R 12 All are hydrogen atoms.

[0102] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 13 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 13 It is a hydrogen atom.

[0103] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 14 Selected from hydrogen atoms, C 1-6 Alkyl and 3- to 6-membered cycloalkyl; in some embodiments, R 14 It is a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 14 It is a hydrogen atom or a methyl group; in some embodiments, R 14 It is a hydrogen atom.

[0104] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein each R 20 and R 21 They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl; in some embodiments, R 20 and R 21 All are hydrogen atoms.

[0105] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 22 It is a hydrogen atom.

[0106] In some embodiments of this disclosure, the compounds represented by general formulas (I) to (V-1) or their pharmaceutically acceptable salts, wherein R 23 Selected from hydrogen atoms, C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl and C 1-6 Alkylene NR 30 R 31 The C 1-6 Alkyl, 3- to 6-membered cycloalkyl, 3- to 6-membered heterocyclic, 3- to 6-membered cycloalkyl C 1-6 Alkyl, 3 to 6-membered heterocyclic C 1-6 Alkyl and C 1-6each alkylene is independently optionally substituted with one or more R * ; R * ; R 30 ; and R 31 are as defined in general formula (I); in some embodiments, R 23 is selected from a hydrogen atom, C 1-6 1-6 alkyl, and 3-6 membered cycloalkyl; in some embodiments, R 23 is a hydrogen atom or C 1-6 1-6 alkyl; in some embodiments, R 23 is a hydrogen atom or methyl.

[0107] In some embodiments of the disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein R 30 and R 31 are the same or different, and each independently a hydrogen atom or C 1-6 1-6 alkyl; in some embodiments, R 30 and R 31 are the same or different, and each independently a hydrogen atom or methyl; in some embodiments, R 30 and R 31 are both hydrogen atoms.

[0108] In some embodiments of the disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein R 32 and R 33 are the same or different, and each independently a hydrogen atom or C 1-6 1-6 alkyl; in some embodiments, R 32 and R 33 are both hydrogen atoms.

[0109] In some embodiments of the disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein v is 2; in some embodiments, v is 1.

[0110] In some embodiments of the disclosure, the compounds of general formulae (I) to (V-1), or pharmaceutically acceptable salts thereof, wherein x is 0, 1, or 2; in some embodiments, x is 0.

[0111] In the present disclosure, general formulae (I) to (V-1) include general formulae (I), (II), (III), (IV), (V), (III-1), (IV-1), and (V-1).

[0112] In some embodiments of the disclosure, the compounds of general formula (I), or pharmaceutically acceptable salts thereof, wherein X 1 is N, and X 2 is CRX2 , X 3 is CR X3 , X 4 is CH; R X2 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; R X3 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; R a is a hydrogen atom; ring A is phenyl or 6-membered heteroaryl; R A is S(O)(NR 4 )R 3 ; R 3 is a methyl group, R 4 is a hydrogen atom; m is 0; ring B is selected from R B is =CR 15 R 16 , R 15 and R 16 are the same or different, and each independently a hydrogen atom or a halogen, the end connected to the ring where X 1 is located, the * end connected to R B , n is 0.

[0113] In some embodiments of the disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; Q is selected from N, N + -O - , CF and CH; R X2 , R X3 and R X4 are the same or different, and each independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; R 3 is a C 1-6 alkyl group; R 4 is a hydrogen atom; ring B is selected from R B is =CR 15 R 16 , R 15 and R 16 are the same or different, and each independently a hydrogen atom or a halogen, the end connected to the ring where X 1 is located, the * end connected to R B , n is 0; p is 0.

[0114] In some embodiments of the disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein X 1N; Q is selected from the group consisting of N, N + -O - , CF and CH; R X2 , R X3 and R X4 are the same or different and each is independently selected from the group consisting of a hydrogen atom, F, Cl, methyl and CF3; R 3 is a methyl group; R 4 is a hydrogen atom; each R 1 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; p is 0, 1 or 2; ring B is selected from the group consisting of R B is =CR 15 R 16 , R 15 and R 16 are the same or different and each is independently a hydrogen atom or F, the end connected to the ring in which X 1 is located, the * end is connected to R B , n is 0.

[0115] In some embodiments of the disclosure, the compound of Formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X2 is a hydrogen atom or C 1-6 alkyl; R X3 is halogen or C 1-6 haloalkyl; R X4 is a hydrogen atom; R 3 is C 1-6 alkyl; R 4 is a hydrogen atom; Q is selected from the group consisting of N, N + -O - , CF and CH; R 1b and R 1c are the same or different and each is independently a hydrogen atom or halogen; s is 0 or 1; r is 0, 1 or 2; r1 is 0, 1 or 2, s1 is 0, 1 or 2, r2 is 0, 1 or 2, s2 is 0, 1 or 2; t is 0, 1 or 2, t1 is 1 or 2; t2 is 0, 1 or 2, t3 is 1 or 2; R 15 and R 16 are the same or different and each is independently a hydrogen atom or halogen; U is N; q is 0.

[0116] In some embodiments of the disclosure, the compound of Formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X2 is a hydrogen atom or methyl; R X3 is Cl or CF3; RX4 For hydrogen atoms; R 3 Methyl; R 4 For hydrogen atoms; Q is N or CH; R 1b and R 1c All are hydrogen atoms; s is 0 or 1; r is 0, 1, or 2; r1 is 0, 1, or 2, s1 is 0, 1, or 2, r2 is 0, 1, or 2, s2 is 0, 1, or 2; t is 0, 1, or 2, t1 is 1 or 2; t2 is 0, 1, or 2, t3 is 1 or 2; R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or F; U is N; q is 0.

[0117] In some embodiments of this disclosure, the compound represented by general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 It is a hydrogen atom or a methyl group; R X3 Cl; R X4 For hydrogen atoms; R 3 Methyl; R 4 For hydrogen atoms; Q is CH; R 1b and R 1c All are hydrogen atoms; s is 0 or 1; r is 1 or 2; r1 is 1, s1 is 1, r2 is 1, s2 is 1; t is 1, t1 is 1; t2 is 1, t3 is 1; R 15 and R 16 They may be the same or different, and each is independently a hydrogen atom or F; U is N; q is 0.

[0118] In some embodiments of this disclosure, the compound represented by general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 For N; R X2 R X3 and R X4 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups; R 3 C 1-6 Alkyl; R 4 It is a hydrogen atom; Q is selected from N, N + -O - CF and CH;R 1b and R 1c They may be the same or different, and each is independently a hydrogen atom or a halogen; s is 0 or 1; r is 0, 1 or 2; r1 is 0, 1 or 2, s1 is 0, 1 or 2, r2 is 0, 1 or 2, s2 is 0, 1 or 2; t is 0, 1 or 2, t1 is 1 or 2; t2 is 0, 1 or 2, t3 is 1 or 2; R 15and R 16 are the same or different and each independently a hydrogen atom or a halogen; U is N; q is 0.

[0119] In some embodiments of the disclosure, the compound represented by the general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X3 is a 3- to 6-membered cycloalkyl group; R X2 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; R X4 is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; R 3 is a C 1-6 alkyl group; R 4 is a hydrogen atom; Q is N or CH; R 1b and R 1c are the same or different and each independently a hydrogen atom or a halogen; s is 0 or 1; r is 1 or 2; r1 is 1, s1 is 1, r2 is 1, s2 is 1; t is 1, t1 is 1; t2 is 1, t3 is 1; R 15 and R 16 are the same or different and each independently a hydrogen atom or a halogen; U is N; q is 0.

[0120] In some embodiments of the disclosure, the compound represented by the general formula (III), (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X3 is a cyclopropyl group; R X2 is selected from a hydrogen atom, F, Cl, a methyl group, CF3 and a cyclopropyl group; R X4 is selected from a hydrogen atom, F, Cl, a methyl group, CF3 and a cyclopropyl group; R 3 is a methyl group; R 4 is a hydrogen atom; Q is N or CH; R 1b and R 1c are the same or different and each independently a hydrogen atom or a halogen; s is 0 or 1; r is 1 or 2; r1 is 1, s1 is 1, r2 is 1, s2 is 1; t is 1, t1 is 1; t2 is 1, t3 is 1; R 15 and R 16 are the same or different and each independently a hydrogen atom or F; U is N; q is 0.

[0121] In some embodiments of the disclosure, the compound represented by the general formula (III-1), (IV-1) or (V-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X4 is selected from a hydrogen atom, a halogen, a C 1-6alkyl and C 1-6 haloalkyl; ring C is 5- or 6-membered cycloalkyl or phenyl; each R C are the same or different and each is independently halogen; u is 0, 1 or 2; R 3 is a C 1-6 alkyl group; R 4 is a hydrogen atom; Q is selected from N, N + -O - , CF and CH; R 1b and R 1c are the same or different and each is independently a hydrogen atom or halogen; s is 0 or 1; r is 1 or 2; r1 is 1, s1 is 1, r2 is 1, s2 is 1; t is 1, t1 is 1; t2 is 1, t3 is 1; R 15 and R 16 are the same or different and each is independently a hydrogen atom or halogen; U is N; q is 0.

[0122] In some embodiments of the present disclosure, the compound represented by the general formula (III-1), (IV-1) or (V-1) or a pharmaceutically acceptable salt thereof, wherein X 1 is N; R X4 is a hydrogen atom; ring C is cyclohexyl or phenyl; each R C are the same or different and each is independently halogen; u is 0, 1 or 2; R 3 is a C 1-6 alkyl group; R 4 is a hydrogen atom; Q is N or CH; R 1b and R 1c are each a hydrogen atom; s is 0 or 1; r is 1 or 2; r1 is 1, s1 is 1, r2 is 1, s2 is 1; t is 1, t1 is 1; t2 is 1, t3 is 1; R 15 and R 16 are the same or different and each is independently a hydrogen atom or halogen; U is N; q is 0.

[0123] Table A Representative compounds of the present disclosure include, but are not limited to:

[0124] Another aspect of the present disclosure relates to a compound represented by the general formula (IA), (IA-2) or a salt thereof,

[0125] wherein, R W is an amino protecting group, preferably Boc;

[0126] ring A, ring B, R B , X1 , X 2 , X 3 , X 4 , R a , R 1 , m, R 3 , R 2 and n are as defined in general formula (I).

[0127] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or (IIA-2) or a salt thereof,

[0128] wherein R W is an amino protecting group, preferably Boc;

[0129] ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 , p, R 3 , R 2 and n are as defined in general formula (II).

[0130] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA), (IIIA-2), (IVA), (IVA-2), (VA) or (VA-2) or a salt thereof,

[0131] wherein R W is an amino protecting group, preferably Boc;

[0132] X 1 , R X2 , R X3 , R X4 , Q, R 1b , R 1c , R 3 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2 and t3 are as defined in general formula (III), (IV) or (V).

[0133] Another aspect of the present disclosure relates to a compound represented by general formula (III-1A), (III-1a), (IV-1A), (IV-1a), (V-1A) or (V-1a) or a salt thereof,

[0134] wherein R W is an amino protecting group, preferably Boc;

[0135] Ring C, R C , u, X 1 , R X4 , Q, R 1b , R 1c , R 3 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2and t3are as defined in general formula (III-1), (IV-1) or (V-1).

[0136] Typical intermediate compounds of the present disclosure or salts thereof include, but are not limited to, those shown in Table B:

[0137] Another aspect of the present disclosure relates to a method of preparing a compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0138] reacting a compound represented by general formula (IA) or a salt thereof with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, or

[0139] deprotecting a compound represented by general formula (IA-2) or a salt thereof to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0140] R W is an amino protecting group, preferably Boc;

[0141] R A is S(O)(NR 4 )R 3 ; R 4 is a hydrogen atom;

[0142] Ring A, Ring B, R B , X 1 , X 2 , X 3 , X 4 , R a , R 1 , m, R 3 , R 2 and n are as defined in general formula (I).

[0143] Another aspect of the present disclosure relates to a method of preparing a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0144] The compound represented by General Formula (IIA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof, or

[0145] The compound represented by General Formula (IIA-2) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof, wherein,

[0146] R W is an amino protecting group, preferably Boc;

[0147] R 4 is a hydrogen atom;

[0148] Ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 , R 2 , R 3 , p and n are as defined in General Formula (II).

