Mrgprx2 receptor modulator and use thereof

Abstract

Provided are an MRGPRX2 receptor modulator and the use thereof. Specifically provided are a compound as represented by general formula (I"), or a stereoisomer, tautomer, racemate, or pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof, and the use thereof in the preparation of a drug for treating / preventing MRGPRX2-mediated diseases. Each group in the general formula (I") is as defined in the description.

Description

A MRGPRX2 receptor modulator and its uses

[0001] Cross-references to related applications

[0002] This application claims Chinese patent application No. 202510381605.8, filed on March 28, 2025; Chinese patent application No. 202510413820.1, filed on April 3, 2025; Chinese patent application No. 202510486137.0, filed on April 17, 2025; Chinese patent application No. 202510747514.1, filed on June 5, 2025; and Chinese patent application No. 202511025750.9, filed on July 24, 2025. The priority of Chinese patent applications filed on September 2, 2025 (application number 202511244907.7), December 16, 2025 (application number 202511898705.4), January 23, 2026 (application number 202610097490.4), and February 6, 2026 (application number 202610171501.9) is hereby incorporated herein by reference in its entirety. Technical Field

[0003] This invention belongs to the pharmaceutical field, and particularly relates to an MRGPRX2 receptor modulator, its stereoisomer, tautomer, racemate, nitride or pharmaceutically acceptable salt, and its use in the preparation of medicaments for treating related diseases. Background Technology

[0004] In rodents, the functional counterparts of human MRGPRX2 are mouse MRGPRB2 and rat MRGPRB3, and these receptors are highly conserved in mast cells. (PNAS, 116(21), 10525-10530.) MRGPRX2 and its orthologs have been shown to participate in the regulation of a variety of pathophysiological processes, including pseudohypersensitivity reactions to drugs, chronic pruritus (such as atopic dermatitis), inflammatory diseases, pain syndromes, tumor-related diseases, skin lesions, wound healing, cardiovascular diseases, and pulmonary inflammation / chronic obstructive pulmonary disease (COPD).

[0005] Expression profile analysis shows that MRGPRX2 is primarily and specifically distributed on mast cells. These innate immune cells are mainly located at the interface between the body and the environment, including barrier sites such as the skin and digestive / respiratory mucosa. Mast cells are rich in various mechanoreceptors and chemoreceptors. Their classical activation pathway, mediated by IgE, triggers the release of granular contents (such as histamine, proteases, and heparin) and the generation of newly synthesized mediators (including thromboxane, prostaglandin D2, leukotrienes C4, tumor necrosis factor-α, chemokines, and platelet-activating factor), thereby initiating an allergic and inflammatory cascade. Histamine, by dilating capillary veins, activating endothelial cells, and enhancing vascular permeability, leads to local tissue edema, erythema, increased temperature, and chemotactic infiltration of inflammatory cells. Furthermore, histamine can induce neuronal sensitization, participating in the occurrence of pain or itching. (Journal of Clinical Investigation, 126(10), 3981-3998.)

[0006] Notably, MRGPRX2 homologs mediate IgE-independent activation mechanisms in mast cells. This receptor family responds to a variety of ligand stimuli, including basic secretagogues (small molecule cationic compounds), cationic peptides, neuropeptides, and antimicrobial peptides, playing a central role in non-IgE-mediated pseudohypersensitivity reactions and neurogenic inflammation. Mast cells can also induce Th17 immune response bias by promoting a chronic inflammatory state in the local microenvironment, thereby participating in the progression of autoimmune diseases. (Frontiers in Cellular Neuroscience, 13, 353.)

[0007] Based on the above mechanisms, receptor modulators that regulate MRGPRX2 hold significant potential in the therapeutic field. However, research on drugs targeting MRGPRX2-related pathways remains limited. Summary of the Invention

[0008] The purpose of this invention is to provide a compound or its stereoisomers, tautomers, racemates, nitrides or pharmaceutically acceptable salts having MRGPRX2 receptor regulatory activity, intermediates thereon and preparation methods thereof, as well as its use in the preparation of medicaments for treating MRGPRX2-related diseases.

[0009] This invention provides a compound of general formula (I), including its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts.

[0010] This invention provides a compound of general formula (I'), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts.

[0011] This invention provides a compound of general formula (I”), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts.

[0012] This invention provides a compound of general formula (IIG), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts.

[0013] This invention provides a compound of general formula (II), including its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts.

[0014] The compound exhibits excellent effects, including high activity, superior physicochemical properties, ease of formulation, excellent pharmacokinetic properties, high bioavailability, and low toxicity.

[0015] The present invention also provides general formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (III-1), (III-2), (III-3), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5), (IV-6), (IV-7), (IV-8), (IV-9), (IV-10), (IV-11), (IV-12), (IV-13), and (IV-14). Compounds, their stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts thereof, represented by general formulas (IV-15), (IV-16), (IV-17), (IV-18), (V-1), (V-2), (V-3), (V-4), (VI-1), (VI-2), (VI-3), (VI-4), (VI-5), (VI-6), (VI-7), (VI-8), (VI-9), (VI-10), (VI-11), and (VI-12)

[0016] In some embodiments, the compound of formula (I) has the structure shown in formula (II-7), formula (II-8), formula (II-9), or formula (II-10):

[0017] In some implementation schemes, Selected from

[0018] In some implementations, each X either does not exist or is independently selected from -C(=O)-(CR) a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-S(=O)(=NR c )-(CR a R b ) p -、-O-(CR a R b ) p -、-S-(CR a R b ) p -、-(CR a R b ) p -、-NR a R b -、-C(=O)-、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、C(=O)O、CR a =N, -3-18-membered heterocyclic-, -3-12-membered carbocyclic- and 5-6-membered heteroaryl;

[0019] In some implementations, each X either does not exist or is independently selected from -C(=O)-(CR) a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b )p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -3-10 heterocyclic group-, -3-10 carbocyclic group-;

[0020] In some implementations, each X either does not exist or is independently selected from -C(=O)-(CR) a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, 3-6 membered heterocyclic groups, -5-9 membered spirocyclic groups, -3-6 membered carbocyclic groups;

[0021] In some implementations, each X either does not exist or is independently selected from -C (=O)-, -O- (CR)-, etc. a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -;

[0022] In some implementations, each X either does not exist or is independently selected from -C(=O)-(CR) a R b ) p-、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-C(=NR c ), CR a =CR b -O-heterocyclic butyl-, -5-7-membered spirocyclic-, -cyclopropyl-, cyclobutyl;

[0023] In some implementations, each X is absent or independently selected from -C(=O)-, CF2, O, CH2, CH2CH2, C(CH3)2, CH(NH2), CH(OH), O-CH2, O-CH2CH2, CH=CH, -S(=O)-, -S(=O)2-, -S(=O)(=NH)-, -S(=O)(=NCH3)-, R a and R b Each is independently hydrogen, halogen, and C. 1- 6-alkyl group, where Rc is hydrogen, OH, or C. 1-6 Alkyl and C 1-6 Alkoxy;

[0024] In some implementations, each X is absent or independently selected from -C(=O)-, CF2, O, CH2, CH2CH2, C(CH3)2, CH(NH2), CH(OH), O-CH2, O-CH2CH2, CH=CH, R a and R b Each is independently hydrogen, halogen, and C. 1-6 Alkyl group, where Rc is hydrogen, OH, or C. 1-6 Alkyl and C 1-6 Alkoxy;

[0025] In some implementations, Z is selected from -C(=O)-, -O-(CR)-. a R b ) p -、-(CR a Rb ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、CR a =CR b and -C(=NR) c )-;

[0026] In some implementations, Z is selected from -C(=O)-, CF2, O, CH2, CH2CH2, C(CH3)2, CH(NH2), CH(OH), O-CH2, O-CH2CH2, CH=CH, R a and R b Each is independently hydrogen, halogen, and C. 1-6 Alkyl, R c For hydrogen, OH, C 1-6 Alkyl and C 1-6 Alkoxy;

[0027] In some implementations, Y is absent or is -CR1R2-;

[0028] In some embodiments, Y is absent or selected from -CH(CH3)-, -CH(CF3)-, -CH(CH2F)-, -CH(CD3)-, -CH(CF2D)-, -CH(CF2OCH3)-, -CH(CF3)-, -CH(CH2OH)-, -CH(CH2OCH3)-, -CH(cyclopropyl)-,

[0029] In some embodiments, Y is absent or selected from -CH(CH3)-, -CH(CF3)-, -CH(CH2OH)-, -CH(CH2OCH3)- and -CH(cyclopropyl)-;

[0030] In some implementations, Y is absent or is -CH(CH3)-;

[0031] In some implementations, ring A is selected from 3-18-membered heterocyclic groups, 5-15-membered heteroaryl groups, and 6-14-membered aryl groups;

[0032] In some embodiments, ring A is selected from 3-12 membered heterocyclic groups or 5-12 membered heteroaryl groups;

[0033] In some embodiments, ring A is selected from 3-10-membered heterocyclic groups, 5-10-membered heteroaryl groups, and 6-10-membered aryl groups;

[0034] In some embodiments, ring A is selected from 3-8 membered heterocyclic groups or 5-8 membered heteroaryl groups;

[0035] In some implementations, ring A is selected from 5-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and 6 membered aryl groups;

[0036] In some embodiments, ring A is selected from tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxopentyl, dithiopentanyl, oxazolidinyl, thiazolinyl, triazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, dioxolidinyl, dithiazolinyl, piperazine, morpholinyl, thiomorpholinyl, trioxolidinyl, 1,4-oxazolidinyl, 1,4-thiazolinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetraazolyl, pyridinyl, pyrimidinyl, pyrazine, 1,3-oxazine, 1,3-thiazolinyl, triazine, oxopyridinyl, pyrazinone, and phenyl.

