Heterocyclic compound, preparation method therefor and medical use thereof

Abstract

The present disclosure relates to a heterocyclic compound, a preparation method therefor and a medical use thereof. Specifically, the present disclosure relates to a heterocyclic compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and a use thereof as a therapeutic agent, in particular, a use thereof as a Nav inhibitor and a use thereof in preparation of a drug for treating and / or relieving pain or pain-related diseases. Each group in the general formula (I) is as defined in the description.

Description

Heterocyclic compounds, preparation methods thereof and their applications in medicine Technical Field

[0001] The present disclosure belongs to the field of medicine and relates to a heterocyclic compound, a method for preparing the same, and its application in medicine. In particular, the present disclosure relates to a heterocyclic compound represented by general formula (I), a method for preparing the same, and a pharmaceutical composition containing the same, as well as its use as a Nav inhibitor and its use in the preparation of a medicament for treating and / or alleviating pain or pain-related diseases. Background Art

[0002] Pain is a complex physiological and psychological activity and one of the most common clinical symptoms. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience, accompanied by actual or potential tissue damage, which is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers and playing an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. Statistics show that about one in five people worldwide 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 throughout the skin, muscles, joints, and visceral tissues of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG), ultimately transmitting them to higher nerve centers, causing pain. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane depolarizes, sodium ion channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and relieve pain.

[0004] Nav is a class of transmembrane ion channel proteins. These proteins are composed of a 260 kDa α subunit and a 30-40 kDa β subunit. Based on the differences in the α subunit, they can be divided into nine subtypes, Nav1.1 to Nav1.9. Different subtypes exhibit distinct tissue distributions and electrophysiological and pharmacological characteristics. Based on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified as TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Nav1.1, Nav1.2, Nav1.3, and Nav1.7 are TTX-S subtypes, with their encoding genes located on human chromosomes 2q23-24. They are abundantly expressed in neurons. Nav1.5, Nav1.8, and Nav1.9 are TTX-R subtypes, with their encoding genes located on human chromosomes 3p21-24. Among them, Nav1.5 is primarily found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Nav1.4 and Nav1.6 are both TTX-S types, abundant in skeletal muscle and the central nervous system, respectively. The local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors, such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain.

[0005] Nav1.8 is a TTX-R type, encoded by the gene SCN10A. It is primarily found in trigeminal ganglion neurons and DRG neurons and exhibits the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise of the action potential is primarily composed of Nav1.8 currents. In some models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly alleviate pain while simultaneously reducing Nav1.8 expression. Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons. Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy for a variety of pain types, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0006] Nav inhibitors used in clinical practice lack subtype selectivity and can only inhibit sodium channels expressed in the heart and central nervous system. Consequently, their therapeutic window is narrow and their scope of application is limited. Nav1.8 is primarily distributed in the peripheral nervous system, so selective inhibition of Nav1.8 can effectively reduce side effects. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, improved pharmacokinetic properties, and fewer side effects.

[0007] Summary of the Invention

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

[0009] in:

[0010] X is O or S;

[0011] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0012] Ring B is a cycloalkyl group or a heterocyclic group;

[0013] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0014] Each R A , each R B and each R C are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyalkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, a cyano group, an amino group, an oxo group, -(CR x R y ) k OR 6 、-(CR x R y ) k NR 3 R 4 , -O-alkylene-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 6 、-C(O)OR 6 、-OC(O)R 6 、-OC(O)OR 6 、-NR 5 C(O)R 6 、-NR 5 C(O)OR 6 、-NR 5 C(O)NR 3 R4 、-C(=NR 5a )R 6 、-C(O)NR 3 -OR 6 、-C(O)NR 3 -NR 3 R 4 、-C(=NR 5a )NR 3 -OR 6 、-C(=NR 5a )NR 3 R 4 、-C(O)-C(O)-NR 3 R 4 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5a )(O)R 6 、-S(=NR 5a )NR 3 R 4 、-S(=NR 5a )R 6 、-S(=NR 5a )(O)NR 3 R 4 、-P(O)R 7 R 8 、=CR 9 R 10 、 -Si(O)NR 3 R 4 、-Si(R 6 )3、-(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k heteroaryl and -alkylene-O-alkylene-cycloalkyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by;

[0015] R 1 Selected from hydrogen atom, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, -alkylene-OR 6 、-alkylene-NR 3 R 4 、-(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl and -(CR x R y ) k heteroaryl;

[0016] R a and R b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, -(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k Heteroaryl, -(CR x R y ) k OR 6 and-(CR x R y ) k NR 3 R 4 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace;

[0017] Each R 01 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyalkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, a cyano group, an amino group, an oxo group, -(CR x R y )k OR 6 、-(CR x R y ) k NR 3 R 4 、-O-alkylene-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 6 、-C(O)OR 6 、-OC(O)R 6 、-OC(O)OR 6 、-NR 5 C(O)R 6 、-NR 5 C(O)OR 6 、-NR 5 C(O)NR 3 R 4 、-C(=NR 5a )R 6 、-C(O)NR 3 -OR 6 、-C(O)NR 3 -NR 3 R 4 、-C(=NR 5a )NR 3 -OR 6 、-C(=NR 5a )NR 3 R 4 、-C(O)-C(O)-NR 3 R 4 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5a )(O)R 6 、-S(=NR 5a )NR 3 R 4 、-S(=NR 5a )R 6 、-S(=NR 5a )(O)NR 3 R 4 、-P(O)R 7 R 8 、=CR 9 R10 、-Si(O)NR 3 R 4 、-Si(R 6 )3、-(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k Heteroaryl and -alkylene-O-alkylene-cycloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium atoms, halogen, hydroxy, cyano, oxo, amino, -NHalkyl, -N(alkyl)2, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH2, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0018] Each R 3 、R 4 、R 5 and R 5a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, -(CR x1 R y1 ) k1 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 、-OC(O)OR 23 、-S(O) v R 23 、-S(O) v OR 23 、-OS(O) v R 23 、-S(O) v NR 20 R 21 、-(CRx1 R y1 ) k1 OR 23 、-(CR x1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 Heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by;

[0019] or R 3 、R 4 Together with the nitrogen atom to which it is attached, a nitrogen-containing heterocyclic group is formed; the nitrogen-containing heterocyclic group is optionally substituted by one or more R 02 replaced by;

[0020] Each R 6 、R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, -(CR x1 R y1 ) k1 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 、-OC(O)OR 23 、-S(O) v R 23 、-S(O) v OR 23 、-OS(O) v R 23 、-S(O) v NR 20 R 21 、-(CR x1 R y1 ) k1 OR 23 、-(CRx1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 Heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally selected from one or more R 02 replaced by;

[0021] R 9 and R 10 are the same or different and are each independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, amino, -NH alkyl, -N(alkyl) 2, -C(O)R 23 、-C(O)OR 23 , alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, -(CR x1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 heteroaryl;

[0022] Each R 02 are the same or different and are each independently selected from a deuterium atom, a halogen, a hydroxyl group, a cyano group, an oxo group, an amino group, -NHalkyl, -N(alkyl)2, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH2, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0023] Each R 20 、R 21 、R 22 and R 23are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, alkoxy group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, and a deuterated alkoxy group;

[0024] R x 、R y 、R x1 and R y1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an -NH alkyl group, an -N(alkyl) 2 , an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0025] v is 0, 1, and 2;

[0026] a is 0, 1, 2, 3, 4, 5, or 6;

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

[0028] c is 0, 1, 2, 3, 4, 5, or 6;

[0029] k is 0, 1, 2, 3, 4, or 5;

[0030] k1 is 0, 1, 2, 3, 4 or 5.

[0031] In some embodiments of the present disclosure, the compound represented by general formula (I) is not the compound disclosed in WO2024046253.

[0032] In some embodiments of the present disclosure, the compound represented by the general formula (I) is not the following compound:

[0033] In some embodiments of the present disclosure, the compound represented by the general formula (I) is not the compound with the CAS registration number:

[0034] 3030916-04-9, 3030916-05-0, 3030916-07-2, 3030916-08-3, 3030916-12-9, 3030916-14-1, 3030916-16-3 and 3030916-17-4. In some embodiments of the present disclosure, the compound represented by the general formula (I) is not

[0035] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- to 10-membered heteroaryl group; in some embodiments, ring A is a phenyl group or a 5- or 6-membered heteroaryl group; in some embodiments, ring A is a phenyl group or a 6-membered heteroaryl group; in some embodiments, ring A is a 6-membered heteroaryl group; in some embodiments, ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and triazinyl; in some embodiments, ring A is pyridyl or phenyl; in some embodiments, ring A is pyridyl; in some embodiments, ring A is phenyl.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 5- to 10-membered heteroaryl group; in some embodiments, ring A is selected from phenyl, pyridyl, pyridine nitrogen oxide and a 9- or 10-membered heteroaryl group (in some embodiments, a 9-membered heteroaryl group); in some embodiments, ring A is a 9-membered heteroaryl group; in some embodiments, ring A is In some embodiments, Ring A is selected from phenyl, In some embodiments, Ring A is

[0037] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for where Y 1 Selected from CR Y1 , N and N + -O - ; Y 2 Selected from CR Y2 , N and N + -O - ; Y 3 Selected from CR Y3 , N and N + -O - ; Y 4 Selected from CR Y4 , N and N + -O - ; Y 5 Selected from CRY5 , N and N + -O - ; Y 1 、Y 2 、Y 3 、Y 4 and Y 5 Not N or N at the same time + -O - ; R Y1 、R Y2 、R Y3 、R Y4 and R Y5 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for Y 3 Selected from CR Y3 , N and N + -O - ; R Y4 R A ; R Y1 、R Y2 、R Y3 and R Y5 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for Y 3 Selected from CR Y3 , N and N + -O - ; R Y4 R A ; R Y1 、R Y2 and R Y3 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for R Y4 R A ; R Y1 and R Y2 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for Y 3 Selected from CR Y3 , N and N+ -O - ; R Y4 is a hydrogen atom or R A (In some embodiments, R A );R Y3 is a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for In some embodiments, for Y 4 Selected from CR Y4 , N and N + -O - ; R Y4 is a hydrogen atom or R A (In some embodiments, R A );R Y3 is a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for R Y3 is a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for

[0038] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from R Y4 is a hydrogen atom or R A (In some embodiments, R A );R Y3 is a hydrogen atom or R A ; a1 is 0, 1 or 2; R A As defined in formula (I); in some embodiments, Selected from

[0039] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring C is a 6- to 10-membered aryl group; in some embodiments, ring C is a phenyl group.

[0040] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein for X1 Selected from CR X1 , N and N + -O - ;X 2 Selected from CR X2 , N and N + -O - ;X 3 Selected from CR X3 , N and N + -O - ;X 4 Selected from CR X4 , N and N + -O - ;X 5 Selected from CR X5 , N and N + -O - ;X 1 、X 2 、X 3 、X 4 and X 5 Not N or N at the same time + -O - ; R X1 、R X2 、R X3 、R X4 and R X5 are the same or different and are each independently a hydrogen atom or R C ; R C As defined in formula (I); in some embodiments, for R X1 、R X2 and R X3 are the same or different and are each independently a hydrogen atom or R C ; R C As defined in formula (I); in some embodiments, for

[0041] 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 (II), general formula (II-M), general formula (II-1), general formula (II-2), general formula (II-B), general formula (II-3) or general formula (II-4) or a pharmaceutically acceptable salt thereof:

[0042] in:

[0043] X 1 Selected from CR X1 , N and N + -O -;

[0044] X 2 Selected from CR X2 , N and N + -O - ;

[0045] X 3 Selected from CR X3 , N and N + -O - ;

[0046] X 4 Selected from CR X4 , N and N + -O - ;

[0047] X 5 Selected from CR X5 , N and N + -O - ;

[0048] Y 1 Selected from CR Y1 , N and N + -O - ;

[0049] Y 2 Selected from CR Y2 , N and N + -O - ;

[0050] Y 3 Selected from CR Y3 , N and N + -O - ;

[0051] Y 4 Selected from CR Y4 , N and N + -O - ;

[0052] Y 5 Selected from CR Y5 , N and N + -O - ;

[0053] X 1 、X 2 、X 3 、X 4 and X 5 Not N or N at the same time + -O - ;

[0054] Y 1 、Y 2、Y 3 、Y 4 and Y 5 Not N or N at the same time + -O - ;

[0055] R X1 、R X2 、R X3 、R X4 and R X5 are the same or different and are each independently a hydrogen atom or R C ;

[0056] R Y1 、R Y2 、R Y3 、R Y4 and R Y5 are the same or different and are each independently a hydrogen atom or R A ;

[0057] Ring B, R A 、R B 、R C 、R a 、R b 、R 1 , X and b are as defined in the general formula (I).