[0149] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formulae (III), (IV) and (V) or a pharmaceutically acceptable salt thereof described above, the method comprising:

[0150] The compound represented by General Formula (IIIA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (III) or a pharmaceutically acceptable salt thereof,

[0151] The compound represented by General Formula (IVA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (IV) or a pharmaceutically acceptable salt thereof,

[0152] The compound represented by General Formula (VA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (V) or a pharmaceutically acceptable salt thereof, wherein,

[0153] R 4 is a hydrogen atom;

[0154] X 1 , R X2 , R X3 , R X4 , Q, R 1b , R 1c , R 3 , U, R 2R 15 R 16 q, r, s, r1, s1, r2, s2, t, t1, t2, and t3 are as defined in the general formula (III), (IV), or (V).

[0155] Another aspect of the present disclosure relates to a method of preparing a compound represented by the above general formula (III), (IV), and (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0156] deprotecting a compound represented by the general formula (IIIA-2) or a salt thereof to obtain a compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof,

[0157] deprotecting a compound represented by the general formula (IVA-2) or a salt thereof to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,

[0158] deprotecting a compound represented by the general formula (VA-2) or a salt thereof to obtain a compound represented by the general formula (V) or a pharmaceutically acceptable salt thereof, wherein,

[0159] R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom;

[0160] X 1 R X2 R X3 R X4 Q, R 1b R 1c R 3 U, R 2 R 15 R 16 q, r, s, r1, s1, r2, s2, t, t1, t2, and t3 are as defined in the general formula (III), (IV), or (V).

[0161] Another aspect of the present disclosure relates to a method of preparing a compound represented by the above general formula (III-1), (IV-1), and (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0162] reacting a compound represented by the general formula (III-1A) or a salt thereof with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0163] The compound represented by General Formula (IV-1A) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0164] The compound represented by General Formula (V-1A) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by General Formula (V-1) or a pharmaceutically acceptable salt thereof,

[0165] wherein R 4 is a hydrogen atom;

[0166] Ring C, R C , u, X 1 , R X4 , Q, R 1b , R 1c , R 3 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2, and t3 are as defined in General Formula (III-1), (IV-1), or (V-1).

[0167] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (III-1), (IV-1), and (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0168] The compound represented by General Formula (III-1a) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (III-1) or a pharmaceutically acceptable salt thereof,

[0169] The compound represented by General Formula (IV-1a) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0170] The compound represented by General Formula (V-1a) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (V-1) or a pharmaceutically acceptable salt thereof,

[0171] wherein R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom;

[0172] Ring C, R C , u, X 1 , R X4 , Q, R 1b , R 1c , R 3 , R 2R 15 R 16 q, r, s, r1, s1, r2, s2, t, t1, t2, and t3 are as defined in general formula (III-1), (IV-1), or (V-1).

[0173] Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0174] The present disclosure further relates to the use of a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0175] The present disclosure further relates to the use of a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0176] The present disclosure further relates to the use of a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for treating and / or alleviating pain and pain-related diseases; 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, primary pain, intestinal pain, idiopathic pain, and visceral pain.

[0177] The present disclosure further relates to a method of inhibiting a voltage-gated sodium channel, comprising administering to a patient in need thereof a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0178] The present 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 general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0179] The present disclosure further relates to a method of treating and / or preventing pain and pain-related diseases, comprising administering to a patient in need thereof a compound of general formula (I) to (V-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0180] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0181] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0182] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0183] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0184] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0185] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0186] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0187] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0188] The present disclosure further relates to a compound of Formula (I) to (V-1) 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.

[0189] The active compounds can be prepared into various forms for administration, preferably in unit dosage form suitable for the administration by any of the routes obvious to those of ordinary skill in the art, and either in single or multiple doses. Expression of the unit dosage forms of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials, powders in vials, granules, lozenges, suppositories, reconstitutable powders or liquid preparations.

[0190] As a general guide, suitable unit doses can be 0.1 to 1000 mg.

[0191] The pharmaceutical compositions of the present disclosure can contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the method of administration, the composition can contain 0.1 to 99% by weight of the active compound.

[0192] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0193] 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.

[0194] 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.

[0195] Pharmaceutical compositions containing an active ingredient can be in forms suitable for oral administration, such as tablets, sugar lozenges, tablets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0196] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0197] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0198] Oil suspensions are formulated by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0199] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0200] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0201] 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.

[0202] 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

[0203] 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 factors: 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 treatment 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.

[0204] Explanation of terms

[0205] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0206] 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 The alkyl group preferably has from 1 to 12 carbon atoms (i.e., C 1-10 The alkyl group preferably 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. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0207] 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 The alkylene group preferably has 1 to 10 carbon atoms (i.e., C 1-10 The alkylene group preferably has 1 to 8 carbon atoms (i.e., C 1-8 The alkylene group preferably has 2 to 7 carbon atoms (i.e., C 2-7 The alkylene group preferably has 1 to 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 preferably 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.

[0208] 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). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C). 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 connection point. Substituents are preferably 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.

[0209] 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 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C64). 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 preferably 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.

[0210] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0211] 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). The cycloalkyl group preferably 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), more preferably 3 to 8 ring atoms (i.e., 3- to 8-membered cycloalkyl), most preferably 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); most preferably 5 or 6 ring atoms.

[0212] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0213] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like.

[0214] 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). The spirocycloalkyl group preferably has from 6 to 14 ring atoms (i.e., 6- to 14-membered spirocycloalkyl), more preferably from 7 to 10 ring atoms (i.e., 7- to 10-membered spirocycloalkyl). The spirocycloalkyl group includes mono- and polyspirocycloalkyl groups (e.g., dispirocycloalkyl groups, etc.), preferably a monospriocycloalkyl group or a dispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospriocycloalkyl group. Non-limiting examples include:

[0215] which can be attached at any position;

[0216] etc.

[0217] 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, or a monocyclic cycloalkyl fused with one or more of heterocyclyl, aryl, or heteroaryl, wherein the point of attachment is on the monocyclic cycloalkyl, which can contain one or more double bonds within its ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered fused cycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), preferably bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, more preferably 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples include:

[0218] which can be attached at any position; and the like.

[0219] 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 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). The bridged cycloalkyl preferably has 6 to 14 carbon atoms (i.e., 6- to 14-membered bridged cycloalkyl), more preferably 7 to 10 carbon atoms (i.e., 7- to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (such as tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

[0220] which can be attached at any position.

[0221] The cycloalkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0222] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (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(s) 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 -0-0-, -0-S-, or -S-S-) in the ring(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). The heterocyclyl group preferably has 3- to 12-membered heterocyclyl (i.e., 3- to 12-membered heterocyclyl), 3- to 10-membered heterocyclyl (i.e., 3- to 10-membered heterocyclyl), and 7- to 10-membered heterocyclyl (i.e., 7- to 10-membered heterocyclyl); further preferably 3- to 8-membered heterocyclyl (i.e., 3- to 8-membered heterocyclyl); more preferably 3- to 6-membered heterocyclyl (i.e., 3- to 6-membered heterocyclyl), 4- to 7-membered heterocyclyl (i.e., 4- to 7-membered heterocyclyl), or 5- or 6-membered heterocyclyl (i.e., 5- or 6-membered heterocyclyl); most preferably 5- or 6-membered heterocyclyl.

[0223] 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.

[0224] Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0225] "Nitrogen-containing heterocyclyl" refers to a heterocyclyl group having at least one (e.g., 1, 2, 3, or 4) nitrogen atom in the heterocyclyl ring, which is defined above. Preferred are 3- to 10-membered nitrogen-containing heterocyclyl groups, more preferred are 4- to 7-membered nitrogen-containing heterocyclyl groups, and most preferred are 5- or 6-membered nitrogen-containing heterocyclyl groups.

[0226] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system which 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). The spiroheterocyclyl preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered spiroheterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered spiroheterocyclyl). The spiroheterocyclyl includes mono- and polyspiroheterocyclyl (e.g., dispiroheterocyclyl, etc.), preferably a monosprioheterocyclyl or dispiroheterocyclyl, more preferably a 3- to 4-, 3- to 5-, 3- to 6-, 4- to 4-, 4- to 5-, 4- to 6-, 5- to 3-, 5- to 4-, 5- to 5-, 5- to 6-, 5- to 7-, 6- to 3-, 6- to 4-, 6- to 5-, 6- to 6-, 6- to 7-, 7- to 5-, or 7- to 6- membered monosprioheterocyclyl. Non-limiting examples include:

[0227] etc.

[0228] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system sharing adjacent ring atoms 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(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -O-O-, -O-S-, or -S-S-) within the ring, 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). The fused heterocyclyl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered fused heterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered fused heterocyclyl). The fused heterocyclyl group includes bicyclic and polycyclic fused heterocyclyl groups (e.g., tricyclic fused heterocyclyl groups, tetracyclic fused heterocyclyl groups, etc.), preferably bicyclic fused heterocyclyl groups or tricyclic fused heterocyclyl groups, more preferably 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 groups. Non-limiting examples include:

[0229] etc.

[0230] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system sharing two non-adjacent ring atoms 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(s) selected from nitrogen, oxygen, and sulfur (said nitrogen optionally oxidized, i.e., N-oxide; said sulfur optionally oxidized, i.e., sulfoxide or sulfone, but not including -O-O-, -O-S-, or -S-S-) within the ring, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered bridged heterocyclyl). The bridged heterocyclyl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered bridged heterocyclyl), more preferably 7 to 10 ring atoms (i.e., 7- to 10-membered bridged heterocyclyl). The bridged heterocyclyl group includes bicyclic and polycyclic bridged heterocyclyl groups (e.g., tricyclic bridged heterocyclyl groups, tetracyclic bridged heterocyclyl groups, etc.), preferably bicyclic bridged heterocyclyl groups or tricyclic bridged heterocyclyl groups. Non-limiting examples include:

[0231] etc.

[0232] Heterocyclyl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0233] 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). The aryl group preferably has 6 to 14 ring atoms (i.e., 6- to 14-membered aryl), more preferably 6 to 10 ring atoms (i.e., 6- to 10-membered aryl). The monocyclic aryl group is, for example, phenyl. The polycyclic aryl group, non-limiting examples include: naphthyl, anthryl, phenanthryl, and the like. The polycyclic aryl group also includes phenyl or naphthyl fused with one or more heterocyclyl or cycloalkyl groups, wherein the point of attachment is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, non-limiting examples include:

[0234] and the like.

[0235] Aryl can be substituted or non-substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0236] The term "heteroaryl" refers to a monocyclic heteroaromatic ring having a conjugated pi-electron system (i.e., monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., polycyclic heteroaryl) having at least one (e.g., 1, 2, 3, or 4) heteroatom(s) selected from nitrogen, oxygen, and sulfur (the nitrogen can optionally be oxidized, i.e., to an N-oxide; the sulfur can optionally be oxidized, i.e., to a sulfoxide or sulfone, but not -O-O-, -O-S-, or -S-S-) within the ring, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5- to 20-membered heteroaryl). The heteroaryl group preferably has 5 to 14 ring atoms (i.e., 5- to 14-membered heteroaryl), more preferably 5 to 10 ring atoms (i.e., 5- to 10-membered heteroaryl), most preferably 5 or 6 ring atoms (i.e., 5- or 6-membered heteroaryl).

[0237] Non-limiting examples of said monocyclic heteroaryl groups include furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridonyl (such as pyrazinyl, pyridazinyl, pyrid-1 -oxido, and the like.

[0238] Non-limiting examples of said polycyclic heteroaryl groups include indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. Said polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aryl groups, wherein the point of attachment 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. Said polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclyl groups, wherein the point of attachment 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:

[0239] and the like.

[0240] Heteroaryl groups can be substituted or non-substituted, and when substituted, they can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0241] The term "cycloalkyloxy" means -O-cycloalkyl, wherein cycloalkyl is as defined above.

[0242] The term "heterocyclyloxy" means -O-heterocyclyl, wherein heterocyclyl is as defined above.