[0037] In some implementations, ring A is selected from 6-membered heteroaryl groups;

[0038] In some implementation schemes, Selected from

[0039] In some implementation schemes, Selected from

[0040] In some implementation schemes, Selected from

[0041] In some implementation schemes, Selected from

[0042] In some implementation schemes, Selected from

[0043] In some implementation schemes, Selected from

[0044] In some implementation schemes, Selected from

[0045] In some implementation schemes, Selected from

[0046] In some implementation schemes, Selected from

[0047] In some embodiments, ring B is selected from 3-12 membered carbocyclic groups or 3-18 membered heterocyclic groups; and ring B is not...

[0048] In some embodiments, ring B is selected from 5-12 membered carbocyclic groups or 5-12 membered heterocyclic groups; and ring B is not...

[0049] In some embodiments, ring B is selected from 7-11 membered carbocyclic groups or 7-11 membered heterocyclic groups; and ring B is not...

[0050] In some implementations, ring B is selected from 5-12 membered heterocyclic groups; and ring B is not...

[0051] In some implementations, ring B is selected from 5-10 membered heterocyclic groups; and ring B is not...

[0052] In some implementations, ring B is selected from 5-7 membered heterocyclic groups; and ring B is not...

[0053] In some embodiments, ring B is selected from 5-10 member N-containing heterocyclic groups; and ring B is not...

[0054] In some embodiments, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms; and ring B is not...

[0055] In some embodiments, ring B is selected from 5-10 member heterocyclic groups containing 1 to 3 N atoms; and ring B is not...

[0056] In some embodiments, ring B is selected from 5-10 member heterocyclic groups containing 1-2 N atoms; and ring B is not...

[0057] In some embodiments, ring B is selected from heterocyclic groups containing 1 to 4 N atoms (5-9); and ring B is not...

[0058] In some embodiments, ring B is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, and 5-15 membered heteroaryl groups;

[0059] In some embodiments, ring B is selected from 5-12 membered carbocyclic groups, 5-12 membered heterocyclic groups, and 5-12 membered heteroaryl groups;

[0060] In some embodiments, ring B is selected from 7-11 membered carbocyclic groups or 7-11 membered heterocyclic groups;

[0061] In some implementations, ring B is selected from 5-12 membered heterocyclic groups.

[0062] In some implementations, ring B is selected from 5-10 membered heterocyclic groups;

[0063] In some implementations, ring B is selected from 5-7 membered heterocyclic groups;

[0064] In some implementation schemes, cyclic B is selected from 5-6 membered heteroaryl groups;

[0065] In some implementations, ring B is selected from 5-10 N-containing heterocyclic groups;

[0066] In some implementations, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms;

[0067] In some implementations, ring B is selected from 5-10 member heterocyclic groups containing 1 to 3 N atoms;

[0068] In some implementations, ring B is selected from 5-10 member heterocyclic groups containing 1-2 N atoms;

[0069] In some embodiments, ring B is selected from 5-9 heterocyclic groups containing 1 to 4 N atoms;

[0070] In some implementations, ring B is selected from 6-11 fused ring groups, 6-11 spirocyclic groups, and 6-11 bridging ring groups;

[0071] In some embodiments, ring B is selected from 6-11-membered benzobicycloalkyl, 6-11-membered benzobiheterocyclic, 6-11-membered benzobiheteroaryl, 6-11-membered spirobibericycloalkyl, and 6-11-membered spirobibericycloalkyl.

[0072] In some embodiments, ring B is selected from 6-10-membered benzodicycloalkyl, 6-10-membered benzodiheterocyclic, 6-10-membered benzodiheteroyl, 6-10-membered spirobadicycloalkyl, and 6-10-membered spirobadiheterocyclic.

[0073] In some embodiments, ring B is selected from 6-10-membered bridged bicycloalkyl groups and 5-6-membered nitrogen-containing aryl groups;

[0074] In some embodiments, ring B is selected from 5-membered cycloalkyl and 3-membered cycloalkyl, 5-membered cycloalkyl and 4-membered cycloalkyl, 5-membered cycloalkyl and 5-membered cycloalkyl, 6-membered cycloalkyl and 4-membered cycloalkyl, 6-membered cycloalkyl and 5-membered cycloalkyl, 5-membered cycloalkyl and 3-membered heterocyclic, 5-membered cycloalkyl and 4-membered heterocyclic, 5-membered cycloalkyl and 5-membered heterocyclic, 6-membered cycloalkyl and 4-membered heterocyclic, 6-membered cycloalkyl and 5-membered heterocyclic, 5-membered heterocyclic and 3-membered cycloalkyl, 5-membered heterocyclic and 4-membered cycloalkyl, 5-membered heterocyclic and 5-membered cycloalkyl, 6-membered heterocyclic and 4-membered cycloalkyl, 6-membered heterocyclic and 5-membered cycloalkyl, 5-membered heterocyclic and 3-membered heterocyclic, 5-membered heterocyclic and 4-membered heterocyclic, 5-membered heterocyclic and 5-membered heterocyclic, 6-membered heterocyclic. 4-membered heterocyclic, 6-membered heterocyclic and 5-membered heterocyclic, 5-membered heteroaryl and 3-membered cycloalkyl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 3-membered heterocyclic, 5-membered heteroaryl and 4-membered heterocyclic, 5-membered heteroaryl and 5-membered heterocyclic, 5-membered heteroaryl and 5-membered cycloalkyl and 6-membered heterocyclic; 6-membered heteroaryl and 4-membered heterocyclic, 6-membered heteroaryl and 5-membered heterocyclic, 5-membered heterocyclic and 6-membered heterocyclic;

[0075] In some embodiments, ring B is selected from 5-membered cycloalkyl spiro-3-membered cycloalkyl, 5-membered cycloalkyl spiro-4-membered cycloalkyl, 5-membered cycloalkyl spiro-5-membered cycloalkyl, 6-membered cycloalkyl spiro-4-membered cycloalkyl, 6-membered cycloalkyl spiro-5-membered cycloalkyl, 5-membered cycloalkyl spiro-3-membered heterocyclic group, 5-membered cycloalkyl spiro-4-membered heterocyclic group, 5-membered cycloalkyl spiro-5-membered heterocyclic group, 6-membered cycloalkyl spiro-4-membered heterocyclic group, 6-membered cycloalkyl spiro-5-membered heterocyclic group, 5-membered heterocyclic spiro-3-membered cycloalkyl, 5-membered heterocyclic spiro-4-membered cycloalkyl, 5-membered heterocyclic spiro-5-membered cycloalkyl, 6-membered heterocyclic spiro-4-membered heterocyclic group, 6-membered heterocyclic spiro-5-membered heterocyclic group, and 5-membered heteroaryl spiro-3-membered cycloalkyl.

[0076] In some implementations, ring B is selected from the following structures:

[0077] In some implementations, ring B is selected from the following structures:

[0078] In some implementations, ring B is selected from the following structures:

[0079] The asterisk (*) is attached to the X group.

[0080] In some implementation schemes, ring B is

[0081] In some implementation schemes, for The ring C is a 5-15 membered heteroaryl or a 10-15 membered heterocyclic group; R B1 For hydrogen or M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0082] Ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl and 5-12-membered heteroaryl;

[0083] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups;

[0084] t is an integer between 0 and 5;

[0085] In some implementation schemes, for R B1 For hydrogen or M is -CH2- or -O-; ring D is phenyl;

[0086] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups;

[0087] t is an integer between 0 and 3;

[0088] In some implementation schemes, Selected from

[0089] In some implementation schemes, Selected from

[0090] In some implementations, as an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups; the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e Replaced;

[0091] In some implementations, as an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups;

[0092] In some implementations, each R e Each is independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, amino, =O, =CR a R b =NR c The alkyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further oxidized by 1-5 R groups. x Replaced;

[0093] In some implementations, as an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-8 Carbocyclic or 5- to 8-membered heterocyclic groups;

[0094] In some implementations, as an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-8 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0095] In some implementations, as an option, an R on ring A A With an R on ring BM They are connected together, thus forming C with their respective connected atoms and the X group. 6-7 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0096] Preferably, the formed structure is

[0097] In some embodiments, the ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups;

[0098] In some embodiments, the ring C is selected from 3-10 membered carbocyclic groups, 6-18 membered heterocyclic groups, 6-14 membered aryl groups, or 5-12 membered heteroaryl groups;

[0099] In some embodiments, the ring C is selected from 6-14 aryl, 5-12 heteroaryl, and 3-15 heterocyclic groups;

[0100] In some embodiments, the ring C is selected from 6-10 aryl, 5-10 heteroaryl, and 10-15 heterocyclic groups;

[0101] In some implementation schemes, the cyclic C is selected from 6-10 aryl groups and 5-6 heteroaryl groups;

[0102] In some embodiments, the ring C is selected from phenyl, naphthyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazolyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, zonolinyl, etc.