[0058] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered cycloalkyl or a 4- to 7-membered heterocyclic group; in some embodiments, ring B is a 4- to 7-membered cycloalkyl; in some embodiments, ring B is a 5- or 6-membered cycloalkyl; in some embodiments, ring B is a cyclopentyl.

[0059] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein X is O.

[0060] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein R 1 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 1 A hydrogen atom.

[0061] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein X 1 CR X1 ;X 2 CR X2 ;X 3 CR X3 ;X 4 CR X4 ;X 5 CR X5 ; R X1 、R X2 、R X3 、R X4 and R X5 As defined in formula (II); in some embodiments, X 1 CR X1 ;X 2 CR X2 ;X 3 CR X3 ;X 4 CH; X 5 CH; R X1 、R X2 and R X3 As defined in formula (II); in some embodiments, X 1 CR X1 ; R X1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X 5 is CH; in some embodiments, X 1 CR X1 ; R X1 is methoxy; X 2 CR X2 ; R X2 F; X 3 CR X3 ; R X3 F; X 4 CH; X 5 For CH.

[0062] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 1 CR Y1 ; R Y1 As defined in formula (I); in some embodiments, Y 1 For CH.

[0063] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 2 CR Y2 ; R Y2 As defined in formula (I); in some embodiments, Y 2 For CH.

[0064] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 4 N or CR Y4 ; R Y4 As defined in formula (II); in some embodiments, Y 4 CR Y4 ; R Y4 As defined in formula (II); in some embodiments, Y 4 CR Y4 ; R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, Y 4 CR Y4 ; R Y4 is -C(O)NH2; in some embodiments, Y 4 is N;

[0065] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 5 CR Y5 ; R Y5 As defined in formula (I); in some embodiments, Y 5 For CH.

[0066] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 1 CR Y1 ; Y 2 CR Y2 ; Y 3 Selected from CR Y3 , N and N + -O - ; Y 4 CR Y4 ; Y 5 CR Y5 ; R Y1 、R Y2 、R Y3 、R Y4 and R Y5 As defined in formula (II); in some embodiments, Y 1 CR Y1 ; Y 2 CR Y2 ; Y 3 N or N + -O - ; Y 4 CR Y4 ; Y 5 CH; R Y1 、R Y2 and R Y4 As defined in formula (II); in some embodiments, Y 1 CR Y1 ; Y 2 CR Y2 ; Y 3 N; Y 4 CR Y4 ; Y 5 CH; R Y1 、R Y2 and R Y4As defined in formula (II); in some embodiments, Y 1 CH; Y 2 CH; Y 3 Selected from CR Y3 , N and N + -O - ; Y 4 CR Y4 ; Y 5 CH; R Y3 and R Y4 As defined in formula (II); in some embodiments, Y 1 CH; Y 2 CH; Y 3 Selected from CR Y3 , N and N + -O - ; Y 4 CR Y4 ; Y 5 CH; R Y3 is halogen; R Y4 Selected from -C(O)NR 3 R 4 、-C(=NR 5a )NR 3 R 4 、-C(O)NR 3 -OR 6 and a 3- to 6-membered cycloalkyl group optionally substituted with one amino group; R 3 and R 4 is a hydrogen atom; R 5a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; R 6 C 1-6 Alkyl; in some embodiments, Y 1 CH; Y 2 CH; Y 3 N; Y 4 CR Y4 ; Y 5 CH; R Y4 As defined in formula (II); in some embodiments, Y 1 CH; Y 2 CH; Y 3 CR Y3 ; Y 4 N or N + -O - ; Y 5 CH; R Y3 As defined in formula (I); in some embodiments, Y 1 CH; Y 2 CH; Y3 CR Y3 ; R Y3 C 1-6 Hydroxyalkyl; Y 4 N; Y 5 is CH; in some embodiments, Y 1 CH; Y 2 CH; Y 3 CR Y3 ; Y 4 N; Y 5 CH; R Y3 As defined in formula (I); in some embodiments, Y 1 CH; Y 2 CH; Y 3 N; Y 4 CR Y4 ; R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 As defined in general formula (I); Y 5 is CH; in some embodiments, Y 1 CH; Y 2 CH; Y 3 N; Y 4 CR Y4 ; R Y4 -C(O)NH2; Y 5 For CH.

[0067] In some embodiments of the present disclosure, the compound represented by formula (I), formula (II), formula (II-M), formula (II-1), formula (II-2), formula (II-B), formula (II-3) or formula (II-4) or a pharmaceutically acceptable salt thereof, wherein for Y 3 Selected from CR Y3 , N and N + -O - ; R Y4 R A ; R Y1 、R Y2 、R Y3 and R Y5 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for Y 3 Selected from CR Y3, N and N + -O - ; R Y4 R A ; R Y1 、R Y2 and R Y3 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for R Y4 R A ; R Y1 and R Y2 are the same or different and are each independently a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for Y 3 Selected from CR Y3 , N and N + -O - ; R Y4 is a hydrogen atom or R A (In some embodiments, R A );R Y3 is a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, for R Y3 is a hydrogen atom or R A (In some embodiments, R A );R A As defined in formula (I); in some embodiments, Selected from R Y4 is a hydrogen atom or R A (In some embodiments, R A );R Y3 is a hydrogen atom or R A ; R A As defined in formula (I); in some embodiments, Selected from and In some embodiments, for In some embodiments, for In some embodiments, for

[0068] In some embodiments of the present disclosure, the compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by general formula (III), general formula (III-M), general formula (III-1), general formula (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof:

[0069] in,

[0070] R Y4 R A ;

[0071] Y 3 Selected from CR Y3 , N and N + -O - ;

[0072] R Y1 、R Y2 、R Y3 and R Y5 are the same or different and are each independently a hydrogen atom or R A ;

[0073] R X1 、R X2 and R X3 are the same or different and are each independently a hydrogen atom or R C ;

[0074] j is 0, 1, 2, or 3;

[0075] R A 、R B 、R C 、R a 、R b and b are as defined in the general formula (I).

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6Halogenated alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl; in some embodiments, R a Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R a Selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 deuterated alkyl; in some embodiments, R a C 1-6 Alkyl or C 1-6 haloalkyl; in some embodiments, R a C 1-6 Alkyl or C 1-6 deuterated alkyl; in some embodiments, R a is methyl or trifluoromethyl; in some embodiments, R a C 1-6 Alkyl; in some embodiments, R a is selected from methyl, trideuterated methyl and trifluoromethyl; in some embodiments, R a is methyl or trideuterated methyl; in some embodiments, R a It is a methyl group.

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R b Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 hydroxyalkyl, 3 to 8 membered cycloalkyl, and 3 to 8 membered heterocyclyl; in some embodiments, R b Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R b Selected from hydrogen atoms, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R b A hydrogen atom.

[0078] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein c is 1, 2 or 3; in some embodiments, c is 3.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein each R C The same or different, and each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, each R C The same or different, and each independently selected from halogen, hydroxyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, each R C The same or different, and each independently halogen or C 1-6 Alkoxy; in some embodiments, each R C are the same or different and are each independently F or methoxy.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R X1 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X1 Selected from hydroxyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X1 C 1-6 Alkoxy; in some embodiments, R X1 It is a methoxy group.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R X2 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X2 is halogen; in some embodiments, R X2 For F.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R X3 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X3 is halogen; in some embodiments, R X3 For F.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R X2 is halogen; and / or R X3 is halogen; in some embodiments, R X2 F; and / or R X3 For F.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R X4 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X4 A hydrogen atom.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein R X5 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyloxy; in some embodiments, R X5 A hydrogen atom.

[0086] In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein a is 1, 2 or 3; in some embodiments, a is 1 or 2; in some embodiments, a is 1.

[0087] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein each R A The same or different, and each independently selected from halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, -C(O)NR 3 R 4 and -C(=NR 5a )NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; R 5a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; in some embodiments, each R A The same or different, and each independently is -C(O)NR 3 R 4 or -C(=NR 5a )NR3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; R 5a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; in some embodiments, R A -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the attached nitrogen atom, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, R A -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R A C 1-6 Hydroxyalkyl or -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R A Selected from -C(O)NH2, In some embodiments, R A C 1-6 Hydroxyalkyl; in some embodiments, R A for In some embodiments, R A It is -C(O)NH2.

[0088] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y1 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R Y1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Y1 A hydrogen atom.

[0089] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y2 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R Y2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Y2 A hydrogen atom.

[0090] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein Y 3 Selected from N, N + -O - and CR Y3 ; R Y3 is halogen; in some embodiments, Y 3 N or CR Y3 ; R Y3 As defined in formula (II); in some embodiments, Y 3 CR Y3 ; R Y3 As defined in formula (II); in some embodiments, Y 3 N or N + -O - In some embodiments, Y 3 is N; in some embodiments, Y 3 N + -O- In some embodiments, Y 3 Selected from CF, N and N + -O - In some embodiments, Y 3 is CH or CF; in some embodiments, Y 3 For CF.

[0091] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Y 3 CR Y3 ; R Y3 As defined in formula (II); in some embodiments, Y 3 CR Y3 ; R Y3 C 1-6 Hydroxyalkyl; in some embodiments, Y 3 CR Y3 ; R Y3 for

[0092] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y3 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, R Y3 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Y3 is a hydrogen atom or a halogen; in some embodiments, R Y3 is halogen; in some embodiments, R Y3 is a hydrogen atom; in some embodiments, R Y3 is F; in some embodiments, R Y3 Selected from hydrogen atoms, halogens and C 1-6 Hydroxyalkyl; in some embodiments, R Y3 Halogen or C 1-6 Hydroxyalkyl; in some embodiments, R Y3 C 1-6Hydroxyalkyl; in some embodiments, R Y3 for In some embodiments, R Y3 for

[0093] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y4 Selected from -C(O)NR 3 R 4 、-C(=NR 5a )NR 3 R 4 、-C(O)NR 3 -OR 6 and a 3- to 6-membered cycloalkyl group optionally substituted with one amino group; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; R 5a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; R 6 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R Y4 Selected from -C(O)NR 3 R 4 、-C(=NR 5a )NR 3 R 4 、-C(O)NR 3 -OR 6 and a 3- to 6-membered cycloalkyl group optionally substituted with one amino group; R 3 and R 4 is a hydrogen atom; R 5a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; R 6 C 1-6 Alkyl; in some embodiments, R Y4 Selected from -C(O)NH2,

[0094] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y4 -C(O)NR 3 R 4 or -C(=NR 5a )NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; R 5a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; in some embodiments, R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the attached nitrogen atom, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R Y4 It is -C(O)NH2.

[0095] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y5 Selected from hydrogen atoms, halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 alkoxy and 3 to 6 membered cycloalkyl; in some embodiments, RY5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, R Y5 A hydrogen atom.

[0096] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 Selected from N, N + -O - and CR Y3 ; R Y3 is halogen; and / or R Y5 is a hydrogen atom; in some embodiments, R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 Selected from CF, N and N + -O - ; and / or R Y5 is a hydrogen atom; in some embodiments, R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 N or N + -O - ; and / or R Y5 is a hydrogen atom; in some embodiments, R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 N; and / or; R Y5 is a hydrogen atom; in some embodiments, R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 N + -O - ; and / or R Y5 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the attached nitrogen atom, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; in some embodiments, R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; in some embodiments, R 3 and R 4 A hydrogen atom.