[0243] The term "aryloxy" means -O-aryl, wherein aryl is as defined above.

[0244] The term "heteroaryloxy" means -O-heteroaryl, wherein heteroaryl is as defined above.

[0245] The term "cycloalkylalkyl" means alkyl substituted by one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0246] The term "heterocyclylalkyl" means alkyl substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0247] The term "arylalkyl" means an alkyl group substituted with one or more aryl groups, wherein aryl, alkyl are as defined above.

[0248] The term "heteroarylalkyl" means an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl, alkyl are as defined above.

[0249] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0250] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0251] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

[0252] The term "hydroxyalkoxy" means an alkoxy group substituted with one or more hydroxyl groups, wherein alkoxy is as defined above.

[0253] The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein alkyl and alkoxy are as defined above; preferably -alkyl-alkoxy; including but not limited to methoxymethyl, ethoxymethyl, methoxyethyl.

[0254] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0255] The term "hydroxyl" means -OH.

[0256] The term "amino" means -NH2.

[0257] The term "cyano" means -CN.

[0258] The term "nitro" means -NO2.

[0259] The term "oxo" or "oxo group" means "=O".

[0260] The term "carbonyl" means C=O.

[0261] TBS means tert-butyldimethylsilyl group.

[0262] The term "amino protecting group" means an easily removed group introduced on the amino group in order to keep the amino group unchanged while reacting at other sites of the molecule. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), formyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl (PMB), and the like.

[0263] 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, conformers, 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 isomer by conventional means. In addition, separation of the enantiomers and diastereomers is typically accomplished by chromatography.

[0264] 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. The compounds of the present disclosure can include all modes of rotational isomers and conformationally restricted states thereof. Atropisomers are also included, the term "atropisomers" refers to stereoisomers that result from restricted rotation about a single bond, in which 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 as a mixture of atropisomers (e.g., an equimolar mixture, a mixture enriched in one atropisomer, etc.) or as a purified atropisomer.

[0265] The compounds of the present disclosure can include all modes of rotational isomers and conformationally restricted states thereof. Atropisomers are also included, the term "atropisomers" refers to stereoisomers that result from restricted rotation about a single bond, in which 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 as a mixture of atropisomers (e.g., an equimolar mixture, a mixture enriched in one atropisomer, etc.) or as a purified atropisomer.

[0266] 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 "tautomers" 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, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. An example of lactam-lactim equilibrium is shown below:

[0267] As when referring to pyrazolyl, it is understood to include either one or a mixture of both tautomers of the following two structures:

[0268] All tautomeric forms are within the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer.

[0269] The compounds of the present disclosure include all suitable isotopic variations of the compounds. The term "isotopic variations" means the replacement of at least one atom with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be introduced into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, preferably deuterium.

[0270] Deuterated drugs have advantages over non-deuterated drugs, such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biohalf-life. All isotopic 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 hydrogen with deuterium can be partial or complete. Partial replacement of hydrogen with deuterium means that at least one hydrogen is replaced with at least one deuterium.

[0271] When a position is designated specifically as deuterium D, the position is understood to have deuterium in an abundance greater than the natural abundance of deuterium (which is 0.015%) by at least 1000-fold (i.e., at least 15% deuterium incorporation). The deuterium in an example compound can have an abundance greater than the natural abundance of deuterium by at least 1000-fold (i.e., at least 15% deuterium incorporation), by at least 2000-fold (i.e., at least 30% deuterium incorporation), by at least 3000-fold (i.e., at least 45% deuterium incorporation), by at least 3340-fold (i.e., at least 50.1% deuterium incorporation), by at least 3500-fold (i.e., at least 52.5% deuterium incorporation), by at least 4000-fold (i.e., at least 60% deuterium incorporation), by at least 4500-fold (i.e., at least 67.5% deuterium incorporation), by at least 5000-fold (i.e., at least 75% deuterium incorporation), by at least 5500-fold (i.e., at least 82.5% deuterium incorporation), by at least 6000-fold (i.e., at least 90% deuterium incorporation), by at least 6333.3-fold (i.e., at least 95% deuterium incorporation), by at least 6466.7-fold (i.e., at least 97% deuterium incorporation), by at least 6600-fold (i.e., at least 99% deuterium incorporation), by at least 6633.3-fold (i.e., at least 99.5% deuterium incorporation), or greater.

[0272] “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.

[0273] “Substituted” or “substitution” means that one or more hydrogen atoms, preferably 1, 2, or 3, more preferably 1 to 3, of a group are independently replaced with a corresponding number of substituents. One of skill in the art can determine, without undue experimentation (through experiment or theory), whether a substitution is possible or not possible. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated bond (e.g., alkene).

[0274] "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 a subject, and to facilitate absorption of the active ingredient.

[0275] "Pharmaceutically acceptable salt" means a salt of a compound of the disclosure that is safe and effective for use in a mammal, and possesses the desired biological activity. The salts can be prepared from the final isolated and purified compounds, or by reacting a suitable salt of the compound with the appropriate base or acid. 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 and organic acids.

[0276] The term "pharmaceutically acceptable" as used herein means that these 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.

[0277] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0278] 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 more preferably within ±5%. As will be understood by those skilled in the art, numbers are often given only to the nearest whole number for simplicity, not limitation, when the parameter is not critical.

[0279] Synthetic methods for compounds of the disclosure

[0280] To achieve the purposes of the present disclosure, the present disclosure adopts the following technical solutions:

[0281] Scheme One

[0282] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

[0283] reacting a compound represented by general formula (IA) or a salt thereof with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0284] R A is S(O)(NR 4 )R 3 ; R 4is a hydrogen atom;

[0285] ring A, ring B, R B , X 1 , X 2 , X 3 , X 4 , R a , R 1 , m, R 3 , R 2 and n are as defined in general formula (I).

[0286] Scheme I-2

[0287] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0288] deprotecting a compound represented by general formula (IA-2) or a salt thereof under acidic conditions to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0289] R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom;

[0290] ring A, ring B, R B , X 1 , X 2 , X 3 , X 4 , R a , R 1 , m, R 3 , R 2 and n are as defined in general formula (I).

[0291] Scheme II

[0292] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0293] reacting a compound represented by general formula (IIA) or a salt thereof with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,

[0294] R 4 is a hydrogen atom;

[0295] ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 , R 2R 3 p and n are as defined in general formula (II).

[0296] Scheme two-2

[0297] The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0298] The compound represented by general formula (IIA-2) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein,

[0299] R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom;

[0300] ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 , R 2 , R 3 p and n are as defined in general formula (II).

[0301] Scheme three

[0302] The present disclosure provides a method for preparing a compound represented by general formula (III), (IV) and (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0303] The compound represented by general formula (IIIA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof,

[0304] The compound represented by general formula (IVA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0305] The compound represented by general formula (VA) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate salt) in the presence of an oxidizing agent to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein,

[0306] R 4 is a hydrogen atom;

[0307] X 1 , R X2 , R X3 , R X4 , Q, R1b , R 1c , R 3 , U, R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2 and t3 are as defined in general formula (III), (IV) or (V).

[0308] Scheme three-2

[0309] The present disclosure provides a method for preparing a compound represented by general formula (III), (IV) and (V) or a pharmaceutically acceptable salt thereof, the method comprising:

[0310] The compound represented by general formula (IIIA-2) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof,

[0311] The compound represented by general formula (IVA-2) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (IV) or a pharmaceutically acceptable salt thereof,

[0312] The compound represented by general formula (VA-2) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (V) or a pharmaceutically acceptable salt thereof, wherein,

[0313] R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom;

[0314] X 1 , R X2 , R X3 , R X4 , Q, R 1b , R 1c , R 3 , U, R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2 and t3 are as defined in general formula (III), (IV) or (V).

[0315] Scheme four

[0316] The present disclosure provides a method for preparing a compound represented by general formula (III-1), (IV-1) and (V-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0317] The compound represented by general formula (III-1A) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0318] The compound represented by general formula (IV-1A) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0319] The compound represented by general formula (V-1A) or a salt thereof is reacted with ammonia or a salt thereof (preferably a carbonate) in the presence of an oxidizing agent to obtain a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof,

[0320] wherein, R 4 is a hydrogen atom;

[0321] ring C, R C , u, X 1 , R X4 , Q, R 1b , R 1c , R 3 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2 and t3 are as defined in general formula (III-1), (IV-1) or (V-1).

[0322] Scheme IV-2

[0323] The present disclosure provides a method for preparing a compound represented by general formula (III-1), (IV-1) and (V-1) or a pharmaceutically acceptable salt thereof, which comprises:

[0324] The compound represented by general formula (III-1a) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof,

[0325] The compound represented by general formula (IV-1a) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (IV-1) or a pharmaceutically acceptable salt thereof,

[0326] The compound represented by general formula (V-1a) or a salt thereof is subjected to a deprotection reaction under acidic conditions to obtain a compound represented by general formula (V-1) or a pharmaceutically acceptable salt thereof,

[0327] wherein, R W is an amino protecting group, preferably Boc; R4 is a hydrogen atom;

[0328] ring C, R C , u, X 1 , R X4 , Q, R 1b , R 1c , R 3 , R 2 , R 15 , R 16 , q, r, s, r1, s1, r2, s2, t, t1, t2and t3are as defined in general formula (III-1), (IV-1) or (V-1).

[0329] In the above synthesis schemes one, two, three and four, the reaction mechanism is oxidation reaction or nitroxide transfer reaction.

[0330] The oxidizing agent in the above synthesis scheme includes but is not limited to iodobenzenediacetic acid, potassium permanganate, m-chloroperbenzoic acid, perbenzoic acid, dibenzoyl peroxide, peroxyacetic acid, hydrogen peroxide, Dess-Martin, sodium hypochlorite, monoperoxyphthalic acid, N-iodosuccinimide, 2-iodoxybenzoic acid, etc.; preferably iodobenzenediacetic acid.

[0331] The reagent providing acidic condition in the above scheme includes but is not limited to hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, 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 and TMSOTf; preferably trifluoroacetic acid.

[0332] The reaction of the above steps is preferably 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 mixtures thereof. DETAILED DESCRIPTION

[0333] The present disclosure is further described below in conjunction with examples, which are not intended to limit the scope of the present disclosure.

[0334] Examples

[0335] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is expressed in 10 -6The NMR measurement is carried out by using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0336] The MS measurement is carried out by using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0337] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector)

[0338] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive)

[0339] The HPLC analysis is carried out by using an Agilent HPLC 1200 DAD, an Agilent HPLC 1200 VWD, and a Waters HPLC e2695-2489 high-performance liquid chromatograph.

[0340] The chiral HPLC analysis measurement is carried out by using an Agilent 1260 DAD high-performance liquid chromatograph.

[0341] The high-performance liquid preparation is carried out by using a Waters 2545-2767, a Waters 2767-SQ Detector 2, a Shimadzu LC-20AP, and a Gilson GX-281 preparative chromatograph.

[0342] The chiral preparation is carried out by using a Shimadzu LC-20AP preparative chromatograph.

[0343] The CombiFlash rapid preparation instrument is a Combiflash Rf200 (TELEDYNE ISCO).

[0344] The thin layer chromatography silica gel plate is a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specification of the silica gel plate used in the thin layer chromatography (TLC) is 0.15 mm to 0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm to 0.5 mm.

[0345] The silica gel column chromatography generally uses 200-300 mesh silica gel of Yantai Huanghai as the carrier.

[0346] The determination of the average inhibition rate of the kinase and IC 50 The NovoStar microplate reader (Germany BMG Company) is used.

[0347] The known starting materials of the present disclosure can be synthesized according to the methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Daejung Chemicals, etc.

[0348] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0349] The argon atmosphere or the nitrogen atmosphere refers to that a reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0350] The hydrogen atmosphere refers to that a reaction bottle is connected to a hydrogen balloon with a volume of about 1 L.

[0351] The pressurized hydrogenation reaction uses a Parr 3916EKX type hydrogenation instrument and a Qinglan QL-500 type hydrogen generator or an HC2-SS type hydrogenation instrument.

[0352] The hydrogenation reaction is generally vacuumed, filled with hydrogen, and the operation is repeated 3 times.