[0103] In some implementations, cyclic C is selected from 6-10 aryl groups;

[0104] In some implementations, the cyclic C is selected from phenyl;

[0105] In some implementations, the cyclic C is selected from 5-6 membered heteroaryl groups;

[0106] In some implementations, the cyclic C is selected from 5-6 N-containing heteroaryl groups;

[0107] In some implementations, cyclic C is selected from 6-membered heteroaryl groups;

[0108] In some implementations, the cyclic C is selected from a 6-membered N-containing heteroaryl group;

[0109] In some implementations, ring C is selected from the following structures:

[0110] In some implementations, ring C is selected from the following structures:

[0111] In some implementations, cyclic C is selected from 5-membered heteroaryl groups;

[0112] In some implementations, the cyclic C is selected from a 5-membered N-containing heteroaryl group;

[0113] In some implementations, cyclic C is selected from 10-membered heteroaryl groups;

[0114] In some implementations, the cyclic C is selected from a 10-membered N-containing heteroaryl group;

[0115] In some implementations, ring C is selected from the following structures:

[0116] Indicates ring C and -NR y Connection sites;

[0117] In some implementation schemes, R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0118] In some implementation schemes, R y Selected from F, Cl, Br, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, and trifluoroisopropyl;

[0119] In some implementation schemes, R y Selected from hydrogen, halogens, C 1-3 alkyl;

[0120] In some implementation schemes, R y Selected from hydrogen, C 1-3 alkyl;

[0121] In some implementation schemes, R y Selected from hydrogen;

[0122] In some implementation schemes, each R1, R2 is independently selected from hydrogen, deuterium, halogen, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1- 6-alkoxy, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy, C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted;

[0123] Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic or 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 The alkyl group is substituted with one or more substituents; in some embodiments, each R1, R2 is independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups;

[0124] In some implementations, each R1, R2 is independently selected from hydrogen, halogen, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0125] In some embodiments, each R1, R2 is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy.

[0126] In some implementations, each R1, R2 is independently selected from hydrogen, halogen, C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0127] In some implementation schemes, each R1 and R2 is independently selected from hydrogen and C. 1-3 alkyl;

[0128] In some implementations, R1 is hydrogen and R2 is C. 1-3 alkyl;

[0129] In some implementations, R1 is hydrogen and R2 is methyl;

[0130] In some implementations, each R MIt does not exist or is selected independently from hydrogen, halogen, deuterium, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ;

[0131] In some implementations, any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0132] In some implementations, each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0133] In some implementations, each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0134] In some implementations, each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0135] In some implementations, each R MNot present or independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, -(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、=CR a R b ;

[0136] In some implementation schemes, R M1 R M2 R M3 and R M4 Each element is independently selected from hydrogen, halogen, hydroxyl group, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0137] Optionally, R M1 and R M2 R M3 and R M4 R M1 and R M3 Any group of atoms connected to it together forms C. 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0138] In some implementations, each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2- 6-olefin, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced;

[0139] In some implementations, each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-8 Carbocyclic groups, -M- (4-8 membered heterocyclic groups);

[0140] In some implementations, each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0141] In some implementations, each R A Each is independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, =CR a R b ;

[0142] In some implementations, each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy groups;

[0143] In some implementations, each R A Each is independently selected from halogens, =O;

[0144] In some implementations, each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0145] In some implementations, each R BEach is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0146] In some implementations, each R B Each independently selected from -MC 3-8 Carbocyclic, -M-(4-8 membered heterocyclic), -M-(6-12 membered aryl), -M-(5-10 membered heteroaryl), wherein the carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0147] In some implementations, each R BEach independently selected from -MC 3-7 Carbocyclic, -M-(5-7 membered heterocyclic), -M-(6-12 membered aryl), -M-(5-10 membered heteroaryl), wherein the carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0148] In some implementations, each R B Each is independently selected from -M-(6-12-membered aryl) and -M-(5-10-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally further surrounded by 1-5 R groups. x Replaced;

[0149] In some implementations, each R B Each is independently selected from -M-(phenyl) or -M-(5-6-membered heteroaryl), wherein the phenyl or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0150] In some implementations, each R B Each is independently selected from -M-(phenyl) or -M-(5-6-membered heteroaryl), wherein the phenyl or heteroaryl group is optionally further surrounded by 1-5 R groups. x The substituted group; among which, the 5-6 membered heteroaryl group is, for example, pyridinyl, pyrimidinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazinyl, triazinyl;

[0151] In some implementation schemes, R B Selected from -M-(phenyl), wherein the phenyl group is optionally further surrounded by 1-3 R groups. x Replaced;

[0152] In some implementation schemes, R B Selected from -M-(phenyl), wherein the phenyl group is substituted with 1-3 halogens;

[0153] In some implementations, M is absent or selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0154] In some implementations, M is absent or selected from -CR a R b -、-O-;

[0155] In some implementations, M is absent or selected from -CH2-, -CHCH3-, and -O-;

[0156] In some implementations, M is selected from -CH2-;

[0157] In some implementations, M is selected from O;

[0158] In some implementations, each R a R b R c R d Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkynyl and amino; the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further surrounded by 1-5 R groups. x Replaced;

[0159] Optional, R a and R b Together with the atoms attached to it, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0160] In some implementations, each R a R b R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy group; the alkyl group, halogenated alkyl group, alkoxy group, or halogenated alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0161] In some implementations, each R a R b R c R d Each is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy.

[0162] In some implementations, each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3Halogenated alkyl; the alkyl group, or halogenated alkyl group, may optionally be further divided by 1-5 R groups. x Replaced;

[0163] Each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0164] In some implementations, each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl; the alkyl group may optionally be further divided by 1-5 R x Replaced;

[0165] In some implementations, each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0166] In some implementations, each R x Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group; in some embodiments, each R x Each is independently selected from halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0167] In some implementations, each R x Each group is independently selected from F, Cl, Br, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOCH3, -NHCOCH2CH3, -N(CH3)2, -NH(CH3), -SF5, -SCF3, =CR a R b Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy;

[0168] In some implementations, each R x Each is independently selected from halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0169] In some implementations, each R x Each is independently selected from halogen, hydroxyl, cyano, amino, =O, =S, =NH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0170] In some implementations, each R x Each is independently selected from halogens, cyano groups, =O, =S, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0171] In some implementations, k is 0 or 1;

[0172] In some implementations, p is an integer between 0 and 3;

[0173] In some implementations, p is an integer between 0 and 2;

[0174] In some implementations, p is an integer between 0 and 1;

[0175] In some implementations, q is an integer between 0 and 3;

[0176] In some implementations, q is an integer between 0 and 2;

[0177] In some implementations, m, n, and s are each an independent integer from 0 to 5;

[0178] In some implementations, m, n, and s are each an independent integer from 1 to 4;

[0179] In some implementations, m is an integer from 1 to 2;

[0180] In some implementations, n is an integer from 1 to 4;

[0181] In some implementations, s is an integer from 1 to 2;

[0182] In some implementations, t is an integer between 0 and 5;

[0183] In some implementations, t is an integer from 1 to 4;

[0184] In some implementations, t is an integer from 1 to 3.

[0185] In some implementations, u and v are each independently 0, 1, or 2.

[0186] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I”), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein,

[0187] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、S(=O)(=NR c )-(CR a R b ) p -、-O-(CR a R b )p -、-S-(CR a R b ) p -、-(CR a R b ) p -、-NR a R b -、-C(=O)-、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-C(=NR c ), -CR a =CR b -、C(=O)O、CR a =N, -3-18-membered heterocyclic-, -3-12-membered carbocyclic- and 5-6-membered heteroaryl;

[0188] Y either does not exist or is -CR1R2-;

[0189] Ring A is selected from 3-18-membered heterocyclic groups, 5-15-membered heteroaryl groups, and 6-14-membered aryl groups;

[0190] Ring B is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, and 5-15 membered heteroaryl groups; and ring B is not...

[0191] Optionally, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups, wherein the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e Replaced;

[0192] The ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups;

[0193] R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0194] Each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted;

[0195] Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic or 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted;

[0196] Each R M It does not exist or is selected independently from hydrogen, halogen, deuterium, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ;

[0197] Or any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0198] Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced;

[0199] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0200] M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0201] Each R a R b R c R d Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkynyl and amino; the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further surrounded by 1-5 R groups. x Replaced;

[0202] Optional, R a and R b Together with the atoms attached to it, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0203] Each R e Each is independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, amino, =O, =CR a R b =NR c The alkyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further oxidized by 1-5 R groups.x Replaced;

[0204] Each R x Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0205] p and q are each independent integers between 0 and 3;

[0206] k is 0 or 1;

[0207] m, n, and s are each an independent integer between 0 and 5.

[0208] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts may be used.

[0209] in,

[0210] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-O-(CR a R b ) p -、-S-(CR a R b ) p -、-(CR a R b ) p -、-NR a R b -、-C(=O)-、-(CR a R b ) p-NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-C(=NR c ), CR a =CR b -3-18-membered heterocyclic group-; -3-12-membered carbocyclic group-;

[0211] Y either does not exist or is -CR1R2-;

[0212] Ring A is selected from 3-18-membered heterocyclic groups, 5-15-membered heteroaryl groups, and 6-14-membered aryl groups;

[0213] Ring B is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, and 5-15 membered heteroaryl groups; and ring B is not...

[0214] An R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups, wherein the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e Replaced;

[0215] The ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups;

[0216] R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0217] Each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 Hydroxyalkyl, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups;

[0218] Each R M It does not exist or is selected independently from hydrogen, deuterium halide, element, hydroxyl group, =O, -(CR) a R b )p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ;

[0219] Or any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0220] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced;

[0221] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a Rb ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0222] M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0223] Each R a R b R c R d Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4alkenyl, C 2-4 Alkynyl and amino; the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further surrounded by 1-5 R groups. x Replaced;

[0224] Optional, R a and R b Together with the atoms attached to it, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0225] Each R e Each is independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, amino, =O, =CR a R b =NR c The alkyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further oxidized by 1-5 R groups. x Replaced; each R x Each is independently selected from halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0226] p and q are each independent integers between 0 and 3;

[0227] m, n, and s are each an independent integer between 0 and 5.

[0228] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein,

[0229] X does not exist or is selected from -C(=O)-(CR) a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-O-(CR a R b ) p -、-S-(CR a R b ) p -、-CR a R b -、-NR a R b -;

[0230] Y either does not exist or is -CR1R2-;

[0231] Ring A is selected from 3-18 membered heterocyclic groups or 5-15 membered heteroaryl groups;

[0232] Ring B is selected from 3-12 membered carbocyclic groups or 3-18 membered heterocyclic groups; and ring B is not a [missing information - likely a specific type of cyclic group].