[0097] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein R 5a Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Alkoxy; in some embodiments, R 5a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; in some embodiments, R 5a Hydroxyl or C 1-6 Alkoxy; in some embodiments, R 5a is hydroxy or methoxy; in some embodiments, R 5a is selected from the group consisting of a hydrogen atom, a hydroxyl group and a methoxy group.

[0098] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein R 6 A hydrogen atom or C 1-6 Alkyl; in some embodiments, R 6 C 1-6 Alkyl; in some embodiments, R 6 It is a methyl group.

[0099] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; in some embodiments, each R B are the same or different and are each independently halogen; in some embodiments, R B For F.

[0100] In some embodiments of the present disclosure, the compounds represented by formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), formula (III-B), formula (III-3) or formula (III-4), or pharmaceutically acceptable salts thereof, wherein b is 0, 1 or 2; in some embodiments, b is 1 or 2; in some embodiments, b is 2.

[0101] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or b is 2; in some embodiments, each R B are the same or different and are each independently halogen; and / or b is 2.

[0102] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein j is 1 or 2; in some embodiments, j is 1.

[0103] In some embodiments of the present disclosure, the compounds represented by formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), formula (III-B), formula (III-3) or formula (III-4), or pharmaceutically acceptable salts thereof, wherein k is 0 or 1; in some embodiments, k is 0.

[0104] In some embodiments of the present disclosure, the compounds represented by formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), formula (III-B), formula (III-3) or formula (III-4), or pharmaceutically acceptable salts thereof, wherein k1 is 0 or 1; in some embodiments, k1 is 0.

[0105] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein R x 、R y 、R x1 and R y1 are the same or different and are each independently a hydrogen atom or a halogen; in some embodiments, R x 、R y 、R x1 and R y1 A hydrogen atom.

[0106] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein each R 6 、R 7 and R 8 The same or different, and each independently is C 1-6 Alkyl; in some embodiments, R 6 、R 7 and R 8 It is a methyl group.

[0107] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are the same or different and are each independently a hydrogen atom or a halogen.

[0108] In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein each R 01 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 In some embodiments of the present disclosure, the compound represented by the general formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), general formula (III-B), general formula (III-3) or general formula (III-4) or a pharmaceutically acceptable salt thereof, wherein each R 02 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0109] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered cycloalkyl group; each R B are the same or different and are each independently halogen; b is 0, 1 or 2; R a C 1-6 Alkyl; R b is a hydrogen atom; X is O; R 1 is a hydrogen atom; Ring A is a pyridyl group; R A -C(O)NR 3 R 4 ; R3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; or R 3 and R 4 Together with the nitrogen atom to which it is connected, it forms a 4- to 7-membered nitrogen-containing heterocyclic group; a is 1; Ring C is phenyl; each R C The same or different, and each independently halogen or C 1-6 Alkoxy; c is 1, 2 or 3.

[0110] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a cyclopentyl group; each R B are the same or different and are each independently halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; X is O; R 1 is a hydrogen atom; Ring C is a phenyl group; each R C The same or different, and each independently halogen or C 1-6 Alkoxy; c is 3; Selected from

[0111] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a cyclopentyl group; each R B are the same or different and are each independently halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; X is O; R 1 is a hydrogen atom; Ring A is a pyridyl group; R A -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; a is 1; Ring C is phenyl; each R C The same or different, and each independently halogen or C 1-6 Alkoxy; c is 3.

[0112] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a cyclopentyl group; each R B are the same or different and are each independently halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; X is O; R 1is a hydrogen atom; for R Y1 is a hydrogen atom; R Y2 is a hydrogen atom; Y 3 N or N + -O - ; R Y5 is a hydrogen atom; R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; Ring C is phenyl; each R C The same or different, and each independently halogen or C 1-6 Alkoxy; c is 3.

[0113] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a cyclopentyl group; each R B are the same or different and are each independently halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; X is O; R 1 is a hydrogen atom; for Ring C is phenyl; each R C The same or different, and each independently halogen or C 1-6 Alkoxy; c is 3.

[0114] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Ring B is a cyclopentyl group; each R B are the same or different and are each independently halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; R 1 is a hydrogen atom; X is O; X 1 CR X1 ; R X1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X5 CH; Y 1 CH; Y 2 CH; Y 3 Selected from N, N + -O - and CF;Y 4 CR Y4 ; R Y4 Selected from -C(O)NR 3 R 4 、-C(=NR 5a )NR 3 R 4 、-C(O)NR 3 -OR 6 and a 3- to 6-membered cycloalkyl group optionally substituted with one amino group; R 3 and R 4 is a hydrogen atom; R 5a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; R 6 C 1-6 Alkyl; Y 5 For CH.

[0115] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered cycloalkyl group; each R B are the same or different and are each independently halogen; b is 0, 1 or 2; R a C 1-6 Alkyl; R b is a hydrogen atom; R 1 is a hydrogen atom; X is O; X 1 CR X1 ; R X1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X 5 CH; Y 1 CH; Y 2 CH; Y 3 N or N + -O - ; Y 4 CR Y4 ; R Y4 -C(O)NR 3 R4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; Y 5 For CH.

[0116] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered cycloalkyl group; each R B are the same or different and are each independently halogen; b is 0, 1 or 2; R a C 1-6 Alkyl; R b is a hydrogen atom; R 1 is a hydrogen atom; X is O; X 1 CR X1 ; R X1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X 5 CH; Y 1 CH; Y 2 CH; Y 3 N; Y 4 CR Y4 ; R Y4 -C(O)NR 3 R 4 ; R 3 and R 4 The same or different, and each independently a hydrogen atom or a C 1-6 Alkyl; Y 5 For CH.

[0117] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein ring B is a 4- to 7-membered cycloalkyl group; each R B are the same or different and are each independently halogen; b is 0, 1 or 2; R a C 1-6 Alkyl; R b is a hydrogen atom; R 1 is a hydrogen atom; X is O; X 1 CR X1 ; RX1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X 5 CH; Y 1 CH; Y 2 CH; Y 3 CR Y3 ; R Y3 C 1-6 Hydroxyalkyl; Y 4 N; Y 5 For CH.

[0118] In some embodiments of the present disclosure, the compound represented by the general formula (II), (II-M), (II-1), (II-2), (II-B), (II-3) or (II-4) or a pharmaceutically acceptable salt thereof, wherein Ring B is a cyclopentyl group; R B is halogen; b is 2; R a C 1-6 Alkyl; R b is a hydrogen atom; R 1 is a hydrogen atom; X is O; X 1 CR X1 ; R X1 C 1-6 Alkoxy; X 2 CR X2 ; R X2 is a halogen; X 3 CR X3 ; R X3 is a halogen; X 4 CH; X 5 for CH; for

[0119] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b is a hydrogen atom; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 is halogen; R Y1 is a hydrogen atom; R Y2is a hydrogen atom; Y 3 Selected from N, N + -O - and CF;R Y4 Selected from -C(O)NH2, R Y5 is a hydrogen atom; j is 1; each R B are the same or different and are each independently halogen; b is 2.

[0120] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b is a hydrogen atom; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 is halogen; R Y1 is a hydrogen atom; R Y2 is a hydrogen atom; Y 3 N or N + -O - ; R Y4 -C(O)NH2; R Y5 is a hydrogen atom; j is 1; each R B are the same or different and are each independently halogen; b is 2.

[0121] In some embodiments of the present disclosure, the compound represented by the general formula (III), (III-M), (III-1), (III-2), (III-B), (III-3) or (III-4) or a pharmaceutically acceptable salt thereof, wherein R a C 1-6 Alkyl; R b is a hydrogen atom; R X1 C 1-6 Alkoxy; R X2 is halogen; R X3 is halogen; R Y1 is a hydrogen atom; R Y2 is a hydrogen atom; Y 3 N; R Y4 -C(O)NH2; R Y5 is a hydrogen atom; j is 1; each R B are the same or different and are each independently halogen; b is 2.

[0122] Table A Typical compounds of the present disclosure include, but are not limited to:

[0123] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof,

[0124] in:

[0125] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0126] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III).

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

[0128] in:

[0129] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0130] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-M).

[0131] Another aspect of the present disclosure relates to a compound represented by general formula (III-1A) or a salt thereof,

[0132] in:

[0133] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0134] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-1).

[0135] Another aspect of the present disclosure relates to a compound represented by general formula (III-2A) or a salt thereof,

[0136] in:

[0137] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0138] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-2).

[0139] Another aspect of the present disclosure relates to a compound represented by general formula (III-BA) or a salt thereof,

[0140] in:

[0141] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0142] R B 、R a 、R b 、R X1 、R X2 、RX3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-B).

[0143] Another aspect of the present disclosure relates to a compound represented by general formula (III-3A) or a salt thereof,

[0144] in:

[0145] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0146] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-3).

[0147] Another aspect of the present disclosure relates to a compound represented by general formula (III-4A) or a salt thereof,

[0148] in:

[0149] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0150] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-4).

[0151] Table B Typical intermediate compounds disclosed herein include, but are not limited to:

[0152] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0153] The compound represented by the general formula (IIIA) or a salt thereof undergoes an aminolysis reaction to obtain the compound represented by the general formula (III) or a pharmaceutically acceptable salt thereof;

[0154] in:

[0155] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0156] R Y4 is -C(O)NH2;

[0157] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III).

[0158] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-M) or a pharmaceutically acceptable salt thereof, the method comprising:

[0159] The compound represented by the general formula (III-MA) or a salt thereof undergoes an aminolysis reaction to obtain a compound represented by the general formula (III-M) or a pharmaceutically acceptable salt thereof;

[0160] in:

[0161] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0162] R Y4 is -C(O)NH2;

[0163] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2、Y 3 、R Y5 , j and b are as defined in the general formula (III-M).

[0164] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0165] The compound represented by the general formula (III-1A) or a salt thereof undergoes an aminolysis reaction to obtain the compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0166] in:

[0167] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0168] R Y4 is -C(O)NH2;

[0169] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-1).

[0170] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0171] The compound represented by the general formula (III-2A) or a salt thereof undergoes an aminolysis reaction to obtain the compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0172] in:

[0173] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0174] R Y4 is -C(O)NH2;

[0175] R B 、R a 、Rb 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-2).

[0176] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-B) or a pharmaceutically acceptable salt thereof, the method comprising:

[0177] The compound represented by the general formula (III-BA) or its salt undergoes aminolysis reaction to obtain the compound represented by the general formula (III-B) or its pharmaceutically acceptable salt;

[0178] in:

[0179] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0180] R Y4 is -C(O)NH2;

[0181] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-B).

[0182] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-3) or a pharmaceutically acceptable salt thereof, the method comprising:

[0183] The compound represented by the general formula (III-3A) or a salt thereof undergoes an aminolysis reaction to obtain the compound represented by the general formula (III-3) or a pharmaceutically acceptable salt thereof;

[0184] in:

[0185] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0186] R Y4 is -C(O)NH2;

[0187] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-3).

[0188] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-4) or a pharmaceutically acceptable salt thereof, the method comprising:

[0189] The compound represented by the general formula (III-4A) or a salt thereof undergoes an aminolysis reaction to obtain the compound represented by the general formula (III-4) or a pharmaceutically acceptable salt thereof;

[0190] in:

[0191] R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; in some embodiments, C 1-6 Alkoxy; in some embodiments, methoxy;

[0192] R Y4 is -C(O)NH2;

[0193] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 , j and b are as defined in the general formula (III-4).

[0194] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0195] The compound represented by general formula (Ia) or its salt undergoes a condensation reaction with the compound represented by general formula (Ib) or its salt to obtain the compound represented by general formula (I) or its pharmaceutically acceptable salt;

[0196] in:

[0197] R tis OH or a halogen; in some embodiments, a chlorine atom;

[0198] Ring A, Ring B, Ring C, R A 、R B 、R C , X, R a 、R b 、R 1 , a, b and c are as defined in the general formula (I).