[0353] The microwave reaction uses a CEM Discover-S 908860 type microwave reactor.

[0354] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0355] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0356] The monitoring of the reaction progress in the examples uses thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system used in the column chromatography for purifying 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 the solvents is adjusted according to the polarity of the compounds, and a small amount of triethylamine and acetic acid and other basic or acidic reagents can also be added for adjustment.

[0357] Example 1

[0358] 2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1

[0359] (S)-2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1-p1

[0360] (R)-2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1-p2

[0361] First step

[0362] tert-Butyl 3-(difluoromethyl)piperidine-1-carboxylate 1b

[0363] tert-Butyl 3-(difluoromethyl)piperidine-1-carboxylate 1b was prepared from tert-butyl 3- oxopiperidine-1-carboxylate 1a (5 g, 25.1 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (4.08 g, 21.12 mmol, Bide Shanghai) in N,N-dimethylacetamide (50 mL) at -50 °C, followed by the addition of potassium tert-butoxide (4.22 g, 36.67 mmol) and the maintenance of the temperature for 20 min. The reaction mixture was added with saturated ammonium chloride solution (13 mL) and 3M hydrochloric acid (32 mL) and stirred for 3 h. The reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system B to give the title compound 1b (1.48 g, yield: 25.3%).

[0364] MS m / z (ESI): 177.9 [M-55].

[0365] Second step

[0366] 3-(difluoromethyl)piperidine hydrochloride 1c

[0367] tert-Butyl 3-(difluoromethyl)piperidine-1-carboxylate 1b was prepared from tert-butyl 3- oxopiperidine-1-carboxylate 1a (5 g, 25.1 mmol) and 2-((difluoromethyl)sulfonyl)pyridine (4.08 g, 21.12 mmol, Bide Shanghai) in N,N-dimethylacetamide (50 mL) at -50 °C, followed by the addition of potassium tert-butoxide (4.22 g, 36.67 mmol) and the maintenance of the temperature for 20 min. The reaction mixture was added with saturated ammonium chloride solution (13 mL) and 3M hydrochloric acid (32 mL) and stirred for 3 h. The reaction mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using eluent system B to give the title compound 1b (1.48 g, yield: 25.3%).

[0368] MS m / z (ESI): 134.0 [M+1].

[0369] Third step

[0370] 2-chloro-6-(3-(difluoromethyl)piperidin-1-yl)-3-(trifluoromethyl)pyridine 1e

[0371] Compound 1d (812 mg, 3.76 mmol), compound 1c (580 mg, 3.42 mmol) were dissolved in 1,4-dioxane (15 mL), N,N-diisopropylethylamine (884 mg, 6.83 mmol) was added, the reaction was stirred at 80 °C for 16 h, 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 (1.02 g, yield: 99%).

[0372] MS m / z (ESI): 313.1 [M+1].

[0373] Fourth step

[0374] 6-(3-(difluoromethyl)piperidin-1-yl)-2-methyl-3-(trifluoromethyl)pyridine 1f

[0375] Compound 1e (1.02 g, 3.26 mmol), 50% trimethyl boroxine in tetrahydrofuran (8.2 g, 32.67 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (239 mg, 326.9 μmol), potassium carbonate (1.36 g, 9.85 mmol) were mixed in 1,4-dioxane (24 mL) and water (6 mL), replaced with nitrogen, heated to 100 °C for 16 h, the reaction solution was filtered after being cooled to room temperature, the filtrate was diluted with water and extracted with ethyl acetate (30 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1f (850 mg, yield: 89.1%).

[0376] MS m / z (ESI): 293.2 [M+1].

[0377] Fifth step

[0378] 3-bromo-2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-5-(trifluoromethyl)pyridine 1g

[0379] Compound 1f (850 mg, 2.9 mmol) was dissolved in dichloromethane (20 mL), N-bromosuccinimide (621.2 mg, 3.49 mmol) was added, and the reaction was stirred for 2 h. 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 1g (740 mg, yield: 68.5%).

[0380] MS m / z (ESI): 371.0 [M+1].

[0381] Sixth step

[0382] Ethyl 2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-5-(trifluoromethyl)nicotinate 1h

[0383] Compound 1g (100 mg, 269.4 μmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (40 mg, 54.7 μmol), triethylamine (164 mg, 1.62 mmol) were dissolved in ethanol (5 mL), replaced with carbon monoxide, heated to 90 °C for 16 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (90 mg, yield: 91.6%).

[0384] MS m / z (ESI): 365.0 [M+1].

[0385] Seventh step

[0386] 2-(3-(Difluoromethyl)piperidin-1-yl)-6-methyl-5-(trifluoromethyl)nicotinic acid 1i

[0387] Compound 1h (90 mg, 247 μmol) was dissolved in methanol (2 mL) and water (1 mL), lithium hydroxide (70 mg, 1.25 μmol) was added, and the reaction was stirred at 70 °C for 16 hours. After the reaction solution was cooled to room temperature, 1M hydrochloric acid was added to adjust the pH to 4, and ethyl acetate (10 mL x 3) was added for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1i (83 mg). The product was used directly in the next step without purification.

[0388] MS m / z (ESI): 337.1 [M+1].

[0389] Eighth step

[0390] 2-(3-(Difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(methylthio)phenyl)-5- (trifluoromethyl)nicotinamide

[0391] 1j

[0392] Compound 1i (90 mg, 267.6 μmol) was dissolved in dichloromethane (2 mL), oxalyl chloride (102 mg, 809.5 μmol) and 2 drops of N,N-dimethylformamide were added under ice-bath, and the reaction was allowed to recover to room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (4 mL). N,N-diisopropylethylamine (208 mg, 1.6 mmol), 3-(methylthio)aniline (75 mg, 528.7 μmol, Shanghai Titan) and 4-dimethylaminopyridine (33 mg, 270.5 μmol) were added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1j (100 mg, yield: 81.6%).

[0393] MS m / z (ESI): 458.3 [M+1].

[0394] Ninth step

[0395] 2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1-p1

[0396] Nicotinamide 1

[0397] (S)-2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1-p1

[0398] (R)-2-(3-(difluoromethyl)piperidin-1-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)-5- (trifluoromethyl)nicotinamide 1-p2

[0399] Compound 1j (100 mg, 218.6 μmol) was dissolved in methanol (5 mL), ammonium carbonate (84 mg, 875 μmol) and iodo-benzene diacetate (212 mg, 658.3 μmol) were added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (63 mg, yield: 59%).

[0400] MS m / z (ESI): 489.4 [M+1].

[0401] 1H NMR (500 MHz, DMSO-de): δ 10.81 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.91 (d, 1H), 7.66 (d, 1H), 7.58 (t, 1H), 4.24 (s, 1H), 4.16 (s, 2H), 3.50 (t, 2H), 3.05 (s, 3H), 2.52 (s, 3H), 2.24 (t, 2H), 1.59 (t, 2H).

[0402] The isomer mixture 1 (57 mg) was purified by chiral column (Shimadzu LC-20AP, Column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.5% diethylamine in methanol), gradient ratio: A:B 70:30, flow rate: 20 mL / min) to give the title compound (28 mg, yield: 49.1 %), (28 mg, yield: 49.1 %).

[0403] Single configuration compound (shorter retention time) (28 mg, yield: 49.1 %)

[0404] MS m / z (ESI): 489.4 [M+1].

[0405] Chiral HPLC analysis: Retention time 11.493 min, purity: 99% (Column: CHIRALPAK IE, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 85:15, flow rate: 1 mL / min).

[0406] 1 H NMR (500 MHz, DMSO-de): δ 10.81 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.91 (d, 1H), 7.66 (d, 1H), 7.58 (t, 1H), 4.24 (s, 1H), 4.16 (s, 2H), 3.50 (t, 2H), 3.05 (s, 3H), 2.52 (s, 3H), 2.24 (t, 2H), 1.59 (t, 2H).

[0407] Single configuration compound (longer retention time) (28 mg, yield: 49.1 %)

[0408] MS m / z (ESI): 489.4 [M+1].

[0409] Chiral HPLC analysis: Retention time 12.300 min, purity: 99% (Chromatography column: CHIRALPAK IE, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 85:15, flow rate: 1 mL / min).

[0410] 1 H NMR (500 MHz, DMSO-d6): δ 10.81 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H), 7.92 (d, 1H), 7.66 (d, 1H), 7.58 (t, 1H), 4.24 (s, 1H), 4.16 (s, 2H), 3.50 (t, 2H), 3.05 (s, 3H), 2.52 (s, 3H), 2.24 (t, 2H), 1.59 (t, 2H).

[0411] Example 2

[0412] 2-(4-(Difluoromethylidene)azepan-1-yl)-N-(2-(S-methanesulfonimidoyl)pyridin-4-yl)-5- (trifluoromethyl)nicotinamide 2

[0413] First step

[0414] 4-(Difluoromethylidene)azepane-1-carboxylic acid tert-butyl ester 2b

[0415] tert-Butyl 4-oxoazepane-1-carboxylate 2a (5 g, 23.44 mmol, Shanghai Titan) and 2- ((difluoromethyl)sulfonyl)pyridine (3.81 g, 19.72 mmol) were dissolved in N,N- dimethylformamide (40 mL), and a solution of potassium tert-butoxide (3.94 g, 35.17 mmol) in N,N-dimethylformamide (50 mL) was added at -50 °C. The temperature was maintained for 20 min, and the reaction solution was added to saturated ammonium chloride solution and 3M hydrochloric acid solution. The temperature was restored to room temperature and stirred for 1 h. The organic phase was extracted with ethyl acetate (50 mL x 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2b (4.2 g, yield: 72.4%).

[0416] MS m / z (ESI): 192.1 [M-55].

[0417] Second step

[0418] 4-(Difluoromethylidene)azepane hydrochloride 2c

[0419] Compound 2b (4.17 g, 16.86 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (36 mL) and stirred for 2 h. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 2c (3 g). The product was used directly in the next step without purification.

[0420] MS m / z (ESI): 148.3 [M+1].

[0421] Third step

[0422] 2-(4-(Difluoromethylidene)azepan-1-yl)-5-(trifluoromethyl)nicotinic acid 2e

[0423] 2-Chloro-5-(trifluoromethyl)nicotinic acid 2d (526 mg, 2.33 mmol, Shanghai Leyue) and the crude compound 2c (429 mg, 2.33 mmol) were dissolved in methanol (2.5 mL) and tetrahydrofuran (3 mL), and triethylamine (707 mg, 7 mmol) was added. The reaction was stirred at 80 °C for 3 h. The reaction solution was concentrated under reduced pressure. The residue was diluted with dichloromethane, washed with saturated sodium chloride solution, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2e (645 mg, yield: 82.2%). MS m / z (ESI): 337.3 [M+1].

[0424] Fourth step

[0425] 2-(4-(Difluoromethylidene)azepan-1-yl)-N-(2-(methylthio)pyridin-4-yl)-5- (trifluoromethyl)nicotinamide 2g

[0426] Compound 2e (300 mg, 892.1 μmol) was dissolved in dichloromethane (4 mL), and oxalyl chloride (450 mg, 3.57 mmol) and 2 drops of N,N-dimethylformamide were added under ice bath. The reaction was restored to room temperature and stirred for 1 h. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (577 mg, 4.46 mmol), 2-(methylthio)pyridin-4-amine 2f (140.2 mg, 984.2 μmol, Shanghai Leyue), and 4-dimethylaminopyridine (109 mg, 893.4 μmol) were added. The reaction was stirred for 16 h. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2g (250 mg, yield: 61.1%).

[0427] MS m / z (ESI): 459.2 [M+1]

[0428] Fifth step

[0429] 2-(4-(difluoromethyl)azepan-1-yl)-N-(2-(S-methanesulfonimidoyl)pyridin-4-yl)-5- (trifluoromethyl)nicotinamide 2

[0430] Compound 2g (250 mg, 545.3 μmol) was dissolved in methanol (12 mL), ammonium carbonate (210 mg, 2.18 mmol) and iodoformic acid (557 mg, 1.63 mmol) were added, the reaction was stirred for 16 hours, the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 2 (160 mg, yield: 59.9%).

