Spirocyclohexyl derivative and use thereof

Abstract

The present invention relates to a spirocyclohexyl derivative and the use thereof. Particularly, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition thereof, and the use of the compound represented by general formula (I) or the pharmaceutical composition thereof, wherein the compound can be used for preventing and / or treating pain, and the substituents in general formula (I) are the same as those defined in the description.

Description

Spirocyclic cyclohexyl derivatives and their uses Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, and in particular to a spirocyclic cyclohexyl derivative and its uses. Background Technology

[0002] Pain is an unpleasant sensory and emotional experience caused by strong stimuli that damage (or potentially damage) tissue. Based on its course, pain can be divided into acute pain and chronic pain. Acute pain typically lasts less than one month; pain that persists for more than one month is called chronic pain. In the United States and Europe, approximately one-fifth of the population suffers from chronic pain, and globally, the prevalence is approximately 12% to 30%. Postoperative pain refers to acute pain that occurs immediately after surgery. It is nociceptive and is the most common and urgent type of acute pain in clinical practice. Almost all patients experience acute postoperative pain. In China, 75% of surgical patients experience significant postoperative pain. In the United States, approximately 46 million inpatients and 53 million outpatients undergo surgery annually, and 80% of these patients experience postoperative pain. Up to 45% of emergency room patients report moderate to severe pain. Severe postoperative pain can affect the function of various systems throughout the body, causing serious complications and even endangering life.

[0003] Currently, there are three main categories of drugs used clinically for pain management: First, nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen. These are numerous and their mechanism of action primarily involves inhibiting cyclooxygenase (COX), blocking the conversion of arachidonic acid into prostaglandins (PG), thereby exerting anti-inflammatory and analgesic effects. Clinically, they are mainly used to treat mild pain, such as pain caused by rheumatism, arthritis, and acute injuries, and can also be used as a combination therapy for moderate to severe pain. Second, opioids, such as morphine, oxycodone, and fentanyl, are mainly used to treat chronic and moderate to severe pain. Third, adjunctive pain management drugs, such as neurotrophic drugs, anticonvulsant drugs (e.g., carbamazepine and oxcarbazepine), and antidepressants (e.g., prozac and duloxetine), can assist analgesics in reducing pain. Due to the limitations of their mechanisms of action, the clinical application of these drugs is greatly restricted. For example, while centrally acting opioids have good analgesic effects, they also have serious side effects such as respiratory depression, constipation, nausea, vomiting, hallucinations, dizziness, and sedation. They are also accompanied by adverse reactions such as drug tolerance, physical dependence, addiction, and drug-induced hyperalgesia. Nonsteroidal anti-inflammatory drugs (NSAIDs), while lacking the side effects of opioids, have insufficient analgesic efficacy and also pose adverse reactions such as gastrointestinal bleeding and cardiovascular risks. Therefore, there is an urgent need for safer and more effective analgesics on the market.

[0004] Opioid receptors include the classical mu(μ) opioid receptor (MOR), kappa(κ) opioid receptor (KOR), and delta(δ) opioid receptor (DOR), as well as the atypical norepinephrine receptor (NOPR; also known as orphanonephrine receptor or opioid receptor-like receptor 1, ORL-1). The endogenous ligands corresponding to MOR, KOR, and DOR have been identified as endorphins, dynorphins, and enkephalins, respectively. The endogenous ligand for NOPR is norepinephrine (also known as orphanonephrine FQ (OFQ)). Studies have found that NOPR agonism provides good analgesic efficacy and can alleviate adverse reactions associated with MOR agonism. Therefore, dual-target agonists of NOPR and MOR have the potential to become novel analgesics. Summary of the Invention

[0005] The present invention provides a compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which has good physicochemical properties, such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety and low toxicity.

[0006] This invention relates to a general formula (I), general formula (Ia), general formula (Ia-1), general formula (Ia-2), general formula (II), general formula (IIA), general formula (II-1), general formula (IIA-1), general formula (II-2), general formula (IIA-2), general formula (II-3), general formula (IIA-3), general formula (II-4), general formula (IIA-4), general formula (II-5), general formula (IIA-5), general formula (II-a), general formula (II-b), general formula (II-a-1), general formula (II-b-1), general formula (II-a-2), general formula (II-b-2), general formula (II-b-2), general formula (II-a-2), general formula (II-b-2), general formula (II-a-1), general formula (II-b-1), general formula (II-b-2), general formula (II-a-2), general formula (II-b-2), general formula (II-a-1), general formula (II-b ... Compounds of formulas II-c, II-d, II-c-1, II-d-1, II-c-2, II-d-2, IV-1, IV-2, IV-3, IV-4, IV-5, IV-6, IV-1a, IV-2a, IV-3a, IV-4a, IV-5a, IV-6a, III, and III-1, their stereoisomers or pharmaceutically acceptable salts thereof:

[0007] It can be represented as a single bond or a double bond;

[0008] In some implementations, ring A is a 5-14 member heterocyclic group;

[0009] In some embodiments, ring A is a 5-membered heteroaryl-phenyl, a 5-membered heteroaryl-5-membered heteroaryl, a 5-membered heteroaryl-6-membered heteroaryl, a 5-membered heteroaryl-phenyl-5-membered heteroaryl, or a 5-membered heteroaryl-phenyl-C. 4-6 Cycloalkyl, wherein the ring attached to the parent structure is a 5-membered heteroaryl or a 6-membered heteroaryl;

[0010] In some implementations, ring A is

[0011] In some implementations, X1, X2, and X3 are each independently a bond, -O-, -S-, -Se-, -CO-, -N-, or -NR. c -、-CR a -、-CR a R b -or-CH2CR a R b - where at least one of X1, X2, and X3 is -O-, -S-, -Se-, -N-, or NR. cAnd at most one of X1, X2 and X3 is a key;

[0012] In some implementations, R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0013] In some implementations, R on the same carbon atom a and R b Linkage forms =CH2, optionally further bonded by 1-2 halogens, C 1-3 Alkyl or C 1-3 Halogenated alkyl substitution;

[0014] In some implementations, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b Link formation C 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group;

[0015] In some implementations, R c Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally further surrounded by 1-5 R groups. x Replaced;

[0016] In some implementations, X1 is -CR a R b -、X2 is -CR a R b -、X3 is -O-;

[0017] In some implementations, X1 is -CR a -、X2 is -CR a - X3 is -O-, provided that It is a double bond;

[0018] In some implementations, X1 is -O- and X2 is -CR a R b -、X3 is -CR a R b -;

[0019] In some implementations, X1 is -CR a R b - X2 is -O-, X3 is -CR a R b -;

[0020] In some implementations, X1 is -CR a - X2 is -CO-, X3 is -NR c -;

[0021] In some implementations, X1 is the key and X2 is -CR a R b -、X3 is -O-;

[0022] In some implementations, X1 is -CO- and X2 is -CR a R b -、X3 is -O-;

[0023] In some implementations, X1 is -CH2CR a R b -、X2 is -CR a R b -、X3 is -O-;

[0024] In some implementations, X1 is -O- and X2 is -CH2CR a R b -、X3 is -O-;

[0025] In some implementations, X1 is -CR a R b -、X2 is -CR a R b-、X3 is -Se-;

[0026] In some implementations, X1 is -CR a R b -; In some implementations, X1 is -CH2-,

[0027] In some implementations, X2 is -CH2-;

[0028] In some implementations, X3 is -O- or -NH-;

[0029] In some implementations, R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-4 cycloalkyl;

[0030] In some implementations, R a and R b Each can be independently hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or cyclopropyl;

[0031] In some implementations, R on the same carbon atom a and R b Linkage forms =CH2, optionally further bonded by 1-2 halogens, C 1-3 Alkyl or C 1-3 Halogenated alkyl substitution;

[0032] In some implementations, R on the same carbon atom a and R b Links form =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 (halogenated alkyl);

[0033] In some implementations, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b The linkage forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, optionally further bounded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C. 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 The group substituted by the alkyl halide group;

[0034] In some implementations, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b The linkage forms cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally further substituted by 1 to 4 groups selected from deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl;

[0035] In some implementations, R a and R b Each is independently hydrogen or C 1-3 Alkyl; or R a and R b Linkages can form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups;

[0036] In some implementations, R c Hydrogen, deuterium, halogens, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl groups, wherein the alkyl group is optionally further oxidized by 1-5 R groups. x Replaced;

[0037] In some implementations, R c The following are the compounds: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, monofluorobutyl, difluorobutyl, trifluorobutyl, -CH2CF2CH2OH;

[0038] In some implementations, R1 is -NR3R4;

[0039] In some embodiments, R3 and R4 are each independently hydrogen, deuterium, halogen, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R... x Replaced;

[0040] In some embodiments, R3 and R4 are linked to form a 3-6 membered heterocyclic alkyl group, optionally further supported by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group;

[0041] In some implementations, r is 0, 1, 2, or 3;

[0042] In some implementations, R1 is -N(C 1-3 Alkyl)2, -N(C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 alkyl)(-CH2-C 3-6 cycloalkyl)

[0043] In some implementations, R1 is -N(C 1-3 Alkyl)2,

[0044] In some implementations, R1 is -N(CH3)2,

[0045] In some implementations, R2 is

[0046] In some embodiments, ring B may or may not be present. When ring B is present, ring B is a 3-6 member monocyclic cycloalkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic cycloalkyl, a 5-12 member fused cycloalkyl, a 3-6 member monocyclic heterocyclic alkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic heterocyclic alkyl, a 5-12 member fused heterocyclic alkyl, a phenyl, a 6-10 member fused aryl, a 5-6 member monocyclic heteroaryl, or an 8-12 member fused heteroaryl.

[0047] In some implementations, L stands for key and C stands for key. 1-3 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0048] In some implementations, L stands for key and C stands for key. 1-3 Alkylene, C 2-4 imidene group, C 2-4 alkyne group, O, S, S(=O), S(=O)2, NR L C (=O), wherein the alkylene, alkenylene, or yntylide groups are optionally surrounded by 1-5 R groups. x Replaced;

[0049] In some implementations, L stands for key and C stands for key. 1-3 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced;

[0050] In some implementations, L is a key;

[0051] In some implementations, L is not a key if ring B does not exist;

[0052] In some implementations, R L For hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0053] In some implementations, R L For hydrogen, deuterium, C 1-3 alkyl;

[0054] In some implementations, each R A Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1- 6-Hydroalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0055] In some implementations, each R A Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1- 3-Hydroalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0056] In some implementations, R A The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, cyclopropyl.

[0057] In some implementations, each R B Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-6 Alkyl), =C(C) 1-6 Alkyl)2、=CH(C 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =C(C) 1-6 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0058] In some implementations, each R BEach of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkyl, C 1-3 deuterated alkoxy group, -SC 1-3 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0059] In some implementations, each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0060] In some implementations, each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl;

[0061] In some implementations... for

[0062] In some implementations... for

[0063] In some implementations, R2 is C 1-6 Alkyl or cyclic B, wherein the cyclic B is optionally further surrounded by 1-4 R B Replaced;

[0064] In some implementations, ring B may or may not exist. When ring B exists, ring B has the following structure:

[0065] In some embodiments, ring B is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, or C. 5-6 Cycloalkyl, more preferably with the following structures: phenyl,

[0066] In some embodiments, ring B is a 5-membered heteroaryl, a 6-membered heteroaryl, or C. 5-6 Cycloalkyl groups, preferably with the following structure:

[0067] In some embodiments, ring B is phenyl or a 5-membered heteroaryl group; in some embodiments, ring B is a 5-membered heteroaryl group.

[0068] In some implementations, each R B Each can be independently represented as hydrogen, deuterium, halogen, =O, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0069] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0070] In some implementations, RA1 For deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0071] In some implementation schemes, R A1 Halogen, hydroxyl, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0072] In some implementations, R A1 For deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0073] In some implementation schemes, R A1 Halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0074] In some implementation schemes, R A1 Halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0075] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0076] In some implementations, R A1 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0077] In some implementations, R A1 For hydrogen, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy;

[0078] In some implementations, R A1 For halogen; in some implementations, R A1 It is fluorine;

[0079] In some implementations, R A1 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, or ethoxy;

[0080] In some implementations, R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0081] In some implementations, R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0082] In some implementation schemes, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0083] In some implementation schemes, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0084] In some implementations, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0085] In some implementations, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy;

[0086] In some implementations, R A2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;

[0087] In some implementations, R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0088] In some implementations, R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0089] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0090] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0091] In some implementations, R A3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0092] In some implementations, R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0093] In some implementations, R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0094] In some implementation schemes, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0095] In some implementation schemes, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0096] In some implementations, R A4 It is hydrogen or halogen;

[0097] In some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0098] In some implementations, R A1 R A2 R A3 and R A4 Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0099] In some implementations, each R B Each can be independently represented as hydrogen, deuterium, halogen, =O, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy group, N(C) 1-3 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0100] In some implementations, each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0101] In some implementations, each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0102] In some implementations, each R B Each of these can be independently identified as hydrogen, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0103] In some implementations, each R B Each of these can be independently identified as hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0104] In some implementations, each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl;

[0105] In some implementations, R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0106] In some implementations, R x The compounds are fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, and trifluoromethoxy.

[0107] In some implementations, the for

[0108] In some implementations, the Selected from the following structures:

[0109] In some implementations, n is 0, 1, 2, 3, 4; in some implementations, n is 0, 1, 2, 3; in some implementations, n is 0, 1, 2; in some implementations, n is 0, 1.

[0110] In some implementations, m is 0, 1, 2, 3, 4; in some implementations, m is 0, 1, 2, 3; in some implementations, m is 0, 1, 2; in some implementations, m is 0, 1; in some implementations, m is 0.

[0111] The first specific technical solution involves a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0112] in:

[0113] It can be represented as a single bond or a double bond;

[0114] Ring A is a 5-14 membered heterocyclic group;

[0115] X1, X2, and X3 are each independently a bond, -O-, -S-, -Se-, -CO-, -N-, -NR. c -、-CR a -、-CR a R b -or-CH2CR a R b - where at least one of X1, X2, and X3 is -O-, -S-, -Se-, -N-, or NR. c And at most one of X1, X2 and X3 is a key;

[0116] R a and R b Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy or C 3-6 cycloalkyl;

[0117] Or, R on the same carbon atom a and R b Linkage forms =CH2, optionally further bonded by 1-2 halogens, C 1-3 Alkyl or C 1-3 Halogenated alkyl substitution;

[0118] Or, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b Link formation C 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group;

[0119] R c Hydrogen, deuterium, halogens, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally further surrounded by 1-5 R groups. x Replaced;

[0120] R1 is -NR3R4;

[0121] R3 and R4 are independently hydrogen, deuterium, halogen, amino, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R... x Replaced;

[0122] Alternatively, R3 and R4 are linked to form a 3-6 membered heterocyclic alkyl group, optionally further surrounded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group;

[0123] r is 0, 1, 2, or 3;

[0124] R2 is

[0125] Ring B may or may not be present. When ring B is present, ring B is a 3-6 member monocyclic cycloalkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic cycloalkyl, a 5-12 member fused cycloalkyl, a 3-6 member monocyclic heterocyclic alkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic heterocyclic alkyl, a 5-12 member fused heterocyclic alkyl, a phenyl, a 6-10 member fused aryl, a 5-6 member monocyclic heteroaryl, or an 8-12 member fused heteroaryl.

[0126] L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced;

[0127] The condition is that L is not a bond when ring B does not exist;

[0128] R L For hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0129] Each R A Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0130] Each R B Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-6 Alkyl), =C(C) 1-6 Alkyl)2、=CH(C 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =C(C) 1-6 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0131] Each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C1-6 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl;

[0132] n is 0, 1, 2, 3, or 4;

[0133] m is 0, 1, 2, 3, or 4.

[0134] Specifically, in the second technical solution, the compound represented by general formula (I) described in the first technical solution, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0135] Ring A is a 5-membered heteroaryl-phenyl, a 5-membered heteroaryl-5-membered heteroaryl, a 5-membered heteroaryl-6-membered heteroaryl, a 5-membered heteroaryl-phenyl-5-membered heteroaryl, or a 5-membered heteroaryl-phenyl-C. 4-6 Cycloalkyl, wherein the ring attached to the parent structure is a 5- or 6-membered heteroaryl group;

[0136] Alternatively, ring A is

[0137] Each R A Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0138] R1 is -N(C) 1-3 Alkyl)2, -N(C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 alkyl)(-CH2-C 3-6 cycloalkyl)

[0139] L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 alkyne group, O, S, S(=O), S(=O)2, NR L C (=O), wherein the alkylene, alkenylene, or yntylide groups are optionally surrounded by 1-5 R groups. x Replaced;

[0140] R L For hydrogen, deuterium, C 1-3 alkyl;

[0141] Each R B Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkyl, C 1-3 deuterated alkoxy group, -SC 1-3 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0142] Each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl;

[0143] The remaining definitions are the same as those in the specific first technical solution.

[0144] Specifically, in the third technical solution, the compound represented by general formula (I) described in the first or second technical solution above, its stereoisomer, or its pharmaceutically acceptable salt, wherein:

[0145] In some implementations, X1 is -CR a R b -、X2 is -CRa R b -、X3 is -O-;

[0146] In some implementations, X1 is -CR a -、X2 is -CR a - X3 is -O-, provided that It is a double bond;

[0147] In some implementations, X1 is -O- and X2 is -CR a R b -、X3 is -CR a R b -;

[0148] In some implementations, X1 is -CR a R b - X2 is -O-, X3 is -CR a R b -;

[0149] In some implementations, X1 is -CR a - X2 is -CO-, X3 is -NR c -;

[0150] In some implementations, X1 is the key and X2 is -CR a R b -、X3 is -O-;

[0151] In some implementations, X1 is -CO- and X2 is -CR a R b -、X3 is -O-;

[0152] In some implementations, X1 is -CH2CR a R b -、X2 is -CR a R b -、X3 is -O-;

[0153] In some implementations, X1 is -O- and X2 is -CH2CR a R b -、X3 is -O-;

[0154] In some implementations, X1 is -CR a R b -、X2 is -CR a R b -、X3 is -Se-;

[0155] In some implementations, R a and R bEach of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy or C 3-4 Cycloalkyl, preferably R a and R b Each can be independently hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, or cyclopropyl;

[0156] In some implementations, R on the same carbon atom a and R b Linkage forms =CH2, optionally further bonded by 1-2 halogens, C 1-3 Alkyl or C 1-3 Halogenated alkyl substitution, preferably R on the same carbon atom a and R b Links form =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 (halogenated alkyl);

[0157] In some implementations, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b The linkage forms a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, optionally further bounded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C. 1-3 Alkyl, C 2-4 alkenyl, C 2- 4-Alynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C1-3 The group substituted by the alkyl halide group, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b The linkage forms cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally further substituted by 1 to 4 groups selected from deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl or cyclopropyl;

[0158] In some implementations, R c Hydrogen, deuterium, halogens, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl groups, wherein the alkyl group is optionally further oxidized by 1-5 R groups. x The preferred alternative is R. c The following are the compounds: hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, monofluoropropyl, difluoropropyl, trifluoropropyl, monofluorobutyl, difluorobutyl, trifluorobutyl, -CH2CF2CH2OH;

[0159] The remaining definitions are the same as those of the specific first or second technical solution.

[0160] Specifically, in the fourth technical solution, the compound represented by general formula (I) described in the aforementioned first, second, or third technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein... for In some implementations... for

[0161] The remaining definitions are the same as those for the specific first, second, or third technical solutions.

[0162] Specifically, in the fifth technical solution, the compound represented by general formula (I) described in the aforementioned first, second, third, or fourth technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0163] R1 is -N(C) 1-3 Alkyl)2, In some implementations, R1 is -N(CH3)2,

[0164] L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced;

[0165] Ring B may or may not exist. If ring B exists, ring B is arbitrarily selected by 1-3 R. B The following structures are replaced:

[0166] Each R B Each can be independently represented as hydrogen, deuterium, halogen, =O, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0167] The remaining definitions are the same as those for the specific first, second, third, or fourth technical solutions.