[0199] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0200] The compound represented by general formula (IIa) or its salt undergoes a condensation reaction with the compound represented by general formula (IIb) or its salt to obtain the compound represented by general formula (II) or its pharmaceutically acceptable salt;

[0201] in:

[0202] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0203] Ring B, X 1 、X 2 、X 3 、X 4 、X 5 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、R 1 、R B , X, R a 、R b and b are as defined in general formula (II).

[0204] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (II-M) or a pharmaceutically acceptable salt thereof, the method comprising:

[0205] The compound represented by the general formula (II-Ma) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIb) or its salt to obtain the compound represented by the general formula (II-M) or its pharmaceutically acceptable salt;

[0206] in:

[0207] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0208] Ring B, X 1 、X2 、X 3 、X 4 、X 5 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、R 1 、R B , X, R a 、R b and b are as defined in formula (II-M).

[0209] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0210] The compound represented by general formula (II-1a) or its salt undergoes a condensation reaction with the compound represented by general formula (IIb) or its salt to obtain the compound represented by general formula (II-1) or its pharmaceutically acceptable salt;

[0211] in:

[0212] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0213] Ring B, X 1 、X 2 、X 3 、X 4 、X 5 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、R 1 、R B , X, R a 、R b and b are as defined in the general formula (II-1).

[0214] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0215] The compound represented by general formula (II-2a) or its salt undergoes a condensation reaction with the compound represented by general formula (IIb) or its salt to obtain the compound represented by general formula (II-2) or its pharmaceutically acceptable salt;

[0216] in:

[0217] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0218] Ring B, X 1 、X 2 、X 3 、X 4 、X 5 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、R 1 、R B , X, R a 、R b and b are as defined in the general formula (II-2).

[0219] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0220] The compound represented by general formula (IIIa) or its salt undergoes a condensation reaction with the compound represented by general formula (IIIb) or its salt to obtain the compound represented by general formula (III) or its pharmaceutically acceptable salt;

[0221] in:

[0222] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0223] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、Y 3 、R Y5 、R Y4 , j and b are as defined in the general formula (III).

[0224] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above general formula (III-M) or a pharmaceutically acceptable salt thereof, the method comprising:

[0225] The compound represented by the general formula (III-Ma) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIb) or its salt to obtain the compound represented by the general formula (III-M) or its pharmaceutically acceptable salt;

[0226] in:

[0227] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0228] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、R Y4 、Y 3 、R Y5 , j and b are as defined in the general formula (III-M).

[0229] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0230] The compound represented by the general formula (III-1a) or its salt undergoes a condensation reaction with the compound represented by the general formula (IIIb) or its salt to obtain the compound represented by the general formula (III-1) or its pharmaceutically acceptable salt;

[0231] in:

[0232] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0233] R B 、R a 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、R Y4 、Y 3 、R Y5 , j and b are as defined in the general formula (III-1).

[0234] Another aspect of the present disclosure relates to a method for preparing the compound represented by the above-mentioned general formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0235] The compound represented by general formula (III-2a) or its salt undergoes a condensation reaction with the compound represented by general formula (IIIb) or its salt to obtain the compound represented by general formula (III-2) or its pharmaceutically acceptable salt;

[0236] in:

[0237] R t is OH or a halogen; in some embodiments, a chlorine atom;

[0238] R B 、Ra 、R b 、R X1 、R X2 、R X3 、R Y1 、R Y2 、R Y4 、Y 3 、R Y5 , j and b are as defined in the general formula (III-2).

[0239] In some embodiments, the ammonia used in the above-mentioned ammonolysis reaction is ammonia gas, liquid ammonia, ammonia water, an alcoholic solution of ammonia or an ammonium salt, etc.; in some embodiments, it is an alcoholic solution of ammonia; in some embodiments, it is a methanolic solution of ammonia.

[0240] In some embodiments, the condensation reaction is carried out under alkaline conditions; the reagents providing alkaline conditions include organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, N,N-diisopropylethylenediamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran or 1,8-diazabicycloundec-7-ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; in some embodiments, the reagent providing alkaline conditions is triethylamine or N,N-diisopropylethylamine; in some embodiments, the reagent providing alkaline conditions is triethylamine.

[0241] When R t When OH is OH, the condensation reaction is carried out in the presence of a condensing agent; the condensing agent includes but is not limited to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N' -tetramethyluronium hexafluorophosphate, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; in some embodiments, the condensing agent is HATU.

[0242] In some embodiments, the condensation reaction is carried out in the presence of a catalyst; in some embodiments, the catalyst is 4-dimethylaminopyridine.

[0243] In some embodiments, the above reaction is 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.

[0244] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure as shown in Formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0245] The present disclosure further relates to the use of a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0246] The present disclosure further relates to the use of a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation 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.

[0247] The present disclosure further relates to the use of a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or alleviating pain or pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, idiopathic pain; in some embodiments, the postoperative pain is selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0248] The present disclosure further relates to a method for inhibiting a voltage-gated sodium channel, comprising administering to a patient in need thereof a compound of Formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0249] The present disclosure further relates to a method for treating and / or preventing a disease or condition mediated by a voltage-gated sodium channel, comprising administering to a patient in need thereof a compound of Formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or a compound shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0250] The present disclosure further relates to a method for treating and / or preventing pain or pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia, which comprises administering to a patient in need thereof a compound of Formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or a compound shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; in some embodiments, the postoperative pain is selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0251] The present disclosure further relates to a compound of Formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or as shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug; in some embodiments, for use as a drug for inhibiting the activity of voltage-gated sodium channels.

[0252] The present disclosure further relates to a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for inhibiting voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0253] The present disclosure further relates to a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a voltage-gated sodium channel inhibitor; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0254] The present disclosure further relates to a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for treating and / or preventing diseases or conditions mediated by voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0255] The present disclosure further relates to a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, 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.

[0256] The present disclosure further relates to a compound of formula (I), (II), (II-M), (II-1), (II-2), (II-B), (II-3), (II-4), (III), (III-M), (III-1), (III-2), (III-B), (III-3), (III-4) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for treating and / or preventing pain or pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; in some embodiments, the postoperative pain is selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0257] The diseases or conditions described herein are diseases or conditions that are treated and / or prevented by inhibiting voltage-gated sodium channels; in some embodiments, the voltage-gated sodium channel is Nav1.8.

[0258] In some embodiments, the disease or condition mediated by voltage-gated sodium channels described in the present disclosure is pain or a pain-related disease, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, or arrhythmia; in some embodiments, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0259] In some embodiments, the neuropathic pain described in the present disclosure is selected from trigeminal neuralgia, postherpetic neuralgia, diabetic neuropathy, painful HIV-related sensory neuralgia, burning syndrome, post-amputation pain, pain after spinal cord injury, phantom pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal autonomic cephalalgia; in some embodiments, the neuropathic pain is selected from postherpetic neuralgia, small fiber neuralgia, diabetic neuropathy, or idiopathic small fiber neuralgia.

[0260] In some embodiments, the musculoskeletal pain described in the present disclosure is selected from osteoarthritis pain, back pain, cold pain, burning pain, and toothache.

[0261] In some embodiments, the intestinal pain described in the present disclosure is selected from inflammatory bowel disease pain or Crohn's disease pain.

[0262] In some embodiments, the inflammatory pain described in the present disclosure is selected from rheumatoid arthritis pain and vulvodynia.

[0263] In some embodiments, the idiopathic pain described in the present disclosure includes fibromyalgia.

[0264] In some embodiments, the acute pain described in the present disclosure comprises acute postoperative pain.

[0265] In some embodiments, the postoperative pain described in the present disclosure includes joint replacement pain, soft tissue surgery pain, bunionectomy pain, herniorrhaphy pain, and abdominoplasty pain; in some embodiments selected from bunionectomy pain, herniorrhaphy pain, and abdominoplasty pain.

[0266] In some embodiments, the disease or disorder described in the present disclosure is selected from acute pain, chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic disorders, neurodegenerative disorders, psychiatric disorders, anxiety disorders, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, headache, neck pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or abnormal gastrointestinal motility.

[0267] The pain or pain-related disease of the present disclosure is selected from the group consisting of femoral cancer pain, non-malignant chronic bone pain, rheumatoid arthritis, osteoarthritis, spinal stenosis, neuropathic low back pain, myofascial pain syndrome, muscle fiber pain, temporomandibular joint pain, chronic visceral pain, abdominal pain, pancreatic pain, IBS pain, chronic and acute headaches, migraines, tension headaches, cluster headaches, chronic and acute neuropathic pain, post-herpetic neuralgia, diabetic neuropathy, HIV-related neuropathy, trigeminal neuralgia, Chuck-Mare-Duchesne neuropathy, hereditary sensory neuropathy, peripheral nerve injury, painful neuroma, ectopic proximal and distal discharges, radiculopathy, chemotherapy-induced neuropathic pain, radiation therapy-induced neuropathic pain, post-mastectomy pain, central pain, spinal cord injury pain, Post-stroke pain, thalamic pain, complex regional pain syndrome, phantom pain, phantom limb pain, intractable pain, acute pain, acute postoperative pain, acute musculoskeletal pain, joint pain, mechanical low back pain, neck pain, tendonitis, injury pain, movement pain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis, intestinal obstruction, hernia, chest pain, cardiac pain, pelvic pain, renal colic, acute labor pain, labor pain, cesarean section pain, acute inflammatory pain, burn pain, traumatic pain, acute intermittent pain, endometriosis, acute herpes zoster pain, sickle cell anemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiple sclerosis (MS) pain, pain in depression, leprosy pain, Behcet's disease disease pain, adiposity dolorosa, phlebitis pain, Guillain-Barre pain, leg pain and dyskinesia, Haglund syndrome, erythromelalgia, Fabry's disease pain, bladder and genitourinary disorders, urinary incontinence, pathological cough, hyperresponsive bladder, painful bladder syndrome, interstitial cystitis (IC), prostatitis, complex regional pain syndrome (CRPS) type I, complex regional pain syndrome (CRPS) type II, widespread pain, paroxysmal severe pain, pruritus, tinnitus or colic-induced pain, or interstitial cystitis pain.

[0268] The diseases or conditions of the present disclosure are selected from acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, nociceptive pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, general neuralgia, epilepsy, epileptic disorders, neurodegenerative disorders, psychiatric disorders, anxiety, depression, bipolar disorder, myotonia, arrhythmias, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, central neuropathic pain of multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, head pain, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., central neuropathic pain after stroke), cervical sprain related diseases, fragility fractures, spinal fractures, ankylosis Spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic widespread pain, diffuse idiopathic skeletal hyperostosis, pain from disc degeneration / herniation, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, spondylitis, transverse myelitis, Ehlers-Danlos syndrome, Fabry disease, mast cell hyperplasia polyarthritis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced oral mucositis, Charcot neuroarthropathy, temporomandibular joint disorder, joint replacement pain, non-cardiac chest pain, vulvar pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0269] The active compound can be formulated into a form suitable for administration by any appropriate route, and the compositions of the present disclosure can be formulated using one or more pharmaceutically acceptable carriers by conventional methods. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0270] As a general guide, the active compounds of the present disclosure are, in some embodiments, presented in unit dosage form, or in a form that a patient can self-administer as a single dose. A unit dosage form of a compound or composition of the present disclosure can be a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. Suitable unit dosage forms can range from 0.1 to 1000 mg.

[0271] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0272] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0273] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0274] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0275] The pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts.

[0276] Tablets contain the active ingredient in admixture with nontoxic, pharmaceutically acceptable excipients suitable for tablet preparation. These excipients may include inert excipients, granulating agents, disintegrants, binders, and lubricants. 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, thereby providing a sustained-release effect over a longer period of time.

[0277] Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or with a water-soluble carrier or oil-soluble vehicle.

[0278] Aqueous suspensions contain the active substance in admixture with excipients suitable for the preparation of aqueous suspensions. Such 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 sweetening agents.

[0279] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding antioxidants.

[0280] The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavorings, preservatives, and antioxidants. Such formulations may also contain demulcents, preservatives, colorants, and antioxidants.