[0431] MS m / z (ESI): 490.4 [M+1]

[0432] 1 H NMR (500 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.63 (d, 1H), 8.56 (d, 1H), 8.38 (d, 1H), 8.06 (d, 1H), 7.86 (dd, 1H), 4.36 (s, 1H), 3.71 (t, 2H), 3.61 (t, 2H), 3.15 (s, 3H), 2.45 (t, 2H), 2.14 (t, 2H), 1.77-1.73 (m, 2H).

[0433] Example 3

[0434] 5-chloro-2-(5-(difluoromethyl)hexahydroazepin-2(1H)-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)nicotinamide 3

[0435] First step

[0436] 5-(difluoromethyl)hexahydroazepino[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester 3b

[0437] tert-Butyl 5-oxohexahydro-pyrrolo[c]pyrrole-2(lH)-carboxylate 3a (1 g, 4.43 mmol, Shanghai Biotech) and 2-((difluoromethyl)sulfonyl)pyridine (1.28 g, 6.62 mmol) were dissolved in N,N-dimethylformamide (9 mL), 1M potassium tert-butoxide in tetrahydrofuran (10.2 mL) was added at -40 °C, the reaction was stirred at -40 °C for 20 minutes, saturated ammonium chloride solution was added to quench the reaction, 2M hydrochloric acid solution was added to adjust the pH to about 3, ethyl acetate (30 mL x 3) was used to extract, the organic phase was combined and concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3b (900 mg, yield: 78.2%).

[0438] Second step

[0439] 5-(difluoromethylidene)octahydro-pyrrolo[c]pyrrole hydrochloride 3c

[0440] Compound 3b (900 mg, 3.47 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (9 mL), and stirred for 3 hours, and the reaction was concentrated under reduced pressure to obtain the crude title compound 3c (600 mg). The product was used directly in the next step without purification.

[0441] Third step

[0442] 2-(5-(difluoromethylidene)hexahydro-pyrrolo[c]pyrrol-2(lH)-yl)-6-methylnicotinic acid methyl ester 3e

[0443] 2-chloro-6-methylnicotinic acid methyl ester 3d (100 mg, 538.77 μmol, Shanghai Titan), compound 3c (105 mg, 536.7 μmol) were dissolved in N,N-dimethylformamide (3 mL), N,N-diisopropyl ethylamine (210 mg, 1.62 mmol) was added, and the reaction was carried out at 100 °C for 1 hour. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3e (100 mg, yield: 60.2%).

[0444] MS m / z (ESI): 309.4 [M+1].

[0445] Fourth step

[0446] 5-chloro-2-(5-(difluoromethylidene)hexahydro-pyrrolo[c]pyrrol-2(lH)-yl)-6-methylnicotinic acid methyl ester 3f

[0447] Compound 3e (100 mg, 324.3 pmol) was dissolved in N,N-dimethylformamide (5 mL), N-chlorosuccinimide (55 mg, 411.8 pmol) was added, and the reaction was carried out at 100 °C for 1 h. 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 3f (70 mg, yield: 63%). MS m / z (ESI): 343.3 [M+1].

[0448] Fifth step

[0449] ((3-(5-chloro-2-(5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6- methylbenzamido)phenyl)(methyl)(oxo)-lambda 6 - sulfanylidene) tert-butyl carbamate 3h

[0450] Compound 3f (50 mg, 145.8 pmol) and ((3-aminophenyl)(methyl)(oxo)- lambda 6 - sulfanylidene) tert-butyl carbamate 3g (45 mg, 166.4 pmol, prepared by the method disclosed in the description of patent application “WO2022192487” on page 132 Intermediate 58) were dissolved in tetrahydrofuran (5 mL), and 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.3 mL) was added under ice bath. The reaction was allowed to recover to room temperature naturally for 2 h. Saturated ammonium chloride solution was added to the reaction solution, and the organic phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was concentrated under reduced pressure to obtain the crude title compound 3h (80 mg). The product was used directly in the next step without purification.

[0451] MS m / z (ESI): 581.4 [M+1].

[0452] Sixth step

[0453] 5-chloro-2-(5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)nicotinamide 3

[0454] The crude compound 3h (80 mg, 137.6 pmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added. The reaction was stirred for 0.5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 pm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 32%-45%, flow rate: 30 mL / min) to obtain the title compound 3 (13.5 mg, yield: 20.3%).

[0455] MS m / z(ESI):481.4[M+1].

[0456] 1 H NMR (500MHz, DMSO-d6): δ10.73(s,1H),8.35-8.31(m,1H),7.93-7.91(m,1H),7.73(s,1H),7.65-7.59(m,1H),7.58-7.55(m,1H),4.2 6(br,1H),3.62-3.58(m,2H),3.19-3.17(m,2H),3.15(s,3H),2.79-2.76(m,2H),2.43(s,3H),2.13-2.10(m,2H),1.27-1.22(m,2H).

[0457] Example 4

[0458] 5-Chloro-2-(4-(difluoromethylene)azacycloheptan-1-yl)-6-methyl-N-(3-(S-methanesulfonyl)phenyl)nicotinamide 4

[0459] Using the synthetic route in Example 3, the starting compound 3c in the third step was replaced with compound 2c to obtain the title compound 4 (20 mg, yield: 28.2%).

[0460] MS m / z(ESI):469.4[M+1].

[0461] 1 H NMR (500MHz, DMSO-d6): δ10.82(s,1H),8.32(s,1H),7.91(d,1H),7.69(s,1H),7.66(d,1H),7.58( t,1H),4.22(s,1H),3.64(t,2H),3.53(t,2H),3.06(s,3H),2.43(s,5H),2.12(d,2H),1.71(s,2H).

[0462] Example 5

[0463] 2-(4-(difluoromethylene)azacycloheptane-1-yl)-6-methyl-N-(3-(S-methanesulfonyl)phenyl)-5-(trifluoromethyl)nicotinamide

[0464] Using the synthetic route in Example 1, the starting compound 1c in the third step was replaced with compound 2c to obtain title compound 5 (230 mg, yield: 67.4%).

[0465] MS m / z (ESI): 503.1 [M+1].

[0466] 1 H NMR (500 MHz, CDC13): δ 8.91 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 8.01 (d, 1H), 7.80 (d, 1H), 7.57 (t, 1H), 3.67 (t, 2H), 3.55 (t, 2H), 3.13 (s, 3H), 2.60 (s, 3H), 2.54-2.51 (m, 2H), 2.25-2.22 (m, 2H), 1.88-1.83 (m, 2H).

[0467] Example 6

[0468] 2-(4-(Difluoromethylidene)azepan-1-yl)-6-methyl-N-(2-(S-methanesulfonimidoyl)pyridin-4-yl)-5- (trifluoromethyl)nicotinamide 6

[0469] The title compound 6 (70 mg, yield: 50.5%) was obtained by using the synthetic route in Example 1, replacing the third step raw material compound 1c with compound 2c, and replacing the eighth step raw material 3-(methylthio)aniline with compound 2f. MS m / z (ESI): 504.1 [M+1].

[0470] 1 H NMR (500 MHz, CDC13): δ 9.37 (s, 1H), 8.66 (d, 1H), 8.16 (s, 1H), 8.13 (s, 1H), 8.06 (d, 1H), 3.64 (t, 2H), 3.52 (t, 2H), 3.26 (s, 3H), 2.62 (s, 3H), 2.54-2.51 (m, 2H), 2.27-2.23 (m, 2H), 1.88-1.83 (m, 2H).

[0471] Example 7

[0472] 2-(5-(Difluoromethylidene)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7

[0473] 2-((3aR,6aS)-(5-(Difluoromethylidene)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-((S)-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7-p1

[0474] 2-((3aR,6aS)-(5-(Difluoromethyl)hexahydroazepino[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-((R)-(S-methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7-p2

[0475] First step

[0476] 2-(6-Chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(difluoromethyl)octahydroazepino[c]pyrrole 7a

[0477] Compound 1d (1.1 g, 5.09 mmol), compound 3c (1 g, 5.11 mmol) were dissolved in N,N-dimethylacetamide (10 mL), N,N-diisopropyl ethylamine (2 g, 15.5 mmol) was added, the reaction was stirred at 80 °C for 3 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 7a (1.2 g, yield: 69.3%).

[0478] MS m / z (ESI): 339.3 [M+1].

[0479] Second step

[0480] 5-(Difluoromethyl)-2-(6-methyl-5-(trifluoromethyl)pyridin-2-yl)octahydroazepino[c]pyrrole 7b

[0481] Compound 7a (1.2 g, 3.54 mmol), 50% trimethyl boroxine in tetrahydrofuran (9 g, 35.8 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (60 mg, 82.1 μmol), potassium carbonate (980 mg, 7.1 mmol) were mixed in 1,4-dioxane (24 mL) and water (6 mL), replaced with nitrogen, heated to 100 °C for 16 hours, the reaction solution was cooled to room temperature, filtered, the filtrate was diluted with water, extracted with ethyl acetate (30 mL x 2), the combined organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7b (800 mg, yield: 70.9%).

[0482] MS m / z (ESI): 319.1 [M+1].

[0483] Third step

[0484] 2-(3-Bromo-6-methyl-5-(trifluoromethyl)pyridin-2-yl)-5-(difluoromethyl)octahydroazepino[c]pyrrole 7c

[0485] Compound 7b (800 mg, 2.51 mmol) was dissolved in dichloromethane (20 mL), N-bromosuccinimide (530 mg, 2.98 mmol) was added, the reaction was stirred for 2 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 7c (850 mg, yield: 85.1%).

[0486] MS m / z (ESI): 397.3 [M+1].

[0487] Fourth step

[0488] 2-(5-(difluoromethyl)hexahydroazepino[c]pyrrol-2(lH)-yl)-6-methyl-5- (trifluoromethyl)nicotinic acid ethyl ester 7d

[0489] Compound 7c (850 mg, 2.14 mmol), l,l'-bis(diphenylphosphino)ferrocene palladium dichloride (100 mg, 136.6 μmol), triethylamine (500 mg, 4.94 mmol) were dissolved in ethanol (15 mL), carbon monoxide was replaced, heated 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 7d (650 mg, yield: 77.8%).

[0490] MS m / z (ESI): 391.1 [M+1].

[0491] Fifth step

[0492] ((3-(2-(5-(difluoromethyl)hexahydroazepino[c]pyrrol-2(lH)-yl)-6-methyl-5- (trifluoromethyl)nicotinamido)phenyl)(methyl)(oxo)-λ 6 - sulfanyl)carbamic acid tert-butyl ester 7e

[0493] Compound 7d (150 mg, 384.2 μmol), compound 3g (110 mg, 406.88 μmol) were dissolved in tetrahydrofuran (10 mL), 1M lithium bis(trimethylsilyl)amide tetrahydrofuran solution (0.6 mL) was added under ice bath, and the reaction was allowed to recover to room temperature for 1 hour, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate (15 mL x 3) was used for extraction, the organic phase was combined and concentrated under reduced pressure to obtain the title compound 7e (230 mg), which was used directly in the next step without purification.

[0494] MS m / z (ESI): 615.5 [M+1].

[0495] Sixth step

[0496] 2-((3aR,6aS)-(5-(difluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-((S)- (S-methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7-p2

[0497] 2-((3aR,6aS)-(5-(difluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-((S)- (S-methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7-p2

[0498] 2-((3aR,6aS)-(5-(difluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-((S)- (S-methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 7-p2

[0499] The crude compound 7e (230 mg, 374.2 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, the reaction was stirred for 1 hour, the reaction solution was concentrated under reduced pressure, saturated potassium carbonate solution was added, extracted with ethyl acetate (10 mL x 3), the organic phase was combined and concentrated under reduced pressure, the residue was purified by high performance liquid chromatography (Gilson-gx-281, column: Boston phlex prep C18, 30*150 mm, 5 μm; mobile phase: water phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 40%-70%, flow rate: 30 mL / min) to obtain the title compound 7 (28 mg, yield: 14.5%).

[0500] MS m / z (ESI): 515.1 [M+1].