[0233] The ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups;

[0234] R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0235] Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0236] Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p-SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0237] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced;

[0238] Each R B Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR aR b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0239] M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0240] Each R a R b R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0241] Each R x Each is independently selected from halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0242] p is an integer between 0 and 3;

[0243] m, n, and s are each an independent integer between 0 and 5.

[0244] As a third embodiment of the present invention, the compound represented by formula (IIG) or formula (II), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are used.

[0245] in,

[0246] Z is selected from -C(=O)-, -O-(CR) a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -C(=O)O-, S(=O)2, 5-6 heteroaryl, CR a =CR b and -C(=NR) c )-;

[0247] Each R M It does not exist or is selected independently from hydrogen, halogen, deuterium, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ;

[0248] Or any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0249] R B1 For hydrogen or M does not exist or is selected from -CR a R b -、-O-、-C(=O),-NHC(=O-),-C(=O)NH-; ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl and 5-12-membered heteroaryl;

[0250] k is 0 or 1;

[0251] m, n, and s are each an independent integer from 1 to 5;

[0252] t is an integer between 0 and 5;

[0253] u and v are each independently 0, 1 or 2;

[0254] The remaining groups are as defined in formula (I”), formula (I’) or formula (I).

[0255] As a third embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein...

[0256] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a Rb ) p -C(=O)-NR c -、-C(=CR a R b )-、C(=O)O、CR a =N, -3-10 heterocyclic-, -3-10 carbocyclic- and 5-6 heteroaryl;

[0257] Y either does not exist or is -CR1R2-;

[0258] Ring A is selected from 3-10-membered heterocyclic groups, 5-10-membered heteroaryl groups, and 6-10-membered aryl groups;

[0259] Ring B is selected from 5-12 membered carbocyclic groups, 5-12 membered heterocyclic groups, and 5-12 membered heteroaryl groups;

[0260] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-8 Carbocyclic or 5- to 8-membered heterocyclic groups;

[0261] The ring C is selected from 6-14 aryl, 5-12 heteroaryl, and 3-15 heterocyclic groups;

[0262] R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0263] Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0264] Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0265] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0266] Each R B Each independently selected from -MC 3-8 Carbocyclic, -M-(4-8 membered heterocyclic), -M-(6-12 membered aryl), -M-(5-10 membered heteroaryl), wherein the carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced;

[0267] M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0268] Each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl; the alkyl group, or halogenated alkyl group, may optionally be further divided by 1-5 R groups. x Replaced;

[0269] Each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0270] Each R x Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group;

[0271] p and q are each independent integers between 0 and 2;

[0272] m, n, and s are each an independent integer from 1 to 4.

[0273] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein...

[0274] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -3-6 membered heterocyclic group-, -5-9 membered spirocyclic group-, -3-6 membered carbocyclic group-;

[0275] Y either does not exist or is -CR1R2-;

[0276] Ring A is selected from 5-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and 6 membered aryl groups;

[0277] Ring B is selected from 5-7 membered heterocyclic groups, 6-11 membered fused cyclic groups, 6-11 membered spirocyclic groups, 6-11 membered bridged cyclic groups, and 5-6 membered heteroaryl groups;

[0278] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-8 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0279] The ring C is selected from 6-10 aryl, 5-10 heteroaryl, and 10-15 heterocyclic groups;

[0280] R ySelected from hydrogen, C 1-3 alkyl;

[0281] Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0282] Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0283] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0284] Each R B Each is independently selected from -M-(6-12-membered aryl) and -M-(5-10-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally further surrounded by 1-5 R groups. x Replaced;

[0285] M does not exist or is selected from -CR a R b -、-O-;

[0286] Each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl; the alkyl group may optionally be further divided by 1-5 R x Replaced;

[0287] Each R c Rd Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0288] Each R x Each is independently selected from halogens, cyano groups, =O, =S, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0289] p and q are each independent integers between 0 and 2;

[0290] m, n, and s are each an independent integer from 1 to 4.

[0291] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (IIG) or formula (II), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein,

[0292] Selected from (For example, ), (For example, ),

[0293] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-S(=O)(=NR c )-, -S(=O)2-, C(=O)O, CR a=N, -3-6-membered heterocyclic-, -5-9-membered spirocyclic-, -3-6-membered carbocyclic- and 5-6-membered heteroaryl;

[0294] Z is selected from -C(=O)-, -O-(CR) a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -C(=O)O-, S(=O)2, 5-6 heteroaryl, CR a =CR b and -C(=NR) c )-;

[0295] Y does not exist or is -CR1R2-

[0296] Each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, -C 1-3 Alkylene-OC 1-3 Alkyl and C 3-6 Carbocyclic group, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The carbocyclic group is optionally selected from deuterium, halogen, hydroxyl, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0297] Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic or 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted;

[0298] The ring C is selected from 6-10 aryl, 5-15 heteroaryl, and 10-15 heterocyclic groups;

[0299] R A1R A2 and R A3 Whether the groups are the same or different, they are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl and C 1-6 Halogenated alkoxy groups.

[0300] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein...

[0301] Ring B is selected from 5-7-membered heterocyclic groups, 6-10-membered benzodicycloalkyl groups, 6-10-membered benzodicycloalkyl groups, 6-10-membered benzodiaryl groups, 6-10-membered spirobicycloalkyl groups, 6-10-membered spirodicycloalkyl groups, 6-10-membered bridged bicycloalkyl groups, and 5-6-membered azaaryl groups; preferably, ring B is selected from the following structures:

[0302] The asterisk (*) is attached to the X group.

[0303] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein...

[0304] Ring B is selected from the following structures:

[0305] The asterisk (*) is attached to the X group.

[0306] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein... for The ring C is a 5-15 membered heteroaryl or a 10-15 membered heterocyclic group; R B1 For hydrogen or M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0307] Ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl and 5-12-membered heteroaryl;

[0308] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups;

[0309] t is an integer between 0 and 5.

[0310] n is an integer from 1 to 5;

[0311] R x As defined in equation (I) or equation (I').

[0312] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein... for R B1 For hydrogen or M is -CH2- or -O-;

[0313] Ring D is phenyl;

[0314] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups;

[0315] t is an integer between 0 and 5.

[0316] Ring C, R B R x And n is as defined in equation (I) or equation (I').

[0317] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein... Selected from

[0318] R B1 For hydrogen or M does not exist or is selected from -CR a R b-, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-;

[0319] Ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl and 5-12-membered heteroaryl;

[0320] Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups;

[0321] t is an integer between 0 and 5.

[0322] n is an integer between 1 and 5.

[0323] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0324] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -3-6 membered heterocyclic group-, -5-9 membered spirocyclic group-, -3-6 membered carbocyclic group-;

[0325] Y either does not exist or is -CR1R2-;

[0326] Ring A is selected from 5-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and 6 membered aryl groups;

[0327] Ring B is selected from the following structures:

[0328] The asterisk (*) is attached to the X group.

[0329] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-8 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0330] The ring C is selected from 6-10 aryl, 5-10 heteroaryl, and 10-15 heterocyclic groups;

[0331] R y Selected from hydrogen, C 1-3 alkyl;

[0332] Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0333] Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0334] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0335] Each R BEach is independently selected from -M-(6-12-membered aryl) and -M-(5-10-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally further surrounded by 1-5 R groups. x Replaced;

[0336] M does not exist or is selected from -CR a R b -、-O-;

[0337] Each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl; the alkyl group may optionally be further divided by 1-5 R x Replaced;

[0338] Each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0339] Each R x Each is independently selected from halogens, cyano groups, =O, =S, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0340] p and q are each independent integers between 0 and 2;

[0341] m, n, and s are each an independent integer from 1 to 4.

[0342] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound has the structures shown in formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (III-1), (III-2), (III-3), (IV-1), and (IV-2):

[0343] Where t is an integer from 0 to 5, and the other groups are as defined in this disclosure.

[0344] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the compound has the structure shown in formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (III-1), (III-2), (III-3), (IV-1), and (IV-2): wherein one of R A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups, wherein the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e What it replaced.

[0345] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0346] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -3-6 membered heterocyclic group-, -5-9 membered spirocyclic group-, -3-6 membered carbocyclic group-;

[0347] Y either does not exist or is -CR1R2-;

[0348] Ring A is selected from 5-6 membered heterocyclic groups, 5-6 membered heteroaryl groups, and 6 membered aryl groups;

[0349] Ring B is selected from the following structures:

[0350] The asterisk (*) is attached to the X group.

[0351] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-8 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0352] The ring C is selected from 6-10 aryl, 5-10 heteroaryl, and 10-15 heterocyclic groups;

[0353] R y Selected from hydrogen, C 1-3 alkyl;

[0354] Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl groups;

[0355] Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0356] Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0357] Each R B Each is independently selected from -M-(6-12-membered aryl) and -M-(5-10-membered heteroaryl), wherein the aryl and heteroaryl groups are optionally further surrounded by 1-5 R groups. x Replaced;

[0358] M does not exist or is selected from -CRa R b -、-O-;

[0359] Each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl; the alkyl group may optionally be further divided by 1-5 R x Replaced;

[0360] Each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced;

[0361] Each R x Each is independently selected from halogens, cyano groups, =O, =S, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups;

[0362] p and q are each independent integers between 0 and 2;

[0363] m, n, and s are each an independent integer from 1 to 4.

[0364] As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0365] Ring A is selected from tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxopentyl, dithiopentanyl, oxazolidinyl, thiazolyl, triazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, dioxalkyl, dithiazolyl, piperazine, morpholinyl, thiomorpholinyl, trioxalkyl, 1,4-oxazolidinyl, 1,4-thioazolidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetraazolyl, pyridinyl, pyrimidinyl, pyrazine, 1,3-oxazine, 1,3-thiazolyl, triazine, oxopyridinyl, pyrazinone, and phenyl.