[0281] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Sterile injectable formulations may be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in an oil phase. The injectable solution or microemulsion may be administered into the patient's bloodstream via local, bolus injection. Alternatively, the solution or microemulsion may be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain this constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous pump.

[0282] Pharmaceutical compositions of the present disclosure may be in the form of sterile water for injection or oil suspensions for intramuscular and subcutaneous administration. The suspensions may be prepared using suitable dispersants or wetting agents and suspending agents as described above according to known techniques. Sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral, nontoxic diluents or solvents. In addition, sterile fixed oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixed oil may be used. In addition, fatty acids may also be used to prepare injections.

[0283] The disclosed compounds can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0284] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0285] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the severity of the disease, the age of the patient, the 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, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dose of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0286] Terminology

[0287] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0288] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group, in some embodiments, is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), in some embodiments an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a deuterium atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0289] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, 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 alkylene group is, in some embodiments, an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), in some embodiments an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene). Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. Alkylene can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. In some embodiments, the substituent is selected from one or more of a deuterium atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0290] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined 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 2-12 The alkenyl group, in some embodiments, is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are, in some embodiments, selected from one or more of a deuterium atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0291] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined 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 2-12 The alkynyl group, in some embodiments, is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituents are, in some embodiments, selected from one or more of a deuterium atom, an alkoxy group, a halogen, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0292] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment, with the substituents being selected, in some embodiments, from one or more of a deuterium atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0293] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3- to 20-membered cycloalkyl). The cycloalkyl group is, in some embodiments, a cycloalkyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered cycloalkyl group) and a cycloalkyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered cycloalkyl group), in some embodiments a cycloalkyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered cycloalkyl group), in some embodiments a cycloalkyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered cycloalkyl group), in some embodiments a cycloalkyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered cycloalkyl group), and in some embodiments a cycloalkyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered cycloalkyl group).

[0294] Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

[0295] The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

[0296] The term "spiroalkyl" refers to a polycyclic ring system that shares a carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds within the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur within the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon 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., a 5- to 20-membered spiroalkyl). The spiroalkyl group is, in some embodiments, a spiroalkyl group having 6 to 14 ring atoms (i.e., a 6- to 14-membered spiroalkyl group), and in some embodiments, a spiroalkyl group having 7 to 10 ring atoms (i.e., a 7- to 10-membered spiroalkyl group). The spirocycloalkyl includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), in some embodiments monospirocycloalkyl or bispirocycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospirocycloalkyl. Non-limiting examples include:

[0297] Its connection point can be at any position;

[0298] wait.

[0299] The term "fused cycloalkyl" refers to a polycyclic ring system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls, or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the 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., 5-20 membered fused cycloalkyl). The fused cycloalkyl, in some embodiments, is a fused cycloalkyl having 6 to 14 ring atoms (i.e., 6-14 membered fused cycloalkyl), and in some embodiments, is a fused cycloalkyl having 7 to 10 ring atoms (i.e., 7-10 membered fused cycloalkyl). The fused cycloalkyl includes bicyclic fused cycloalkyl and polycyclic fused cycloalkyl (such as tricyclic fused cycloalkyl, tetracyclic fused cycloalkyl, etc.), in some embodiments bicyclic fused cycloalkyl or tricyclic fused cycloalkyl, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused cycloalkyl. Non-limiting examples include:

[0300] Its connection point can be at any position;

[0301] wait.

[0302] The term "bridged cycloalkyl" refers to a full-carbon polycyclic ring system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds within the 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 is, in some embodiments, a bridged cycloalkyl having 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and in some embodiments, a bridged cycloalkyl having 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), and in some embodiments, a bicyclic bridged cycloalkyl or a tricyclic bridged cycloalkyl. Non-limiting examples include:

[0303] Its connection point can be at any position.

[0304] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0305] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl) containing at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxoed, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-) in the ring, and having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclyl group is, in some embodiments, a heterocyclyl group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 3 to 10 ring atoms (i.e., a 3- to 10-membered heterocyclyl group) and a heterocyclyl group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 4 to 7 ring atoms (i.e., a 4- to 7-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclyl group); in some embodiments, a heterocyclyl group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclyl group) or a heterocyclyl group having 3 to 4 ring atoms (i.e., a 3- to 4-membered heterocyclyl group).

[0306] Non-limiting examples of the monocyclic heterocyclic group include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl.

[0307] The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

[0308] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS- or -SS-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical is a spiro heterocyclic radical (i.e., a 6 to 14 yuan spiro heterocyclic radical) with 6 to 14 ring atoms in some embodiments, and is a spiro heterocyclic radical (i.e., a 7 to 10 yuan spiro heterocyclic radical) with 7 to 10 ring atoms in some embodiments. The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a dispiro heterocyclic radical etc.), in some embodiments a monospiro heterocyclic radical or a dispiro heterocyclic radical, in some embodiments 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan monospiro heterocyclic radical. Non-limiting examples include:

[0309] wait.

[0310] The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but excluding -OO-, -OS-, or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more cycloalkyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic heterocyclyl, 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., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic radical is, in some embodiments, a fused heterocyclic radical having 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic radical), and in some embodiments, a fused heterocyclic radical having 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic radical). The fused heterocyclic radical includes bicyclic and polycyclic fused heterocyclic radicals (e.g., tricyclic fused heterocyclic radicals, tetracyclic fused heterocyclic radicals, etc.), in some embodiments, a bicyclic fused heterocyclic radical or a tricyclic fused heterocyclic radical, and in some embodiments, a 3-yuan / 4-yuan, 3-yuan / 5-yuan, 3-yuan / 6-yuan, 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 3-yuan, 5-yuan / 4-yuan, 5-yuan / 5-yuan, 5-yuan / 6-yuan, 5-yuan / 7-yuan, 6-yuan / 3-yuan, 6-yuan / 4-yuan, 6-yuan / 5-yuan, 6-yuan / 6-yuan, 6-yuan / 7-yuan, 7-yuan / 5-yuan or 7-yuan / 6-yuan bicyclic fused heterocyclic radical. Non-limiting examples include:

[0311] wait.

[0312] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds within the ring and at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), 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., a 5- to 20-membered bridged heterocyclyl). In some embodiments, the bridged heterocyclyl is a bridged heterocyclyl having 6 to 14 ring atoms (i.e., a 6- to 14-membered bridged heterocyclyl), and in some embodiments, a bridged heterocyclyl having 7 to 10 ring atoms (i.e., a 7- to 10-membered bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), and in some embodiments, it is a bicyclic bridged heterocyclic group or a tricyclic bridged heterocyclic group. Non-limiting examples include:

[0313] wait.

[0314] The heterocyclyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0315] The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., a monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., a polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 6- to 14-membered aromatic group). The aryl group, in some embodiments, is an aromatic group having 6 to 10 ring atoms (i.e., a 6- to 10-membered aromatic group). The monocyclic aromatic group is, for example, a phenyl group. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthrenyl, etc. The polycyclic aromatic group also includes a phenyl group fused to one or more heterocyclic groups or cycloalkyl groups, or a naphthyl group fused to one or more heterocyclic groups or cycloalkyl groups, wherein the connection point is on the phenyl group 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:

[0316] wait.

[0317] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, an oxo group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0318] The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatom selected from nitrogen, oxygen, and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but excluding -OO-, -OS-, or -SS-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). In some embodiments, the heteroaryl is a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), and in some embodiments, a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

[0319] The monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl and wait.

[0320] The polycyclic heteroaryl groups include, but are not limited to, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, and the like. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more aromatic 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 heteroaromatic ring system. The polycyclic heteroaryl groups also include monocyclic heteroaryl groups fused to one or more cycloalkyl or heterocyclic groups, wherein the point of attachment is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

[0321] wait.

[0322] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are, in some embodiments, selected from one or more of a deuterium atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0323] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0324] The term "heterocyclylalkyl" refers to an alkyl group substituted by one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0325] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkoxy and alkyl are as defined above.

[0326] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0327] The term "heterocyclyloxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0328] The term "aryloxy" refers to an aryl-O- group in which the aryl group is as defined above.

[0329] The term "heteroaryloxy" refers to a heteroaryl-O- group in which heteroaryl is as defined above.

[0330] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0331] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0332] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0333] The term "alkoxyalkyl" refers to an alkyl group substituted by one or more alkoxy groups, wherein alkyl and alkoxy are as defined above.

[0334] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0335] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0336] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0337] The term "hydroxyalkoxy" refers to an alkoxy group substituted with one or more hydroxy groups, wherein alkoxy is as defined above.

[0338] The term "methylidene" refers to =CH2.

[0339] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0340] The term "hydroxy" refers to -OH.

[0341] The term "mercapto" refers to -SH.

[0342] The term "amino" refers to -NH2.

[0343] The term "cyano" refers to -CN.

[0344] The term "nitro" refers to -NO2.

[0345] The term "oxo" or "oxo" refers to "=0".

[0346] The term "carbonyl" refers to C=O.

[0347] The term "acetyl" refers to -C(O)CH3.

[0348] The term "amido" refers to -C(O)NH2.

[0349] The term "carboxy" refers to -C(O)OH.

[0350] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0351] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. This includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, - and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformers and mixtures thereof (e.g., racemates, mixtures of diastereomers). The substituents in the compounds disclosed herein may have additional asymmetric atoms. All of these stereoisomers and mixtures thereof are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or chiral auxiliary agents, or, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), it can be formed into diastereomeric salts with an appropriate optically active acid or base, and then diastereomeric separation can be performed by conventional methods known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is often accomplished by chromatography.

[0352] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both and Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z or E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both Z and E are included; The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations.

[0353] In the chemical structures of the compounds described herein, the bond to the stereogenic center of the compound is or like In the formula, the relative configuration of the stereogenic center is represented by for mixture.

[0354] In the chemical structures of the compounds disclosed herein, "rac" is short for racemate (also known as raceme), which refers to an equimolar mixture of a pair of enantiomers. For example, when the compound has only one chiral center, "rac" refers to an equimolar mixture of the (R) configuration and the (S) configuration; when the compound has two chiral centers, "rac" refers to an equimolar mixture of the (R,R) configuration and the (S,S) configuration; or an equimolar mixture of the (R,S) configuration and the (S,R) configuration. Specifically, "rac-(1R,2R)" means that the compound is a racemate, which is an equimolar mixture of the (1R,2R) configuration and the (1S,2S) configuration.

[0355] The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. This includes all possible tautomers, i.e., existing as a single isomer or as a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of an enamine-imine equilibrium is shown below:

[0356] "Amidines", also known as iminoamides, are compounds in which the carbonyl oxygen atom in the amide molecule is replaced by an imino group. The imino and amino groups of the amidines can convert into each other to form tautomers. The tautomerism of amidines is shown below:

[0357] For example, when referring to pyrazolyl, it is understood to include either of the following two structures or a mixture of two tautomers:

[0358] Another example:

[0359] Another example:

[0360] All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

[0361] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium, D),3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., in some embodiments, deuterium.

[0362] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0363] Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D," are understood to have an abundance of deuterium at that position that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0364] "Optional" or "optionally" means that the event or circumstances described subsequently may but need not occur, and includes both situations in which the event or circumstances occur and do not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes both situations in which the alkyl is substituted with halogen or cyano and situations in which the alkyl is not substituted with halogen and cyano.

[0365] "Substitution" or "substituted" means that one or more hydrogen atoms, in some embodiments 1 to 6, and in some embodiments 1 to 3 hydrogen atoms, in a group are independently replaced by a corresponding number of substituents. One skilled in the art will be able to determine (by experiment or theory) whether substitution is possible or not without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

[0366] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or pharmaceutically acceptable salts thereof, and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0367] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective for use in mammals and possess the desired biological activity. They can be prepared during the final isolation and purification of the compound, or separately by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0368] The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0369] As used herein, the singular form "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0370] 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 in some embodiments, within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, a number is generally given for illustrative purposes only and is not limiting. DETAILED DESCRIPTION

[0371] The present disclosure is further described below with reference to embodiments, but these embodiments do not limit the scope of the present disclosure.