[0501] 1 H NMR (500 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.30 (s, 1H), 7.98-7.85 (m, 2H), 7.68-7.53 (m, 2H), 4.20 (br, 1H), 3.76-3.61 (m, 2H), 3.28-3.19 (m, 2H), 3.06 (s, 3H), 2.85-2.73 (m, 2H), 2.60-2.53 (m, 2H), 2.50 (s, 3H), 2.20-2.08 (m, 2H).

[0502] The isomer mixture 7 (20 mg) was purified by chiral column (Shimadzu LC-20AP, Column: CHIRALPAK IG, 20*250mm, 5μιη; Mobile phase A: n-hexane, Mobile phase B: Ethanol (containing 0.5% 7M Ammonium hydroxide solution), Gradient ratio: A:B 70:30, Flow rate: 20 mL / min) to get the title compound (7.5 mg, yield: 37.5%), (7.5 mg, yield: 37.5%).

[0503] Single isomeric compound (shorter retention time) (7.5 mg, yield: 37.5%)

[0504] MS m / z (ESI): 515.1 [M+1].

[0505] Chiral HPLC analysis: Retention time 5.472 min, Purity: 99% (Column: CHIRALPAK IE, 5μιη, 4.6*150mm; Mobile phase: A: n-hexane, Mobile phase B: Ethanol (containing 0.1% Diethylamine), Gradient ratio: A:B 70:30, Flow rate: 1 mL / min).

[0506] 1 H NMR (500 MHz, DMSO-d6): δ 10.77 (s, 1H), 8.30 (s, 1H), 7.98-7.85 (m, 2H), 7.68-7.53 (m, 2H), 4.20 (s, 1H), 3.76-3.61 (m, 2H), 3.30-3.20 (m, 2H), 3.05 (s, 3H), 2.85-2.75 (m, 2H), 2.60-2.53 (m, 2H), 2.50 (s, 3H), 2.20-2.08 (m, 2H).

[0507] Single isomeric compound (longer retention time) (7.5 mg, yield: 37.5%)

[0508] MS m / z (ESI): 515.1 [M+1].

[0509] Chiral HPLC analysis: Retention time 5.472 min, Purity: 99% (Column: CHIRALPAK IE, 5μιη, 4.6*150mm; Mobile phase: A: n-hexane, Mobile phase B: Ethanol (containing 0.1% Diethylamine), Gradient ratio: A:B 70:30, Flow rate: 1 mL / min).

[0510] 1H NMR (500 MHz, DMSO-d6): δ 10.78 (s, 1H), 8.31 (s, 1H), 7.96-7.85 (m, 2H), 7.67-7.57 (m, 2H), 4.20 (s, 1H), 3.76-3.63 (m, 2H), 3.37-3.25 (m, 2H), 3.06 (s, 3H), 2.85-2.75 (m, 2H), 2.60-2.53 (m, 2H), 2.50 (s, 3H), 2.21-2.08 (m, 2H).

[0511] Example 8

[0512] 2-(5-(Difluoromethylidene)hexahydroazepino[c]pyrrol-2(lH)-yl)-6-methyl-N-(2-(S- methanesulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)nicotinamide 8

[0513] -4-yl)-5-(trifluoromethyl)nicotinamide 8

[0514] The title compound 8 (6 mg, yield: 22.5%) was obtained by using the synthetic route in Example 1, replacing the third step raw material compound 1c with compound 3c, and replacing the eighth step raw material 3-(methylthio)aniline with compound 2f. MS m / z (ESI): 516.1 [M+1].

[0515] 1 H NMR (500 MHz, CD3OD): δ 8.61 (d, 1H), 8.49 (d, 1H), 7.93 (s, 1H), 7.90 (dd, 1H), 3.74-3.71 (m, 2H), 3.35-3.32 (m, 2H), 3.26 (s, 3H), 2.79-2.76 (m, 2H), 2.63-2.55 (m, 2H), 2.54 (d, 3H), 2.23-2.16 (m, 2H).

[0516] Example 9

[0517] 2-(6-(Difluoromethylidene)-2-azaspiro[3.3]heptan-2-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 9

[0518] The title compound 9 (10 mg, yield: 7.2%) was obtained by using the synthetic route in Example 1, replacing the first step raw material compound 1a with tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (Shanghai Leyen).

[0519] MS m / z (ESI): 501.1 [M+1].

[0520] 1 H NMR (500 MHz, CDC13): δ 8.14 (t, 1H), 8.10-8.04 (m, 2H), 8.03 (s, 1H), 7.83-7.79 (m, 1H), 7.60 (t, 1H), 4.16 (s, 4H), 3.15 (s, 3H), 2.89 (t, 4H), 2.60 (d, 3H).

[0521] Example 10

[0522] 5-Chloro-2-(3-(difluoromethyl)pyrrolidin-l-yl)-6-methyl-N-(3-(S-methanesulfonimidoyl)phenyl)nicotinamide 10

[0523] Using the synthetic route in Example 3, replacing the first step starting material compound 3a with N-tert-butoxycarbonyl-3-pyrrolidinone (Shanghai Shaoyuan) to obtain the title compound 10 (8 mg, yield: 32.7%).

[0524] MS m / z (ESI): 441.4 [M+1].

[0525] 1 H NMR (500 MHz, CDC13): δ 9.97 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 8.00-7.98 (m, 1H), 7.97-7.77 (m, 1H), 7.57 (t, 1H), 4.12-4.10 (m, 2H), 3.55-3.52 (m, 2H), 3.15 (s, 3H), 2.67-2.63 (m, 2H), 2.57 (s, 3H).

[0526] Example 11

[0527] 2-(5-(Difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-N-(3-(S- methanesulfonimidoyl)phenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide 11

[0528] Using the synthetic route in Example 3, replacing the third step starting material compound 3d with 2-chloro-5,6,7,8-tetrahydroquinoline-3-carboxylic acid methyl ester (prepared using the method disclosed in the specification of patent application “WO2023211990” on page 176, Compound 19) to obtain the title compound 11 (10 mg, yield: 40.1%).

[0529] MS m / z (ESI): 487.3 [M+1].

[0530] 1 H NMR (500 MHz, CDC13): δ 10.11 (s, 1H), 8.24 (s, 1H), 7.91 (d, 1H), 7.87 (s, 1H), 7.75 (dt, 1H), 7.54 (t, 1H), 3.63 (dt, 2H), 3.13 (s, 3H), 2.94 - 2.78 (m, 4H), 2.73 (t, 2H), 2.62 - 2.46 (m, 2H), 2.29 - 2.15 (m, 2H), 1.93 - 1.75 (m, 4H), 1.37 - 1.19 (m, 2H).

[0531] Example 12

[0532] 2-(5-(Difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6,7-difluoro-N-(3-(S- methanesulfonimidoyl)phenyl)quinoline-3-carboxamide 12

[0533] 2-((3aR,6aS)-(5-(Difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6,7-difluoro-N- (3-((S)-S-methanesulfonimidoyl)phenyl)quinoline-3-carboxamide 12-p1

[0534] 2-((3aR,6aS)-(5-(Difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6,7-difluoro-N- (3-((R)-S-methanesulfonimidoyl)phenyl)quinoline-3-carboxamide 12-p2

[0535] Using the synthetic route in Example 3, the third step raw material compound 3d was replaced by 2-chloro-6,7-difluoroquinoline-3-carboxylic acid ethyl ester (prepared by the method disclosed in the patent application “CN116462662A” on page 35, Example 9) to obtain the title compound 12 (29 mg, yield: 43.2%).

[0536] The isomer mixture 12 (25 mg) was purified by chiral column separation (Shimadzu LC-20AP, column: CHIRALPAK IE, 20*250 mm, 10 μm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.5% 7M ammonium methanol solution), gradient ratio: A:B 80:20, flow rate: 20 mL / min) to obtain the title compound (10 mg, yield: 40%), (10 mg, yield: 40%).

[0537] 1H NMR (500 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.32 (d, 2H), 8.05 - 7.80 (m, 2H), 7.75 - 7.50 (m, 3H), 4.23 (s, 1H), 3.75 (s, 2H), 3.07 (s, 3H), 2.83 (s, 2H), 2.57 (d, 2H), 2.15 (d, 2H), 1.24 (s, 2H).

[0538] Chiral HPLC analysis of isomer mixture 12: Retention time 15.276 min (50%), 18.705 min (50%), (column: CHIRALPAK IE, 5 pm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 85:15, flow rate: 1 mL / min).

[0539] Single configuration compound (short retention time) (15.276 min, 10 mg, yield: 40%)

[0540] MS m / z (ESI): 519.4 [M+1].

[0541] 1 H NMR (500 MHz, CDC13): δ 8.81 (s, 1H), 8.33 (s, 1H), 8.23 (t, 1H), 8.07 - 8.00 (m, 1H), 7.83 (ddd, 1H), 7.62 (t, 1H), 7.57 (dd, 1H), 7.52 - 7.43 (m, 1H), 5.43 - 5.30 (m, 1H), 3.91 - 3.78 (m, 2H), 3.38 (dt, 2H), 3.16 (s, 3H), 2.89 (s, 2H), 2.60 (d, 2H), 2.25 (dd, 2H).

[0542] Single configuration compound (long retention time) (18.705 min, 10 mg, yield: 40%)

[0543] MS m / z (ESI): 519.4 [M+1].

[0544] 1H NMR (500 MHz, CDC13): δ 8.83 (s, 1H), 8.32 (s, 1H), 8.23 (t, 1H), 8.04 (dt, 1H), 7.83 (d, 1H), 7.62 (t, 1H), 7.56 (dd, 1H), 7.51 - 7.43 (m, 1H), 3.84 (ddd, 2H), 3.38 (dt, 2H), 3.16 (s, 3H), 2.89 (d, 2H), 2.60 (d, 2H), 2.24 (dd, 2H).

[0545] Example 13

[0546] 2-(5-(Fluoromethylidene)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 13

[0547] First Step

[0548] 5-(Fluoromethylidene)hexahydropentacyclo[c]pyrrol-2(lH)-carboxylic acid tert-butyl ester 13b

[0549] Fluoromethyl)triphenylphosphonium tetrafluoroborate (2.54 g, 6.62 mmol, Shanghai Titan) was dissolved in tetrahydrofuran (20 mL), and 1M potassium bis(trimethylsilyl)amide in tetrahydrofuran (6.6 mL) was added dropwise at -78°C. After 1 hour of reaction at the same temperature, a tetrahydrofuran solution (10 mL) of compound 3a (1 g, 4.43 mmol) was added, and the reaction was continued for 1 hour at the same temperature. After the temperature was returned to room temperature, the reaction was continued for 2 hours. The reaction solution was added to saturated ammonium chloride solution, and extracted with ethyl acetate (50 mL x 2). The organic phase was combined and concentrated under reduced pressure to obtain the crude product of the title compound 13b (1 g). The product was used directly in the next step without purification.

[0550] Second Step

[0551] 2-(5-(Fluoromethylidene)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 13

[0552] Using the synthetic route in Example 1, the third to ninth steps were used, and the third step raw material compound 1b was replaced with compound 13b to obtain the title compound 13 (45 mg, yield: 42.1%).

[0553] MS m / z (ESI): 497.4 [M+1].

[0554] 1H NMR (500 MHz, CD3OD): δ 8.41 (s, 1H), 7.96 (d, 1H), 7.88 (s, 1H), 7.80 (d, 1H), 7.63 (t, 1H), 6.59 (d, 1H), 3.81-3.73 (m, 2H), 3.42-3.35 (m, 2H), 3.19 (s, 3H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 1H), 2.59-5.51 (m, 4H), 2.32-2.25 (m, 1H), 2.22-2.15 (m, 1H).

[0555] Example 14

[0556] 2-(5-(Difluoromethyl)hexahydrocyclopenta[c]pyrrol-2(lH)-yl)-4-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 14

[0557] First step

[0558] 5-(Difluoromethyl)-2-(4-iodo-5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole 14b

[0559] 2-chloro-4-iodo-5-(trifluoromethyl)pyridine 14a (300 mg, 975.8 μmol, National Pharmaceutical) and compound 3c (200 mg, 1.02 mmol) were dissolved in N,N- dimethylformamide (8 mL), N,N-diisopropyl ethylamine (380 mg, 2.94 mmol) was added, and the reaction was carried out at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 14b (320 mg, yield: 76.2%).