[0168] Specifically, in the sixth technical solution, the compound represented by general formula (I) described in the aforementioned first, second, or fifth technical solutions, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0169] R1 is -N(C) 1-3 Alkyl)2, In some implementations, R1 is -N(CH3)2,

[0170] X1 is -CR a R b -; In some implementations, X1 is -CH2-,

[0171] R a and R b Each is independently hydrogen or C 1-3 Alkyl, or R a and R b Linkages can form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups;

[0172] X2 is -CH2-;

[0173] X3 is either -O- or -NH-;

[0174] for

[0175] R A1 R A2 R A3 and R A4 Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, hydroxyl, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A1 For halogen; in some implementations, R A1 It is fluorine; in some embodiments, R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; in some embodiments, R A2 It is hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy; in some embodiments, R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1- 6-alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl. In some implementations, R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy or C 1- 3-Haloalkoxy; in some embodiments, R A4 It is hydrogen or halogen; in some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0176] R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0177] In some implementations, it satisfies the following condition: (1) when R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br, C 1-6 alkoxy; (2) when R A1 R A2 R A4 When both are hydrogen, R A3 Not OH, methyl, thiazole, or pyridine; (3) When R A1 R A3 R A4 When both are hydrogen, R A2 Not F; (4) When R A1 R A4 When both are hydrogen, R A2 R A3 (5) When R is not simultaneously Cl; A1 R A3 When both are hydrogen, R A2 R A4 (6) When R is not simultaneously Cl; A3 R A4 When both are hydrogen, R A1 R A2 Not simultaneously Cl; (7) R A1 R A2 R A3 and R A4 They are not both hydrogen;

[0178] In some embodiments, when R1 is -N(CH3)2 and R2 is phenyl, the following condition is satisfied: (1) when R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br, C 1-6alkoxy; (2) when R A1 R A2 R A4 When both are hydrogen, R A3 Not OH, methyl, thiazole, or pyridine;

[0179] (3) When R A1 R A3 R A4 When both are hydrogen, R A2 Not F; (4) When R A1 R A4 When both are hydrogen, R A2 R A3 Not both Cl;

[0180] (5) When R A1 R A3 When both are hydrogen, R A2 R A4 (6) When R is not simultaneously Cl; A3 R A4 When both are hydrogen, R A1 R A2 Not simultaneously Cl; (7) R A1 R A2 R A3 and R A4 They are not both hydrogen;

[0181] In some implementations, when R A3 R A4 When both are hydrogen, R A1 R A2 Not both Cl;

[0182] The remaining definitions are the same as those for the specific first, second, or fifth technical solutions.

[0183] Specifically, the seventh technical solution refers to the compound represented by general formula (I) described in the aforementioned first, second, fifth, or sixth technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further shown as general formula (Ia), general formula (Ia-1), or general formula (Ia-2):

[0184] in:

[0185] R1 is -N(C) 1-3 Alkyl)2, In some implementations, R1 is -N(CH3)2,

[0186] X3 is either -O- or -NH-;

[0187] RA1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, hydroxyl, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A1 For halogen; in some implementations, R A1 It is fluorine;

[0188] R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; in some embodiments, R A2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;

[0189] R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1- 3-alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0190] R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A4 It is hydrogen or halogen; in some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0191] Ring B is a 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic cycloalkyl, 5-12 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic heterocyclic alkyl, 5-12 member fused heterocyclic alkyl, phenyl, 6-10 member fused aryl, 5-6 member monocyclic heteroaryl, 8-12 member fused heteroaryl, preferably phenyl, 5-hemaryl, 6-hemaryl, C 5-6 Cycloalkyl groups, preferably with ring B being phenyl or a 5-membered heteroaryl group, and more preferably with the following structures: phenyl,

[0192] Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0193] R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0194] m is 0, 1, 2, or 3;

[0195] In some implementations, when R A3 R A4 When both are hydrogen, R A1 R A2 They are not both Cl.

[0196] Specifically, the eighth technical solution refers to the compound represented by general formula (I) described in the aforementioned first, second, fifth, sixth, or seventh technical solutions, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein general formula (I) is further shown as general formula (II) or general formula (II-1):

[0197] in:

[0198] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0199] R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0200] R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced;

[0201] R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, or -SO2-C. 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0202] Each R B Each can be independently represented as hydrogen, deuterium, halogen, =O, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkyl, C 1-3 Deuterated alkoxy group, N(C) 1-3 Alkyl group 2, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced;

[0203] In some implementations, each R B Each of these can be independently identified as hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0204] Each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl;

[0205] m is 0, 1, 2, or 3;

[0206] The premise is that the following conditions are met: (1) When R A1 R A2 R A4 When both are hydrogen, R A3 Not F, Br, OH, methyl, methoxy, thiazole, or pyridine; (2) when R A1 R A4 When both are hydrogen, R A2 R A3 (3) When R is not simultaneously Cl; A1 R A3 When both are hydrogen, R A2 R A4 (4) When R is not simultaneously Cl; A1 R A2 When both are hydrogen, R A3 R A4 (5) R A1 R A2 R A3 and R A4 They are not both hydrogen.

[0207] Specifically, in the ninth technical solution, the compound represented by general formula (I) described in the aforementioned first, second, fifth, sixth, or seventh technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented as general formula (II), general formula (IIA), general formula (II-1), general formula (IIA-1), general formula (II-2), general formula (IIA-2), general formula (II-3), general formula (IIA-3), general formula (II-4), general formula (IIA-4), general formula (II-5), and general formula (IIA-5):

[0208] in:

[0209] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, hydroxyl, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A1 For halogen; in some implementations, R A1 It is fluorine;

[0210] R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-6Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; in some embodiments, R A2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;

[0211] R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C1- 3-alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0212] R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A4 It is hydrogen or halogen; in some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0213] Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C1-6 Halogenated alkoxy groups;

[0214] R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0215] m is 0, 1, 2, or 3;

[0216] The premise is: when R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br or C 1-6 Alkoxy;

[0217] In some implementations, general formulas (II), (IIA), (II-1), (IIA-1), (II-2), and (IIA-2) satisfy the following condition: (1) when R A1 R A2 R A4 When both are hydrogen, R A3 Not OH, methyl, thiazole, pyridine; (2) when R A1 R A3 R A4 When both are hydrogen, R A2 Not F; (3) When R A1 R A4 When both are hydrogen, R A2 R A3 (4) When R is not simultaneously Cl; A1 R A3 When both are hydrogen, R A2 R A4 (5) When R is not simultaneously Cl; A3 R A4 When both are hydrogen, R A1 R A2 Not simultaneously Cl; (6)R A1 R A2 R A3 and R A4 They are not both hydrogen;

[0218] In some implementations, when R A3 R A4 When both are hydrogen, R A1 R A2 They are not both Cl.

[0219] Specifically, the tenth technical solution refers to the compound represented by general formula (I) described in the aforementioned first, second, fifth, sixth, or seventh technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented as general formula (II-a), general formula (II-b), general formula (II-a-1), general formula (II-b-1), general formula (II-a-2), general formula (II-b-2), general formula (II-c), general formula (II-d), general formula (II-c-1), general formula (II-d-1), general formula (II-c-2), and general formula (II-d-2):

[0220] in:

[0221] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, hydroxyl, cyano, amino, -SF5, -SCF3, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1- 6-hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A1 Halogen, cyano, C 1-3 Alkyl, C 1- 3-Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A1 For halogen; in some implementations, R A1 It is fluorine;

[0222] RA2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A2 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy; in some embodiments, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy; in some embodiments, R A2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;

[0223] R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, RA3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 It is hydrogen, halogen, cyano, C 1- 3-alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; in some implementations, R A3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0224] R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; in some embodiments, R A4 It is hydrogen, deuterium, halogen, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; in some embodiments, R A4It is hydrogen or halogen; in some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0225] Ring B is a 5-membered heteroaryl, 6-membered heteroaryl, or C 5-6 Cycloalkyl, preferably with ring B being a 5-membered heteroaryl group, preferably with the following structure:

[0226] Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0227] R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0228] m is 0, 1, 2, or 3;

[0229] The premise is: when R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br or C 1-6 Alkoxy;

[0230] In some embodiments, general formulas (II-a), (II-b), (II-a-1), (II-b-1), (II-a-2), and (II-b-2) satisfy the following condition: (1) when R2 is cyclopentyl, cyclohexyl, R B When it is hydrogen, R A1 R A2 R A3 and R A4 (2) When R2 is not both hydrogen; R B For hydrogen, R A1 R A3 and R A4 When it is hydrogen, R A2 Not fluorine;

[0231] In some implementations, when R A3 R A4 When both are hydrogen, R A1 R A2 They are not both Cl.

[0232] Specifically, in the eleventh technical solution, the compound represented by general formula (I) described in the aforementioned first, second, or fifth technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented as general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV-6), general formula (IV-1a), general formula (IV-2a), general formula (IV-3a), general formula (IV-4a), general formula (IV-5a), and general formula (IV-6a):

[0233] in:

[0234] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0235] R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0236] R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0237] R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0238] R2 is C 1-6 Alkyl or cyclic B, wherein the cyclic B is optionally further surrounded by 1-4 R B Replaced;

[0239] Ring B, R a R b and R B The definition is the same as that of the specific first, second, third, fifth, sixth, or seventh technical solutions.

[0240] Specifically, the twelfth technical solution refers to the general formulas (I), (Ia), (Ia-1), (Ia-2), (II), (IIA), (II-1), (IIA-1), (II-2), (IIA-2), (II-3), (IIA-3), (II-4), (IIA-4), (II-5), (IIA-5), (II-a), (II-b), (II-a-1), (II-b-1), and (II-a-2) described in the aforementioned sixth, seventh, eighth, ninth, tenth, or eleventh technical solutions. Compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, represented by general formulas (II-b-2), (II-c), (II-d), (II-c-1), (II-d-1), (II-c-2), (II-d-2), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-1a), (IV-2a), (IV-3a), (IV-4a), (IV-5a), and (IV-6a), which satisfy one or more of the following embodiments:

[0241] In some implementations, R A1 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy;

[0242] In some implementations, R A1 For hydrogen, halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy;

[0243] In some implementations, R A1 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, or ethoxy;

[0244] In some implementations, R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy;

[0245] In some implementations, R A2 For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Alkoxy;

[0246] In some implementations, R A2It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy, or ethoxy;

[0247] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0248] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0249] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0250] In some implementations, R A3 It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 The alkyl group, cyclopropyl group, cyclobutyl group, 5-membered heterocyclic alkyl group, 6-membered heterocyclic alkyl group, 5-membered heteroaryl group, 6-membered heteroaryl group, -O-cyclopropyl group, or -O-cyclobutyl group, wherein the alkyl group, cyclopropyl group, cyclobutyl group, heterocyclic alkyl group, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0251] In some implementations, RA3 The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0252] In some implementations, R A4 It is hydrogen or halogen;

[0253] In some implementations, R A4 It can be hydrogen, fluorine, chlorine, or bromine;

[0254] In some implementations, each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0255] In some implementations, each R B Each of these can be independently identified as hydrogen, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0256] The remaining definitions are the same as those for the specific first, second, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh technical solutions.

[0257] Specifically, the thirteenth technical solution refers to the general formulas (I), (Ia), (Ia-1), (Ia-2), (II), (IIA), (II-1), (IIA-1), (II-2), (IIA-2), (II-3), (IIA-3), (II-4), (IIA-4), (II-5), (IIA-5), (II-a), (II-b), (II-a-1), and (II-b-1) described in the aforementioned sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth technical solutions. Compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, represented by general formulas (II-a-2), (II-b-2), (II-c), (II-d), (II-c-1), (II-d-1), (II-c-2), (II-d-2), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-1a), (IV-2a), (IV-3a), (IV-4a), (IV-5a), and (IV-6a), wherein:

[0258] R A1 It is a halogen, preferably fluorine;

[0259] R A2 It is hydrogen, halogen or C 1-6 Alkoxy; preferably hydrogen, halogen or C 1-3 Alkyl groups, more preferably hydrogen, fluorine, chlorine, bromine, methoxy, or ethoxy groups;

[0260] R A3 It is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine;

[0261] R A4 It is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine;

[0262] The condition is that when R A3 R A4 When both are hydrogen, R A1 R A2 Not both Cl;

[0263] The remaining definitions are the same as those for the specific first, second, third, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth technical solutions.

[0264] Specifically, the fourteenth technical solution refers to the general formulas (I), (Ia), (Ia-1), (Ia-2), (II), (IIA), (II-1), (IIA-1), (IIA-1), (II-2), (IIA-2), (II-3), (IIA-3), (II-4), (IIA-4), (II-5), (IIA-5), (II-a), (II-b), (II-a-1), (II-b-1), and (II-b-1) mentioned in the aforementioned sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth technical solutions. Compounds of formula (II-a-2), general formula (II-b-2), general formula (II-c), general formula (II-d), general formula (II-c-1), general formula (II-d-1), general formula (II-c-2), general formula (II-d-2), general formula (IV-1), general formula (IV-2), general formula (IV-3), general formula (IV-4), general formula (IV-5), general formula (IV-6), general formula (IV-1a), general formula (IV-2a), general formula (IV-3a), general formula (IV-4a), general formula (IV-5a), and general formula (IV-6a), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein... Selected from the following structures:

[0265] The remaining definitions are the same as those for the specific first, second, third, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth technical solutions.

[0266] Specifically, the fifteenth technical solution refers to the compound represented by general formula (I) described in the aforementioned first, second, third, fourth, or fifth technical solutions, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further shown as general formula (III) or general formula (III-1):

[0267] in:

[0268] In the general formula (III) and general formula (III-1) As described in the aforementioned fourth technical solution;

[0269] R2 is C 1-6 Alkyl or cyclic B, wherein the cyclic B is optionally further surrounded by 1-4 R B Replaced;

[0270] Ring B, R A R B The definition of n is the same as that of the specific first, second, third, fourth, or fifth technical solutions.

[0271] Specifically, in the sixteenth technical solution, the compounds represented by general formula (I), general formula (III), or general formula (III-1), their stereoisomers, or pharmaceutically acceptable salts thereof described in the aforementioned first, second, third, fourth, fifth, or fifteenth technical solutions, satisfy one or more of the following embodiments:

[0272] In some implementations, R A It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0273] In some implementations, R A It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0274] In some implementations, R A It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-4 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced;

[0275] In some implementations, R A It is hydrogen, halogen, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3The alkyl group, cyclopropyl group, cyclobutyl group, 5-membered heterocyclic alkyl group, 6-membered heterocyclic alkyl group, 5-membered heteroaryl group, 6-membered heteroaryl group, -O-cyclopropyl group, or -O-cyclobutyl group, wherein the alkyl group, cyclopropyl group, cyclobutyl group, heterocyclic alkyl group, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0276] In some implementations, R A The following groups are used: hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl.

[0277] In some implementations, each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups;

[0278] In some implementations, each R B Each of these can be independently identified as hydrogen, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

[0279] The remaining definitions are the same as those of the specific first, second, third, fourth, fifth, or fifteenth technical solutions.

[0280] Specifically, in the seventeenth technical solution, the general formula (I) is selected from compounds in Table 1, Table 2, or Table 3 below:

[0281] Table 1:

[0282] Table 2:

[0283] Table 3:

[0284] Secondly, the present invention also provides a pharmaceutical composition comprising any of the compounds described in any of the foregoing technical solutions, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0285] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0286] Furthermore, the present invention also provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in any of the foregoing technical solutions in the preparation of a medicament, preferably the medicament being a medicament for treating / preventing NOP and opioid receptor-mediated diseases; in some embodiments, the NOP and opioid receptor-mediated diseases are selected from pain.

[0287] The present invention also provides a method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably pain.

[0288] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammals described in the present invention include humans.

[0289] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound, conjugate, or pharmaceutically acceptable salt thereof disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0290] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of any of the compounds shown above, their stereoisomers, or their pharmaceutically acceptable salts.

[0291] The present invention further relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of any of the compounds shown above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, in any of the above amounts of 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0292] The present invention further relates to a method for treating a disease in mammals, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or multiple doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0293] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims of this invention, wherein the amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is the same as that in the preceding pharmaceutical composition.

[0294] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0295] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0296] Synthetic route

[0297] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0298] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals in the catalogue can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services to standard chemical supply plants (such as those listed above).

[0299] the term

[0300] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0301] 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 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. When the alkyl group is substituted with a substituent, the substituent is no longer subject to further substitution.

[0302] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0303] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0304] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically comprising 2 to 18 carbon atoms, further comprising 2 to 8 carbon atoms, further comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable linker. When the alkynyl group is substituted by a substituent, the substituent is not further substituted.

[0305] "Cycloalkyl" refers to a fully saturated hydrocarbon ring, whether substituted or unsubstituted, which can be monocyclic, bicyclic, or polycyclic. Bicyclic or polycyclic rings can be fused, spirocyclic, or bridged rings. Unless otherwise specified, they typically have 3 to 20 carbon atoms. When it is a monocyclic cycloalkyl ring, it preferably has 3-15 carbon atoms, more preferably 3-10 carbon atoms, even more preferably 3-8 carbon atoms, more preferably 3-6 carbon atoms, and even more preferably 3-5 carbon atoms, 3-4 carbon atoms, or 4-5 carbon atoms. When it is a bicyclic or polycyclic cycloalkyl ring, it preferably has 4-12 carbon atoms, more preferably 4-11 carbon atoms, even more preferably 5-11 carbon atoms, more preferably 6-11 carbon atoms, and even more preferably 6-10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. wait.

[0306] "Cycloalkenyl" refers to a non-aromatic hydrocarbon ring, whether substituted or unsubstituted, containing at least one unsaturated bond. It can be monocyclic, bicyclic, or polycyclic, and bicyclic or polycyclic rings can be fused, spirocyclic, or bridged. Non-limiting examples include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0307] "Heterocyclic alkyl" refers to a fully saturated heterocycle, which generally has 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to a carbon atom, the heterocyclic alkyl also contains 1 to 5 heteroatoms selected from N, S, O, Si, P, B, and Se as ring members. Non-limiting examples include azirrobutyl, morpholino, piperazinyl, piperidinyl, tetrahydropyranyl, and oxocyclic butyl.

[0308] "Heterocyclic alkenyl" refers to a non-aromatic heterocycle containing at least one unsaturated bond, generally having 4 to 12 ring members, preferably 4 to 10 ring members, more preferably 4 to 7 ring members, and even more preferably 5 or 6 ring members. In addition to a carbon atom, the heterocyclic alkyl group also contains 1 to 3 heteroatoms selected from N, S, O, Si, P, B, and Se as ring members. Non-limiting examples include nitrogen-heterocyclic butyl, morpholinyl, piperazine, piperidinyl, tetrahydropyranyl, and oxocyclic butyl.

[0309] "Heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring. Unless otherwise specified, it contains 1 to 3 heteroatoms selected from N, O, S, P, B, and Se, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl groups and heteroaryl groups. The N and S atoms in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl and oxaspiro[3.3]heptyl, wait.

[0310] "Carbocyclic" or "carbocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic carbocyclic group, including monocyclic carbocyclic, bicyclic bridged ring, bicyclic fused ring, and bicyclic spirocyclic groups, etc. Unless otherwise specified, it has 3 to 12 carbon atoms, preferably 3 to 10 carbon atoms, and more preferably 3 to 6 carbon atoms. Its definition includes cycloalkyl and aryl groups. In non-limiting embodiments, monocyclic carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or phenyl. The double-ring bridge includes... Etc., double-ring parallel rings include etc., double-ring spiral rings include wait.

[0311] "Aryl" refers to a substituted or unsubstituted 5- to 15-membered aromatic carbon ring, including monocyclic and fused-ring aromatic groups. Preferably, it is a 5- to 10-membered aromatic ring, more preferably a 5- to 8-membered aromatic ring; the aryl ring may be fused to a non-aryl ring (e.g., heteroaryl, heterocycloalkyl, or cycloalkyl ring), wherein the aryl ring is the linking site. "xy-membered aryl" indicates that the total number of aryl ring atoms is x to y, which can be a phenyl fused or non-aromatic ring, wherein the aromatic ring is the linking site. For example, "7-12-membered aryl" indicates that the aryl group serves as the linking site, and the total number of ring atoms is 7-12, such as benzocyclobutyl or benzocyclopentyl. Non-limiting examples include phenyl, naphthyl, anthraceneyl, phenanthrene, etc.

[0312] The aryl group may optionally be further replaced by any substituent.