[0372] Example

[0373] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).-6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), and tetramethylsilane (TMS) was used as the internal standard.

[0374] MS was measured using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid spectrometer / mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0375] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0376] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0377] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0378] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0379] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0380] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0381] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0382] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0383] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0384] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0385] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0386] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0387] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0388] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0389] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0390] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0391] Unless otherwise specified in the examples, the reaction temperature is room temperature.

[0392] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, and C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0393] Example 1

[0394] rac-4-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinamide 1-p1 (a pair of enantiomers)

[0395] rac-4-((2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinamide 1-p2 (a pair of enantiomers)

[0396] first step

[0397] Ethyl 3,3-difluoro-2-(methoxymethoxy)cyclopent-1-ene-1-carboxylate 1b

[0398] Ethyl 3,3-difluoro-2-hydroxycyclopent-1-ene-1-carboxylate 1a (108 g, 562.03 mmol, prepared by the method disclosed in Example 42 on page 49 of the specification of patent application "WO2015028848") was dissolved in N,N-dimethylformamide (1.0 L), stirred evenly, cooled to 0°C, and N,N-diisopropylethylamine (146 g, 1.13 mol) was added. Bromomethyl methyl ether (118 g, 944.27 mmol, Shanghai Shaoyuan) was added dropwise. The temperature was maintained for 1 hour and then concentrated under reduced pressure. Ethyl acetate was added for dilution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1b (37 g, yield: 27.8%).

[0399] Step 2

[0400] (3,3-Difluoro-2-(methoxymethoxy)cyclopent-1-en-1-yl)methanol 1c

[0401] Compound 1b (37.0 g, 156.64 mmol) was dissolved in tetrahydrofuran (1.0 L), cooled to 0°C, and a 1 M solution of diisobutylaluminum hydride in n-hexane (344.7 mL) was added dropwise. After maintaining the temperature for 1 hour, methanol was added dropwise to quench the reaction. Sodium sulfate decahydrate was added and stirred for 0.5 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent System B to give the title compound 1c (11.7 g, yield: 38.4%).

[0402] Step 3

[0403] (((3,3-Difluoro-2-(methoxymethoxy)cyclopent-1-en-1-yl)methoxy)methyl)benzene 1d

[0404] Compound 1c (11.7 g, 60.2548 mmol) was dissolved in N,N-dimethylformamide (200 mL), cooled to 0°C, and sodium hydride (3.62 g, 90.5 mmol, 60% purity) was added. The temperature was maintained and stirred for 0.5 hours. Benzyl bromide (15.46 g, 90.4 mmol) was added dropwise at 0°C. The mixture was returned to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 1d (12 g, yield: 70%).

[0405] Step 4

[0406] 5-((Benzyloxy)methyl)-2,2-difluorocyclopentan-1-one 1e

[0407] Compound 1d (5.0 g, 17.59 mmol) was dissolved in dichloromethane (50 mL), cooled to 0°C, and a 4 M solution of hydrogen chloride in 1,4-dioxane (50 mL) was added. The mixture was stirred at this temperature for 1 hour. The reaction solution was concentrated under reduced pressure to give the crude title compound 1e (4.2 g). The product was used directly in the next reaction without purification.

[0408] Step 5

[0409] rac-(1R,5S)-5-((Benzyloxy)methyl)-2,2-difluoro-1-methylcyclopentan-1-ol 1f (a pair of enantiomers)

[0410] The crude compound 1e (4.2 g, 17.5 mmol) was added to tetrahydrofuran (50 mL), cooled to -78°C, and a 3 M solution of methylmagnesium bromide in 2-methyltetrahydrofuran (29.4 mL) was added dropwise. The mixture was naturally returned to room temperature with stirring and the reaction was allowed to proceed for 3 hours. Methanol was then added dropwise to quench the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent System B to give the title compound 1f (900 mg, yield: 20%).

[0411] Step 6

[0412] rac-(1R,5S)-2,2-difluoro-5-(hydroxymethyl)-1-methylcyclopentan-1-ol 1g (a pair of enantiomers)

[0413] Compound 1f (900 mg, 3.51 mmol) was dissolved in methanol (20 mL), and palladium-carbon hydrogenation catalyst (dry) (200 mg, 1.88 mmol) was added. The mixture was replaced with hydrogen and stirred for 1 hour. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain 1 g (500 mg) of the crude title compound. The product was used directly in the next reaction without purification.

[0414] Step 7

[0415] rac-(1R,2R)-3,3-difluoro-2-hydroxy-2-methylcyclopentane-1-carbaldehyde 1h (a pair of enantiomers)

[0416] The crude compound 1g (450mg, 2.71mmol) was dissolved in dichloromethane (25mL), and pyridine (2.15g, 27.2mmol) and Dess-Martin periodinane (2.30g, 5.42mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Dichloromethane was added to the reaction solution for dilution, and the mixture was washed with saturated sodium bicarbonate solution and saturated ammonium chloride solution in sequence. The organic phase was collected, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1h (100mg, yield: 22.4%).

[0417] Step 8

[0418] Ethyl rac-3-((1R,2R)-3,3-difluoro-2-hydroxy-2-methylcyclopentyl)-3-oxopropanoate 1i (a pair of enantiomers)

[0419] Ethyl diazoacetate (209 mg, 1.83 mmol, Shanghai Titan) and tin dichloride (69 mg, 305.78 μmol) were dissolved in dichloromethane (15 mL), cooled to 0°C, and a dichloromethane solution (2 mL) of compound 1h (100 mg, 609.2 μmol) was added dropwise. The mixture was naturally returned to room temperature and stirred for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1i (110 mg, yield: 72.1%).

[0420] Step 9

[0421] Ethyl rac-2-diazo-3-((1R,2R)-3,3-difluoro-2-hydroxy-2-methylcyclopentyl)-3-oxopropanoate 1j (a pair of enantiomers)

[0422] Dissolve p-Toluenesulfonyl azide (131 mg, 664.25 μmol, Shanghai Titan) in acetonitrile (5 mL) and add compound 1i (110 mg, 439.6 μmol) and triethylamine (135 mg, 186 μmol) at 0°C. Return the reaction mixture to room temperature for 3 hours. The reaction solution is concentrated under reduced pressure and the residue is purified by silica gel column chromatography with eluent system B to obtain the title compound 1j (70 mg, yield: 74.1%).

[0423] Step 10

[0424] rac-(3aR,6aR)-6,6-difluoro-6a-methyl-3-oxohexahydro-2H-pentacyclo[b]furan-2-carboxylic acid ethyl ester 1k (a pair of enantiomers)

[0425] Dimeric rhodium acetate (15 mg, 33.9 μmol) was added to toluene (5 mL), replaced with argon, heated to 100 ° C and stirred for 10 minutes, and a toluene solution (1 mL) of compound 1j (90 mg, 325.8 μmol) was added dropwise. The reaction was stirred at 100 ° C for 1 hour. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1k (80 mg). The product was used directly in the next reaction without purification.

[0426] Step 11

[0427] rac-(3aR,6aR)-6,6-difluoro-6a-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-3a,5,6,6a-tetrahydro-4H-pentacyclo[b]furan-2-carboxylic acid ethyl ester 1l (a pair of enantiomers)

[0428] The crude compound 1k (80 mg, 322.3 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (84 mg, 649.9 μmol) was added. The temperature was cooled to -78°C, and a dichloromethane solution (1 mL) of trifluoromethanesulfonic anhydride (120 mg, 425.3 μmol) was slowly added dropwise. The temperature was maintained and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 1l (80 mg, yield: 65%).

[0429] Step 12

[0430] rac-(3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methyl-3a,5,6,6a-tetrahydro-4H-pentacyclo[b]furan-2-carboxylic acid ethyl ester 1m (a pair of enantiomers)

[0431] Compound 1l (70 mg, 184.1 μmol), 3,4-difluoro-2-methoxyphenylboronic acid (55 mg, 278 μmol, Shanghai Bidex), tetrakistriphenylphosphine palladium (22 mg, 19 μmol), potassium phosphate (118 mg, 556.6 μmol) were mixed in water (0.6 mL) and 1,4-dioxane (3 mL), replaced with nitrogen, heated to 90°C with stirring for 2 hours, and the reaction solution was cooled to room temperature and added with water. The mixture was extracted with ethyl acetate (5 mL×3). The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. 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 1m (50 mg, yield: 63.1%).

[0432] Step 13

[0433] rac-(2S,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxylic acid ethyl ester 1n-1 (a pair of enantiomers)

[0434] and

[0435] Mixture of rac-(2R,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxylic acid ethyl ester 1n-2 (a pair of enantiomers)

[0436] Compound 1m (45 mg, 120.2 μmol) was dissolved in methanol (10 mL), and 10% palladium carbon catalyst (wet) (450 mg) was added. The reaction was stirred under a hydrogen atmosphere for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 1n-1 and 1n-2 (40 mg), which was used directly in the next reaction without purification.

[0437] MS m / z(ESI):377.1[M+1].

[0438] Step 14

[0439] rac-(2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxylic acid 1o-1 (a pair of enantiomers)

[0440] and

[0441] A mixture of rac-(2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxylic acid 1o-2 (a pair of enantiomers)

[0442] A crude mixture of compounds 1n-1 and 1n-2 (40 mg, 106.29 μmol) was dissolved in tetrahydrofuran (2 mL), potassium tert-butoxide (41 mg, 366.1 μmol) was added at 0°C, and the reaction was stirred at the maintained temperature for 1 hour. The reaction solution was adjusted to pH 1 with 2M hydrochloric acid solution, extracted with ethyl acetate (5 mL × 3), and the organic phases were combined, washed with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the filtrate was concentrated under reduced pressure to obtain a crude mixture of the title compounds 1o-1 and 1o-2 (35 mg), which was used directly in the next reaction without purification.

[0443] MS m / z(ESI):347.3[M-1].

[0444] Step 15

[0445] Methyl rac-4-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinate 1p-1 (a pair of enantiomers)

[0446] and

[0447] Mixture of rac-4-((2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinic acid methyl ester 1p-2 (a pair of enantiomers)

[0448] A crude mixture of compounds 1o-1 and 1o-2 (35 mg, 100.5 μmol) was dissolved in dichloromethane (2 mL), and 2 drops of N,N-dimethylformamide and oxalyl chloride (39 mg, 307.26 μmol) were added. The mixture was stirred and reacted for 2 hours. The reaction solution was concentrated under reduced pressure and then dissolved in dichloromethane (2 mL). Methyl 4-aminopyridine-2-carboxylate (31 mg, 203.7 μmol, Shanghai Shaoyuan), triethylamine (31 mg, 306.35 μmol) and a catalytic amount of 4-dimethylaminopyridine were added. The mixture was stirred and reacted 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 give a crude mixture of the title compounds 1p-1 and 1p-2 (30 mg, yield: 61.8%).

[0449] MS m / z(ESI):483.2[M+1].

[0450] Step 16

[0451] rac-4-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinamide 1-p1 (a pair of enantiomers)

[0452] rac-4-((2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-pentacyclo[b]furan-2-carboxamido)picolinamide 1-p2 (a pair of enantiomers)

[0453] A crude mixture of compounds 1p-1 and 1p-2 (30 mg, 62.19 μmol) was dissolved in 7 M ammonia methanol solution (505 μL), stirred for 16 hours, and then concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to give the title compounds (3 mg, yield: 10.3%) and (15 mg, yield: 51.6%).

[0454] A mixture of a pair of enantiomers (shorter retention time) (3 mg, yield: 10.3%)

[0455] MS m / z(ESI):468.2[M+1].

[0456] HPLC analysis: retention time 1.41 minutes, purity: 99% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0457] 1H NMR (500MHz, CD3OD): δ8.49(d,1H),8.23(d,1H),7.85(dd,1H),7.15-7.11(m,1H),7.01-6.96(m,1H),4.75(d,1H),3.98(d ,3H),3.59(t,1H),2.74(t,1H),2.53-2.41(m,1H),2.20-2.13(m,1H),1.94-1.85(m,1H),1.67-1.57(m,1H),1.53(d,3H).