[0560] MS m / z (ESI): 431.1 [M+1].

[0561] Second step

[0562] 5-(Difluoromethyl)-2-(4-methyl-5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrole 14c

[0563] Compound 14b (300 mg, 697.4 μmol), methylboronic acid (150 mg, 2.5 mmol), 1,1'- bis(diphenylphosphino)ferrocene palladium dichloride (20 mg, 27.3 μmol), potassium carbonate (300 mg, 2.17 mmol) were mixed in 1,4-dioxane (10 mL) and water (4 mL), replaced with nitrogen, heated at 90 °C for 16 hours, the reaction solution was reduced to room temperature, filtered, the filtrate was diluted with water, extracted with ethyl acetate (30 mL x 2), the combined organic phase was dried with anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 14c (180 mg, yield: 81%).

[0564] MS m / z (ESI): 319.3 [M+1].

[0565] Third step

[0566] 2-(5-(Difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-4-methyl-N-(3-(S- methanesulfonimidoyl)phenyl)-5-(trifluoromethyl)nicotinamide 14

[0567] Using the fifth to ninth steps in the synthetic route in Example 1, the fifth step raw material compound If was replaced with compound 14c to obtain the title compound 14 (3 mg, yield: 7.1%).

[0568] MS m / z (ESI): 515.5 [M+1].

[0569] 1 H NMR (500 MHz, CD3OD): δ 8.41 (s, 1H), 7.97-7.91 (m, 1H), 7.88 (s, 1H), 7.80-7.76 (m, 1H), 7.65-7.57 (m, 1H), 3.81-3.68 (m, 2H), 3.42-3.35 (m, 2H), 3.17 (s, 3H), 2.88-2.79 (m, 2H), 2.64-2.56 (m, 2H), 2.54 (s, 3H), 2.25-2.16 (m, 2H).

[0570] Example 15

[0571] 5-Chloro-2-(5-(difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-4,6-dimethyl-N-(3-(S- methanesulfonimidoyl)phenyl)nicotinamide 15

[0572] First step

[0573] 2,5-dichloro-4,6-dimethylnicotinic acid methyl ester 15b

[0574] Dissolve 2,5-dichloro-4,6-dimethylnicotinic acid 15a (500 mg, 2.27 mmol, Shanghai Leyan) in N,N-dimethylformamide (10 mL), add iodomethane (700 mg, 4.93 mmol), potassium carbonate (1 g, 7.23 mmol), react at 100 °C for 1 hour, after the reaction solution is cooled to room temperature, filter, and the filtrate is concentrated under reduced pressure to obtain the crude title compound 15b (530 mg). The product is used directly in the next step without purification.

[0575] MS m / z (ESI): 234.1 [M+1].

[0576] Second step

[0577] 5-chloro-2-(5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-4,6-dimethyl-N-(3-(S- methanesulfonimidoyl)phenyl)nicotinamide 15

[0578] Using the synthetic route in Example 3, replace the third step raw material compound 3d with compound 15b to obtain the title compound 15 (2.2 mg, yield: 5%).

[0579] MS m / z (ESI): 495.4 [M+1].

[0580] 1 H NMR (500 MHz, CD3OD): δ 8.42 (s, 1H), 7.91 (d, 1H), 7.79 (d, 1H), 7.62 (t, 1H), 3.80-3.65 (m, 2H), 3.41-3.35 (m, 2H), 3.17 (s, 3H), 2.84-2.73 (m, 2H), 2.61-2.50 (m, 2H), 2.47 (s, 3H), 2.33 (s, 3H), 2.20-2.09 (m, 2H).

[0581] Example 16

[0582] 2-(5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6,6-difluoro-N-(3-(S- methanesulfonimidoyl)phenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide 16

[0583] First step

[0584] 2-chloro-6,6-difluoro-5,6,7,8-tetrahydroquinoline-3-carboxylic acid methyl ester 16b

[0585] Methyl 6,6-difluoro-2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate 16a (5 g, 20.55 mmol, prepared using the method disclosed in the specification page 382 Preparation 118 of patent application “WO2023245166”) was dissolved in phosphorus oxychloride (50 mL) and reacted at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the pH was adjusted to neutral with a saturated sodium bicarbonate solution, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with elution system B to obtain the title compound 16b (3.7 g, yield: 68.7%).

[0586] MS m / z (ESI): 262.3 [M+1].

[0587] Second step

[0588] 2-(5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6,6-difluoro-N-(3-(S- methanesulfonimidoyl)phenyl)-5,6,7,8-tetrahydroquinoline-3-carboxamide 16

[0589] Using the synthetic route in Example 3, the third step raw material compound 3d was replaced with compound 16b to obtain the title compound 16 (30 mg, yield: 24.6%).

[0590] MS m / z (ESI): 523.4 [M+1].

[0591] 1 H NMR (500 MHz, CDC13): δ 9.42 (s, 1H), 8.20 (s, 1H), 8.00-7.98 (m, 1H), 7.76-7.75 (m, 2H), 7.62-7.54 (m, 1H), 3.70-3.66 (m, 2H), 3.22-2.98 (m, 7H), 2.86-2.82 (m, 2H), 2.60-2.53 (m, 2H), 2.34-2.19 (m, 6H).

[0592] Example 17

[0593] 5-cyclopropyl-2-((3aR,6aS)-5-(difluoromethyl)hexahydropyrrolo[c]pyrrol-2(lH)-yl)-6- methyl-N-(3-(S-methanesulfonimidoyl)phenyl)nicotinamide 17

[0594] First step

[0595] (3aR,6aS)-5-(difluoromethyl)hexahydro-pyrrolo[c]pyrrole-2(lH)-carboxylic acid tert-butyl ester 17b

[0596] tert-Butyl (3aR,6aS)-5-oxohexahydro-pyrrolo[c]pyrrole-2(lH)-carboxylate 17a (15 g, 66.58 mmol, Shanghai Bide) and 2-((difluoromethyl)sulfonyl)pyridine (15.4 g, 79.9 mmol) were dissolved in N,N-dimethylformamide (150 mL), 1M potassium tert-butoxide in tetrahydrofuran (153 mL) was added at -50 °C, the temperature was kept and the reaction was stirred for 20 minutes, saturated ammonium chloride solution was added to quench the reaction, 2M hydrochloric acid solution was added to adjust the pH to about 3, and ethyl acetate (100 mL x 3) was added to extract the organic phase, the organic phase was combined and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 17b (10 g, yield: 57.9%).

[0597] Second step

[0598] (3aR,6aS)-5-(difluoromethyl)octahydro-pyrrolo[c]pyrrole hydrochloride 17c

[0599] Compound 17b (13 g, 50.1 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (130 mL) and stirred for 2 hours, and the reaction was concentrated under reduced pressure to obtain the crude title compound 17c (8 g), which was used directly in the next step without purification.

[0600] Third step

[0601] 2-((3aR,6aS)-5-(difluoromethyl)hexahydro-pyrrolo[c]pyrrol-2(lH)-yl)-6-methylnicotinic acid methyl ester 17d

[0602] Compound 3d (1 g, 5.38 mmol) and compound 17c (900 mg, 5.65 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (2.23 g, 16.16 mmol) was added, and the reaction was stirred at 100 °C for 16 hours, the reaction was filtered after being cooled to room temperature, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 17d (1.2 g, yield: 72.2%).

[0603] MS m / z (ESI): 309.4 [M+1].

[0604] Fourth step

[0605] 2-((3aR,6aS)-5-(difluoromethyl)hexahydro-pyrrolo[c]pyrrol-2(lH)-yl)-5-iodo-6-methylnicotinic acid methyl ester 17e

[0606] Compound 17d (1.2 g, 3.89 mmol) was dissolved in N,N-dimethylformamide (25 mL), N-iodosuccinimide (1 g, 4.44 mmol) was added, and the reaction was carried out at 100°C for 1 hour. Water was added to the reaction solution, and extraction was performed with ethyl acetate (30 mL x 3). The organic phases were combined, and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 17e (1.3 g, yield: 76.9%).

[0607] MS m / z (ESI): 435.2 [M+1].

[0608] Fifth step

[0609] 5-cyclopropyl-2-((3aR,6aS)-5-(difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6- methyl nicotinic acid methyl ester 17f

[0610] Compound 17e (100 mg, 230.3 μmol), cyclopropylboronic acid (50 mg, 582.1 μmol, Shanghai Titan), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (20 mg, 27.3 μmol), potassium carbonate (70 mg, 506.5 μmol) were mixed in 1,4-dioxane (3 mL) and water (1 mL), and the nitrogen was replaced. The reaction was carried out at 110°C for 1.5 hours in a microwave. After the reaction solution was cooled to room temperature, it was filtered, water was added to dilute the filtrate, extraction was performed with ethyl acetate (10 mL x 2), the organic phases were combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure after the drying agent was removed by filtration. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 17f (65 mg, yield: 81%).

[0611] MS m / z (ESI): 349.5 [M+1].

[0612] Sixth step

[0613] 5-cyclopropyl-2-((3aR,6aS)-5-(difluoromethyl)hexahydropentacyclo[c]pyrrol-2(lH)-yl)-6- methyl-N-(3-(S-methanesulfonimidoyl)phenyl)nicotinamide 17

[0614] Using the synthetic route in Example 3, the starting material compound 3f in the fifth step was replaced with compound 17f to obtain the title compound 17 (5 mg, yield: 30.1%).

[0615] MS m / z (ESI): 487.5 [M+1]

[0616] 1H NMR (500 MHz, DMSO-d6): δ 10.55 (s, 1H), 8.33 (d, 1H), 7.91 (d, 1H), 7.70-7.48 (m, 2H), 7.25 (d, 1H), 4.17 (s, 1H), 3.65-3.48 (m, 2H), 3.22-3.11 (m, 2H), 3.04 (s, 3H), 2.80-2.67 (m, 2H), 2.60-2.49 (m, 2H), 2.46 (s, 3H), 2.19-2.04 (m, 2H), 1.87-1.77 (m, 1H), 0.93-0.77 (m, 2H), 0.65-0.46 (m, 2H).

[0617] Biological evaluation

[0618] Test 1, determination of the Nav1.8 inhibitory activity of the compounds of the present disclosure

[0619] The purpose of the experiment is to detect the effect of the compound on Nav1.8 ion channel in vitro experiment. Nav1.8 ion channel is stably expressed on HEK293 cells. After the Nav1.8 current is stabilized, the size of Nav1.8 current before and after compound treatment can be compared to obtain the effect of the compound on Nav1.8 ion channel.

[0620] 1 Experimental materials and instruments

[0621] 1) patch clamp amplifier: patch clamp PC-505B (WARNER instruments)

[0622] 2) digital-to-analog converter: Digidata 1440A (Axon instruments)

[0623] 3) micro manipulator: MP-225 (SUTTER instrument)

[0624] 4) inverted microscope: TL4 (Olympus)

[0625] 5) glass microelectrode puller: PC-10 (NARISHIGE)

[0626] 6) microelectrode glass capillary: B12024F (Wuhan Micro- Probe Scientific Instrument Co., Ltd.)

[0627] 7) dimethyl sulfoxide (DMSO) (Sigma-Aldrich, D2650)

[0628] 8) TTX (Affix Scientific, AF3014)

[0629] 2 Experimental procedure

[0630] 2.1 Compound preparation

[0631] Compounds for extracellular and intracellular solutions were purchased from Sigma, except NaOH and KOH for pH titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). The intracellular solution (mM) was: aspartate, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound solutions contained 1 μM TTX.

[0632] Test compounds were stored at 9 mM in dimethylsulfoxide (DMSO). On the day of testing, they were dissolved in extracellular solution to the required concentration.

[0633] 2.2 Manual patch clamp test procedure

[0634] 1) After the compound was prepared into a solution of the specified concentration, the drug solution was added to each channel in order of concentration from low to high, and each channel was labeled.

[0635] 2) The cell was transferred to the perfusion chamber, a positive pressure was applied to the electrode, the electrode tip was in contact with the cell, the air pump three-way valve was adjusted to the three-way state, and then a negative pressure was applied to the electrode to form a high resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current path.