[0313] "Heteroaromatic ring" or "heteroaryl" refers to an aromatic ring, whether substituted or unsubstituted, containing at least one heteroatom or group selected from N, S, O, P, Si, B, Se and their oxidation states. It can be monocyclic, bicyclic, or polycyclic, and can be bridged, fused, or spirocyclic. When bicyclic or polycyclic, it can be a fusion of a heteroaryl group with a non-heteroaryl ring, such as a cycloalkyl, heterocyclic alkyl, or aryl group, or a fusion of two heteroaryl groups, where the heteroaryl ring is the linking site. "xy-membered heteroaryl" indicates that the total number of heteroaryl ring atoms is x to y, which can be a 5-6-membered heteroaryl group, or a 5-6-membered heteroaryl group fused with other rings (e.g., cycloalkyl, heterocyclic alkyl, aromatic rings), where the heteroaromatic ring is the linking site. For example, "5-12-membered heteroaryl" indicates that the heteroaryl group serves as the linking site, and the total number of ring atoms is 5-12, such as pyridocyclobutyl or pyridocyclopentyl. Non-limiting embodiments include furanyl, thiopheneyl, pyrrolyl, oxazolyl, thiazolyl, imidazoleyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indoleyl, purineyl, The heteroaryl group may be optionally further substituted with any substituent.

[0314] "Spirocyclic" refers to a 5- to 20-membered polycyclic group consisting of substituted or unsubstituted rings sharing a single carbon atom (called a spiro atom). It may contain 0 to 5 double bonds and 0 to 5 heteroatoms or groups selected from N, O, S, P, Si, and their oxidation states. Preferably, it is a 6- to 14-membered spirocyclic group, more preferably a 6- to 12-membered group, and even more preferably a 6- to 10-membered spirocyclic group. The spirocyclic group can be formed between cycloalkyl groups or heterocycloalkyl groups; preferably, it is a tri-spirotri- (representing a three-membered ring spirotri-), tri-spirote, tri-spiropenta, tri-spirohexa, tetra-spirote, tetra-spiropenta, tetra-spirohexa, penta-spiropenta, or penta-spiropenta; non-limiting examples include...

[0315] The spiroring may optionally be further replaced by any substituent.

[0316] "Built rings" refer to polycyclic groups in which rings share two adjacent atoms. One or more rings may contain zero or more double bonds and may be substituted or unsubstituted. Each ring in a built ring system may contain 0 to 5 heteroatoms selected from N, S, O, P, and Si and their oxidation states. Preferably, the rings are 5 to 20 nucleotides, more preferably 5 to 14 nucleotides, more preferably 5 to 12 nucleotides, and even more preferably 5 to 10 nucleotides. Preferred are tri-built tetracyclic rings (representing built rings formed by a three-membered ring and a four-membered ring; according to IUPC nomenclature, this could be a built ring with a three-membered ring or a four-membered ring as the base ring, and the same applies below), tri-built pentacyclic rings, tri-built hexacyclic rings, tetra-built tetracyclic rings, tetra-built pentacyclic rings, tetra-built hexacyclic rings, penta-built pentacyclic rings, penta-built hexacyclic rings, and hexa-built hexacyclic rings. Non-limiting examples include purines, quinolines, isoquinolines, benzopyran, benzofuran, and benzothiophene. The cyclic ring may optionally be further replaced by any substituent.

[0317] A "bridged ring" refers to two rings sharing two non-adjacent atoms, which may contain zero or more double bonds and may be substituted or unsubstituted. One or more rings may contain 0 to 5 heteroatoms selected from N, S, O, P, and Si, and their oxidation states. The ring atoms comprise 5 to 20 atoms, preferably 5 to 14 atoms, more preferably 5 to 12 atoms, and even more preferably 5 to 10 atoms. Non-limiting examples include adamantane, etc.

[0318] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.

[0319] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linking point. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0320] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0321] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-Trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0322] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 2-Dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0323] The term "alkyl subunit" refers to a divalent free alkyl structure formed by the loss of two hydrogen atoms, wherein the alkyl group is as defined above. Non-limiting examples include: methyl subunits. Ethyl subunit 1-Methylethylidene

[0324] The term "halogenated alkyl subunit" refers to an alkyl subunit substituted with one or more halogens, wherein the alkyl subunit is as defined above. Non-limiting examples include: fluoromethyl subunits. Difluoromethylidene

[0325] The term "mercapto" refers to -SH. The term "hydroxyl" refers to -OH. The term "nitro" refers to -NO2. The term "amino" refers to -NH2. The term "cyano" refers to -CN. The term "carboxyl" refers to -C(O)OH. The term "aldehyde" refers to -CHO. The term "oxo" or "oxo-group" refers to =O. The term "carbonyl" refers to C=O. The term "aminoacyl" refers to -C(O)NH2. The term "sulfonyl" refers to -S(O)2. The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above. The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above. The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. The term "alkylamino" refers to an amino group substituted with one or two alkyl groups, also written as -N-(alkyl)2 or -NH-alkyl, where the alkyl group is as defined above. Non-limiting examples include dimethylamino, monomethylamino, diethylamino, monoethylamino, etc. The term "alkenyl" refers to a divalent straight-chain or branched alkenyl group. The term "alkynyl" refers to a divalent straight-chain or branched alkynyl group.

[0326] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0327] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0328] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0329] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0330] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C 2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..."10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0331] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0332] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0333] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Furthermore, when a structural unit is substituted, even if the structural unit is marked with a hydrogen atom, it does not mean that the hydrogen atom cannot be substituted, but rather that any position in the structural unit including the hydrogen atom can be substituted. For example, structural unit... Substitution means that any position, including the hydrogen atom on the nitrogen atom, can be substituted. Combinations of substituents and / or variables are only permitted if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing each carbon atom in a group as optionally being replaced by a heteroatom, the condition is that it does not exceed the normal valence of all atoms in the group under the current condition, and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -CO-(C 3-8 cycloalkyl), -CO- (3-8 membered heterocycloalkyl), -CO- (C 5-12 aryl), -CO- (5-12 membered heteroaryl), hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1- 6-alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl, amino, phosphonic acid, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-HC(=O)NH(C 1-6 Alkyl groups, -NHC(=O)NH2, -CH=N(C 1-6 Alkyl), -CH=NO(C) 1-6 alkyl), -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0334] If a substituent is described as "optionally...substituted", then the substituent may be unsubstituted or may be substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, then one or more hydrogen atoms on that atom or group may be substituted by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is a subunit (e.g., ... When the substituent is hydrogen, it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this can also indicate that the corresponding group is "unsubstituted" or "unreplaced". Unless otherwise specified, as used herein, the connection point of the substituent can be any suitable position of the substituent.

[0335] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0336] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0337] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of linking in the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes the cases of AMWB and AWMB, with AMWB being preferred.

[0338] The compounds of this invention can exist in specific geometric or stereoisomeric forms. Stereoisomers are isomers that exist in molecules with the same order of atomic or atomic groups connected together, but arranged differently in space. All such compounds of this invention include cis-trans isomers, optical isomers, and racemic mixtures and other mixtures thereof, such as cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched with enantiomers or diastereomers; all such mixtures are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. The purification and separation of such substances can be achieved using standard techniques known in the art.

[0339] The compounds of this invention also include their tautomer forms. Tautomers refer to compounds that can interconvert through a reversible chemical reaction known as tautomerization, typically caused by the associated migration of hydrogen atoms and π bonds (double or triple bonds), resulting in a transformation of one functional group into another. Examples include the following paired compounds: aldehyde / ketone–enol, imine–enamine.

[0340] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0341] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 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 Grade I, with deuterium as the preferred grade.

[0342] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0343] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0344] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0345] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0346] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0347] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0348] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0349] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0350] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

[0351] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0352] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0353] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0354] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0355] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Attached Figure Description

[0356] Figure 1: Effects of control compounds TRN-228 and 13-1 on latency in mice during the hot plate test.

[0357] Figure 2: Maximum possible percentage of efficacy (%MPE) of control compound TRN-228 and compound 13-1 in mouse hot plate test.

[0358] Figure 3: %MPE-dose relationship curve of the control compound TRN-228 in the mouse hot plate test.

[0359] Figure 4: %MPE-dose relationship curve of compound 13-1 in mouse hot plate test.

[0360] Figure 5: %MPE-dose relationship curve of compound 21 in mouse hot plate test.

[0361] Figure 6: %MPE-dose relationship curve of compound 36 in mouse hot plate test. Detailed Implementation

[0362] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0363] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0364] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0365] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100×4.6mm, 3.5μM);

[0366] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) are 0.15mm-0.20mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4mm-0.5mm in diameter.

[0367] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0368] Retention time was determined by HPLC analysis. HPLC analysis method: Instrument: Shimadzu LC-20AT; Column: Yuexu, Column model: Ultimate C18 4.6*50mm, 3μm. Chromatographic conditions: Detection wavelength 254nm / 210nm; Flow rate: 1.0ml / min; Column temperature: 35℃; Injection volume: 2μl; Acquisition time: 10min; Mobile phase A was 0.05% TFA solution, and mobile phase B was acetonitrile. Gradient elution program: Mobile phase A (95%) to mobile phase B (95%).

[0369] Abbreviations: DCM: dichloromethane; THF: tetrahydrofuran; EA: ethyl acetate; PE: petroleum ether; DMF: N,N-dimethylformamide; EtOH: ethanol; NMP: N-methylpyrrolidone; LiHMDS: lithium bis(trimethylsilylamine); Pd(dppf)Cl2: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; Pd(dppf)Cl2.DCM: [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex; tBuXPhos Pd G3: Methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II); Ruphos-Pd-G3: Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II).

[0370] Example

[0371] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available conventional products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0372] Example 1:

[0373] Step 1: Compound 1A (0.8 g, 3.49 mmol) (prepared according to WO2015197861) and 1B (0.76 g, 3.49 mmol) were dissolved in DCM (20 mL), and trimethylsilyl trifluoromethanesulfonate (0.85 g, 3.84 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 16 h. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated into compound 1 by silica gel column chromatography. Compound 1-1 (0.4 g, 26% yield) and compound 1-2 (0.35 g, 23% yield) were further prepared by high performance liquid chromatography.

[0374] HPLC Preparation Method: 1. Instruments: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm) 2. Dissolve the sample in acetonitrile / water and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 20min.

[0375] Compound 1-1: LC-MS (ESI): m / z = 384.1 [M-44] + Retention time: 4.47 min.

[0376] 1 H NMR(400MHz,DMSO-d6)δ11.39(s,1H),7.77(s,1H),7.52–7.50(m,1H),7.37–7.25(m,6H),3.91–3.8 9(m,2H),2.74–2.72(m,2H),2.56–2.52(m,2H),2.32–2.25(m,2H),2.06(s,6H),1.81–1.74(m,4H).

[0377] Compounds 1-2: LC-MS (ESI): m / z = 429.2 [M+H] + Retention time: 4.28 min.

[0378] 1 H NMR(400MHz, Methanol-d4)δ7.67–7.65(m,1H),7.55–7.46(m,4H),7.41–7.37(m,1H),7.27–7.21 (m,2H),4.06–4.03(m,2H),2.79–2.64(m,4H),2.22–2.14(m,4H),2.06(s,6H),2.03–1.94(m,2H).

[0379] Example 2:

[0380] Step 1: Compounds 2A (4.8 g, 20 mmol) and 1B (4.35 g, 20 mmol) were dissolved in DCM (100 mL). Trimethylsilyl trifluoromethanesulfonate (4.89 g, 22 mmol) was added dropwise under ice bath conditions. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. After the reaction was completed, saturated sodium bicarbonate was added to quench the reaction. The mixture was extracted twice with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain compounds 2B-1 (3.63 g, yield 41%, Rf = 0.52EA / PE = 1:1) and 2B-2 (3.86 g, yield 44%, Rf = 0.15EA / PE = 1:1).

[0381] Step 2: Compound 2B-1 (0.44 g, 1.0 mmol) and 1-methylpyrazole-3-boronic acid pinacol ester (0.31 g, 1.5 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Pd(dppf)Cl2·DCM (82 mg, 0.10 mmol) and potassium carbonate (0.28 g, 2.0 mmol) were added, and the mixture was stirred until homogeneous. The reaction was carried out at 85 °C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (80 mL) was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 2-1 (0.16 g, yield 36%) was obtained by silica gel column chromatography and high performance liquid chromatography.

[0382] LC-MS(ESI): m / z = 396.2 [M-44] + .

[0383] 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.87–7.71(m,2H),7.67(s,1H),7.60–7.47(m,3H),7.43–7.20(m,3H),6 .61(d,1H),3.90(t,2H),3.87(s,3H),2.72(t,2H),2.56(d,2H),2.24(d,2H),2.06(s,6H),1.95-1.72(m,4H).

[0384] Compound 2B-2 (0.44 g, 1.0 mmol) and pinacol ester of 1-methylpyrazole-3-boronate (0.31 g, 1.5 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Pd(dppf)Cl2·DCM (82 mg, 0.10 mmol) and potassium carbonate (0.28 g, 2.0 mmol) were added, and the mixture was stirred until homogeneous. The reaction was carried out at 85 °C for 4 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (80 mL) was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 2B-2 (0.21 g, 48% yield) was obtained by silica gel column chromatography and high performance liquid chromatography.

[0385] HPLC Preparation Method: 1. Instruments: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm) 2. Dissolve the sample in acetonitrile / water and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 20min.

[0386] LC-MS (ESI): m / z = 441.3 [M+H] + .

[0387] 1 H NMR(400MHz,Methanol-d4)δ7.78(d,1H),7.59–7.48(m,5H),7.46–7.36(m,2H),7.16(dd,1H),6.53(d ,1H),4.04(t,2H),3.89(s,3H),2.78(t,2H),2.66(d,2H),2.26-2.09(m,8H),1.96(d,2H),1.68(t,2H)

[0388] Example 3:

[0389] Step 1: Using compound 2B-1 (0.44 g, 1.0 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (0.31 g, 1.5 mmol) as starting materials, compound 3-1 (0.15 g, 34% yield) was synthesized according to the second step of Example 2.

[0390] LC-MS (ESI): m / z = 396.3 [M-44] + .

[0391] 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.01(s,1H),7.77(s,1H),7.54(s,1H),7.44–7.18(m ,7H),3.89(t,2H),3.85(s,3H),2.74–2.53(m,4H),2.28(t,2H),2.06(s,6H),1.75(t,4H).

[0392] The compound 3-2 (0.15 g, 34% yield) was synthesized using compound 2B-2 (0.44 g, 1.0 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (0.31 g, 1.5 mmol) as starting materials according to the second step of Example 2. The compound 3-2 was obtained by HPLC separation.

[0393] HPLC Preparation Method: 1. Instruments: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm) 2. Dissolve the sample in acetonitrile / water and filter through a 0.45μm filter to prepare the sample solution. 3. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (5mM ammonium acetate); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 20min.

[0394] LC-MS (ESI): m / z = 441.3 [M+H] + .

[0395] 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.81 (s, ¹H), 7.72 (d, ¹H), 7.60–7.46 (m, 5H), 7.41 (t, ¹H), 7.20–7.10 (m, 2H), 4.04 (t, 2H), 3.89 (s, 3H), 2.77 (t, 2H), 2.66 (d, 2H), 2.20 (t, 2H), 2.11 (s, 6H), 1.96 (d, 2H), 1.69 (t, 2H). Example 4:

[0396] Step 1: Dissolve reactant 4A (1.74 g, 5.66 mmol) in dry tetrahydrofuran (40 mL), cool to -78 °C, and add LiHMDS (30 mL, 1 M THF solution) dropwise to the system. After stirring for 30 minutes, add iodomethane (4.26 g, 30 mmol) dropwise, and slowly raise the temperature to room temperature for 1 h. After the reaction is complete, quench the reaction with saturated ammonium chloride, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and separate the residue by silica gel column chromatography to obtain target compound 4B (1.4 g, 74% yield).

[0397] 1 H NMR (400MHz, Methanol-d4) δ8.11(dd,1H),7.53(s,1H),7.15(dd,1H),7.04(t,1H),3.64(s,3H),1.67(s,9H),1.63(s,6H).

[0398] Step 2: Compound 4B (1.4 g, 4.17 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (7 mL) was added. After stirring thoroughly, the mixture was reacted at room temperature for 4 hours. After the reaction was completed, the system was concentrated under reduced pressure to obtain 4C, which was then directly reacted in the next step.

[0399] Step 3: Compound 4C (0.98 g, 4.17 mmol) was dissolved in THF (30 mL), and lithium aluminum hydride (0.16 g, 4.17 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was brought to room temperature and reacted for 1 h. The mixture was then cooled to 0 °C, and under these conditions, water (0.2 mL), 15% sodium hydroxide (0.2 mL), and water (0.6 mL) were added dropwise to quench the reaction. After stirring for ten minutes, the mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound 4D (0.61 g, yield 71%).

[0400] LC-MS (ESI): m / z = 208.1 [M+H] + .

[0401] Step 4: Using compounds 4D (0.21 g, 1.0 mmol) and 1B (0.24 g, 1.0 mmol) as starting materials, the synthesis was carried out according to the first step of Example 1. The compounds 4-1 (0.17 g, yield 42%, Rf = 0.53EA / PE = 2:1) and 4-2 (0.15 g, yield 37%, Rf = 0.12EA / PE = 2:1) were obtained by silica gel column chromatography.

[0402] Compound 4-1: LC-MS (ESI): m / z = 362.1 [M-44] + Retention time: 4.66 min.

[0403] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.37(d,4H),7.32–7.20(m,3H),6.84(t,1H) ),3.49(s,2H),2.54(d,2H),2.24(t,2H),2.06(s,6H),1.77(t,4H),1.28(s,6H).

[0404] Compound 4-2: LC-MS (ESI): m / z = 407.3 [M+H] + Retention time: 4.23 min.

[0405] 1 H NMR(400MHz,Methanol-d4)δ7.61–7.47(m,4H),7.47–7.39(m,1H),7.17(dd,1H),7.07(dd,1H),6 .71(t,1H),3.61(s,2H),2.71(d,2H),2.31–2.08(m,8H),1.97(d,2H),1.67(t,2H),1.34(s,6H);

[0406] Example 5:

[0407] Step 1: Compound 2B-1 (0.50 g, 1.14 mmol) and morpholine (0.5 g, 5.70 mmol) were dissolved in 1,4-dioxane (20 mL), and Ruphos-Pd-G3 (95 mg, 0.11 mmol) and cesium carbonate (1.11 g, 3.42 mmol) were added. After stirring thoroughly, the mixture was reacted at 100 °C for 16 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrates were combined, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 5-1 (0.18 g, yield 35.5%).

[0408] LC-MS (ESI): m / z = 446.3 [M+H] + .

[0409] 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.36-7.20(m,6H),6.86-6.79(m,2H),3.87-3.85(m,2H),3.76-3.74(m,4 H),3.01-2.98(m,4H),2.63-2.60(m,2H),2.55-2.52(m,2H),2.28-2.21(m,2H),2.04(s,6H),1.79-1.70(m,4H).

[0410] Using compound 2B-2 (0.50 g, 1.14 mmol) and morpholine (0.5 g, 5.70 mmol) as raw materials, compound 5-2 (0.14 g, yield 27.6%) was obtained by silica gel column chromatography following the above synthetic method.

[0411] LC-MS (ESI): m / z = 446.3 [M+H]+ .

[0412] 1 H NMR(400MHz,Methanol-d4)δ7.83-7.81(m,2H),7.69-7.59(m,4H),7.29(d,1H),7.19(dd,1H),4.08-4.02(m,6H),3.6 2-3.59(m,4H),2.95-2.92(m,2H),2.80(t,2H),2.66(s,6H),2.48-2.41(m,2H),2.13-2.09(m,2H),1.80-1.73(m,2H).

[0413] Example 6:

[0414] Step 1: Using compound 2B-1 (0.15 g, 0.34 mmol) and potassium isopropenyl trifluoroborate (0.06 g, 0.41 mmol) as starting materials, the compound 6-1 (40 mg, yield 29.25%) was synthesized according to the second step of Example 2. The compound 6-1 was obtained by silica gel column chromatography.

[0415] LC-MS(ESI): m / z = 356.2 [M-44] + .

[0416] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),7.47(s,1H),7.37–7.36(m,4H),7.29–7.23(m,3H),5.32(s,1H),4.96(s,1H),3. 90–3.89(m,2H),2.69–2.67(m,2H),2.52–2.51(m,2H),2.31–2.24(m,2H),2.16(s,3H),2.06(s,6H),1.81–1.72(m,4H).

[0417] The compound 6-2 (0.20 g, 54.8%) was synthesized using compound 2B-2 (0.40 g, 0.91 mmol) and potassium isopropenyl trifluoroborate (0.16 g, 1.1 mmol) as starting materials according to the second step of Example 2. The compound 6-2 was obtained by silica gel column chromatography.