[0366] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-7 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0367] The ring C is selected from phenyl, naphthyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazolyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, zolinyl, etc.

[0368] As a ninth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0369] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-S(=O)(=NR c -, -S(=O)-, -S(=O)2-, -oxocyclobutyl-, -5-7-membered spirocyclic-, -cyclopropyl-, cyclobutyl;

[0370] Y either does not exist or is -CR1R2-;

[0371] R y Selected from F, Cl, Br, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, and trifluoroisopropyl;

[0372] Each R1 and R2 is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, cyclopropyl, vinyl, ethynyl, propynyl, -CH=CF2, CD3, CF2D, CF2Cl, CF2OCH3;

[0373] Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted;

[0374] Each R M Not present or independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, -(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、=CR a R b ;

[0375] Each R A Each is independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, =CR a R b ;

[0376] Each R BEach is independently selected from -M-(phenyl) or -M-(5-6-membered heteroaryl), wherein the phenyl or heteroaryl group is optionally further surrounded by 1-5 R groups. x The substituted group; among which, the 5-6 membered heteroaryl group is, for example, pyridinyl, pyrimidinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazinyl, triazinyl;

[0377] M does not exist or is selected from -CR a R b -、-O-;

[0378] Each R a R b R c R d Each is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy.

[0379] Each R x Each group is independently selected from F, Cl, Br, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOCH3, -NHCOCH2CH3, -N(CH3)2, -NH(CH3), -SF5, -SCF3, =CR a R b Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy;

[0380] p and q are each independent integers between 0 and 2;

[0381] m, n, and s are each an independent integer from 1 to 4.

[0382] As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein...

[0383] Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p-、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -oxocyclobutyl-, -5-7 spirocyclic-, -cyclopropyl-, cyclobutyl;

[0384] Y either does not exist or is -CR1R2-;

[0385] Ring A is selected from tetrahydropyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, dioxopentyl, dithiopentanyl, oxazolidinyl, thiazolyl, triazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, dioxalkyl, dithiazolyl, piperazine, morpholinyl, thiomorpholinyl, trioxalkyl, 1,4-oxazolidinyl, 1,4-thioazolidinyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetraazolyl, pyridinyl, pyrimidinyl, pyrazine, 1,3-oxazine, 1,3-thiazolyl, triazine, oxopyridinyl, pyrazinone, and phenyl.

[0386] Ring B is selected from the following structures:

[0387] The asterisk (*) is attached to the X group.

[0388] As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 6-7 Carbocyclic or 6- to 8-membered heterocyclic groups;

[0389] The ring C is selected from phenyl, naphthyl, pyrrolyl, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazolyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, zolinyl, etc.

[0390] R y Selected from F, Cl, Br, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, and trifluoroisopropyl;

[0391] Each R1 and R2 is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy.

[0392] Each R M Not present or independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, -(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、=CR a R b ;

[0393] Each R A Each is independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, =CR a R b ;

[0394] Each R B Each is independently selected from -M-(phenyl) or -M-(5-6-membered heteroaryl), wherein the phenyl or heteroaryl group is optionally further surrounded by 1-5 R groups. x The substituted group; among which, the 5-6 membered heteroaryl group is, for example, pyridinyl, pyrimidinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazinyl, triazinyl;

[0395] M does not exist or is selected from -CR a R b -、-O-;

[0396] Each R a R b R c R d Each is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy.

[0397] Each R x Each group is independently selected from F, Cl, Br, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOCH3, -NHCOCH2CH3, -N(CH3)2, -NH(CH3), -SF5, -SCF3, =CR a R b Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy;

[0398] p and q are each independent integers between 0 and 2;

[0399] m, n, and s are each an independent integer from 1 to 4.

[0400] As an eleventh embodiment of the present invention, the compound represented by the aforementioned general formula, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein...

[0401] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0402] As a twelfth embodiment of the present invention, the compound represented by general formula (III-1), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are used.

[0403] Wherein, ring B is selected from 6-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 6-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 6-10 member heterocyclic groups containing 1 to 2 N atoms, more preferably from 6-10 member mono-heterocyclic groups containing 1 to 2 N atoms, 6-10 member fused heterocyclic groups containing 1 to 2 N atoms, and 6-10 member spiro-heterocyclic groups containing 1 to 2 N atoms, and preferably from the following structures:

[0404] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0405] As a thirteenth embodiment of the present invention, the compound represented by general formula (III-2), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0406] Wherein, ring B is selected from 6-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 6-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 6-10 member heterocyclic groups containing 1 to 2 N atoms, more preferably from 6-10 member fused heterocyclic groups containing 1 to 2 N atoms, 6-10 member spirocyclic groups containing 1 to 2 N atoms, and 6-10 member bridged heterocyclic groups containing 1 to 2 N atoms, and preferably from the following structures:

[0407] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0408] As the fourteenth embodiment of the present invention, the compound represented by general formula (III-3), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0409] Wherein, ring B is selected from 6-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 6-9 member heterocyclic groups containing 1 to 4 N atoms, more preferably from 6-10 member fused heterocyclic groups containing 1 to 4 N atoms, 6-9 member bridged heterocyclic groups containing 1 to 4 N atoms, and preferably from the following structures:

[0410] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0411] As a fifteenth embodiment of the present invention, the compound represented by general formula (V-1), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0412] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 2 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0413] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0414] As a sixteenth embodiment of the present invention, the compound represented by general formula (V-2), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0415] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0416] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0417] As the seventeenth embodiment of the present invention, the compound represented by general formula (V-3), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0418] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0419] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0420] As the eighteenth embodiment of the present invention, the compound represented by general formula (V-4), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0421] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0422] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0423] As the nineteenth embodiment of the present invention, the compound represented by general formula (VI-10), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0424] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0425] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0426] As a twentieth embodiment of the present invention, the compound represented by general formula (VI-11), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0427] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0428] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0429] As a twenty-first embodiment of the present invention, the compound represented by general formula (VI-12), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are included.

[0430] Wherein, ring B is selected from 5-10 member heterocyclic groups containing 1 to 4 N atoms, preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member heterocyclic groups containing 1 to 3 N atoms, more preferably from 5-10 member fused heterocyclic groups containing 1 to 3 N atoms, 5-10 member spirocyclic groups containing 1 to 3 N atoms, and 5-10 member bridged heterocyclic groups containing 1 to 3 N atoms, and preferably from the following structures:

[0431] The asterisk (*) is attached to the X group.

[0432] t is an integer from 0 to 5, and the definitions of the other groups are as shown in any of the aforementioned embodiments.

[0433] As a twenty-second embodiment of the present invention, the compounds shown in formulas (II-7), (II-8), (II-9), or (II-10) mentioned above, wherein,

[0434] R M1 R M2 R M3 and R M4 Each element is independently selected from hydrogen, halogen, hydroxyl group, =O, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, =CR a R b ;

[0435] Optionally, R M1 and R M2 R M3 and R M4 R M1 and R M3 Any group of atoms connected to it together forms C. 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted;

[0436] The remaining groups are as defined in formula (II).

[0437] As the twenty-third embodiment of the present invention, the compounds shown in the aforementioned formulas (IIG), (II), (II-7), (II-8), (II-9) or (II-10) are wherein X is C(O) and Z is -O-CH2-; or X is -O-CH2- and Z is C(O).

[0438] As the twenty-fourth embodiment of the present invention, wherein... Selected from (For example, ), (For example, and ),

[0439] R a Rb R c and R A1 As defined in this article.

[0440] As a twenty-fifth embodiment of the present invention, the compound represented by the aforementioned general formula (IIG) or general formula (II), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein, Selected from Y is CR1R2; k is 0 or 1; for R B1 for M does not exist or is selected from -CR a R b -, -O- and -C (=O);

[0441] Ring D is phenyl.

[0442] The twenty-sixth embodiment of the present invention, wherein for (For example, );

[0443] Each R a R b Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0444] Y is -CR1R2-; each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups;

[0445] Selected from

[0446] The remaining groups are as defined in this document.

[0447] As the twenty-seventh embodiment of the present invention, the compound represented by the foregoing general formula, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein the compound is selected from, but not limited to, the structures in Table A below:

[0448] Table A

[0449] As a twenty-eighth embodiment of the present invention, the aforementioned general formula compound, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein the compound is selected from, but not limited to, the structures in Table B below:

[0450] Table B

[0451] The present invention also provides a deuterated compound of formula (IIG), formula (II), Table A or Table B, wherein one or more hydrogen atoms are replaced by deuterium atoms in its structure.

[0452] The present invention also provides a pharmaceutical composition or pharmaceutical formulation comprising the compound described in any of the foregoing embodiments, its stereoisomers, tautomers, racemates, nitrides or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers.

[0453] Furthermore, the pharmaceutical composition or pharmaceutical preparation of the present invention contains 1-1500 mg of the compound described in any of the preceding embodiments, its stereoisomers, tautomers, racemates, nitrides or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers.

[0454] In some embodiments, the pharmaceutical composition of the present invention may be in unit dosage form (the amount of the active pharmaceutical ingredient in a unit dosage form is also referred to as a "dosage strength").

[0455] 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 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. ;

[0456] In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 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, etc. The compounds of the present invention, or their stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, in the range of mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 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, and 1500 mg.

[0457] The present invention also provides the use of the compounds described in any of the foregoing embodiments, their stereoisomers, tautomers, racemates, nitrides or pharmaceutically acceptable salts, or pharmaceutical compositions or pharmaceutical preparations described in any of the foregoing embodiments in the preparation of medicaments for the treatment / prevention of MRGPRX2-related diseases.

[0458] In some implementations, the MRGPRX2-related diseases are selected from autoimmune diseases.