[0636] 3) After the cell membrane was broken and the current was stable, perfusion was performed at different concentrations in turn. If the current is stable for at least one minute, the next concentration can be changed for perfusion. The perfusion time for each concentration is not more than five minutes.

[0637] 4) The perfusion chamber was washed. The drug solution was washed from high to low concentration, and each concentration of drug solution was washed for 20 s. Finally, the extracellular solution was washed for 1 min.

[0638] 2.3 Test voltage equation

[0639] The cell was clamped at -80 mV, then depolarized to 10 mV with a 10 ms square wave to obtain Nav1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it was stable, the test compound was perfused, and the intensity of inhibition was calculated after the response was stable.

[0640] 3. Data analysis

[0641] The data will be stored in a computer system for analysis. Data collection and analysis use pCLAMP 10 (Molecular Devices, Union City, CA).

[0642] The inhibitory activity of the compounds of the present disclosure on Nav1.8 is determined by the above experiment, and the IC 50 values are shown in Table 1.

[0643] Table 1, IC50values of the compounds of the present disclosure on the inhibition of Nav1.8 channel activity 50

[0644] Conclusion: The compounds in the present disclosure have obvious inhibitory effect on Nav1.8 channel activity.

[0645] Test Example 2, Inhibitory effect of the compounds of the present disclosure on human liver microsomal CYP1A2 enzyme activity

[0646] The inhibitory effect of the compounds of the present disclosure on human liver microsomal CYP1A2 enzyme activity is determined by the following experimental method:

[0647] I. Experimental materials and instruments

[0648] 1. Phosphate buffer (20xPBS, purchased from Shengong),

[0649] 2. NADPH (ACROS, A2646-71-1),

[0650] 3. Human liver microsomes (Corning Gentest, Cat No, 452161, Lot No. 9050002, Donor, 35)

[0651] 4. ABIQTrap 4000 liquid chromatograph-mass spectrometer (AB Sciex),

[0652] 5. ZORBAX Extend-C18, 3x50mm, 3.5μm (USA, Agilent),

[0653] 6. CYP1A2 probe substrate phenacetin (China Institute for Drug Control, Cat No. 100095-200204)

[0654] 7. Positive control inhibitor alpha-naphthoflavone (SIGMA, Lot No. SLBF5267V)

[0655] II. Experimental steps

[0656] Prepare 100 mM PBS buffer, prepare 15 mM MgCl2and 5 mM NADPH solution with the buffer, then prepare 0.5 mg / ml microsomal solution with the 15 mM MgCl2, dilute the 30 mM stock solution with DMSO to a series of 30 mM, 10 mM, 3 mM, 1 mM, 0.3 mM, 0.03 mM, 0.003 mM, 0 mM solution I, then dilute the above series of solution I with PBS buffer to obtain a series of test solution II (60, 20, 6, 2, 0.6, 0.06, 0.006, 0 μM) by 500 times. Prepare phenazopyridine into a 30 mM stock solution with DMSO. Dilute the phenazopyridine stock solution to 60 μM working solution with PBS buffer.

[0657] Take 20 μL of 0.5 mg / mL microsomal solution prepared in 15 mM MgCl2, respectively, and take 20 μL of substrate working solution (12 μM phenazopyridine) and 50 μL of compound working solution (60, 20, 6, 2, 0.6, 0.06, 0.006, 0 μM), respectively, and mix well. The positive control group uses the same concentration of alpha-naphthoflavone instead of the compound. At the same time, 5 mM NADPH solution is pre-incubated at 37°C for 5 minutes. After 5 minutes, add 10 μL of NADPH to each well to start the reaction and incubate for 30 minutes. All incubation samples are set in duplicate. After 30 minutes, add 250 μL of acetonitrile containing internal standard to all samples, mix well, shake at 800 rpm for 10 minutes, then centrifuge at 3700 rpm for 20 minutes. Take 50 μL of supernatant and mix with 140 μL of ultrapure water, then transfer to LC-MS / MS analysis.

[0658] The values of the IC of the tested compound on the inhibition of CYP1A2 enzyme activity were calculated by Graphpad Prism 50 Table 3.

[0659] Table 3. IC values of the compounds of the present disclosure on the inhibition of human liver microsomal CYP1A2 enzyme activity 50 Table 3.

[0660] Conclusion: The compounds of the present disclosure have weak inhibition on the activity of human liver microsomal CYP1A2 enzyme, suggesting a low risk of metabolic drug interaction based on CYP1A2.

Claims

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof: ###00001### (I) wherein: Ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is cycloalkyl or heterocyclyl; R B R 15 R 16 ; R A selected from S(O)(NR 4 )R 3 , S(O) v R 3 , C(O)R 3 , C(O)NR 4 R 5 , and a hydrogen atom; R 15 and R 16 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, NR 20 R 21 , C(O)NR 20 R 21 , C(O)R 23 , OR 23 , S(O) v R 23 , cycloalkyl, heterocyclyl, aryl, and heteroaryl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R * ; or R 15 and R 16 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclyl, each of said cycloalkyl and heterocyclyl is independently optionally substituted with one or more R * ; R 3 R 4 R 5 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 20 R 21 , C(O)NR 20 R 21 , NR 22 C(O)R 23 , C(O)R 23 , C(O)OR 23 , OC(O)R 23 , S(O) v R 23 , S(O) v OR 23 , OS(O) v R 23 , S(O) v NR 20 R 21 , OR 23 , a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; wherein each of said alkyl group, alkoxy group, alkenyl group, alkynyl group, alkoxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group is independently optionally substituted with one or more R 01 ; R a is 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 alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclyl group; each R 1 the same or different, and each is independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, amino, (CR aa R bb ) x NR 11 R 12 , (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 02 ; each R 2 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, (CR aa R bb ) x NR 11 R 12 , (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently optionally substituted with one or more R 02 ; X 1 selected from N, N + O - and CR X1 ; X 2 selected from N, N + O - and CR X2 ; X 3 selected from N, N + O - and CR X3 ; X 4 selected from N, N + O - and CR X4 ; R X1 R X2 R X3 R X4 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, (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , OS(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more R 03 ; or R X1 or R X2 and the carbon atom to which they are attached, or R X2 or R X3 and the carbon atom to which they are attached, or R X3 or R X4 and the carbon atom to which they are attached, together form a ring C, which is optionally substituted by one or more R C ​ Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; each R 01 , R 02 , R 03 , and R C are the same or different and each is independently selected from oxo, =S, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cyano, nitro, amino, (CR aa R bb ) x NR 11 R 12 , (CR aa R bb ) x C(O)NR 11 R 12 , (CR aa R bb ) x NR 13 C(O)R 14 , NR 13 C(O)NR 11 R 12 , (CR aa R bb ) x C(O)R 14 , C(O)OR 14 , OC(O)R 14 , OC(O)OR 14 , (CR aa R bb ) x S(O) v R 14 , S(O) v OR 14 , OS(O) v R 14 , (CR aa R bb ) x S(O) v NR 11 R 12 , NR 13 S(O) v R 14 , (CR aa R bb ) x C(=NR 13 )R 14 , S(=NR 13 )R 14 , S(=NR 13 )(O)R 14 , P(O)R 11 R 12 , OR 14 , =CR 15 R 16 , =NR 13 , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each of said alkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl is independently optionally substituted with one or more R * . each R 20 , R 21 , R 22 , R 23 , R 11 , R 12 , R 13 , and R 14 are the same or different and each is independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, NR 30 R 31 , C(O)NR 30 R 31 , alkyleneNR 30 R 31 , alkyleneC(O)NR 30 R 31 , NR 32 C(O)R 33 , C(O)R 33 , C(O)OR 33 , OR 33 , S(O) v R 33 , a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkylalkyl group, a heterocyclylalkyl group, an arylalkyl group, and a heteroarylalkyl group; each of said alkyl group, alkoxy group, alkoxyalkyl group, alkenyl group, alkynyl group, alkylene 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 * ; each R aa and R bb are the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxy group, a hydroxyalkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cyano group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; each R * are the same or different and each is independently selected from oxo, =S, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, cyano, alkenyl, alkynyl, NR 30 R 31 , C(O)NR 30 R 31 , alkyleneNR 30 R 31 , alkyleneC(O)NR 30 R 31 , C(O)R 33 , C(O)OR 33 , OR 33 , S(O) v R 33 , S(O) v OR 33 , S(O) v NR 30 R 31 , C(=NR 32 )R 33 , S(=NR 32 )R 33 , S(=NR 32 )(O)R 33 , P(O)R 30 R 31 , nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, and heteroarylalkyl; each R 30 , R 31 , R 32 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 alkenyl group, an alkynyl group, 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; or R 30 , R 31 and the nitrogen atom to which they are attached together form a heterocyclyl group, which is optionally substituted with one or more selected from the group consisting of oxo, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, and alkoxyalkyl; m is 0, 1, 2, 3, 4, 5 or 6; n is 0, 1, 2, 3, 4, 5 or 6; each v is the same or different, and each is independently 0, 1 or 2; and x is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or 5 or 6 membered heteroaryl; preferably, ring A is selected from phenyl, * end is connected to NR a connection.

3. A compound or pharmaceutically acceptable salt thereof according to claim 1 or 2 which is a compound of general formula (II) or a pharmaceutically acceptable salt thereof: ###0002### (II) wherein: Q is selected from N, N + -O - and CR 1a ; R 1a is a hydrogen atom or R 1 ; p is 0, 1, 2 or 3; Rings B, R B , X 1 , R X2 , R X3 , R X4 , R 1 to R 4 and n are as defined in claim 1.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a compound of general formula (III), (IV) or (V): ###00006### (III) (IV) (V) or a pharmaceutically acceptable salt thereof. wherein: R 1b and R 1c are the same or different and each independently a hydrogen atom or R 1 ; U is CR 2a or N; R 2a is a hydrogen atom or R 2 ; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2, s is 0, 1 or 2; r1 is 0, 1 or 2, s1 is 0, 1 or 2, r2 is 0, 1 or 2, s2 is 0, 1 or 2; t is 0, 1, 2 or 3, t1 is 1 or 2; t2 is 0, 1, 2 or 3, t3 is 1 or 2; X 1 , R X2 , R X3 , R X4 , Q, R 1 to R 4 , R 15 and R 16 as defined in claim 3.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N. 1 N.

6. A compound according to any one of claims 1 to 5, wherein R X2 , R X3 and R X4 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group and a 3- to 6-membered cycloalkyl group, or R X2 , R X3 and the carbon atom to which they are attached together form a 5- or 6-membered cycloalkyl group or a phenyl 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; preferably, R X2 , R X3 and R X4 are the same or different and each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group; or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 12-membered heterocyclyl; preferably, ring B is selected from the ring to which X is attached, the *end is attached to R 1 the ring to which X is attached, the *end is attached to R B the ring to which X is attached, the *end is attached to R 8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 15 and R 16 are the same or different and each independently a hydrogen atom or a halogen.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and 3- to 6-membered cycloalkyl groups, and / or R 4 It is a hydrogen atom; preferably, R 3 C 1-6 Alkyl, and / or R 4 It is a hydrogen atom.

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 (IIA) or (IIA-2) or a salt thereof: ###00006### (IIA) (IIA-2) wherein R W is an amino protecting group, preferably Boc; ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 , p, R 3 , R 2 and n are as defined in claim 3.

12. The compound according to claim 11, or a salt thereof, selected from the following compounds:

13. A process for the preparation of a compound of formula (II) or a pharmaceutically acceptable salt thereof, which process comprises: a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the reaction is carried out in the presence of an oxidizing agent, or a compound represented by General Formula (IIA-2) or a salt thereof is subjected to a deprotection reaction to obtain a compound represented by General Formula (II) or a pharmaceutically acceptable salt thereof, wherein, R W is an amino protecting group, preferably Boc; R 4 is a hydrogen atom; ring B, R B , X 1 , R X2 , R X3 , R X4 , Q, R 1 to R 3 , p and n are as defined in claim 3.

14. A pharmaceutical composition containing 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 Nav1.

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; preferably, the pain is selected from the group consisting of chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain and visceral pain.

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