[0418] LC-MS (ESI): m / z = 401.3 [M+H] + .

[0419] 1H NMR(400MHz, Methanol-d4)δ7.62–7.60(m,2H),7.57–7.53(m,2H),7.48–7.46(m,2H),7.22–7.19(m,1H),7.09–7.07(m,1H),5.26 (s,1H),4.93(s,1H),4.05–4.02(m,2H),2.77–2.70(m,4H),2.28–2.22(m,8H),2.16(s,3H),2.00–1.96(m,2H),1.74–1.66(m,2H).

[0420] Example 7:

[0421] Step 1: Compound 6-1 (100 mg, 0.27 mmol) was dissolved in methanol (20 mL), and 10% palladium on carbon (50 mg) was added. The reaction was carried out under a hydrogen atmosphere for 1 hour. After the reaction was completed, the palladium on carbon was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the target compound 7-1 (32 mg, yield 31.84%).

[0422] LC-MS(ESI): m / z = 358.2 [M-44] + .

[0423] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.37–7.36(m,4H),7.28–7.22(m,2H),7.20(s,1H),6.94–6.91(m,1H),3.89–3.86(m,2H), 2.95–2.90(m,1H),2.66–2.63(m,2H),2.55–2.52(m,2H),2.33–2.24(m,2H),2.06(s,6H),1.81–1.72(m,4H),1.24–1.22(m,6H).

[0424] The compound 6-2 (100 mg, 0.27 mmol) was used as the starting material to synthesize the compound according to the above procedure. The compound 7-2 (38 mg, yield 37.8%) was obtained by silica gel column chromatography.

[0425] LC-MS (ESI): m / z = 403.3 [M+H] + .

[0426] 1H NMR(400MHz, Methanol-d4)δ7.56–7.54(m,2H),7.52–7.48(m,2H),7.41–7.37( m,1H),7.19–7.18(m,1H),7.06–7.03(m,1H),6.89–6.86(m,1H),4.04–4.01(m, 2H),2.93–2.88(m,1H),2.74–2.72(m,2H),2.67–2.64(m,2H),2.22–2.16(m,2H ),2.08(s,6H),1.97–1.93(m,2H),1.72–1.65(m,2H),1.25(m,3H),1.23(s,3H).

[0427] Example 8:

[0428] Step 1: Compound 8A (1 g, 5.9 mmol) was dissolved in diethyl ether (30 mL). Oxaloyl chloride (3.80 g, 29.97 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature for 6 h. After the reaction was complete, methanol (4 mL) was added dropwise under ice bath conditions to quench the reaction. After the addition was complete, the reaction was allowed to continue at room temperature for 1 h. The reaction solution was concentrated under reduced pressure and then diethyl ether (20 mL) was added. After stirring for ten minutes, the mixture was filtered. The filter cake was washed with diethyl ether (30 mL) and dried to obtain compound 8B (1.4 g, 93% yield).

[0429] Step 2: Compound 8B (1.4 g, 5.48 mmol) was dissolved in THF (30 mL). Lithium aluminum tetrahydrogen (1.4 g, 35.55 mmol) was added in portions under ice bath conditions, and the reaction was raised to 60 °C for 6 h. The mixture was then cooled to 0 °C, and under these conditions, water (1.4 mL), 15% sodium hydroxide (1.4 mL), and water (4.2 mL) were added dropwise to quench the reaction. After stirring for ten minutes, the mixture was filtered. The filtrate was concentrated under reduced pressure and then separated by silica gel column chromatography to obtain compound 8C (1.18 g, yield 84.19%).

[0430] LC-MS (ESI): m / z = 214.1 [M+H] + .

[0431] Step 3: Using compound 8C (427 mg, 2 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compounds 8-1 (231 mg, yield 28%, Rf = 0.52EA / PE = 2:1) and 8-2 (286 mg, yield 35%, Rf = 0.13EA / PE = 2:1) were obtained by silica gel column chromatography.

[0432] Compound 8-1: 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.42(d,1H),7.39-7.34(m,5H),7.30-7.22(m,1H),3 .87(t,2H),2.64(t,2H),2.54(d,2H),2.24(t,2H),2.06(s,6H),1.76(t,2H),1.74(d,2H).

[0433] LC-MS (ESI): m / z = 368.1 [M-44] + Retention time: 4.574 min.

[0434] Compound 8-2: 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),7.49-7.39(m,4H),7.38-7.29(m,2H),7.26(d,1H),3 .92(t,2H),2.64(t,2H),2.46(d,2H),1.99(t,2H),1.92(s,6H),1.82(d,2H),1.56(t,2H).

[0435] LC-MS (ESI): m / z = 413.2 [M+H] + Retention time: 4.425 min.

[0436] Example 9:

[0437] Step 1: Using compound 9A (1g, 6.54mmol) as the starting material, compound 9B (853mg, yield 54%) was synthesized according to the first step of Example 8.

[0438] LC-MS(ESI): m / z = 240.0 [M+H] + .

[0439] Step 2: Using compound 9B (853 mg, 3.57 mmol) as the starting material, compound 9C (616 mg, 88% yield) was synthesized according to the second step of Example 8.

[0440] LC-MS (ESI): m / z = 198.1 [M+H] + .

[0441] Step 3: Using compound 9C (395 mg, 2 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compounds 9-1 (110 mg, yield 14%, Rf = 0.50 EA / PE = 2:1) and 9-2 (140 mg, yield 17%, Rf = 0.12 EA / PE = 2:1) were obtained by silica gel column chromatography.

[0442] Compound 9-1: LC-MS (ESI): m / z = 352.2 [M-44] + Retention time: 4.531 min.

[0443] 1 H NMR(400MHz,DMSO-d6)δ11.29(s,1H),7.40-7.32(m,4H),7.29-7.22(m,1H),6.94(dd,1H),6.7 1(dt,1H),3.87(t,2H),2.78(t,2H),2.53(d,2H),2.24(t,2H),2.05(s,6H),1.81-1.70(m,4H).

[0444] Compound 9-2: LC-MS (ESI): m / z = 397.2 [M+H] + Retention time: 4.473 min.

[0445] 1 H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.49-7.38(m,4H),7.37-7.31(m,1H),6.78(dd,1H),6.67(d t,1H),3.92(t,2H),2.77(t,2H),2.47(d,2H),1.98(t,2H),1.92(s,6H),1.81(d,2H),1.56(t,2H).

[0446] Example 10:

[0447] Step 1: Compound 2B-1 (440 mg, 1 mmol) and cyclopropylboronic acid (172 mg, 2 mmol) were dissolved in toluene (30 mL) and water (10 mL). Palladium acetate (45 mg, 0.2 mmol), tri-tert-butylphosphine tetrafluoroborate (116 mg, 0.4 mmol), and potassium phosphate (636 mg, 3 mmol) were added sequentially, and the reaction was carried out overnight at 100 °C under a nitrogen atmosphere. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 10-1 (71 mg, yield 18%).

[0448] LC-MS(ESI): m / z = 356.2 [M-44] + .

[0449] 1 H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.39-7.33(m,4H),7.29-7.22(m,1H),7.19(d,1H),7.07(s,1H),6.78(dd,1H),3.87(t,2H),2. 63(t,2H),2.52(d,2H),2.26(t,2H),2.06(s,6H),1.98-1.93(m,1H),1.77(d,2H),1.74(t,2H),0.90-0.84(m,2H),0.63-0.57(m,2H).

[0450] Compound 10-2 (98 mg, 25% yield) was synthesized from compound 2B-2 (440 mg, 1.0 mmol) and cyclopropylboronic acid (172 mg, 2 mmol) using the same procedure described above.

[0451] LC-MS (ESI): m / z = 401.3 [M+H] + .

[0452] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.48-7.40(m,4H),7.36-7.29(m,1H),7.07-7.01(m,2H),6.71(dd,1H),3.92(t,2H),2.62( t,2H),2.47(d,2H),1.99(t,2H),1.93(s,6H),1.92-1.87(m,1H),1.79(d,2H),1.58(t,2H),0.88-0.81(m,2H),0.59-0.54(m,2H).

[0453] Example 11:

[0454] Step 1: Compound 2B-1 (660 mg, 1.5 mmol) and potassium vinylfluoroborate (402 mg, 3 mmol) were dissolved in dioxane (30 mL) and water (10 mL). Pd(dppf)Cl2 (220 mg, 0.3 mmol) and potassium carbonate (415 mg, 4.5 mmol) were added sequentially, and the reaction was carried out overnight at 100 °C under a nitrogen atmosphere. The solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 11-1 (110 mg, yield 19%).

[0455] LC-MS(ESI): m / z = 342.2 [M-44] + .

[0456] 1 H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.43(s,1H),7.39-7.34(m,4H),7.31-7.24(m,2H),7.23-7.20(m,1H),6.78(dd,1H ),5.67(d,1H),5.06(d,1H),3.89(t,2H),2.67(t,2H),2.53(d,2H),2.27(t,2H),2.06(s,6H),1.77(t,2H),1.75(d,2H).

[0457] Compound 11-2 (160 mg, yield 27%) was synthesized from compound 2B-2 (660 mg, 1.5 mmol) and potassium vinyl fluoroborate (402 mg, 3 mmol) using the same procedure described above.

[0458] LC-MS (ESI): m / z = 387.2 [M+H] + .

[0459] 1 H NMR(400MHz,DMSO-d6)δ10.54(s,1H),7.60-7.41(m,4H),7.40(s,1H),7.38-7.27(m,1H),7.18-7.11(m,2H),6.74(dd,1H ),5.63(d,1H),5.03(d,1H),3.94(t,2H),2.67(t,2H),2.47(d,2H),1.99(t,2H),1.94(s,6H),1.82(d,2H),1.59(t,2H).

[0460] Example 12:

[0461] Step 1: Using compound 12A (1.53 g, 9.99 mmol) as the starting material, compound 12B (1.7 g, yield 71.14%) was synthesized according to the first step of Example 8.

[0462] 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.49(d,1H),7.51–7.18(m,2H),3.90(s,3H).

[0463] Step 2: Using compound 12B (1.7 g, 7.1 mmol) as the starting material, the synthesis was carried out according to the second step of Example 8, and compound 12C (1.18 g, yield 84.19%) was obtained by silica gel column chromatography.

[0464] LC-MS (ESI): m / z = 198.1 [M+H] + .

[0465] Step 3: Using compounds 12C (0.24 g, 1.22 mmol) and 1B (0.27 g, 1.22 mmol) as starting materials, compounds 12-1 (0.16 g, 33% yield, Rf = 0.48EA / PE = 2:1) and 12-2 (0.13 g, 27% yield, Rf = 0.10EA / PE = 2:1) were synthesized following the first step of Example 1.

[0466] Compound 12-1: LC-MS (ESI): m / z = 352.1 [M-44] + Retention time: 4.30 min.

[0467] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),7.37(d,4H),7.30-7.22(m,1H),7.11(dd,1H),7.05-6.9 6(m,1H),3.88(t,2H),2.81(t,2H),2.54(d,2H),2.25(t,2H),2.05(s,6H),1.82-1.69(m,4H).

[0468] Compound 12-2: LC-MS (ESI): m / z = 397.2 [M+H] + Retention time: 3.72 min.

[0469] 1 H NMR(400MHz, Methanol-d4)δ7.85–7.78(m,2H),7.70–7.57(m,3H),6.92–6.74(m,2H),4.04(t, 2H),2.96–2.87(m,4H),2.65(s,6H),2.48-2.35(m,2H),2.19–2.07(m,2H),1.80-1.68(m,2H).

[0470] Example 13:

[0471] Step 1: Compound 13A (1.1 g, 7.18 mmol) was dissolved in diethyl ether (30 mL). Oxaloyl chloride (2.73 g, 21.54 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to rise to room temperature for 6 h. After the reaction was complete, methanol (4 mL) was added dropwise under ice bath conditions to quench the reaction. After the addition was complete, the reaction was allowed to continue at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and diethyl ether (20 mL) was added. After stirring for ten minutes, the mixture was filtered. The filter cake was washed with diethyl ether (30 mL) and dried to obtain compound 13B (1.2 g, 70% yield). LC-MS (ESI): m / z = 240.1 [M+H] + .

[0472] Step 2: Compound 13B (1.2 g, 5.02 mmol) was dissolved in THF (30 mL). Lithium aluminum tetrahydrogen (0.76 g, 20.08 mmol) was added in portions under ice bath conditions. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 6 h. The mixture was then cooled to 0 °C, and the reaction was quenched by adding water (0.8 mL), 15% sodium hydroxide (0.8 mL), and water (2.4 mL) dropwise. After stirring for ten minutes, the mixture was filtered. The filtrate was concentrated under reduced pressure and then separated by silica gel column chromatography to obtain compound 13C (0.76 g, 80% yield). LC-MS (ESI): m / z = 198.1 [M+H] + .

[0473] Step 3: Compounds 13C (0.3 g, 1.52 mmol) and 1B (0.33 g, 1.52 mmol) were dissolved in DCM (20 mL), and trimethylsilyl trifluoromethanesulfonate (0.85 g, 3.84 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. The reaction was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain compounds 13-1 (0.2 g, yield 33%, Rf = 0.53EA / PE = 2:1) and 13-2 (0.12 g, yield 19%, Rf = 0.12EA / PE = 2:1).

[0474] Compound 13-1: LC-MS (ESI): m / z = 352.1 [M-44] + Retention time: 4.32 min.

[0475] 1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.36–7.34(m,4H),7.27–7.23(m,1H),7.05–7.02(m,1H),6.90–6.84(m,1 H),3.89–3.86(m,2H),2.66–2.63(m,2H),2.54–2.53(m,2H),2.42–2.35(m,2H),2.05(s,6H),1.79–1.70(m,4H).

[0476] Compound 13-2: LC-MS (ESI): m / z = 397.2 [M+H] + Retention time: 3.67 min.

[0477] 1 H NMR(400MHz, Methanol-d4)δ7.55–7.52(m,4H),7.42–7.38(m,1H),6.88–6.86(m,1H),6.60–6.55(m,1H),4 .02–4.00(m,2H),2.71–2.63(m,4H),2.20–2.13(m,2H),2.05(s,6H),1.95–1.91(m,2H),1.75–1.66(m,2H).

[0478] Example 14:

[0479] Step 1: Using compound 14A (1.1 g, 7.18 mmol) as the starting material, compound 14B (1.1 g, 64% yield) was obtained following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 240.1 [M+H] + .

[0480] Step 2: Using compound 14B (1.1 g, 4.60 mmol) as the starting material, compound 14C (0.6 g, 66% yield) was obtained by following the procedure in Step 2 of Example 8. LC-MS (ESI): m / z = 198.1 [M+H] + .

[0481] Step 3: Using compound 14C (0.3 g, 1.52 mmol) and intermediate 1B (0.33 g, 1.52 mmol) as starting materials, the mixture was synthesized according to the first step of Example 1. The mixture was then subjected to silica gel column chromatography to obtain compound 14-1 (0.2 g, yield 33%, Rf = 0.52EA / PE = 2:1) and compound 14-2 (0.2 g, yield 33%, Rf = 0.13EA / PE = 2:1).

[0482] Compound 14-1: LC-MS (ESI): m / z = 352.1 [M-44] + Retention time: 4.23 min.

[0483] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.38–7.33(m,5H),7.28–7.23(m,2H),3.88–3.86(m,2 H),2.64–2.62(m,2H),2.55–2.53(m,2H),2.28–2.21(m,2H),2.05(s,6H),1.79–1.72(m,4H).

[0484] Compound 14-2: LC-MS (ESI): m / z = 397.2 [M+H] + Retention time: 3.67 min.

[0485] 1 H NMR(400MHz, Methanol-d4)δ7.55–7.47(m,4H),7.40–7.36(m,1H),7.16–7.12(m,1H),6.98–6.93(m,1H),4 .02–4.00(m,2H),2.70–2.64(m,4H),2.21–2.06(m,2H),2.05(s,6H),1.95–1.92(m,2H),1.70–1.63(m,2H).

[0486] Example 15:

[0487] Step 1: Compound 2B-1 (0.31 g, 0.71 mmol) and zinc cyanide (0.41 g, 3.5 mmol) were dissolved in N,N-dimethylformamide (20 mL), and tBuXPhos Pd G3 (112 mg, 0.15 mmol) was added. After stirring, the mixture was reacted overnight at 85 °C under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and water (80 mL) was added. The mixture was extracted with dichloromethane (100 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain compound 15-1 (0.15 g, 55% yield).

[0488] Compound 15-1: LC-MS (ESI): m / z = 341.1 [M-44] + .

[0489] 1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),7.93(s,1H),7.52-7.46(m,1H),7.43-7.33(m,5H),7.30-7.22(m,1H), 3.93-3.56(m,2H),2.74-2.65(m,2H),2.60-2.50(m,2H),2.35-2.20(m,2H),2.05(s,6H),1.83-1.70(m,4H).

[0490] Using compound 2B-2 (0.47 g, 1.1 mmol) and zinc cyanide (0.25 g, 2.1 mmol) as raw materials, compound 15-2 was obtained by following the synthesis method of compound 15-1. Then, the trifluoroacetate of compound 15-2 (0.21 g, yield 54%) was prepared by high performance liquid chromatography.

[0491] HPLC Preparation Method: Instrument: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm). The sample was dissolved in acetonitrile / water and filtered through a 0.45μm filter to prepare the sample solution. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 15min.

[0492] Compound 15-2: LC-MS (ESI): m / z = 386.1 [M+H] + .

[0493] 1 H NMR(400MHz, Methanol-d4)δ7.86–7.78(m,3H),7.71–7.61(m,3H),7.34–7.24(m,2H),4.06-4.04(m,2H),2.96 -2.88(m,2H),2.81-2.76(m,2H),2.67-2.62(m,6H),2.44-2.40(m,2H),2.20–2.05(m,2H),1.77-1.75(m,2H).

[0494] Example 16:

[0495] Step 1: Using compound 16A (1.10 g, 5.47 mmol) as the starting material, compound 16B (1.26 g, yield 79.11%) was obtained following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 288.1 [M+H] + .

[0496] Step 2: Using compound 16B (0.66 g, 2.30 mmol) as the starting material, compound 16C (383 mg, yield 69.88%) was obtained by following the procedure in Step 2 of Example 8. LC-MS (ESI): m / z = 246.1 [M+H] + .

[0497] Step 3: Compound 16C (383 mg, 1.56 mmol) and compound 1B (339 mg, 1.56 mmol) were dissolved in DCM (15 mL), and trimethylsilyl trifluoromethanesulfonate (519 mg, 2.34 mmol) was added dropwise. After the addition was complete, the reaction was carried out at room temperature for 6 h. The reaction was quenched by adding saturated sodium bicarbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain compound 16-1 (0.25 g, yield 37%, Rf = 0.54EA / PE = 2:1) and compound 16-2 (Rf = 0.13EA / PE = 2:1). Compound 16-2 was further prepared by high performance liquid chromatography to obtain trifluoroacetate of compound 16-2 (0.35 g, yield 50%).

[0498] HPLC Preparation Method: Instrument: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm). The sample was dissolved in acetonitrile / water and filtered through a 0.45μm filter to prepare the sample solution. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 15min.

[0499] Compound 16-1: LC-MS (ESI): m / z = 400.1 [M-44] + .

[0500] 1 H NMR(400MHz,DMSO-d6)δ11.18(s,1H),7.42-7.33(m,6H),7.30-7.23(m,1H),7.03-7.96(m,1 H),3.94-3.83(m,2H),2.73-2.45(m,4H),2.34-2.19(m,2H),2.06(s,6H),1.84-1.67(m,4H).

[0501] Compound 16-2: LC-MS (ESI): m / z = 445.1 [M+H] + .

[0502] 1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),7.79-7.73(m,2H),7.70–7.52(m,3H),7.34(d,1H),7.24(d,1H),6.96-6.90(m,1H),3. 98-3.95(m,2H),2.87(d,2H),2.70-2.69(m,2H),2.55-2.43(m,6H),2.28-2.24(m,2H),1.96-1.90(m,2H),1.63-1.61(m,2H).

[0503] Example 17:

[0504] Step 1: Using compound 17A (0.71 g, 4.70 mmol) as the starting material, compound 17B (0.76 g, yield 69.12%) was obtained by following the procedure in Step 1 of Example 8.

[0505] LC-MS (ESI): m / z = 236.1 [M+H] + .

[0506] Step 2: Using compound 17B (0.76 g, 3.24 mmol) as the starting material, compound 17C (0.41 g, yield 64.22%) was obtained by following the procedure in Step 2 of Example 8.