[0458] A mixture of a pair of enantiomers (longer retention time) (15 mg, yield: 51.6%)

[0459] MS m / z(ESI):468.2[M+1].

[0460] HPLC analysis: retention time 1.42 minutes, purity: 92% (chromatographic column: ACQUITY C18, 1.7 μm, 2.1*50 mm; mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10%-95%).

[0461] 1 H NMR (500MHz, CD3OD): δ8.49(d,1H),8.27(d,1H),7.90(dd,1H),7.21-7.17(m,1H),7.01-6.96(m,1H),4.94(d,1H),4 .14(dd,1H),3.98(d,3H),2.96-2.91(m,1H),2.23-2.01(m,2H),1.69-1.61(m,1H),1.54(d,3H),1.44-1.37(m,1H).

[0462] Example 2

[0463] 4-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)picolinamide 2-p1

[0464] 4-((2S,3R,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)picolinamide 2-p2

[0465] or

[0466] 4-((2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)picolinamide 2-p3

[0467] 4-((2R,3S,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)picolinamide 2-p4

[0468] The compound with a longer retention time among compounds 1-p1 and 1-p2 (13 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK AS, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B 80:20, flow rate: 20 mL / min) to give the title compound (5 mg, yield: 38.4%).

[0469] Single configuration compound (shorter retention time) (5 mg, yield: 38.4%)

[0470] MS m / z(ESI):468.2[M+1].

[0471] Chiral HPLC analysis: retention time 6.604 minutes, purity: 99% (chromatographic column: CHIRALPAK AS-H, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 90:10, flow rate: 1 mL / min).

[0472] 1 H NMR (500MHz, CD3OD): δ8.49(d,1H),8.27(d,1H),7.90(dd,1H),7.21-7.17(m,1H),7.01-6.96(m,1H),4.94(d,1H),4 .14(dd,1H),3.98(d,3H),2.96-2.91(m,1H),2.23-2.01(m,2H),1.69-1.61(m,1H),1.54(d,3H),1.44-1.37(m,1H).

[0473] Single configuration compound (longer retention time) (5 mg, yield: 38.4%)

[0474] MS m / z(ESI):468.2[M+1].

[0475] Chiral HPLC analysis: retention time 24.947 minutes, purity: 99% (chromatographic column: CHIRALPAK AS-H, 5 μm, 4.6*150 mm; mobile phase: A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 90:10, flow rate: 1 mL / min).

[0476] 1 H NMR (500MHz, CD3OD): δ8.49(d,1H),8.27(d,1H),7.90(dd,1H),7.21-7.17(m,1H),7.01-6.96(m,1H),4.94(d,1H),4 .14(dd,1H),3.98(d,3H),2.96-2.91(m,1H),2.23-2.01(m,2H),1.69-1.61(m,1H),1.54(d,3H),1.44-1.37(m,1H).

[0477] Example 3

[0478] 2-Aminocarbonyl-4-((2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)pyridine 1-oxide 3-p1

[0479] or

[0480] 2-Aminocarbonyl-4-((2S,3R,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)pyridine 1-oxide 3-p2

[0481] or

[0482] 2-Aminocarbonyl-4-((2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)pyridine 1-oxide 3-p3

[0483] or

[0484] 2-Aminocarbonyl-4-((2R,3S,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamido)pyridine 1-oxide 3-p4

[0485] The compound with a longer retention time obtained by chiral resolution in Example 2 (12 mg, 25.7 μmol) was dissolved in dichloromethane (0.5 mL), and m-chloroperbenzoic acid (11 mg, 54.1 mmol, purity 85%) was added. The reaction mixture was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min) to obtain the title compound (5 mg, yield: 40.2%).

[0486] MS m / z(ESI):484.4[M+1].

[0487] 1 H NMR (500MHz, DMSO-d6): δ10.67(s,1H),10.60(d,1H),8.56(d,1H),8.31(d,1H),8.22(d,1H),7.91(dd,1H),7.25-7.22(m,1H),7.20-7.14 (m,1H),4.94(d,1H),4.08(dd,1H),3.98(d,3H),2.89-2.84(m,1H),2.21-2.02(m,2H),1.53-1.46(m,1H),1.46(d,3H),1.28-1.24(m,1H).

[0488] Example 4

[0489] (2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p1-1

[0490] (2S,3R,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p1-2

[0491] or

[0492] (2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p2-1

[0493] (2R,3S,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p2-2

[0494] first step

[0495] (R)-1-(5-Nitropyridin-2-yl)ethane-1,2-diol 4b

[0496] 5-Nitro-2-vinylpyridine 4a (1 g, 6.67 mmol, prepared by the method disclosed in "Organic Letters, 2015, vol. 17, #9, p. 2214-2217") was dissolved in tert-butanol (30 mL) and water (30 mL). AD-mix-β (15.6 g, 20 mmol, Sigma-Aldrich) was added at 0°C, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium thiosulfate solution. The organic phase was dried over anhydrous sodium sulfate and the desiccant was filtered to remove the desiccant. The filtrate was concentrated under reduced pressure to give the crude title compound 4b (1.1 g), which was used directly in the next reaction without purification.

[0497] MS m / z(ESI):185.1[M+1].

[0498] Step 2

[0499] (R)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine 4c

[0500] The crude compound 4b (1.1 g, 6.0 mmol) was dissolved in 2-methyltetrahydrofuran (30 mL) and acetone (30 mL), and 2,2-dimethoxypropane (15.6 g, 20 mmol, Shanghai Titan) and p-toluenesulfonic acid monohydrate (1.14 g, 6.0 mmol) were added. The reaction mixture was stirred for 16 hours. Ethyl acetate was added to the reaction solution to dilute it, and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to give the title compound 4c (910 mg, yield: 67.9%).

[0501] MS m / z(ESI):225.2[M+1].

[0502] Step 3

[0503] (R)-6-(2,2-Dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine 4d

[0504] Compound 4c (500 mg, 2.23 mmol) was dissolved in ethyl acetate (10 mL), and palladium-carbon hydrogenation catalyst (dry) (200 mg) was added. The mixture was replaced with hydrogen and stirred for 2 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 4d (420 mg). The product was used directly in the next reaction without purification.

[0505] MS m / z(ESI):195.0[M+1].

[0506] Step 4

[0507] (2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4e-1 (mixture of two isomers)

[0508] and

[0509] (2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4e-2 (mixture of two isomers)

[0510] A crude mixture of compounds 1o-1 and 1o-2 (200 mg, 574.2 μmol) was dissolved in dichloromethane (3 mL), and 2 drops of N,N-dimethylformamide and oxalyl chloride (145.8 mg, 1.14 mmol) were added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and then dissolved in dichloromethane (1 mL). Compound 4d (111.53 mg, 574.2 μmol), N,N-diisopropylethylamine (222.6 mg, 1.7 mmol) and a catalytic amount of 4-dimethylaminopyridine were added. The mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30mL / min) to obtain a crude mixture of the title compounds 4e-1 and 4e-2 (100mg, yield: 33.2%).

[0511] MS m / z(ESI):525.2[M+1].

[0512] Step 5

[0513] (2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p1 (mixture of two isomers)

[0514] or

[0515] (2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p2 (mixture of two isomers)

[0516] The crude mixture of compounds 4e-1 and 4e-2 (100 mg, 190.6 μmol) was dissolved in dichloromethane (1 mL), and a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL) was added. The reaction mixture was stirred for 4 hours, and the reaction solution was concentrated under reduced pressure. The pH was adjusted to neutral with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined, and the residue was purified by high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30 mL / min). Compound 4-p1 or 4-p2 with a longer retention time (45 mg, yield: 46.5%) was collected.

[0517] Chiral HPLC analysis of 4-p1 or 4-p2: retention time 7.079 minutes (49.2%), 11.963 minutes (50.7%), (chromatographic column: CHIRALPAK IG, 5 μm, 4.6*150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0518] Step 6

[0519] (2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p1-1

[0520] (2S,3R,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p1-2

[0521] or

[0522] (2S,3R,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p2-1

[0523] (2R,3S,3aR,6aS)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-6,6-difluoro-6a-methylhexahydro-2H-penta[b]furan-2-carboxamide 4-p2-2

[0524] Compound 4-p1 or 4-p2 (41 mg) was separated by chiral column (Gilson 281, chromatographic column: CHIRALPAK IG, 20*250 mm, 5 μm; mobile phase A: n-hexane, mobile phase B: ethanol, gradient ratio: A:B 80:20, flow rate: 20 mL / min) to give the title compound (13 mg, yield: 63.4%), (12 mg, yield: 58.5%).

[0525] Single configuration compound (shorter retention time) (13 mg, yield: 63.4%)

[0526] MS m / z(ESI):485.2[M+1].

[0527] Chiral HPLC analysis: retention time 6.498 minutes, purity: 99% (chromatographic column: CHIRALPAK IG, 5 μm, 4.6*150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0528] 1H NMR (500MHz, CD3OD): δ8.72(d,1H),8.09(dd,1H),7.55(d,1H),7.22(ddd,1H),7.00(q,1H),4.97(s,1H),4.74(dd,1H),4.14(dd,1 H),4.01(d,3H),3.81(dd,1H),3.67(dd,1H),2.99-2.91(m,1H),2.25-2.15(m,1H),2.10-2.03(m,1H),1.56(d,4H),1.43(td,1H).

[0529] Single configuration compound (longer retention time) (12 mg, yield: 58.5%)

[0530] MS m / z(ESI):485.2[M+1].

[0531] Chiral HPLC analysis: retention time 10.956 minutes, purity: 99% (chromatographic column: CHIRALPAK IG, 5 μm, 4.6*150 mm; mobile phase A: n-hexane, mobile phase B: ethanol (containing 0.1% diethylamine), gradient ratio: A:B 70:30, flow rate: 1 mL / min).

[0532] 1 H NMR (500MHz, CD3OD): δ8.73(d,1H),8.08(dd,1H),7.55(d,1H),7.22(ddd,1H),7.04-6.95(m,1H),4.96(d,1H),4.74(dd,1H),4.14( dd,1H),4.01(d,3H),3.81(dd,1H),3.67(dd,1H),2.95(dt,1H),2.25-2.14(m,1H),2.08(dq,1H),1.58-1.53(m,4H),1.43(tt,1H).

[0533] Biological evaluation

[0534] Test Example 1: Determination of the inhibitory activity of the disclosed compounds on Nav1.8

[0535] The purpose of this experiment is to investigate the effects of compounds on the Nav1.8 ion channel in vitro. The Nav1.8 ion channel is stably expressed in HEK293 cells. After the Nav1.8 current stabilizes, the magnitude of the Nav1.8 current before and after compound application is compared to determine the compound's effect on the Nav1.8 channel.

[0536] 1. Experimental materials and instruments

[0537] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp 700A (Axon instrument)

[0538] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon instruments)

[0539] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0540] 4) Inverted microscope: TL4 (Olympus)

[0541] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0542] 6) Microelectrode glass capillary: B12024F (Wuhan Weitan Scientific Instrument Co., Ltd.)

[0543] 7) Dimethyl sulfoxide (DMSO): D2650 (Sigma-Aldrich)

[0544] 8)TTX AF3014 (Affix Scientific)

[0545] 2. Experimental steps

[0546] 2.1 Compound preparation

[0547] All compounds used to prepare intracellular and extracellular solutions, except for NaOH and KOH used for acid-base titration, were purchased from Sigma (St. Louis, MO). The extracellular solution consisted of: NaCl, 137 mM; KCl, 4 mM; CaCl₂, 1.8 mM; MgCl₂, 1 mM; HEPES, 10 mM; and glucose, 10 mM; pH 7.4 (NaOH titration). The intracellular solution consisted of: aspartic acid, 140 mM; MgCl₂, 2 mM; EGTA, 11 mM; and HEPES, 10 mM; pH 7.2 (CsOH titration). All test and control compound solutions contained 1 μl of TTX.