[0459] In some embodiments, the MRGPRX2-related diseases described in this invention are selected from chronic spontaneous urticaria, chronic induced urticaria, mast cell hyperplasia, atopic dermatitis, cystitis, migraine, asthma, Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

[0460] This invention also provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound shown in any of the foregoing embodiments, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, or a pharmaceutical composition or formulation shown in any of the foregoing embodiments, preferably the therapeutically effective amount being 1-1500 mg, wherein the disease is selected from autoimmune diseases. In some embodiments, the mammals described in this invention include humans. In some embodiments, the diseases described in this invention are selected from chronic spontaneous urticaria, chronic induced urticaria, mast cell hyperplasia, atopic dermatitis, cystitis, migraine, asthma, Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

[0461] A method for treating a mammalian disease, the method comprising administering to a subject a compound of the present invention, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, at a daily dose of 1-1500 mg / day, said daily dose being a single dose or divided doses. 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, and 75-1000 mg / day. 100-1000mg / day, 200-1000mg / day, 25-800mg / day, 50-800mg / day, 100-800mg / day, 200-800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day. In some embodiments, the daily dose includes, but is not limited to, 1mg / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, and 1500mg / day.

[0462] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising the compound of the invention, its stereoisomers, tautomers, racemates, or pharmaceutically acceptable salts, wherein the amounts of the compound of the invention, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are the same as those in the pharmaceutical composition described above.

[0463] In this invention, the amounts of the compound of the invention, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts are, in each case, converted to the form of free base.

[0464] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0465] the term

[0466] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0467] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P,32 P.

[0468] “CN” refers to cyano.

[0469] "Halogen" refers to F, Cl, Br or I.

[0470] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0471] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0472] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0473] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0474] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0475] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl groups 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, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent, or tetravalent.

[0476] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0477] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0478] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0479] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithial, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

[0480] A "spirocyclic" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted rings share a single atom (called a spiro atom). The number of ring atoms in a spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 7 to 11, or 6 to 10. One or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally, 0 to 5 double bonds selected from N, O, or S (=O). n Heteroatoms (n is 0, 1, or 2), such as 7-10 spirobicycloalkyl, 7-10 spirobicycloalkyl, such as 5-membered cycloalkylspiro3-membered cycloalkyl, 5-membered cycloalkylspiro4-membered cycloalkyl, 5-membered cycloalkylspiro5-membered cycloalkyl, 6-membered cycloalkylspiro4-membered cycloalkyl, 6-membered cycloalkylspiro5-membered cycloalkyl, 5-membered cycloalkylspiro3-membered heterocyclic group, 5-membered cycloalkylspiro4-membered heterocyclic group, 5-membered cycloalkylspiro5-membered heterocyclic group, 6-membered cycloalkylspiro4-membered heterocyclic group. The compounds include: 6-membered cycloalkyl spiro-5-membered heterocyclic groups, 5-membered heterocyclic spiro-3-membered heterocyclic groups, 5-membered heterocyclic spiro-4-membered heterocyclic groups, 5-membered heterocyclic spiro-5-membered heterocyclic groups, 6-membered heterocyclic spiro-4-membered heterocyclic groups, 6-membered heterocyclic spiro-5-membered heterocyclic groups, 5-membered heterocyclic spiro-3-membered heterocyclic groups, 5-membered heterocyclic spiro-4-membered heterocyclic groups, 5-membered heterocyclic spiro-5-membered heterocyclic groups, 6-membered heterocyclic spiro-4-membered heterocyclic groups, 6-membered heterocyclic spiro-5-membered heterocyclic groups, and 5-membered heteroaryl spiro-3-membered heterocyclic groups. Non-limiting examples include: "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0481] "Circular fused" or "circular fused group" refers to a polycyclic group in which each ring in a system shares a pair of adjacent atoms with other rings in the system. One or more rings may contain zero or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted. Each ring in a circular fused system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to those selected from N, S (=O)). nOr O, where n is 0, 1, or 2). The number of ring atoms in a fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10, such as 7-11-membered fused-bicycloalkyl, 7-11-membered fused-biheterocyclic, and 7-11-membered fused-biheteroaryl, such as 5-membered cycloalkyl fused-3-membered cycloalkyl, 5-membered cycloalkyl fused-4-membered cycloalkyl, 5-membered cycloalkyl fused-5-membered cycloalkyl, 6-membered cycloalkyl fused-4-membered cycloalkyl, 6-membered cycloalkyl fused-5-membered cycloalkyl, 5-membered cycloalkyl fused-3-membered cycloalkyl fused-4-membered cycloalkyl, 5-membered cycloalkyl fused-5-membered cycloalkyl, 6-membered cycloalkyl fused-4-membered cycloalkyl, 6-membered cycloalkyl fused-5-membered cycloalkyl, 5-membered heterocyclic fused-3-membered cycloalkyl, 5-membered heterocyclic fused-4-membered cycloalkyl, 5-membered heterocyclic fused-5-membered cycloalkyl, 6-membered heterocyclic fused-4-membered cycloalkyl, 6-membered heterocyclic fused-5-membered cycloalkyl, and 5-membered heterocyclic fused-3-membered heterocyclic cycloalkyl. Cycloyl, 5-membered heterocyclic and 4-membered heterocyclic, 5-membered heterocyclic and 5-membered heterocyclic, 6-membered heterocyclic and 4-membered heterocyclic, 6-membered heterocyclic and 5-membered heterocyclic, 5-membered heteroaryl and 3-membered cycloalkyl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 3-membered heterocyclic 5-membered heteroaryl-4-membered heterocyclic, 5-membered heteroaryl-5-membered heterocyclic, 5-membered heteroaryl-6-membered heterocyclic, 6-membered heteroaryl-4-membered heterocyclic, 6-membered heteroaryl-5-membered heterocyclic, 5-membered cycloalkyl-5-membered heterocyclic, 6-membered cycloalkyl-5-membered heterocyclic, 5-membered cycloalkyl-6-membered heterocyclic, 5-membered heterocyclic-5-membered heterocyclic, 6-membered heterocyclic-5-membered heterocyclic, 5-membered heterocyclic-6-membered heterocyclic. Non-limiting examples include: "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0482] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0483] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0484] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0485] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0486] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0487] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0488] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0489] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0490] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0491] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0492] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. The atoms C, N, and S on the ring may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0493] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4, or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(CH2). m -C(=O)-R a -O-(CH2) m -C(=O)-R a -(CH2) m -C(=O)-NR b R c -(CH2) m S(=O) n R a -(CH2) m -Alkenyl-R a OR d Or -(CH2) m -alkynyl-R a (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0494] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is substituted by 1, 2, 3, 4 or 5 substituents selected from ... . For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0495] The XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered elements. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0496] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 ….C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0497] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0498] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0499] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0500] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0501] "Pharmaceutical composition" refers to one or more compounds described in this invention, or a mixture of their stereoisomers, tautomers, deuterated derivatives, racemates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectics, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0502] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0503] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0504] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0505] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0506] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0507] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0508] 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. -6The 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).

[0509] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0510] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0511] 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.

[0512] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0513] To achieve the objectives of this invention, those skilled in the art can prepare the compounds of this invention by combining the literature with known organic synthesis techniques, using commercially available chemicals and / or compounds described in chemical literature as starting materials. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Maclean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfaisa (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Shanghai Demo, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, Anengji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, and Bailingwei Technology Co., Ltd., etc.

[0514] 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).

[0515] Synthesis Method 1

[0516] A compound of general formula (IA) or a salt thereof undergoes a nucleophilic addition reaction with a compound of general formula (IB) or a salt thereof under the action of a base to give a compound of general formula (IC) or a pharmaceutically usable salt thereof.

[0517] In the reaction of the above scheme, the base includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, 3,5-dimethylpyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis(trimethylsilyl)aminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0518] The reaction in the above scheme is preferably carried out in a solvent, which includes, but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, pyridine, and mixtures thereof.

[0519] The preferred condensing reagents for the above-mentioned reaction scheme include, but are not limited to: EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), HATU (urea hexafluorophosphate), DIC (diisopropylcarbodiimide), PyBOP (benzotriazol-1-yloxytripyrrolidinylphosphonium), HBTU (benzotriazolium hexafluorophosphate), BOP (benzotriazol-1-yloxytris(dimethylamino)phosphonium), CDI (carbonyldiimidazole), TBTU (benzotriazolium tetrafluoroborate), DMT-MM (4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholine chloride), etc.

[0520] Synthesis Method 2

[0521] A compound of general formula (IIG-a) or a salt thereof reacts with a compound of general formula (IIG-b) or a salt thereof in the presence of a base to give a compound of general formula (IIG) or a pharmaceutically usable salt thereof.

[0522] Where R Z It is a leaving group such as halogen (e.g., Cl, Br or I), trifluoromethanesulfonate (OTf), methanesulfonate (OMs).

[0523] In the reaction of the above scheme, the base includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, 3,5-dimethylpyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis(trimethylsilyl)aminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0524] Synthesis Method 3

[0525] The compound of general formula (II-10a) or its salt reacts with the compound of general formula (II-10b) or its salt in the presence of a base to give the compound of general formula (II-10) or its pharmaceutically usable salt.

[0526] Where Y is CR 1 R 2 ;R Z It is a leaving group such as halogen (e.g., Cl, Br or I), trifluoromethanesulfonate (OTf), methanesulfonate (OMs).

[0527] In the reaction of the above scheme, the base includes organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, pyridine, 3,5-dimethylpyridine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, bis(trimethylsilyl)aminolithium, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1,8-diazabicycloundec-7-ene. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide.

[0528] The following embodiments are synthesized according to the method described above.

[0529] The following embodiments are synthesized according to the method described above.