[0507] LC-MS (ESI): m / z = 194.1 [M+H] + .

[0508] Step 3: Using compound 17C (0.41 g, 2.09 mmol) and compound 1B (0.50 g, 2.29 mmol) as raw materials, the mixture was synthesized according to the first step of Example 1. The mixture was separated by silica gel column chromatography to obtain compound 17-1 (0.30 g, yield 37%, Rf = 0.48EA / PE = 2:1) and compound 17-2 (Rf = 0.10EA / PE = 2:1). The trifluoroacetate of compound 17-2 (0.42 g, yield 51%) was further prepared by high performance liquid chromatography.

[0509] HPLC Preparation Method: Instrument: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm). The sample was dissolved in acetonitrile / water and filtered through a 0.45μm filter to prepare the sample solution. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 15min.

[0510] Compound 17-1: LC-MS (ESI): m / z = 348.1 [M-44] + Retention time: 4.46 min.

[0511] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.39-7.32(m,4H),7.29-7.22(m,1H),7.15(d,1H),7.07( d,1H),3.90-3.80(m,2H),2.67-2.47(m,4H),2.33-2.19(m,5H),2.05(s,6H),1.83-1.68(m,4H).

[0512] Compound 17-2: LC-MS (ESI): m / z = 393.1 [M+H] + Retention time: 4.17 min.

[0513] 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),7.84–7.75(m,2H),7.68–7.58(m,3H),7.09-7.04(d,1H),7.00(d,1H),3.98-3.90( m,2H),2.85-2.81(m,2H),2.64-2.61(m,2H),2.55-2.43(m,6H),2.35–2.19(m,5H),1.98-1.88(m,2H),1.65-1.53(m,2H).

[0514] Example 18:

[0515] Step 1: 18A (5 g, 37.55 mmol), Boc anhydride (9.83 g, 45.06 mmol), triethylamine (7.60 g, 75.1 mmol), and 4-dimethylaminopyridine (0.04 g, 0.38 mmol) were added to a reaction flask and stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 18B (8.10 g, yield 92.47%). LC-MS (ESI): m / z = 234.1 [M+H] + .

[0516] Step 2: 18B (5 g, 21.44 mmol), cyclopropyl trifluoromethanesulfonate (4.89 g, 25.73 mmol), and cesium carbonate (13.97 g, 42.88 mmol) were added to DMF (50 mL), and the reaction was carried out at 100 °C for 16 hours under a nitrogen atmosphere. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 18C (1 g, yield 26.93%). LC-MS (ESI): m / z = 174.1 [M+H] + .

[0517] Step 3: Using compound 18C (1 g, 7.88 mmol) as the starting material, compound 18D (1.1 g, yield 53.85%) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 260.1 [M+H] + .

[0518] Step 4: Using compound 18D (1 g, 3.86 mmol) as the starting material, compound 18E (700 mg, yield 83.53%) was synthesized following step 2 of Example 8. LC-MS (ESI): m / z = 218.1 [M+H] + .

[0519] Step 5: Using compound 18E (200 mg, 0.92 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compounds 18-1 (35 mg, yield 9.13%, Rf = 0.48EA / PE = 2:1) and 18-2 (35 mg, yield 9.13%, Rf = 0.16EA / PE = 2:1) were obtained by silica gel column chromatography.

[0520] Compound 18-1: LC-MS (ESI): m / z = 372.2 [M-44] + ;

[0521] 1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),7.41–7.32(m,4H),7.29–7.23(m,1H),7. 23–7.18(m,1H),7.07–7.03(m,1H),6.74–6.68(m,1H),3.91–3.84(m,2H),3.82– 3.76(m,1H),3.19–3.15(m,1H),2.66–2.60(m,2H),2.57–2.52(m,1H),2.33–2.1 8(m,2H),2.05(s,6H),1.83–1.66(m,4H),0.77–0.70(m,2H),0.66–0.58(m,2H).

[0522] Compound 18-2: LC-MS (ESI): m / z = 417.3 [M+H] + ;

[0523] 1 H NMR(400MHz,CD3OD)δ7.75–7.70(m,2H),7.65–7.53(m,3H),7.08–7.04(m,1 H),7.04–7.00(m,1H),6.71–6.66(m,1H),4.08–4.01(m,2H),3.77–3.69(m, 1H),2.87–2.77(m,2H),2.76–2.71(m,2H),2.49(s,6H),2.41–2.30(m,2H), 2.09–1.99(m,2H),1.78–1.67(m,2H),0.76–0.69(m,2H),0.69–0.63(m,2H).

[0524] Example 19:

[0525] Step 1: Using compound 2B-1 (0.2 g, 0.45 mmol) and pinacol ester of 2-methylthiazol-5-boronic acid (0.1 g, 0.45 mmol) as starting materials, compound 19-1 (22 mg, 10% yield) was synthesized according to the second step of Example 2.

[0526] LC-MS(ESI): m / z = 413.1 [M-44] + .

[0527] 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),7.86(s,1H),7.59(s,1H),7.37–7.35(m,5H),7.30–7.26(m,2H),3. 90–3.88(m,2H),2.70–2.68(m,2H),2.65(s,3H),2.31–2.24(m,2H),2.07–2.06(m,8H),1.81–1.74(m,4H).

[0528] The compound 19-2 (15 mg, 7% yield) was synthesized using compound 2B-2 (0.2 g, 0.45 mmol) and pinacol ester of 2-methylthiazol-5-boronate (0.1 g, 0.45 mmol) as starting materials according to the second step of Example 2.

[0529] LC-MS (ESI): m / z = 458.3 [M+H] + .

[0530] 1 H NMR(400MHz,DMSO-d6)δ10.66(s,1H),7.83(s,1H),7.55(s,1H),7.47–7.44(m,4H),7.34–7.32(m,1H),7.24–7.19(m,2H),3.96–3.9 2(m,2H),2.71–2.68(m,2H),2.63(s,3H),2.49–2.47(m,2H),2.04–1.97(m,2H),1.93(s,6H),1.84–1.81(m,2H),1.62–1.57(m,2H).

[0531] Example 20:

[0532] Step 1: Compound 20A (5.5 g, 24.66 mmol) was dissolved in sulfuric acid (30 mL) under ice bath conditions. Potassium nitrate (2.74 g, 27.13 mmol) was then added in portions. After the addition was complete, the mixture was allowed to rise naturally to room temperature, and the reaction was continued with stirring for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, dried over the organic phase, filtered, and the filtrate was concentrated under reduced pressure and then separated by rapid column chromatography to obtain the target compound 20B (5.06 g, yield 76.55%).

[0533] 1 H NMR (400MHz, DMSO-d6) δ7.95 (dt, 1H), 4.04 (t, 3H).

[0534] Step 2: Dissolve 20B (5.06 g, 18.88 mmol) in EtOH (50 mL) and water (10 mL), then add reduced iron powder (5.27 g, 94.40 mmol) and ammonium chloride (2.02 g, 37.76 mmol) sequentially, and react at 80 °C for 1 hour. Filter with diatomaceous earth, wash with ethyl acetate, concentrate the filtrate under reduced pressure, and separate by rapid column chromatography to obtain 20C (2.53 g, yield 56.3%).

[0535] 1 H NMR (400MHz, CDCl3) δ7.02 (dd, 1H), 3.98 (s, 3H), 3.68 (s, 2H).

[0536] Step 3: Compound 20C (2.53 g, 10.63 mmol) and trimethylsilylacetylene (4.18 g, 42.52 mmol) were dissolved in triethylamine (40 mL). 1,1-bis(diphenylphosphine)ferrocene palladium dichloromethane complex (0.87 g, 1.06 mmol) and cuprous iodide (0.20 g, 1.06 mmol) were added. After stirring thoroughly, the mixture was reacted at 85 °C for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain compound 20D (2.06 g, yield 75.90%). LC-MS (ESI): m / z = 256.1 [M+H] + .

[0537] Step 4: Compound 20D (2.06 g, 8.07 mmol) was dissolved in NMP (30 mL), and potassium tert-butoxide (2.72 g, 24.21 mmol) was added. After stirring until homogeneous, the mixture was reacted at 120 °C for 1 hour. The reaction solution was cooled to room temperature, and the reaction was quenched with water. The mixture was extracted with ethyl acetate, washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain compound 20E (1.26 g, yield 85.27%).

[0538] 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),7.21(t,1H),7.11(dd,1H),6.50(dd,1H),4.01(s,3H).

[0539] Step 5: Using compound 20E (1.26 g, 6.88 mmol) as the starting material, 20F (1.6 g, yield 86.39%) was synthesized following the procedure in Step 1 of Example 8.

[0540] 1H NMR (400MHz, CDCl3) δ8.87(s,1H),8.52(d,1H),7.96(d,1H),4.04(s,3H),3.96(s,3H).

[0541] Step 6: Using compound 20F (1.6 g, 5.94 mmol) as the starting material, 20G (0.8 g, yield 59.24%) was synthesized following Step 2 of Example 8. LC-MS (ESI): m / z = 228.1 [M+H] + .

[0542] Step 7: Using compound 20G (0.23 g, 1 mmol) and 1B (0.22 g, 1 mmol) as starting materials, the synthesis was carried out according to the first step of Example 1. Compound 20 (0.086 g, yield 19.92%, Rf = 0.48EA / PE = 2:1) was obtained by silica gel column chromatography.

[0543] LC-MS(ESI): m / z = 382.1 [M-44] + .

[0544] 1 H NMR(400MHz,DMSO-d6)δ11.43(s,1H),7.36(d,4H),7.30–7.18(m,1H),7.09(d,1H),3.9 3–3.79(m,5H),2.60(t,2H),2.52(d,2H),2.37(t,2H),2.06(s,6H),1.80–1.65(m,4H).

[0545] Example 21:

[0546] Step 1: Compound 21A (1.00 g, 7.40 mmol) was dissolved in diethyl ether (19 mL). Oxaloyl chloride (2.82 g, 22.20 mmol) was added dropwise under ice bath conditions. After complete addition, the mixture was brought to room temperature and reacted for 6 h. After the reaction was complete, methanol (4 mL) was added dropwise under ice bath conditions to quench the reaction. After complete addition, the mixture was brought to room temperature and reacted for another 1 h. The reaction solution was concentrated under reduced pressure, and diethyl ether (12 mL) was added. After stirring for ten minutes, the mixture was filtered. The filter cake was washed with diethyl ether (12 mL) and dried to obtain compound 21B (1.38 g, 84% yield). LC-MS (ESI): m / z = 222.0 [M+H] + .

[0547] Step 2: Compound 21B (1.38 g, 6.24 mmol) was dissolved in THF (40 mL). Lithium aluminum hydride (1.18 g, 31.20 mmol) was added in portions under ice bath conditions, and the reaction was raised to 60 °C for 6 h. The mixture was then cooled to 0 °C, and under these conditions, water (1.4 mL), 15% sodium hydroxide (1.4 mL), and water (4.2 mL) were added dropwise to quench the reaction. After stirring for ten minutes, anhydrous sodium sulfate was added, and stirring continued for another ten minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound 21C (0.91 g, 81% yield). LC-MS (ESI): m / z = 180.0 [M+H] + .

[0548] Step 3: Compound 21C (180 mg, 1.00 mmol) and 1B (220 mg, 1.01 mmol) were dissolved in DCM (17 mL), and trimethylsilyl trifluoromethanesulfonate (240 mg, 1.08 mmol) was added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 h. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain compound 21 (150 mg, yield 39%, Rf = 0.49EA / PE = 2:1).

[0549] Compound 21: LC-MS (ESI): m / z = 334.1 [M-44] + .

[0550] 1 H NMR(400MHz,DMSO-d6)δ11.38(s,1H),7.40-7.32(m,4H),7.30-7.18(m,2H),6.97-6.81(m,2H), 3.89(t,2H),2.67(t,2H),2.57-2.50(m,2H),2.45-2.35(m,2H),2.07(s,6H),1.81-1.70(m,4H).

[0551] Example 22:

[0552] Step 1: Using compound 22A (0.34 g, 2.00 mmol) as the starting material, 22B (0.32 g, yield 62.44%) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 256.1 [M+H] + .

[0553] Step 2: Starting with compound 22B (0.32 g, 1.25 mmol), the second step of Example 8 was followed to synthesize 22C (0.085 g, yield 31.78%). LC-MS (ESI): m / z = 214.1 [M+H] + .

[0554] Step 3: Compound 22C (0.085 g, 0.40 mmol starting material) was synthesized according to the first step of Example 1. The compound 22 (0.052 g, yield 31.65%, Rf = 0.48EA / PE = 2:1) was obtained by silica gel column chromatography.

[0555] LC-MS (ESI): m / z = 368.1 [M-44] + .

[0556] 1 H NMR(400MHz,DMSO-d6)δ11.28(s,1H),7.36(d,4H),7.32–7.16(m,2H),7.07(dd,1 H),3.87(t,2H),2.65(t,2H),2.55–2.40(m,4H).2.07(s,6H),1.84–1.56(m,4H).

[0557] Example 23:

[0558] Step 1: Using compound 23A (1.1 g, 5.00 mmol) as the starting material, compound 23B (1.12 g, yield 94.39%) was synthesized following step 3 of Example 20. LC-MS (ESI): m / z = 238.1 [M+H] + .

[0559] Step 2: Using compound 23B (1.12 g, 4.72 mmol) as the starting material, compound 23C (0.72 g, yield 92.38%) was synthesized according to step 4 of Example 20.

[0560] Step 3: Using compound 23C (0.33 g, 2.00 mmol) as the starting material, compound 23D (0.38 g, yield 75.71%) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 252.0 [M+H] + .

[0561] Step 4: Using 23D (0.36 g, 1.43 mmol) as the starting material, the compound was synthesized according to Step 2 of Example 8 to obtain 23E (P0, 0.21 g, yield 70.04%). LC-MS (ESI): m / z = 210.1 [M+H] + .

[0562] Step 5: Using compound 23E (0.18 g, 0.86 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 23 (0.21 g, yield 59.75%, Rf = 0.47EA / PE = 2:1) was obtained by silica gel column chromatography.

[0563] LC-MS(ESI): m / z = 364.1 [M-44] + .

[0564] 1 H NMR(400MHz,DMSO-d6)δ11.07(s,1H),7.35(d,4H),7.24(d,1H),6.72(dd,1H),6.54(dd,1H) ,3.92(s,3H),3.85(t,2H),2.59(d,2H),2.48–2.35(m,4H),2.06(s,6H),1.82–1.57(m,4H).

[0565] Example 24:

[0566] Step 1: Compound 24A (2.5 g, 9.96 mmol) was dissolved in dry 1,4-dioxane (30 mL). Then, bis(triphenylphosphine)palladium dichloride (1.36 g, 1.94 mmol), cuprous iodide (550 mg, 2.91 mmol), and triethylamine (2.94 g, 29.07 mmol) were added. Finally, trimethylsilylacetylene (2.86 g, 29.07 mmol) was added. After the addition was complete, the reaction was carried out at 50 °C for 16 hours under a nitrogen atmosphere. The reaction was stopped when the starting material disappeared as monitored by TLC. The mixture was cooled to room temperature, extracted, dried, filtered, and the filtrate was concentrated. The residue was purified by silica gel separation (PE:EA = 20:1) to obtain compound 24B (2.3 g, yield: 86.22%). LC-MS (ESI): m / z = 276.0 [M+H] + .

[0567] Step 2: Compound 24B (2.3 g, 8.35 mmol) was dissolved in NMP (30 mL), and potassium tert-butoxide (2.81 g, 25.05 mmol) was added. The mixture was reacted at 120 °C for 1 hour. The reaction was stopped when the starting material disappeared as detected by TLC. The mixture was cooled to room temperature, extracted, dried, filtered, and the filtrate was concentrated. The residue was purified by silica gel separation (PE:EA = 15:1) to obtain compound 24C (1.4 g, yield: 82.50%).

[0568] 1 H NMR (400MHz, CDCl3) δ8.52(s,1H),7.49-7.47(m,1H),7.36-7.34(t,1H),7.24-7.22(m,1H),6.62-6.61(m,1H).

[0569] Step 3: Using 24C (1.4 g, 6.89 mmol) as the starting material, compound 24D (1.6 g, yield: 80.28%) was synthesized following the synthesis method described in Step 1 of Example 8. LC-MS (ESI): m / z = 304.0 [M+H] + .

[0570] Step 4: Using 24D (0.8 g, 2.77 mmol) as the starting material, compound 24E (0.58 g, yield: 84.82%) was synthesized following the synthesis method described in Step 2 of Example 8. LC-MS (ESI): m / z = 248.0 [M+H] + .

[0571] Step 5: Using 24E (0.25 g, 1.01 mmol) as the starting material, and following the synthesis method in Step 1 of Example 1, compound 24 (0.1 g, yield: 22.15%, Rf = 0.52EA / PE = 2:1) was obtained by silica gel column chromatography.

[0572] LC-MS(ESI): m / z = 402.1 [M-44] + .

[0573] 1 H NMR(400MHz,DMSO-d6)δ11.27(s,1H),7.55-7.52(m,1H),7.37-7.35(d,4H),7.28-7.23(m,2H),3.88-3.86(t ,2H),2.70-2.67(t,2H),2.55-2.54(d,2H),2.48(d,2H),2.07(s,6H),1.83-1.76(m,2H),1.70-1.67(d,2H).

[0574] Example 25:

[0575] Step 1: Compound 25A (2.2 g, 15.38 mmol) was dissolved in DCM (20 mL), and the mixture was cooled to -78 °C under nitrogen protection. N-bromosuccinimide (2.74 g, 15.38 mmol) was slowly added, and the mixture was reacted at -78 °C for 1 h after the addition was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain compound 25B (3.3 g, 97% yield). LC-MS (ESI): m / z = 222.1 [M+H] + .

[0576] Step 2: Using compound 25B (3.3 g, 14.93 mmol) as the starting material, compound 25C (3.3 g, 92% yield) was synthesized according to Step 3 of Example 20. LC-MS (ESI): m / z = 240.0 [M+H] + .

[0577] Step 3: Using compound 25C (3.3 g, 13.80 mmol) as the starting material, compound 25D (2.1 g, 91% yield) was synthesized according to step 4 of Example 20. LC-MS (ESI): m / z = 168.1 [M+H] + .

[0578] Step 4: Using compound 25D (1.1 g, 6.58 mmol) as the starting material, compound 25E (1.2 g, 71% yield) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 254.0 [M+H] + .

[0579] Step 5: Using compound 25E (0.9 g, 3.56 mmol) as the starting material, compound 25F (0.6 g, 80% yield) was synthesized following step 2 of Example 8. LC-MS (ESI): m / z = 212.1 [M+H] + .

[0580] Step 6: Using compound 25F (0.2 g, 0.94 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 25 (120 mg, yield 31%, Rf = 0.52EA / PE = 2:1) was obtained by silica gel column chromatography.

[0581] LC-MS (ESI): m / z = 366.1 [M-44] + .

[0582] 1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),7.35–7.25(m,5H),7.02–7.00(m,1H),3.91–3.86(m ,2H),2.62–2.56(m,4H),2.40–2.35(m,2H),2.24(s,3H),2.06(s,6H),1.75–1.69(m,4H).

[0583] Example 26:

[0584] Step 1: Using compound 26A (2.26 g, 10 mmol) as the starting material, compound 26B (2.29 g, 86% yield) was synthesized according to step 3 of Example 20. LC-MS (ESI): m / z = 244.1 [M+H] + .

[0585] Step 2: Using compound 26B (2.29 g, 8.6 mmol) as the starting material, compound 26C (1.37 g, 85% yield) was synthesized according to step 4 of Example 20. LC-MS (ESI): m / z = 172.0 [M+H] + .

[0586] Step 3: Using compound 26C (1.37 g, 7.3 mmol) as the starting material, compound 26D (1.44 g, 77% yield) was synthesized according to step 5 of Example 20. LC-MS (ESI): m / z = 258.0 [M+H] + .

[0587] Step 4: Using compound 26D (1.44 g, 5.6 mmol) as the starting material, compound 26E (0.79 g, 65% yield) was synthesized according to step 6 of Example 20. LC-MS (ESI): m / z = 216.1 [M+H] + .

[0588] Step 5: Using compound 26E (215 mg, 1.0 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 26 (174 mg, yield 42%, Rf = 0.48EA / PE = 2:1) was obtained by silica gel column chromatography.

[0589] LC-MS (ESI): m / z = 370.1 [M-44] + .