[0548] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.

[0549] 2.2 Manual patch clamp test process

[0550] 1) After the compound is prepared into a solution of the specified concentration, the solution is added to each channel in order from low to high concentration, and each channel is marked.

[0551] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and place the electrode tip in contact with the cell. Set the three-way valve of the vacuum device to the three-way position. Then, apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue applying negative pressure to rupture the cell membrane, creating a current path.

[0552] 3) After the cell membrane current stabilizes, perfuse at different concentrations. If the current remains stable for at least one minute, switch to the next concentration. Each concentration should be perfused for no more than five minutes.

[0553] 4) Clean the perfusion tank. Rinse the cells in descending order of concentration, rinsing for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

[0554] 2.3 Test voltage equation (resting) and results

[0555] Cells were clamped at -80 mV and then depolarized to 10 mV with a 10-millisecond square wave to elicit Nav1.8 currents. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was measured and, after stabilization, the test compound was perfused. Once the response stabilized, the strength of the blockade was calculated.

[0556] 3. Data Analysis

[0557] Data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Management will review the results. Current stability refers to the presence of a limited range of current variation over time. The magnitude of this stable current is used to calculate the effect of the compound at that concentration.

[0558] The inhibitory activity of the disclosed compounds on Nav1.8 was determined by the above test, and the measured IC 50 See Table 1 for values.

[0559] Table 1. IC values ​​of the compounds disclosed herein for inhibition of Nav1.8 channel activity 50

[0560] Conclusion: The compounds disclosed in the present invention have a significant inhibitory effect on the activity of Nav1.8 channels.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, in: X is O or S; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is a cycloalkyl group or a heterocyclic group; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R A , each R B and each R C are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyalkoxy group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a hydroxyl group, a cyano group, an amino group, an oxo group, -(CR x R y ) k OR 6 、-(CR x R y ) k NR 3 R 4 , -O-alkylene-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 6 、-C(O)OR 6 、-OC(O)R 6 、-OC(O)OR 6 、-NR 5 C(O)R 6 、-NR 5 C(O)OR 6 、-NR 5 C(O)NR 3 R 4 、-C(=NR 5a )R 6 、-C(O)NR 3 -OR 6 、-C(O)NR 3 -NR 3 R 4 、-C(=NR 5a )NR 3 -OR 6 、-C(=NR 5a )NR 3 R 4 、-C(O)-C(O)-NR 3 R 4 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5a )(O)R 6 、-S(=NR 5a )NR 3 R 4 、-S(=NR 5a )R 6 、-S(=NR 5a )(O)NR 3 R 4 、-P(O)R 7 R 8 , =CR 9 R 10 、-Si(O)NR 3 R 4 、-Si(R 6 )3, -(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k heteroaryl and -alkylene-O-alkylene-cycloalkyl; wherein the alkyl, alkoxy, alkenyl, alkynyl, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replaced by; R 1 is selected from the group consisting of hydrogen, alkyl, halogenated alkyl, deuterated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, -alkylene-OR 6 、-Alkylene-NR 3 R 4 、-(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl and -(CR x R y ) k heteroaryl; R a and R b are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkenyl group, an alkynyl group, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a deuterated alkoxy group, -(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k Heteroaryl, -(CR x R y ) k OR 6 and-(CR x R y ) k NR 3 R 4 wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace; Each R 01 are the same or different and are each independently selected from a deuterium atom, a halogen, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a hydroxyalkoxy group, an alkoxyalkyl group, alkenyl, alkynyl, hydroxyl, cyano, amino, oxo, -(CR x R y ) k OR 6 、-(CR x R y ) k NR 3 R 4 , -O-alkylene-NR 3 R 4 、-C(O)NR 3 R 4 、-C(O)R 6 、-C(O)OR 6 、-OC(O)R 6 、-OC(O)OR 6 、-NR 5 C(O)R 6 、-NR 5 C(O)OR 6 、-NR 5 C(O)NR 3 R 4 、-C(=NR 5a )R 6 、-C(O)NR 3 -OR 6 、-C(O)NR 3 -NR 3 R 4 、-C(=NR 5a )NR 3 -OR 6 、-C(=NR 5a )NR 3 R 4 、-C(O)-C(O)-NR 3 R 4 、-S(O) v NR 3 R 4 、-NR 5 S(O) v R 6 、-S(O) v R 6 、-S(=NR 5a )(O)R 6 、-S(=NR 5a )NR 3 R 4 、-S(=NR 5a )R 6 、-S(=NR 5a )(O)NR 3 R 4 、-P(O)R 7 R 8 , =CR 9 R 10 、-Si(O)NR 3 R 4 、-Si(R 6 )3, -(CR x R y ) k Cycloalkyl, -(CR x R y ) k Heterocyclic group, -(CR x R y ) k Aryl, -(CR x R y ) k Heteroaryl and -alkylene-O-alkylene-cycloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of deuterium atoms, halogen, hydroxyl, cyano, oxo, amino, -NH alkyl, -N(alkyl)2, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH2, alkenyl, alkynyl, alkyl, haloalkyl, deuterated alkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 3 , R 4 , R 5 and R 5a are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, a hydroxyalkyl group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, -(CR x1 R y1 ) k1 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 、-OC(O)OR 23 、-S(O) v R 23 、-S(O) v OR 23 、-OS(O) v R 23 、-S(O) v NR 20 R 21 、-(CR x1 R y1 ) k1 OR 23 、-(CR x1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 Heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 02 replaced by; or R 3 , R 4 Together with the nitrogen atom to which it is attached, it forms a nitrogen-containing heterocyclic group; the nitrogen-containing heterocyclic group is optionally substituted by one or more R 02 replaced by; Each R 6 , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, -(CR x1 R y1 ) k1 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 、-OC(O)OR 23 、-S(O) v R 23 、-S(O) v OR 23 、-OS(O) v R 23 、-S(O) v NR 20 R 21 、-(CR x1 R y1 ) k1 OR 23 、-(CR x1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 Heteroaryl; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently selected from one or more R 02 replaced by; R 9 and R 10 are the same or different and are each independently selected from hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, amino, -NH alkyl, -N(alkyl)2, -C(O)R 23 、-C(O)OR 23 , alkenyl, alkynyl, alkyl, halogenated alkyl, deuterated alkyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, -(CR x1 R y1 ) k1 Cycloalkyl, -(CR x1 R y1 ) k1 Heterocyclic group, -(CR x1 R y1 ) k1 Aryl and -(CR x1 R y1 ) k1 heteroaryl; Each R 02 are the same or different and are each independently selected from a deuterium atom, a halogen, a hydroxyl, a cyano group, an oxo group, an amino group, -NH alkyl, -N(alkyl)2, -C(O)OH, -C(O)alkyl, -C(O)Oalkyl, -C(O)NH2, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkyl group oxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 20 , R 21 , R 22 and R 23 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; wherein the alkyl group, the alkoxy group, the alkenyl group, the alkynyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently optionally substituted by one or more substituents selected from a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group and a deuterated alkoxy group; R x , R y , R x1 and R y1 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, a halogen, a hydroxyl group, a cyano group, an amino group, -NH alkyl, -N(alkyl)2, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a deuterated alkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, a deuterated alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; v is 0, 1, and 2; a is 0, 1, 2, 3, 4, 5 or 6; b is 0, 1, 2, 3, 4, 5 or 6; c is 0, 1, 2, 3, 4, 5 or 6; k is 0, 1, 2, 3, 4, or 5; k1 is 0, 1, 2, 3, 4 or 5.

2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is phenyl or a 5- to 10-membered heteroaryl group; preferably, ring A is pyridyl.

3. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring C is a 6- to 10-membered aryl group; preferably, ring C is a phenyl group.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof: in: X 1 Selected from CR X1 , N and N + -O - ; X 2 Selected from CR X2 , N and N + -O - ; X 3 Selected from CR X3 , N and N + -O - ; X 4 Selected from CR X4 , N and N + -O - ; X 5 Selected from CR X5 , N and N + -O - ; Y 1 Selected from CR Y1 , N and N + -O - ; Y 2 Selected from CR Y2 , N and N + -O - ; Y 3 Selected from CR Y3 , N and N + -O - ; Y 4 Selected from CR Y4 , N and N + -O - ; Y 5 Selected from CR Y5 , N and N + -O - ; X 1 , X 2 , X 3 , X 4 and X 5 Not N or N at the same time + -O - ; Y 1 , Y 2 , Y 3 , Y 4 and Y 5 Not N or N at the same time + -O - ; R X1 , R X2 , R X3 , R X4 and R X5 are the same or different and are each independently a hydrogen atom or R C ; R Y1 , R Y2 , R Y3 , R Y4 and R Y5 are the same or different and are each independently a hydrogen atom or R A ; Ring B, R A , R B , R C , R a , R b , R 1 , x and b are as defined in claim 1.

5. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein ring B is a 4- to 7-membered cycloalkyl group or a 4- to 7-membered heterocyclic group; preferably, ring B is a cyclopentyl group.

6. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein X is O.

7. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof: in, R Y4 For R A ; Y 3 Selected from CR Y3 , N and N + -O - ; R Y1 , R Y2 , R Y3 and R Y5 are the same or different and are each independently a hydrogen atom or R A ; R X1 , R X2 and R X3 are the same or different and are each independently a hydrogen atom or R C ; j is 0, 1, 2, or 3; R A , R B , R C , R a , R b and b as defined in claim 1.

8. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R a C 1-6 Alkyl; preferably, R a It is methyl.

9. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R b A hydrogen atom.

10. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 9, wherein R X1 Selected from hydroxyl, C 1-6 alkoxy and 3 to 6-membered cycloalkyloxy; preferably, R X1 C 1-6 Alkoxy; More preferably, R X1 It is a methoxy group.

11. A compound represented by general formula (I) according to any one of claims 4 to 10 or a pharmaceutically acceptable salt thereof, wherein R X2 is halogen; and / or R X3 is halogen; preferably, R X2 is F; and / or R X3 For F.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 11, wherein R Y1 is a hydrogen atom; and / or R Y2 is a hydrogen atom; and / or Y 3 Selected from N, N + -O - and CR Y3 ; R Y3 is halogen; and / or R Y5 A hydrogen atom.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 4 to 12, wherein R Y4 Selected from -C(O)NR 3 R 4 、-C(=NR 5a )NR 3 R 4 、-C(O)NR 3 -OR 6 and a 3- to 6-membered cycloalkyl group optionally substituted with one amino group; R 3 and R 4 is a hydrogen atom; R 5a Selected from hydrogen atoms, hydroxyl groups and C 1-6 Alkoxy; R 6 C 1-6 Alkyl; preferably, R Y4 Selected from -C(O)NH2, More preferably, R Y4 It is -C(O)NH2.

14. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein each R B are the same or different and are each independently selected from halogen, C 1-6 Alkyl and C 1-6 haloalkyl; and / or b is 2; preferably, each R B are the same or different and are each independently halogen; and / or b is 2.

15. A compound or a pharmaceutically acceptable salt thereof selected from the following compounds:

16. A compound represented by the general formula (III-1A) or a salt thereof: in: R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; preferably C 1-6 Alkoxy; more preferably methoxy; R B , R a , R b , R X1 , R X2 , R X3 , R Y1 , R Y2 , Y 3 , R Y5 , j and b as defined in claim 7.

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

18. A method for preparing a compound represented by general formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (III-1A) or a salt thereof undergoes an aminolysis reaction to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof; in: R w Selected from halogen, hydroxyl and C 1-6 Alkoxy; preferably C 1-6 Alkoxy; more preferably methoxy; R Y4 is -C(O)NH2; R B , R a , R b , R X1 , R X2 , R X3 , R Y1 , R Y2 , Y 3 , R Y5 , j and b are as defined in claim 7.

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

20. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 19 in the preparation of a medicament for inhibiting voltage-gated sodium channels; preferably, the voltage-gated sodium channel is Nav1.

8.

21. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 19 in the preparation of a medicament for treating and / or alleviating pain or pain-related diseases, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia; preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

Images