[0530] List of reagent abbreviations and their corresponding reagent names:

[0531] The following are examples of specific preparation methods:

[0532] Example 1 (Compound 1)

[0533] Step 1: Synthesis of compound 1E:

[0534] Compound 1E-1 (synthetic method referred to page 212 of patent CN116217554A, synthesis of intermediate 9-2) (1.00 g, 4.96 mmol) was added to ethanol (10 mL), followed by slow addition of sodium hydroxide aqueous solution (7.4 mL, 1 M). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid was slowly added dropwise to adjust the pH to acidic. The resulting mixture was filtered, the filter cake was collected, and concentrated and dried under reduced pressure to obtain compound 1E (796.0 mg).

[0535] MS m / z(ESI) = 173.9 [M+1] + .

[0536] Step 2: Synthesis of compound 1C:

[0537] Intermediate 1A (synthesis method referred to page 38 of patent WO2022073905A1, synthesis of intermediate 2) (150.0 mg, 0.43 mmol), compound 1B (124.9 mg, 0.62 mmol) and triethylamine (127.2 mg, 1.26 mmol) were dissolved in anhydrous dichloromethane (4.0 mL). The reaction mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The crude product was purified by thin-layer chromatography on silica gel plates (developing solvent: PE:EA = 2:1) to obtain compound 1C (86.0 mg).

[0538] MS m / z(ESI) = 476.2[M+1] + .

[0539] Step 3: Synthesis of Compound 1D:

[0540] Compound 1C (86.0 mg, 0.18 mmol) and trifluoroacetic acid (0.6 mL) were dissolved in anhydrous dichloromethane (3.0 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 1D (78.0 mg, crude product), which was directly used in the next step of the reaction.

[0541] MS m / z(ESI) = 376.1 [M+1] + .

[0542] Step 4: Synthesis of Compound 1:

[0543] Compound 1D (78.0 mg, crude), HATU (137.6 mg, 0.36 mmol), compound 1E (40.8 mg, 0.24 mmol), and triethylamine (251.7 μL, 1.81 mmol) were dissolved in anhydrous N,N-dimethylformamide (3.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 35-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 1 (35.6 mg).

[0544] MS m / z(ESI) = 531.1 [M+1] + .

[0545] 1H NMR (400MHz, DMSO-d6) δ12.01(s,1H),10.57(d,J=47.2Hz,1H),8.83(d,J=5.4Hz,1H),8.46 (d,J=1.2Hz,1H),7.76(d,J=1.8Hz,1H),7.49(ddt,J=14.5,9.2,4.3Hz,2H),7.19(t,J=7.9H z,1H),6.57(s,1H),3.89(dd,J=12.8,4.1Hz,1H),3.68(d,J=5.1Hz,1H),3.08–2.86(m,1H) ,2.86–2.64(m,4H),1.31(dd,J=14.1,6.8Hz,3H),0.93–0.62(m,1H),0.55(q,J=6.2Hz,1H).

[0546] Example 2 (Compound 2)

[0547] Step 1: Synthesis of compound 2B:

[0548] Intermediate 1A (synthesis method referred to page 38 of patent WO2022073905A1, synthesis of intermediate 2) (150.0 mg, 0.43 mmol), compound 2A (91.0 mg, 0.62 mmol), and triethylamine (127.2 mg, 1.26 mmol) were dissolved in anhydrous dichloromethane (4.0 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by thin-layer chromatography on silica gel plates (developing solvent: PE:EA, 3:1) to obtain compound 2B (76.0 mg).

[0549] MS m / z(ESI) = 490.2[M+1] + .

[0550] Step 2: Synthesis of compound 2C:

[0551] Compound 2B (76.0 mg, 0.16 mmol) and trifluoroacetic acid (0.6 mL) were dissolved in anhydrous dichloromethane (3.0 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 2C (78.0 mg, crude product), which was directly used in the next reaction step.

[0552] MS m / z(ESI) = 390.2[M+1] + .

[0553] Step 3: Synthesis of Compound 2:

[0554] Compound 2C (78.0 mg, crude), HATU (117.8 mg, 0.31 mmol), compound 1E (34.9 mg, 0.20 mmol), and triethylamine (215.6 μL, 1.55 mmol) were dissolved in anhydrous N,N-dimethylformamide (3.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 35-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 2 (21.5 mg).

[0555] MS m / z(ESI) = 545.2 [M+1] + .

[0556] 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),10.27(d,J=25.3Hz,1H),8.82(d,J=6.0Hz,1H),8. 62–8.14(m,1H),7.62(s,1H),7.49(ddt,J=14.4,9.2,4.4Hz,1H),7.18(t,J=8.5Hz,2H),6 .57(s,1H),4.17(dd,J=26.4,12.4Hz,1H),3.55(s,1H),3.24(m,2H),3.24–3.12(m,2H), 2.99(dd,J=35.3,12.6Hz,1H),1.91(s,1H),1.77(s,1H),1.66–1.49(m,2H),1.26(s,3H).

[0557] Example 3 (Compound 3)

[0558] Step 1: Synthesis of compound 3C:

[0559] Compound 3A (1.00 g, 3.31 mmol), compound 3B (934 mg, 3.97 mmol), Pd(dppf)Cl2 (242 mg, 0.330 mmol), and potassium carbonate (915 mg, 6.62 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 120 °C for 1 hour in a microwave reactor. After the reaction was complete, ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 3C (700 mg). MS m / z (ESI) = 331.2 [M+1] + .

[0560] Step 2: Synthesis of Compound 3D

[0561] Compound 3C (700 mg, 2.12 mmol) was dissolved in 5 mL of 48% hydrobromic acid aqueous solution, and the reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and acetonitrile (10 mL) and water (10 mL) were added to the crude product. After lyophilization, compound 3D (400 mg, crude product) was obtained and used directly in the next reaction. MS m / z (ESI) = 217.1 [M+1] + .

[0562] Step 3: Synthesis of Compound 3:

[0563] Compound 3D (300 mg, crude), compound 1A (150 mg, 0.420 mmol), and triethylamine (424 mg, 4.20 mmol) were dissolved in anhydrous N,N-dimethylacetamide (3.0 mL). The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 25-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 3 (65.5 mg). MS m / z (ESI) = 494.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),10.59(s,1H),8.83(d,J=1.3Hz,1H),8.44(d,J =1.4Hz,1H),7.75(dd,J=9.5,2.6Hz,1H),7.62(s,1H),7.56–7.43(m,2H),7.40(s,1H) ,7.18(t,J=8.6Hz,1H),6.41(d,J=9.5Hz,1H),4.05(dd,J=9.9,4.4Hz,2H),3.99(d,J =6.4Hz, 2H), 3.79 (d, J = 6.9Hz, 1H), 2.97 (q, J = 5.6, 5.1Hz, 2H), 1.32 (d, J = 6.9Hz, 3H).

[0564] Example 4 (Compound 4)

[0565] Step 1: Synthesis of compound 4B:

[0566] Compound 4A (1.00 g, 4.05 mmol), compound 3B (1.14 g, 4.86 mmol), Pd(dppf)Cl2 (296 mg, 0.410 mmol), and potassium carbonate (1.12 g, 8.09 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The reaction mixture was stirred at 120 °C for 1 hour in a microwave reactor. After the reaction was complete, ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with saturated brine (50 mL × 3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0-20%) to give compound 4B (170 mg). MS m / z (ESI) = 276.1 [M+1] + .

[0567] Step 2: Synthesis of compound 4C:

[0568] Compound 4B (170 mg, 0.610 mmol) was dissolved in 5 mL of 48% hydrobromic acid aqueous solution, and the reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and acetonitrile (10 mL) and water (10 mL) were added to the crude product. After lyophilization, compound 4C (158 mg, crude product) was obtained. MS m / z (ESI) = 162.0 [M+1] + .

[0569] Step 3: Synthesis of Compound 4:

[0570] Compound 4C (150 mg, 0.93 mmol), compound 1A (332 mg, 0.930 mmol), and triethylamine (1.3 mL, 9.3 mmol) were dissolved in N,N-dimethylacetamide (5 mL). The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 31-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 4 (26 mg). MS m / z (ESI) = 439.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.90(s,1H),11.20(s,1H),8.75(d,J=1.5Hz,1H),8.48(d,J=1.4Hz,1H),8.13(s,1H),7.95–7.84(m,2H),7. 79(dd,J=9.4,2.5Hz,1H),7.57–7.41(m,2H),7.24–7.11(m,1H),6.48(d,J=9.3Hz,1H),5.65(d,J=7.4Hz,1H),1.74(d,J=7.4Hz,3H).

[0571] Example 5 (Compound 5)

[0572] Step 1: Synthesis of compound 5C:

[0573] Compound 5A (0.790 g, 4.32 mmol), compound 5B (1.10 g, 5.08 mmol), HATU (2.64 g, 6.93 mmol), and N,N-diisopropylethylamine (1.20 g, 9.25 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PE = 0%–70%) to give compound 5C (2.30 g). MS m / z (ESI) = 369.1 [M+1] + .

[0574] Step 2: Synthesis of compound 5D:

[0575] Compound 5C (1.15 g, 2.76 mmol) was dissolved in DMF (12 mL). Sodium hydride (132 mg, 3.31 mmol, 60% purity) was added under nitrogen atmosphere at 0 °C. The mixture was slowly heated to room temperature, and the reaction mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to 0 °C, quenched with saturated ammonium chloride aqueous solution (20 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA / PEA = 0%–70%) to give compound 5D (316 mg). MS m / z (ESI) = 349.1 [M+1] + .

[0576] Step 3: Synthesis of compound 5E:

[0577] Compound 5D (316 mg, 0.907 mmol) and trifluoroacetic acid (1 mL) were dissolved in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 5E (350 mg, crude product), which was directly used in the next reaction. MS m / z (ESI) = 249.1 [M+1] + .