[0590] 1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),7.39-7.32(m,4H),7.29-7.23(m,1H),7.13-7.07(m,1H ),3.88(t,2H),2.81(t,2H),2.52(d,2H),2.37(t,2H),2.06(s,6H),1.75(t,2H),1.73(d,2H).

[0591] Example 27:

[0592] Step 1: Using 27A (4.2 g, 19.62 mmol) as the starting material, compound 27B (4.1 g, yield: 69.63%) was synthesized following the synthesis method described in Step 1 of Example 8. LC-MS (ESI): m / z = 299.9 [M+H] + .

[0593] Step 2: 27B (4.1 g, 13.66 mmol) was dissolved in dry tetrahydrofuran (100 mL). Lithium aluminum hydride (1.56 g, 40.98 mmol) was slowly added in portions at 0 °C. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. The reaction was stopped when the starting material disappeared as monitored by TLC. The mixture was cooled to 0 °C, and the reaction was quenched by adding water (1.56 g), 15% sodium hydroxide aqueous solution (1.56 mL), and water (4.68 mL) sequentially. After stirring for ten minutes, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel separation (PE:EA = 2:1) to obtain compound 27C (2.8 g, yield: 79.40%). LC-MS (ESI): m / z = 258.0 [M+H] + .

[0594] Step 3: Using 27C (0.25g, 0.97mmol) as the starting material, and following the synthesis method in Step 1 of Example 1, compound 27 (80mg, yield: 18.06%, Rf = 0.48EA / PE = 2:1) was synthesized by silica gel column chromatography.

[0595] LC-MS(ESI): m / z = 412.0 [M-44] + .

[0596] 1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),7.37-7.35(d,4H),7.27-7.18(m,3H),3.88-3.85(t,2H), 2.66-2.63(t,2H),2.54(d,2H),2.45(d,2H),2.07(s,6H),1.81-1.74(m,2H),1.70-1.67(d,2H).

[0597] Example 28:

[0598] Step 1: 28A (1.5 g, 7.0 mmol), Pd(dppf)Cl2 (0.51 g, 0.70 mmol), and toluene (20 mL) were added to a reaction flask. Under nitrogen protection, the mixture was heated to 80 °C and stirred for 15 minutes. Then, methylmagnesium chloride (0.52 g, 7.01 mmol) was added using a syringe, and the mixture was heated to 90 °C and stirred for another hour. The reaction was confirmed by TLC. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 28B (0.9 g, yield 86.09%). LC-MS (ESI): m / z = 150.3 [M+H]+.

[0599] Step 2: Using compound 28B (0.90 g, 6.03 mmol) as the starting material, compound 28C (0.72 g, yield 50.73%) was obtained following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 236.0 [M+H] + .

[0600] Step 3: Using compound 28C (0.40 g, 1.70 mmol) as the starting material, compound 28D (0.30 g, yield 91.30%) was obtained by following the procedure in step 2 of Example 8. LC-MS (ESI): m / z = 194.1 [M+H] + .

[0601] Step 4: Using compound 28D (0.2 g, 1.04 mmol) and compound 1B (0.25 g, 1.14 mmol) as raw materials, the compound was synthesized according to the first step of Example 1. The compound 28 (0.2 g, yield 49.23%, Rf = 0.46EA / PE = 2:1) was obtained by silica gel column chromatography.

[0602] LC-MS (ESI): m / z = 393.2 [M+H] + .

[0603] 1H NMR(400MHz,DMSO-d6)δ11.22(s,1H),7.36–7.35(m,4H),7.26–7.25(m,1H),6.99(s,1H),6.71-6.68(m,1H),3.88-3.8 6(m,2H),2.64-2.63(m,2H),2.54-2.51(m,2H),2.41-2.36(m,5H),2.06(s,6H),1.79-1.75(m,2H),1.72-1.69(m,2H).

[0604] Example 29:

[0605] Step 1: Using compound 27 (170 mg, 0.37 mmol) as the starting material, and following the synthesis method described in Step 1 of Example 28, compound 29 (30 mg, yield: 20.56%) was obtained by silica gel column chromatography.

[0606] LC-MS(ESI): m / z = 348.1 [M-44] + .

[0607] 1 H NMR(400MHz,DMSO-d6)δ10.68(s,1H),7.37-7.36(d,4H),7.26-7.23(m,1H),6.95-6.92(d,1H),6.70-6.68(d,1H),3.8 8-3.85(t,2H),2.67-2.56(m,4H),2.52(s,3H),2.42-2.36(m,2H),2.07(s,6H),1.82-1.78(d,2H),1.75-1.69(m,2H).

[0608] Example 30:

[0609] Step 1: Using compound 27 (170 mg, 0.37 mmol) as the starting material, and following the synthesis method described in Step 1 of Example 15, compound 30 (60 mg, yield: 40.01%) was obtained by silica gel column chromatography.

[0610] LC-MS (ESI): m / z = 359.1 [M-44] + .

[0611] 1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),7.63-7.62(d,1H),7.51-7.49(d,1H),7.37-7.36(d,4H),7.27-7.24(d,1H),3.89- 3.96(t,2H),2.69-2.67(d,2H),2.56-2.52(d,2H),2.47-2.40(d,2H),2.07(s,6H),1.81-1.77(d,2H),1.73-1.69(d,2H).

[0612] Example 31:

[0613] Step 1: Using compound 31A (0.26 g, 1.70 mmol) as the starting material, compound 31B (0.19 g, 47% yield) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 240.1 [M+H] + .

[0614] Step 2: Using compound 31B (0.26 g, 1.03 mmol) as the starting material, compound 31C (0.12 g, yield 59%) was synthesized according to Step 2 of Example 8. LC-MS (ESI): m / z = 196.0 [MH] - .

[0615] Step 3: Using compound 31C (110 mg, 0.56 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 31 (36 mg, yield 16%, Rf = 0.50EA / PE = 2:1) was obtained by silica gel column chromatography.

[0616] LC-MS(ESI): m / z = 352.0 [M-44] + .

[0617] 1 H NMR(400MHz,CD3OD)δ7.45-7.26(m,5H),6.73-6.67(m,1H),6.58-6.52(m,1H)3.96(t,2 H),2.88(t,2H),2.67-2.64(m,2H),2.35-2.23(m,2H),2.15(s,6H),1.93-1.86(m,4H).

[0618] Example 32:

[0619] Step 1: Using compound 32A (synthesized according to patent WO2008101660A1, 200 mg, 0.87 mmol) and intermediate 13C (140 mg, 0.71 mmol) as starting materials, the method in Step 1 of Example 1 was followed. Compound 32-1 (50 mg, yield 17.24%) and compound 32-2 (60 mg, yield 20.69%) were obtained by HPLC separation.

[0620] HPLC preparation method: Instrument: CAS-05-PREP-HPLC K; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-80% B gradient elution flow rate: 30 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 6 min; Sample preparation: Sample concentration 10 mg / ml, acetonitrile solution injection: 1 ml each time.

[0621] Compound 32-1: LC-MS (ESI): m / z = 409.1 [M+H] + Retention time: 4.254 min.

[0622] 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.44–7.28(m,5H),7.06–7.03(m,1H),6.92–6.86(m,1H),3.87–3.8 4(m,2H),3.00–2.97(m,4H),2.65–2.62(m,2H),2.45–2.38(m,2H),2.13–2.07(m,2H),1.76–1.67(m,6H).

[0623] Compound 32-2: LC-MS (ESI): m / z = 409.2 [M+H] + Retention time: 3.153 min.

[0624] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),7.80–7.78(m,2H),7.60–7.57(m,3H),7.16–7.13(m,1H),7.03–7.02(m,1H),4.11–4.0 0(m,4H),3.89–3.86(m,2H),2.68–2.62(m,4H),2.44–2.36(m,1H),2.21–2.04(m,4H),2.00–1.96(m,2H),1.83–1.75(m,1H).

[0625] Example 33:

[0626] Step 1: Compound 21B (3.0 g, 13.57 mmol) was dissolved in dioxane (20 mL) and water (20 mL). Palladium on carbon (0.3 g, 10% wt) and sodium hypophosphite monohydrate (8.71 g, 81.45 mmol) were added. The mixture was stirred at 100 °C for 1.5 h, cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography to obtain compound 33A (1.27 g, 45% yield). LC-MS (ESI): m / z = 208.1 [M+H] + .

[0627] Step 2: Under ice bath conditions, compound 33A (1.27 g, 6.14 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.24 g, 12.27 mmol), 4-dimethylaminopyridine (48.47 mg, 0.40 mmol), and di-tert-butyl dicarbonate (2.00 g, 9.21 mmol) were added. After the addition was complete, the ice bath was removed and the mixture was brought to room temperature. The mixture was stirred for 3 h, concentrated, and then subjected to silica gel column chromatography to obtain compound 33B (1.34 g, 71% yield).

[0628] Step 3: Under ice bath conditions, compound 33B (1.27 g, 4.12 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the sequential addition of DBU (1.88 g, 12.37 mmol) and diphenyl(vinyl)sulfonium trifluoromethanesulfonate (1.94 g, 5.36 mmol). The reaction was continued for 1 h. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench the reaction. Water (80 mL) and ethyl acetate (100 mL × 3) were added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography and high performance liquid chromatography to prepare compound 33C (0.89 g, yield 65%).

[0629] Step 4: Using compound 33C (890 mg, 2.67 mmol) as the starting material, compound 33D (560 mg, 90% yield) was synthesized following step 2 of Example 4. LC-MS (ESI): m / z = 234.1 [M+H] + .

[0630] Step 5: Using compound 33D (560 mg, 2.40 mmol) as the starting material, compound 33E (300 mg, 61% yield) was synthesized according to step 3 of Example 4. LC-MS (ESI): m / z = 206.1 [M+H] + .

[0631] Step 6: Using compound 33E (200 mg, 0.98 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. Compound 33 was obtained by silica gel column chromatography (Rf = 0.48EA / PE = 2:1). Compound 33 was further prepared by high performance liquid chromatography to obtain trifluoroacetate of compound 33 (161 mg, yield 41%).

[0632] HPLC Preparation Method: Instrument: Waters AutoP Preparative Liquid Chromatography; Column: SunFire@Prep C18 (19mm × 250mm). The sample was dissolved in acetonitrile / water and filtered through a 0.45μm filter to prepare the sample solution. Preparative Chromatographic Conditions: a. Composition of mobile phases A and B: Mobile phase A: acetonitrile; Mobile phase B: water (0.1% TFA); b. Gradient elution, 10-70%; c. Flow rate: 15ml / min; d. Elution time: 15min.

[0633] LC-MS(ESI): m / z = 360.1 [M-44] + .

[0634] 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),7.78-7.71(m,2H),7.60-7.51(m,3H),7.15-7.03(m,1H),7.01-6.86(m,2H),3.6 5(s,2H),3.05-2.92(m,2H),2.74(s,6H),2.35-2.21(m,2H),2.18-2.01(m,4H),1.32-1.30(m,2H),0.82-0.79(m,2H).

[0635] Example 34:

[0636] Step 1: Using compound 32A (310 mg, 1.34 mmol) and intermediate 21C (200 mg, 1.12 mmol) as starting materials, the first step of Example 1 was followed in the synthesis. Compound 34-1 (25 mg, yield 5.74%) and compound 34-2 (18 mg, yield 4.13%) were obtained by HPLC separation.

[0637] HPLC preparation method: Instrument: CAS-05-PREP-HPLC K; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-85% B; Gradient elution flow rate: 30 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 6.0 min; Sample preparation: Sample concentration 15 mg / ml, acetonitrile solution injection: 1 ml each time.

[0638] Compound 34-1: LC-MS (ESI): m / z = 391.2 [M+H] + Retention time: 4.170 min.

[0639] 1 H NMR(400MHz,DMSO-d6)δ11.38(s,1H),7.44–7.40(m,2H),7.37–7.35(m,2H),7.32 7.28(m,1H),7.23–7.21(m,1H),6.96–6.85(m,2H),3.87–3.85(m,2H),3.00–2.96( m,4H),2.68–2.65(m,2H),2.45–2.38(m,2H),2.14–2.11(m,2H),1.73–1.66(m,6H).

[0640] Compound 34-2: LC-MS (ESI): m / z = 391.2 [M+H] + Retention time: 2.978 min.

[0641] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.50–7.46(m,4H),7.36–7.33(m,1H),7.19–7.17(m,1H),6.91–6.86(m,1H),6.82–6.7 7(m,1H),3.95–3.92(m,2H),2.89–2.86(m,4H),2.69–2.66(m,2H),2.16–2.13(m,2H),1.99–1.94(m,2H),1.79–1.64(m,6H).

[0642] Example 35:

[0643] Step 1: Compound 35A (5.00 g, 35.42 mmol) was dissolved in concentrated sulfuric acid (0.09 g, 0.92 mmol) in THF (75 mL), and the mixture was cooled to -75 °C under nitrogen protection. NBS (6.94 g, 38.97 mmol) was suspended in THF (70 mL), and the suspension was slowly added (over 45 min) to the low-temperature reaction system. After the addition was complete, the reaction was continued at low temperature for 1 hour. Na₂CO₃ (2.00 g, 18.87 mmol) was added to the low-temperature reaction system, and the mixture was then brought to room temperature. The reaction solution was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 35B (2.01 g, 25% yield). LC-MS (ESI): m / z = 219.9 [M+H] + .

[0644] Step 2: Using compound 35B (1.50 g, 6.82 mmol) as the starting material, compound 35C (1.02 g, 63% yield) was synthesized according to step 3 of Example 20. LC-MS (ESI): m / z = 238.1 [M+H] + .

[0645] Step 3: Using compound 35C (700 mg, 2.95 mmol) as the starting material, compound 35D (226 mg, 46% yield) was synthesized according to step 4 of Example 20. LC-MS (ESI): m / z = 166.2 [M+H] + .

[0646] Step 4: Using compound 35D (190 mg, 1.15 mmol) as the starting material, compound 35E (159 mg, 55% yield) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 252.2 [M+H] + .

[0647] Step 5: Using compound 35E (139 mg, 0.55 mmol) as the starting material, compound 35F (79 mg, 68% yield) was synthesized according to step 2 of Example 8. LC-MS (ESI): m / z = 210.1 [M+H] +

[0648] Step 6: Using compound 35F (79 mg, 0.38 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 35 (16 mg, yield 10%, Rf = 0.50EA / PE = 2:1) was obtained by silica gel column chromatography.

[0649] LC-MS(ESI): m / z = 364.2 [M-44] + .

[0650] 1 ¹H NMR (400MHz, DMSO-d6) δ 11.18 (s, 1H), 7.37–7.35 (m, 4H), 7.28–7.23 (m, 1H), 7.10 (d, 1H), 6.86 (t, 1H), 3.86 (t, 2H), 3.84 (s, 3H), 2.63 (t, 2H), 2.51–2.50 (m, 2H), 2.42–2.34 (m, 2H), 2.06 (s, 6H), 1.82–1.61 (m, 4H). Example 36:

[0651] Step 1: Using compound 36A (2.00 g, 9.62 mmol) as the starting material, compound 36B (1.20 g, 55% yield) was synthesized according to step 3 of Example 20. LC-MS (ESI): m / z = 226.1 [M+H] + .

[0652] Step 2: Using compound 36B (1.00 g, 4.44 mmol) as the starting material, compound 36C (0.48 g, 70% yield) was synthesized according to step 4 of Example 20. LC-MS (ESI): m / z = 152.0 [MH] - .

[0653] Step 3: Using compound 36C (300 mg, 1.96 mmol) as the starting material, compound 36D (325 mg, 69% yield) was synthesized following the procedure in Step 1 of Example 8. LC-MS (ESI): m / z = 240.1 [M+H] + .

[0654] Step 4: Using compound 36D (250 mg, 1.05 mmol) as the starting material, compound 36E (120 mg, yield 58%) was synthesized according to step 2 of Example 8. LC-MS (ESI): m / z = 196.0 [MH] - .

[0655] Step 5: Using compound 36E (120 mg, 0.61 mmol) as the starting material, the synthesis was carried out according to the first step of Example 1. The compound 36 (14 mg, yield 5%, Rf = 0.51EA / PE = 2:1) was obtained by silica gel column chromatography.

[0656] LC-MS (ESI): m / z = 352.1 [M-44] + .

[0657] 1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),7.37-7.35(m,4H),7.28–6.94(m,3H),3.88(t,2 H),2.66(t,2H),2.54-2.53(m,2H),2.41-2.34(m,2H),2.07(s,6H),1.80-1.69(m,4H).

[0658] Example 37:

[0659] Step 1: Using compound 37A (synthesized according to patent US20170197949A1, 200 mg, 0.91 mmol) and intermediate 21C (150 mg, 0.83 mmol) as starting materials, the method of step 1 in Example 1 was followed. Compound 37-1 (24 mg, yield 7.46%) and compound 37-2 (21 mg, yield 6.52%) were obtained by HPLC separation.

[0660] HPLC preparation method: Instrument: CAS-05-PREP-HPLC S; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-80% B; Gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 8.0 min; Sample preparation: Sample concentration 5 mg / ml, acetonitrile solution injection: 1 ml each time.

[0661] Compound 37-1: LC-MS (ESI): m / z = 385.1 [M+H] + Retention time: 1.847 min.

[0662] 1 H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.25–7.22(m,2H),7.05–7.03(m,1H),7.02 -6.97(m,1H),6.92–6.84(m,2H),3.98–3.95(m,2H),2.80–2.77(m,2H),2.38–2. 32(m,4H),2.27–2.23(m,1H),2.19(s,6H),2.17–2.13(m,1H),1.90–1.87(m,2H).

[0663] Compound 37-2: LC-MS (ESI): m / z = 385.0 [M+H] + Retention time: 2.044 min.

[0664] 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),7.50–7.49(m,1H),7.20–7.18(m,1H),7.15–7.13(m,1H),7.05–7.04(m,1H),6.93–6.88(m,1H),6.86– 6.79(m,1H),3.94–3.91(m,2H),2.69–2.67(m,2H),2.29–2.26(m,2H), 2.08–2.06(m,2H),2.02(s,6H),1.95–1.88(m,2H),1.82–1.79(m,2H).

[0665] Example 38:

[0666] Step 1: Using compound 38A (synthesized according to patent WO2012013343A1, 110 mg, 0.50 mmol) and intermediate 21C (90 mg, 0.50 mmol) as raw materials, the method in Step 1 of Example 1 was followed. Compound 38-1 (2.86 mg, yield 1.48%) and compound 38-2 (1.51 mg, yield 0.78%) were obtained by HPLC separation.

[0667] HPLC preparation method: Instrument: CAS-05-PREP-HPLC S; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-85% B gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 8.0 min; Sample preparation: Sample concentration 5 mg / ml, acetonitrile solution injection: 1 ml each time.

[0668] Compound 38-1: LC-MS (ESI): m / z = 385.1 [M+H] + Retention time: 1.854 min.

[0669] 1H NMR (400MHz, CD3OD) δ7.88–7.87(m,1H),7.66–7.64(m,1H),7.44–7.42(m,1H),7.26–7.24(m,1H),6.93–6.87(m,1H),6.79–6. 74(m,1H),6.11–6.10(m,1H),3.66–3.56(m,2H),3.41–3.35(m,4H),2.95–2.76(m,10H),2.43–2.36(m,1H),2.27–2.19(m,1H).

[0670] Compound 38-2: LC-MS (ESI): m / z = 385.0 [M+H] + Retention time: 2.028 min.

[0671] 1 H NMR (400MHz, CD3OD) δ7.94–7.93(m,1H),7.74–7.72(m,1H),7.46–7.44(m,1H),7.19–7.17(m,1H),6.92–6.87(m,1H),6.77–6.72(m,1H),4.55(br s,1H),4.05–4.03(m,2H),2.78–2.75(m,4H),2.67(s,6H),2.43–2.36(m,2H),2.11–2.07(m,2H),1.94–1.86(m,2H).

[0672] Example 39:

[0673] Step 1: Compound 39A (3.00 g, 18.29 mmol) was dissolved in dry tetrahydrofuran (30 mL). Under nitrogen protection, 1 M ethyl magnesium bromide solution (18.50 mL, 18.29 mmol) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred at room temperature for 4 h. Then, it was slowly added dropwise to dry tetrahydrofuran (30 mL) containing 39B (3.00 g, 14.27 mmol, synthesized according to patent WO2019121670A1). After the addition was complete, the reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL), and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography to obtain 39C (140 mg, yield 3.66%). LC-MS (ESI): m / z = 269.1 [M+H] + .

[0674] Step 2: Compound 39C (140 mg, 0.52 mmol) was dissolved in dry dichloromethane (4 mL). A 4M ethyl acetate hydrochloride solution (2 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was stirred under ice bath conditions for 1 h. The solution was then concentrated under reduced pressure to obtain crude 39D (110 mg, yield 94.00%), which was directly used in the next step of the reaction. LC-MS (ESI): m / z = 225.1 [M+H] + .

[0675] Step 3: Using compound 39D (100 mg, 0.45 mmol) and intermediate 21C (80 mg, 0.45 mmol) as raw materials, the mixture was synthesized according to the first step of Example 1. Compound 39-1 (4.60 mg, yield 2.67%) and compound 39-2 (6.10 mg, yield 3.54%) were obtained by HPLC separation.

[0676] HPLC preparation method: Instrument: CAS-05-Semi-prep K; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 15%-90% B gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 16 min; Sample preparation: Sample concentration 5 mg / ml, acetonitrile solution injection: 1 ml each time.

[0677] Compound 39-1: LC-MS (ESI): m / z = 341.2 [M-44] + Retention time: 3.549 min.

[0678] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),7.19–7.17(m,1H),7.01–6.99(m,1H),6.92–6.83(m,2H),6.68–6.63(m,1H),4.75–4.71(m,1 H),4.16–4.10(m,1H),4.02–3.96(m,1H),3.43(s,6H),2.71–2.67(m,1H),2.41–2.33(m,2H),2.06–2.02(m,2H),1.93–1.89(m,4H).

[0679] Compound 39-2: LC-MS (ESI): m / z = 386.1 [M+H] + &341.1[M-44] + Retention time: 2.945 min.

[0680] 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),7.19–7.17(m,1H),6.98–6.96(m,1H),6.92–6.81(m,2H),6.66–6.63(m,1H),4.76–4.7 4(m,1H),4.40–4.38(m,1H),3.54-3.45(m,2H),3.33–3.26(m,8H),2.70–2.65(m,1H),2.42–2.29(m,2H),1.96–1.86(m,3H).

[0681] Example 40:

[0682] Step 1: Using compounds 40A (2.00 g, 12.19 mmol) and 39B (2.00 g, 9.51 mmol) as starting materials, compound 40B (110 mg, yield 4.31%) was synthesized according to the first step of Example 39. LC-MS (ESI): m / z = 269.1 [M+H] + .

[0683] Step 2: Using compound 40B (110 mg, 0.41 mmol) as the starting material, compound 40C (90 mg, yield 97.89%) was synthesized according to Step 2 of Example 39. LC-MS (ESI): m / z = 225.2 [M+H] + .

[0684] Step 3: Using compound 40C (65 mg, 0.28 mmol) and intermediate 21C (50 mg, 0.28 mmol) as raw materials, the mixture was synthesized according to the first step of Example 1. Compound 40-1 (2.76 mg, yield 2.57%) and compound 40-2 (1.66 mg, yield 1.54%) were obtained by HPLC separation.

[0685] HPLC preparation method: Instrument: CAS-05-Semi-prep K; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-95% B gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 16 min; Sample preparation: Sample concentration 8 mg / ml, acetonitrile solution injection: 1.2 ml each time.

[0686] Compound 40-1: LC-MS (ESI): m / z = 341.1 [M-44] + Retention time: 2.944 min.

[0687] 1 H NMR (400MHz, CD3OD) δ7.18–7.16(m,1H),6.97–6.95(m,1H),6.92–6.87(m,1H),6.82–6.77(m,2H),6.75–6.70(m,1H),4.56–4. 50(m,2H),3.72–3.57(m,2H),3.32–3.30(m,7H),2.77–2.70(m,1H),2.58–2.52(m,1H),2.34–2.28(m,1H),2.08–1.93(m,4H).

[0688] Compound 40-2: LC-MS (ESI): m / z = 386.1 [M+H] + &341.1[M-44] + Retention time: 2.846 min.

[0689] 1 H NMR (400MHz, CD3OD) δ7.18–7.16(m,1H),6.97–6.95(m,1H),6.92–6.87(m,1H),6.82–6.77(m,2H),6.75–6.71(m,1H),4.60–4.47(m,4H) ,3.74–3.71(m,3H),3.67-3.58(m,2H),3.37–3.31(m,4H),2.77–2.70(m,1H),2.58–2.51(m,1H),2.35–2.29(m,1H),1.88–1.85(m,2H).

[0690] Example 41:

[0691] Step 1: Compound 41B (90 mg, yield 3.53%) was synthesized from compound 41A (2.00 g, 12.19 mmol) and 39B (2.00 g, 9.51 mmol) according to the first step of Example 39. LC-MS (ESI): m / z = 269.1 [M+H] + .

[0692] Step 2: Using compound 41B (90 mg, 0.34 mmol) as the starting material, compound 41C (70 mg, yield 93.05%) was synthesized following Step 2 of Example 39. LC-MS (ESI): m / z = 225.1 [M+H] + .

[0693] Step 3: Using compound 41C (65 mg, 0.28 mmol) and intermediate 21C (50 mg, 0.28 mmol) as raw materials, the mixture was synthesized according to the first step of Example 1. Compound 41-1 (1.69 mg, yield 1.21%) and compound 41-2 (8.72 mg, yield 6.24%) were obtained by HPLC separation.

[0694] HPLC preparation method: Instrument: CAS-05-Semi-prep K; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 10%-95% B gradient elution flow rate: 20 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 16 min; Sample preparation: Sample concentration 5 mg / ml, acetonitrile solution injection: 0.5 ml each time.

[0695] Compound 41-1: LC-MS (ESI): m / z = 341.1 [M-44] + Retention time: 3.536 min.

[0696] 1 H NMR (400MHz, CD3OD) δ8.49–8.48(m,1H),7.26–7.25(m,1H),7.21–7.19(m,1H),7.12–7.11(m,1H),6.94–6.91(m,1H),6.81–6.79(m, 1H),4.00–3.97(m,2H),3.49–3.47(m,2H),3.14–3.12(m,2H),2.76–2.74(m,2H),2.40–2.37(m,2H),2.25(s,6H),2.21–2.17(m,2H).

[0697] Compound 41-2: LC-MS (ESI): m / z = 386.1 [M+H] + &341.1[M-44] + Retention time: 2.986 min.

[0698] 1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),8.65–8.63(m,1H),7.36–7.33(m,1H),7.21–7.19(m,1H),6.93–6.80(m,2 H),3.93-3.91(m,2H),2.69–2.67(m,2H),2.28–2.25(m,2H),2.12–2.04(m,2H),2.01(s,6H),1.86–1.84(m,4H).

[0699] Example 42:

[0700] Step 1: Compound 42A (6.19 g, 53.28 mmol) was dissolved in dichloromethane (120 mL), cooled to 0 °C, and trifluoroacetic acid (50.6 g, 444 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 30 minutes. Compound 21A (6 g, 44.4 mmol) was dissolved in DCM (30 mL) and slowly added dropwise. After the addition was complete, the mixture was slowly raised to room temperature and stirred for 2 hours. The reaction was confirmed to be complete by TLC. The pH was adjusted to alkaline by adding saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain crude compound 42B, which was directly used in the next reaction (10 g, crude product). LC-MS (ESI): m / z = 207.0 [M+H] + .

[0701] Step 2: Under nitrogen protection, lithium aluminum hydride (11 g, 291 mmol) was dissolved in ultra-dry tetrahydrofuran (120 mL). The mixture was cooled to 0 °C, and compound 42B (10 g, 48.5 mmol, dissolved in 30 mL of ultra-dry tetrahydrofuran) was slowly added dropwise. After the addition was complete, the mixture was heated to reflux and reacted for 3 hours. The reaction was confirmed to be complete by LC-MS. The mixture was then cooled to 0 °C, and water (11 mL), 15% sodium hydroxide solution (11 mL), and water (33 mL) were added dropwise sequentially. After the addition was complete, the mixture was slowly heated to room temperature and stirred for 1 hour. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound 42C (4.5 g, yield 52.06%). LC-MS (ESI): m / z = 179.1 [M+H] + .

[0702] Step 3: Under nitrogen protection, compounds 42C (500 mg, 2.81 mmol) and 1B (611 mg, 2.81 mmol) were dissolved in ultra-dry methanol (20 mL), and anhydrous magnesium sulfate (2 g) was added. After the addition was complete, the mixture was stirred overnight at room temperature. The methanol was removed by concentration under reduced pressure, and ultra-dry 1,2-dichloroethane (30 mL) and trifluoroacetic acid (4.5 mL) were added sequentially. After the addition was complete, the mixture was stirred at room temperature for 5 hours, and the reaction was confirmed to be complete by LC-MS. The mixture was diluted with a 5 / 1 dichloromethane / methanol mixture, filtered through a diatomaceous earth filter, and the filtrate was concentrated to remove the solvent. The pH of the residue was adjusted to alkaline with saturated sodium bicarbonate solution, and the solid precipitated. The solid was filtered, washed with water, and dried to obtain the crude product. After two preparative HPLC purifications, compounds 42-1 (40 mg, yield 3.77%) and crude compound 42-2 (700 mg, yield 66.1%) were obtained.

[0703] HPLC preparation methods: First preparation: Instrument: CAS-05-PREP-HPLC T, column: C18; mobile phase: A: 0.1% TFA in water; B: acetonitrile; flow rate: 75 mL / min, column temperature: 25℃, wavelength: 220 & 254 nm. Crude compounds 42-1 and 42-2 were obtained. Second preparation: Instrument: CAS-05-PREP-HPLC K, column: C18; mobile phase: A: 10 mmol / L NH4HCO3 in water; B: acetonitrile; flow rate: 35 mL / min, column temperature: 25℃, wavelength: 220 & 254 nm. Compound 42-1 (40 mg) was obtained.

[0704] Compound 42-1: LC-MS (ESI): m / z = 378.2 [M+H] + Retention time: 2.882 min.

[0705] 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),7.43–7.32(m,4H),7.27–7.21(m,1H),7.16–7.14(m,1H),6.91–6.79(m,2 H),2.96–2.93(m,2H),2.56–2.52(m,2H),2.44–2.36(m,4H),2.06(s,6H),1.95–1.84(m,3H),1.53–1.50(m,2H).

[0706] Compound 42-2: LC-MS (ESI): m / z = 378.2 [M+H] + Retention time: 3.179 min.

[0707] 1 H NMR(400MHz, DMSO-d6&D2O)δ11.30(s,1H),7.79–7.77(m,2H),7.69–7.66(m,3H),7.31–7.30(m,1H),7.0 3–6.93(m,2H),3.63–3.60(m,2H),3.06–2.99(m,4H),2.59(s,6H),2.31–2.25(m,4H),2.12–2.09(m,2H).

[0708] Example 43:

[0709] Step 1: Using compound 32A (420 mg, 1.84 mmol) and intermediate 36E (300 mg, 1.52 mmol) as starting materials, the first step of Example 1 was followed in the synthesis. Compound 43-1 (70 mg, yield 11.26%) and compound 43-2 (100 mg, yield 16.09%) were obtained by HPLC separation.

[0710] HPLC preparation method: Instrument: CAS-05-Semi-prep AA; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 50%-90% B gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 16 min; Sample preparation: Sample concentration 10 mg / ml, acetonitrile solution injection: 1 ml each time.

[0711] Compound 43-1: LC-MS (ESI): m / z = 409.2 [M+H] + Retention time: 1.442 min.

[0712] 1 H NMR(400MHz,DMSO-d6)δ11.25(s,1H),7.51–7.50(m,4H),7.41–7.37(m,1H),7.15–7.13(m,1H),6.98–6.91(m,1H), 3.95–3.92(m,2H),3.06–2.97(m,4H),2.67–2.66(m,2H),2.22–2.19(m,2H),1.99–1.98(m,2H),1.80–1.69(m,6H).

[0713] Compound 43-2: LC-MS (ESI): m / z = 409.2 [M+H] +Retention time: 1.599 min.

[0714] 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),7.42–7.39(m,2H),7.36–7.34(m,2H),7.30–7.27(m,1H),7.16–7.14(m,1H),7.01–6.9 9(m,1H),3.85–3.82(m,2H),2.99–2.96(m,4H),2.65–2.62(m,2H),2.43–2.37(m,2H),2.11–2.09(m,2H),1.72–1.68(m,6H).

[0715] Example 44:

[0716] Step 1: Using compound 37A (410 mg, 1.84 mmol) and intermediate 36E (300 mg, 1.52 mmol) as raw materials, the first step of Example 1 was followed in the synthesis. Compound 44-1 (40 mg, yield 6.53%) and compound 44-2 (110 mg, yield 17.96%) were obtained by HPLC separation.

[0717] HPLC preparation method: Instrument: CAS-05-Semi-prep AA; Column: C18 Column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: ACN; Gradient: 45%-90% B gradient elution flow rate: 25 mL / min; Column temperature: 25℃; Wavelength: 210 nm & 254 nm; Cycle time: 16 min; Sample preparation: Sample concentration 8 mg / ml, acetonitrile solution injection: 1 ml each time.

[0718] Compound 44-1: LC-MS (ESI): m / z = 403.1 [M+H] + &358.2[M-44] + Retention time: 1.386 min.

[0719] 1 H NMR(400MHz,DMSO-d6)δ11.35(s,1H),7.50–7.49(m,1H),7.17–7.13(m,2H),7.05 7.04(m,1H),6.99–6.92(m,1H),3.93–3.90(m,2H),2.67–2.64(m,2H),2.28–2.25(m,2H),2.07–1.98(m,8H),1.93–1.78(m,4H).

[0720] Compound 44-2: LC-MS (ESI): m / z = 403.3 [M+H] + &358.1[M-44] + Retention time: 1.534 min.

[0721] 1 H NMR(400MHz,DMSO-d6)δ11.60(s,1H),7.43–7.42(m,1H),7.20–7.17(m,1H),7.09–7.06(m,1H),7.03–6.96(m,2 H),3.91–3.88(m,2H),2.68–2.66(m,2H),2.38–2.30(m,4H),2.15(s,6H),1.99–1.92(m,2H),1.70–1.67(m,2H).

[0722] Biological testing evaluation

[0723] The present invention will be further described and explained below with reference to test examples, but these embodiments are not intended to limit the scope of the present invention.

[0724] 1. Assay for the agonistic activity of the orphanone receptor (NOPR)

[0725] CHO cells overexpressing the orphanone receptor (NOPR) (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37°C and 5% CO2. On the day of the experiment, 1×Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revvity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1×Stimulation Buffer, count them, and adjust the cell density to 1×10⁻⁶. 5Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37°C for 10 min. Then, 10 nL / well of Forskolin (2 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37°C for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 ×10000, Activation Rate (%) = (Ratio) 受试物 -Ratio 阴性对照 ) / (Ratio 阳性对照 -Ratio 阴性对照 )×100. EC was fitted using GraphPad Prism software. 50 value.

[0726] Experimental results: NOPR EC for some specific compounds 50 (nM) is shown in Table 1, where A represents EC. 50 ≤10nM, B means 10nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0727] Table 1 Note: * indicates trifluoroacetate.

[0728] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity towards NOPR.

[0729] 2. Assay for the agonistic activity of mu-opioid receptors (MOR)

[0730] CHO cells overexpressing the mu opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37°C and 5% CO2. On the day of the experiment, 1×Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding experimental well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1×Stimulation Buffer, count them, and adjust the cell density to 2.2×10⁻⁶. 5 Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37°C for 10 min. Then, 10 nL / well of Forskolin (6 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37°C for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 ×10000, Activation Rate (%) = (Ratio) 受试物 -Ratio 阴性对照 ) / (Ratio 阳性对照 -Ratio 阴性对照 )×100. EC was fitted using GraphPad Prism software. 50 value.

[0731] Experimental results: MOR EC of some specific compounds 50 (nM) is shown in Table 2, where A represents EC. 50≤10nM, B means 10nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0732] Table 2 Note: * indicates trifluoroacetate.

[0733] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity for MOR.

[0734] 3. Kappa opioid receptor (KOR) agonistic activity assay

[0735] CHO cells overexpressing the kappa opioid receptor (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37°C and 5% CO2. On the day of the experiment, 1×Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9-10 concentration points), and then 10 nL / well was transferred to the corresponding well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1×Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5 Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37°C for 10 min. Then, 10 nL / well of Forskolin (1 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37°C for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 ×10000, Activation Rate (%) = (Ratio) 受试物 -Ratio 阴性对照 ) / (Ratio 阳性对照 -Ratio 阴性对照 )×100. EC was fitted using GraphPad Prism software. 50 value.

[0736] Experimental results: KOR EC of some specific compounds 50 (nM) is shown in Table 3, where A represents EC. 50 ≤20nM, B means 20nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0737] Table 3 Note: * indicates trifluoroacetate.

[0738] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity toward KOR.

[0739] 4. Assay for the agonistic activity of delta-opioid receptors (DOR)

[0740] CHO cells overexpressing delta-opioid receptors (constructed in the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.) were cultured in F-12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B. Cells were cultured in an incubator at 37°C and 5% CO2. On the day of the experiment, 1×Stimulation Buffer was prepared according to the LANCE Ultra cAMP kit (Revity, TRF0264) instructions. The test sample stock solution was diluted with DMSO (9–10 concentration points), and then 10 nL / well was transferred to the corresponding well using ECHO. For cell treatment, the old medium was removed and the cells were rinsed once with PBS, then 1 mL of 0.25% Trypsin-EDTA solution was added, and the cells were incubated at 37°C for approximately 2 minutes. When the cells detached from the bottom of the dish, approximately 5 mL of preheated (37°C) complete medium was added. Gently pipette the cell suspension to separate aggregated cells, then transfer them to sterile centrifuge tubes and collect the cells by centrifugation at 1000 rpm for 5 minutes. Resuspend the cells in 1×Stimulation Buffer, count them, and adjust the cell density to 2×10⁶ cells / mL. 5Cells / mL, seeded at 10 μL / well in a 384-well plate containing the test sample, centrifuged, and incubated at 37°C for 10 min. Then, 10 nL / well of Forskolin (0.5 mM) solution was transferred to the corresponding well using ECHO, centrifuged, and incubated at 37°C for 30 min. Eu-cAMP was diluted 50-fold with detection buffer, and 4 μL was added to the corresponding well. Ultra-anti-cAMP was diluted 150-fold with detection buffer, and 4 μL was added to the corresponding well. After centrifugation, the cells / well was incubated at room temperature for 1 hour. After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader at a wavelength of 330 nm excitation. The final concentration of DMSO was 0.1%. The Ratio and activation rate were calculated using the following formula: Ratio = Signal 665 / Signal 620 ×10000, Activation Rate (%) = (Ratio) 受试物 -Ratio 阴性对照 ) / (Ratio 阳性对照 -Ratio 阴性对照 )×100. EC was fitted using GraphPad Prism software. 50 value.

[0741] Experimental results: DOR EC of some specific compounds 50 (nM) is shown in Table 4, where A represents EC. 50 ≤10nM, B means 10nM < EC 50 ≤100nM, C represents EC 50 >100nM.

[0742] Table 4

[0743] Conclusion: The compounds of the present invention, such as the compounds in the examples, have excellent agonistic activity toward DOR.

[0744] 5. In vitro plasma stability test

[0745] A prepared compound solution is added to a certain amount of biological matrix to prepare stability samples at two concentration levels (low-concentration quality control sample and high-concentration quality control sample), with three copies of each concentration level. Under the required experimental conditions, the peak area ratio of the sample after a certain period of time / the peak area ratio of the sample at point 0 is multiplied by 100% to obtain the stability test result of the compound.

[0746] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good in vitro plasma stability.

[0747] 6. Rat pharmacokinetic test

[0748] Experimental animals: Male SD rats, approximately 180–220g, 6–8 weeks old, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0749] Experimental design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water, and were fed 4 hours after drug administration.

[0750] Blood samples of 0.10 mL were collected via the orbital cavity before and after isoflurane anesthesia and placed in EDTAK2 centrifuge tubes. The samples were centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0751] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats.

[0752] 7. Mouse pharmacokinetics test

[0753] Experimental animals: Male C57 mice, 22-25g, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0754] Experimental design: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted for 12-14 hours before administration but allowed free access to water, and were fed 4 hours after administration.

[0755] Blood samples of 0.04 mL were collected via the orbital cavity before and after isoflurane anesthesia and placed in EDTAK2 centrifuge tubes. The samples were centrifuged at 5000 rpm for 10 min at 4°C to collect plasma. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0756] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

[0757] 8. Pharmacokinetics of Beagle Dogs

[0758] Experimental animals: Male beagle dogs, weighing approximately 8–11 kg, purchased from Beijing Mars Biotechnology Co., Ltd.

[0759] Experimental method: On the day of the experiment, beagles were randomly grouped according to their body weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0760] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0761] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good pharmacokinetic properties in ghrelin.

[0762] 9. Pharmacokinetics in monkeys

[0763] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 2.5-5 years old, purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0764] Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0765] Blood samples of 1.0 mL were collected from venous sites in the extremities before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min. All samples were stored at -80°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0766] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in monkeys.

[0767] 10. hERG potassium ion channel function test

[0768] Experimental platform: Electrophysiological manual patch-clamp system

[0769] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channels

[0770] Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamp voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ig). hERG The step voltage was applied from -80 mV to +20 mV for 2 seconds, then repolarized to -50 mV for 1 second before returning to -80 mV. This voltage stimulation was applied every 10 seconds, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0771] Data processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition degree of different compound concentrations on the hERG potassium current (the peak hERG tail current induced at -50mV) was calculated using the following formula: Inhibition% = [1 – (I / Io)] × 100%

[0772] Wherein, Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0773] Compound IC 50 The following equation was used to fit and calculate the result using GraphPad Prism 5 software: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0774] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0775] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit the hERG potassium channel current.

[0776] 11. CYP450 enzyme inhibition test

[0777] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0778] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit the five isoenzymes of human liver microsomal cytochrome P450 (CYP).

[0779] 12. Liver microsomal stability test

[0780] This experiment used liver microsomes from five genera—human, canine, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0781] At 37°C, 1 μM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T1 / 2 was calculated using the ln value of the drug residue in the incubation system and the incubation time. The intrinsic clearance rate (CL) of liver microsomes was further calculated. int(mic) and hepatic intrinsic clearance rate CL int(Liver) .

[0782] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good stability in liver microsomes.

[0783] 13. Caco-2 Permeability Test

[0784] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37 ± 1 °C for 2 hours, the cell plate was removed, and appropriate amounts of sample were transferred from both the apical and basal sides to new 96-well plates. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. Leakage of fluorescein was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0785] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0786] 14. Mouse hot plate test

[0787] Female C57 / BL6J mice (6-8 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for approximately one week before the experiment began. A hot plate apparatus (UGO BASILE SRL) was turned on, and the temperature was set to 56°C. After the temperature stabilized, the mouse was gently lifted by the base of its tail with the right thumb and forefinger, while the body was supported by the left palm. The mouse was quickly and smoothly placed in the center of the hot plate, and the mouse's pain response was observed, such as licking / biting its hind paws, rapid paw lifting or shaking, and jumping (limbs leaving the plate). Animals with a response latency of 8-25 seconds were selected for the study. The animals were divided into a solvent control group (Vehicle) and a test substance test group. The solvent or test substance was administered via tail vein injection. The mouse's pain response latency was tested again at a preset time point after administration. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Post-administration latency - Pre-administration latency) / (30 - Pre-administration latency) × 100. GraphPad Prism software was used to perform statistical analysis on the data to compare differences between groups and evaluate the analgesic effect of the test drug. The results are shown in Table 5 and Figures 1-6.

[0788] Table 5

[0789] The control compound TRN-228 has the following structure:

[0790] Conclusion: In the mouse hot plate test, the compounds of the present invention, such as compounds 13-1, 20, 21, 31, 33, 34-1, 36, and 37-1 in the examples, inhibited the pain response in animals in a dose-dependent manner, demonstrating good analgesic efficacy, which was superior to the control compound TRN-228.

[0791] 15. Mouse hot tail flicking test

[0792] Male ICR mice (6-8 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for approximately one week before being placed on the YLS-12A mouse tail photoanalgia testing platform. After setting the power, the start button was pressed and the experiment began. The animal was placed in the photoanalgia's dedicated restraint, ensuring its tail was aligned with the sensor and the heat transfer plate. The start button was pressed to begin timing. When the animal moved its tail away from the sensor due to heat pain, both infrared radiation and the timer stopped simultaneously. The tail-flick latency was recorded. Mice with a latency of less than 7 seconds were selected and randomly divided into a solvent control group (Vehicle) and a test substance group. The solvent or test substance was administered via tail vein injection, and the tail-flick latency was measured again at a preset time point after administration. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Post-administration latency - Pre-administration latency) / (16.01 - Pre-administration latency) × 100. GraphPad Prism software was used to perform statistical analysis on the data to compare differences between groups and evaluate the analgesic effect of the test drug.

[0793] Conclusion: In the mouse hot tail-flick experiment, the compounds of the present invention, such as the compounds in the examples, dose-dependently prolonged the tail-flick latency in animals and had good analgesic efficacy.

[0794] 16. Rat paw incision-induced mechanical pain sensitization model

[0795] Male SD rats (6-8 weeks old) purchased from Viton Lever Laboratories underwent environmental acclimatization training for approximately one week before the Von Frey test, allowing the rats to become fully familiar with the testing environment and the operator. The specific procedures and processes for this experiment are as follows:

[0796] (1) Preparation for adaptive training: Place the rats in a transparent plexiglass test cage in advance and allow them to adapt for 20 to 30 minutes.

[0797] (2) Adaptive Training: Using calibrated Von Frey fiber kits (0.6–26.0 g), a medium-strength Von Frey fiber (e.g., 8.0 g) was used to begin stimulation. If the rat exhibited a rapid withdrawal response to the stimulation, it was marked as a positive response. If no positive response was observed, a larger adjacent stimulus was given; if a positive response occurred, a smaller stimulus was given, and so on. After the first negative and positive straddling occurred, four more consecutive measurements were taken. A positive response was recorded as X, and a negative response as O. The interval between two stimuli was at least 5 seconds to allow for the elimination of the previous stimulus. The bending angle of the Von Frey fiber was controlled between 15 and 30 degrees. Finally, starting from the last negative response before the first positive straddling, a total of 6-digit measurements were obtained to calculate the rat's 50% withdrawal threshold. Training continued for 3 days.

[0798] (3) Preparation for foot incision surgery: After cleaning the scalpel, forceps, scissors, suture needles and other instruments, sterilize them by high pressure steam sterilization to ensure a sterile operating environment.

[0799] (4) Anesthesia and positioning: Rats were anesthetized with isoflurane inhalation. After complete anesthesia (loss of righting reflex and voluntary movement), they were fixed in a prone position on a temperature-controlled operating table. The left hind limb was fully abducted and fixed to expose the surgical area on the sole of the foot. The skin on the sole of the left hind foot was strictly disinfected with povidone-iodine solution.

[0800] (5) Surgical incision preparation: Using a No. 11 scalpel blade, make a longitudinal skin incision about 1 cm long on the bottom of the left hind foot, about 0.5 cm from the heel, towards the toes. Use forceps to lift the plantar muscle underneath and separate it through the longitudinal incision (without damaging the origin, insertion and attachment points of the plantar muscle). Gently press the incision to stop bleeding and remove any blood accumulation in the surgical area.

[0801] (6) Postoperative care: The muscles and skin were sutured with 4-0 absorbable sutures to ensure good closure of the incision, with no obvious bleeding or tissue exposure. After the operation, the rats were put back into the cage and raised separately.

[0802] (7) Baseline mechanical pain threshold test: The baseline test is performed about 2 hours after surgery to measure the mechanical withdrawal threshold of the non-incision area (such as the sole) of the foot on the operated side. The specific operation procedure is the same as that of the adaptation training phase.

[0803] (8) Grouping and administration: Based on the 50% PWT calculated 2 hours after surgery, animals weighing 1–4 g were selected for enrollment. Rats were evenly distributed into the solvent control group (Vehicle) and the test substance test group. The solvent or test substance was administered via tail vein injection, and then the 50% PWT was measured at different time points.

[0804] (9) Statistical analysis: GraphPad Prism software was used to perform statistical analysis on the data to compare the differences between groups and evaluate the analgesic effect of the test substance. The results are shown in Table 6.

[0805] Table 6

[0806] Conclusion: In a rat model of mechanical pain sensitization induced by plantar lesion, the compounds of the present invention, such as compounds 13-1, 21, and 36 in Examples, increased the mechanical pain threshold in an efficacy-dependent manner, indicating that the test substances have good analgesic effects.

[0807] 17. Mouse respiratory depression experiment

[0808] Female C57 / BL6J mice (6-8 weeks old), purchased from Vital River Laboratory Animal Technology Co., Ltd., were acclimatized in an SPF-grade animal facility for approximately one week before the experiment began. The FinePointe Whole Body Volume Profile (WBP) system was calibrated and validated, and the measured parameters (such as respiratory rate and tidal volume) were set up for use. After administering the appropriate dose of solvent or test substance to each group of animals, they were placed in the measurement container, and data collection began. The measurement period included both the acclimatization and measurement periods. After the measurement, the data for each animal's parameters within that time period were obtained using the instrument software. The mean values ​​were calculated to obtain the average respiratory rate, average tidal volume, and other data for that time period. GraphPad Prism software was used for statistical analysis of the data to compare differences between groups and assess the effect of the test substance on mouse respiration.

[0809] Conclusion: In the mouse respiratory depression experiment, at the effective dose, the compounds of the present invention, such as the compounds in the examples, had no effect or only a slight effect on respiratory depression in mice.

[0810] 18. Rat rotarod test

[0811] Male SD rats (4-6 weeks old) purchased from Vital River Laboratory Animal Technology Co., Ltd. were acclimatized in an SPF-grade animal facility for 3-5 days. Before drug administration testing, the rats underwent rotarod acclimatization training. Rats were placed on a 6cm diameter rotarod at a rotation speed of 15 rpm / min. Each training round lasted 120 seconds, with 4 rounds per day for 3 consecutive days. The rotarod was set every other day according to the acclimatization training program, with 120 seconds used as the cutoff value for the animal's latency on the rotarod. Animals with a latency of 120 seconds in all four rounds were selected for drug administration. The latency on the rotarod was measured after drug administration. Three consecutive tests were conducted, and the average value was obtained. The maximum possible percentage of efficacy (%MPE) was then calculated using the following formula: (Liquefied group latency on the rotarod - Drug administration group latency on the rotarod) / Solvent group latency on the rotarod × 100. GraphPad Prism software was used for statistical analysis of the data to compare differences between groups and assess the effect of the test substance on the rat's motor ability.

[0812] Conclusion: In rat rotarod experiments, at the effective dose, the compounds of the present invention, such as those in the examples, had no effect on rat rotarod behavior.

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: It can be represented as a single bond or a double bond; Ring A is a 5-14 membered heterocyclic group; X1, X2and X3are each independently a bond, -O-, -S-, -Se-, -CO-, -N-, -NR c -, -CR a -, -CR a R b -, or -CH2CR a R b -, wherein at least one of X1, X2and X3is -O-, -S-, -Se-, -N- or NR c , and at most one of X1, X2and X3is a bond; R a and R b each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkamino, C 1-6 alkylthio, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl; or, R a and R b linkage =CH2, optionally further substituted with 1-2 halo, C 1-3 alkyl or C 1-3 haloalkyl; Or, R on the same carbon atom a and R b or R on adjacent carbon atoms a and R b Link formation C 3-6 Cycloalkyl or 3-6-membered heterocycloalkyl, optionally further composed of 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group; R c is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 halogenated alkyl, C 1-6 alkoxy, wherein the alkyl, alkoxy groups are optionally further substituted by 1-5 R x groups; R1 is -NR3R4; R3 and R4 are independently hydrogen, deuterium, halogen, amino, and C, respectively. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -(CH2) r -C 3-6 Cycloalkyl, -(CH2) r -(4-6-membered heterocyclic alkyl), wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R... x Replaced; Alternatively, R3 and R4 are linked to form a 3-6 membered heterocyclic alkyl group, optionally further surrounded by 1-4 groups selected from deuterium, halogen, hydroxyl, cyano, amino, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits or C 1-6 The group substituted by the alkyl halide group; r is 0, 1, 2, or 3; R2 is Ring B may or may not be present. When ring B is present, ring B is a 3-6 member monocyclic cycloalkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic cycloalkyl, a 5-12 member fused cycloalkyl, a 3-6 member monocyclic heterocyclic alkyl, a 5-8 member bridged cycloalkyl, a 6-12 member spirocyclic heterocyclic alkyl, a 5-12 member fused heterocyclic alkyl, a phenyl, a 6-10 member fused aryl, a 5-6 member monocyclic heteroaryl, or an 8-12 member fused heteroaryl. L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 The alkylene group, wherein one or more CH2 groups are optionally surrounded by 1-3 groups selected from O, S, S(=O), S(=O)2, NR L The C (=O) groups are replaced by alkylene, alkenylene, or yntylide groups, which are optionally replaced by 1-5 R groups. x Replaced; The condition is that L is not a bond when ring B does not exist; R L For hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Each R A Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced; Each R B Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkyl, C 1-6 deuterated alkoxy group, -SC 1-6 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-6 Alkyl), =C(C) 1-6 Alkyl)2、=CH(C 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =C(C) 1-6 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-6 Alkyl), =CH(C) 1-6 Halogenated alkyl), =CF(C) 1-6 Alkyl), =CF(C) 1-6 Halogenated alkyl), =C(C 1-6 Alkyl)2、=C(C 1-6 Alkyl)(C 1-6 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy, C 1-6 alkylamine group, C 3-6 cycloalkyl or 4-6 membered heterocyclic alkyl; n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, Ring A is a 5-membered heteroaryl-phenyl, a 5-membered heteroaryl-5-membered heteroaryl, a 5-membered heteroaryl-6-membered heteroaryl, a 5-membered heteroaryl-phenyl-5-membered heteroaryl, or a 5-membered heteroaryl-phenyl-C. 4-6 Cycloalkyl, wherein the ring attached to the parent structure is a 5- or 6-membered heteroaryl group; Alternatively, ring A is Each R A Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, =O, -SF5, -SCF3, -SO2-C 1-3 Alkyl group, -SO2NH-C 1-3 Alkyl group, -NHSO2-C 1-3 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylamine, hydroxyalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further characterized by 1-5 R groups. x Replaced; R1 is -N(C) 1-3 Alkyl)2, -N(C 1-3 Alkyl)(C 3-6 cycloalkyl), -N(C) 1-3 alkyl)(-CH2-C 3-6 cycloalkyl) L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 alkyne group, O, S, S(=O), S(=O)2, NR L C (=O), wherein the alkylene, alkenylene, or yntylide groups are optionally surrounded by 1-5 R groups. x Replaced; R L is hydrogen, deuterium, C 1-3 alkyl; Each R B Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkyl, C 1-3 deuterated alkoxy group, -SC 1-3 Haloalkyl, =CH2, =CF2, =CHF, =CH(C 1-3 Alkyl), =C(C) 1-3 Alkyl)2、=CH(C 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =C(C) 1-3 (halogenated alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, -O- (4-6 membered heterocycloalkyl), -C(=O)-C 3-6 Cycloalkyl, -C(=O)-(4-6 membered heterocycloalkyl), -NHC(=O)-C 3-6 Cycloalkyl, -C(=O)NH-C 3-6 Cycloalkyl, -NHC(=O)- (4-6 membered heterocyclic alkyl), -C(=O)NH- (4-6 membered heterocyclic alkyl), wherein the alkyl, amino, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x Replaced; Each R x Each of these groups can be independently classified as deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -SF5, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SCF3, =CH2, =CF2, =CHF, =CH(C) 1-3 Alkyl), =CH(C) 1-3 Halogenated alkyl), =CF(C) 1-3 Alkyl), =CF(C) 1-3 Halogenated alkyl), =C(C 1-3 Alkyl)2、=C(C 1-3 Alkyl)(C 1-3 Halogenated alkyl), =C 3-6 Cycloalkyl, =(4-6 membered heterocycloalkyl), C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Deuterated alkoxy, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl.

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R1 is -N(C) 1-3 Alkyl)2, L stands for bond, C 1-3 Alkylene, C 2-4 imidene group, C 2-4 The alkylene, alkenylene, or ynylene group is optionally surrounded by 1-5 R groups. x Replaced; Ring B may or may not exist. When ring B exists, ring B has the following structure: Each R B Each can be independently represented as hydrogen, deuterium, halogen, =O, -SF5, -SCF3, or C. 1-3 Alkyl, C 2-3 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Haloalkyl, N(C) 1-3 Alkyl)2, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, or heterocyclic alkyl may optionally be further surrounded by 1-5 R groups. x What it replaced.

4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R1 is -N(C) 1-3 Alkyl)2, R1 is preferably -N(CH3)2. X1 is -CR a R b -, preferably X1 is -CH2-, R a and R b Each is independently hydrogen or C 1-3 Alkyl, or R a and R b Linkages can form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups; X2 is -CH2-; X3 is either -O- or -NH-; for R A1 R A2 R A3 and R A4 Each can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups.

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formula (Ia), general formula (Ia-1), and general formula (Ia-2): in: R1 is -N(C) 1-3 Alkyl)2, R1 is preferably -N(CH3)2. X3 is either -O- or -NH-; R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Ring B is a 3-6 member monocyclic cycloalkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic cycloalkyl, 5-12 member fused cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-8 member bridged cycloalkyl, 6-12 member spirocyclic heterocyclic alkyl, 5-12 member fused heterocyclic alkyl, phenyl, 6-10 member fused aryl, 5-6 member monocyclic heteroaryl, 8-12 member fused heteroaryl, preferably phenyl, 5-hemaryl, 6-hemaryl, C 5-6 Cycloalkyl, more preferably with the following structures: phenyl, Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; m is 0, 1, 2, or 3.

6. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further shown in general formulas (II), (IIA), (II-1), (IIA-1), (II-2), (IIA-2), (II-3), (IIA-3), (II-4), (IIA-4), (II-5), and (IIA-5): in: R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; m is 0, 1, 2, or 3; When R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br, C 1-6 Alkyl group.

7. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, General formula (I) is further illustrated as follows: General formula (II-a), General formula (II-b), General formula (II-a-1), General formula (II-b-1), General formula (II-a-2), General formula (II-b-2), General formula (II-c), General formula (II-d), General formula (II-c-1), General formula (II-d-1), General formula (II-c-2), General formula (II-d-2): in: R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A2 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R A3 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or -SO2-C. 1-6 Alkyl group, -SO2NH-C 1-6 Alkyl group, -NHSO2-C 1-6 Alkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3- 6-cycloalkyl, 5-6-membered heterocycloalkyl, 5-6-membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x Replaced; R A4 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; Ring B is a 5-membered heteroaryl, 6-membered heteroaryl, or C 5-6 Cycloalkyl groups, preferably with the following structure: Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 alkylamine group, C 1-6 Alkylthio, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R x For deuterium, halogen, hydroxyl, cyano, -SF5, -SCF3, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy groups; m is 0, 1, 2, or 3; The premise is: when R A1 R A2 R A4 For hydrogen, R A3 Not selected from F, Br, C 1-6 Alkyl group.

8. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 4-7, characterized in that, R A1 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy groups, preferably hydrogen, halogen, or C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 1-3 Alkoxy, more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy or ethoxy, and / or; R A2 For hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy groups, preferably hydrogen, halogen, or C 1-3 Alkyl or C 1-3 Alkoxy, more preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy, and / or; R A3 It is hydrogen, halogen, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x The preferred substitutes are hydrogen, halogen, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl group is optionally further reinforced by 1-5 R groups. x The substituted compounds are more preferably hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, vinyl, cyclopropyl, etc. and / or; R A4 It is hydrogen or halogen, preferably hydrogen, fluorine, chlorine or bromine, and / or; Each R B Each can be independently represented by hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -SF5, -SCF3, or C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 alkylamine group, C 1-3 Alkylthio, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy or C 1-3 The halogenated alkoxy group is preferably hydrogen, fluorine, chlorine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, or trifluoromethyl.

9. The compound according to claim 8, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, The It has the following structure:

10. The compound according to claim 1, its stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the structures in Table 1, Table 2 or Table 3.

11. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

12. The pharmaceutical composition according to claim 11, comprising 1-1500 mg of the compound of any one of claims 1-10, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

13. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-10, or the pharmaceutical composition according to claim 11 or 12, in the preparation of a medicament for the treatment / prevention of NOP and opioid receptor-mediated diseases.

14. The use according to claim 13, wherein the NOP and opioid receptor-mediated diseases are selected from pain.

15. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-10, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 11 or 12, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is selected from pain.

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