[0578] Step 4: Synthesis of Compound 5:

[0579] Compound 5E (350 mg, crude), compound 1A (404 mg, 1.13 mmol), and triethylamine (1.43 g, 14.1 mmol) were dissolved in anhydrous N,N-dimethylacetamide (4 mL). The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 50-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 5 (120 mg). MS m / z (ESI) = 526.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.82(s,1H),8.47(d,J=1.2Hz,1H),7.88(dd,J=8.9,5.0Hz,1H), 7.52-7.44(m,2H),7.18(t,J=8.5Hz,1H),6.74(dd,J=8.9,2.4Hz,1H),6.56(d,J=2.5Hz,1H),4.48(dd,J =12.1,7.9Hz,1H),4.23(d,J=11.8Hz,1H),4.10(d,J=17.0Hz,1H),3.85(s,1H),3.79(s,3H),3.59-3.55 (m,1H),3.49–3.40(m,1H),2.87–2.78(m,1H),2.76-2.60(m,2H),2.52-2.46(m,1H),1.30–1.16(m,3H).

[0580] Example 6 (Compound 6)

[0581] Step 1: Synthesis of compound 6F-2:

[0582] Compound 6F-1 (5.00 g, 44.2 mmol), 2,4-difluorobenzyl chloride (7.19 g, 44.2 mmol), and K₂CO₃ (12.2 g, 88.4 mmol) were sequentially added to DMF (50 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated ammonium chloride aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether: 20%–50%) to give compound 6F-2 (7.7 g). MS m / z (ESI) = 240.0 [M+1] + .

[0583] Step 2: Synthesis of compound 6F-3:

[0584] Compound 6F-2 (500 mg, 2.09 mmol) and Pd / C (0.30 g, 1.67 mmol, 10%) were added to MeOH (10 mL), and the reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 6F-3 (406 mg), which was directly used in the next reaction. MS m / z (ESI) = 210.0 [M+1] + .

[0585] Step 3: Synthesis of compound 6F:

[0586] Compound 6F-3 (100 mg, 0.478 mmol), DCC (118 mg, 0.573 mmol), 2-bromopropionic acid (87.7 mg, 0.573 mmol), and silver nitrate (12 mg, 0.071 mmol) were dissolved in DCM (3 mL). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give compound 6F (100 mg), which was used directly in the next reaction. MS m / z (ESI) = 346.0 [M+1] + .

[0587] Step 4: Synthesis of compound 6B:

[0588] Compound 6A (1.00 g, 5.09 mmol), compound 5B (1.10 g, 5.09 mmol), and triethylamine (0.103 g, 10.3 mmol) were dissolved in 10 mL of acetonitrile. The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride aqueous solution (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 6B (1.40 g). MS m / z (ESI) = 376.0 [M+1] + .

[0589] Step 5: Synthesis of compound 6C:

[0590] Compound 6B (1.20 g, 3.19 mmol) was dissolved in N,N-dimethylformamide (15 mL), and sodium hydride (153 mg, 3.83 mmol, 60% purity) was added at 0 °C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 6C (900 mg). MS m / z (ESI) = 340.2 [M+1] + .

[0591] Step 6: Synthesis of compound 6D:

[0592] Compound 6C (450 mg, 1.32 mmol), potassium hydroxide (222 mg, 3.97 mmol), 2-di-tert-butylphospho-3,4,5,6-tetramethyl-2',4',6'-triisopropylbenzyl (127 mg, 0.26 mmol), and Pd2(dba)3 (107 mg, 0.13 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was purged with nitrogen three times, and the reaction mixture was stirred at 100 °C for 5 hours in a microwave apparatus. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane: 0-10%) to give compound 6D (400 mg). MS m / z (ESI) = 322.2 [M+1] + .

[0593] Step 7: Synthesis of compound 6E:

[0594] Compound 6D (400 mg, 1.24 mmol) was dissolved in a 1,4-dioxane solution (5 mL, 4 M) of hydrochloric acid, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give compound 6E (400 mg), which was used directly in the next reaction.

[0595] Step 8: Synthesis of Compound 6:

[0596] Compound 6F (100 mg, 0.291 mmol), triethylamine (0.400 mL, 2.90 mmol), and compound 6E (150 mg, 0.582 mmol) were dissolved in DMA (6 mL). The reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 30 × 250 mm, 7 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 15-95%; column temperature: 25 °C; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain 6 (3.5 mg). MS m / z (ESI): 485.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ11.28(s,1H),9.95(s,1H),7.57(d,J=1.6Hz,1H),7.50–7.42(m,1H) ,7.36–7.27(m,2H),7.22(d,J=1.6Hz,1H),7.17–7.10(m,1H),5.76(d,J=2.1Hz,1H),5.20(s ,2H),4.15(d,J=12.5Hz,1H),3.66(s,1H),3.48(d,J=14.0Hz,1H),2.77(d,J=7.7Hz,1H),2. 61(d,J=9.2Hz,3H),2.35(d,J=18.0Hz,2H),2.21(s,1H),2.11(s,1H),1.11(d,J=6.7Hz,3H).

[0597] Example 7 (Compound 7)

[0598] Compound 6E (500 mg, 2.26 mmol), compound 1A (100 mg, 0.27 mmol), and triethylamine (2.20 mL, 16.1 mmol) were dissolved in anhydrous N,N-dimethylacetamide (10 mL), and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was complete, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 29-95%; column temperature: 25℃; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 7 (4.90 mg). MS m / z (ESI) = 499.2 [M+1] + .

[0599] Example 8 (Compound 8)

[0600] Step 1: Synthesis of compound 8C:

[0601] Compound 8B (2.0 g, crude) (see page 71 of patent WO2019152419A1, Synthesis of Intermediate D-8), sodium carbonate (1.82 g, 17.2 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (700 mg, 0.85 mmol), and compound 8A (2.00 g, 7.42 mmol) (see page 101 of patent WO2022047093A1, Step 1) were added to 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was stirred in a microwave at 100 °C for 2 hours. After the reaction was complete, the resulting mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to give compound 8C (400 mg). MS m / z (ESI) = 365.1 [M+1] + . 1 H NMR(400MHz, CDCl3) δ8.26(d,J=3.5Hz,1H),7.04(s,1H),6.93(s,1H),4.75(d,J=1 .0Hz, 2H), 4.02 (d, J = 1.2Hz, 3H), 3.87 (t, J = 4.5Hz, 2H), 3.80 (s, 2H), 1.53 (s, 9H).

[0602] Step 2: Synthesis of compound 8D:

[0603] Compound 8C (400 mg, 1.10 mmol) was dissolved in hydrobromic acid (5 mL), and the reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain compound 8D (200 mg, crude product), which was used directly in the next step. MS m / z (ESI) = 250.0 [M+1] + .

[0604] Step 3: Synthesis of Compound 8

[0605] Compound 8D (200 mg), triethylamine (1.00 mL, 7.19 mmol), and intermediate 1A were dissolved in DMA (5 mL), and the reaction mixture was stirred at 60 °C for 1.5 hours. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% FA / H2O); gradient: 5-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 8 (20 mg). MS m / z (ESI) = 528.1 [M+1] + . 1HNMR(400MHz,DMSO-d6)δ10.62(s,1H),8.84(d,J=1.4Hz,1H),8.48–8.42(m,1H),7.64(s,1H),7.56–7.41(m,2 H),7.25–7.12(m,1H),6.78(s,1H),6.63(s,1H),3.95–3.69(m,5H),3.03–2.88(m,2H),1.30(d,J=6.8Hz,3H).

[0606] Example 9 (Compound 9)

[0607] Compound 5 (30.0 mg, 0.0570 mmol) was dissolved in anhydrous dichloromethane (1.50 mL), and boron tribromide (0.40 mL, 0.010 mmol) was added at -78 °C. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, methanol (2 mL) was added to quench the reaction mixture. The mixture was purified by preparative high-performance liquid chromatography (HPLC) (column: Welch-Xtimate-C18; 30 × 250 mm, 7 μm; mobile phase: acetonitrile-water (0.1% HCOOH / H2O); gradient: 38-95%; column temperature: 25 °C; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 9 (7.23 mg). MS m / z (ESI) = 512.1 [M+1] + .

[0608] Example 10 (Compound 10)

[0609] Step 1: Synthesis of Compound 10B:

[0610] Under nitrogen protection at room temperature, compound 10A (synthetic method referred to on page 327 of patent WO2020132269A1, the synthesis method of intermediate 3) (400 mg, 1.08 mmol), compound 8B (synthetic method referred to on page 45 of patent WO202349723, the synthesis method of intermediate 8) (582 mg, 2.16 mmol), tetraphenylphosphine palladium (250 mg, 0.216 mmol), and potassium carbonate (448 mg, 3.24 mmol) were dissolved in 1,4-dioxane (24 mL) and water (8 mL). The reaction mixture was stirred at 90 °C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE = 0%-30%) to give compound 10B (287 mg). MS m / z (ESI) = 433.2 [M+1] + .

[0611] Step 2: Synthesis of Compound 10C

[0612] Compound 10B (280 mg, 0.647 mmol) was added to an aqueous solution of hydrogen bromide (4 mL, 48%). The reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was lyophilized to give compound 10C (258 mg). MS m / z (ESI) = 319.1 [M+1] + .

[0613] Step 3: Synthesis of Compound 10

[0614] Compound 10C (258 mg, 0.810 mmol), triethylamine (0.233 mL, 1.68 mmol), and compound 1A (100 mg, 0.279 mmol) were dissolved in anhydrous N,N-dimethylacetamide (2 mL). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 10-90%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 10 (8.17 mg). MS m / z (ESI) = 596.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.65(s,1H),8.80(d,J=1.4Hz,1H),8.45(d,J=1.5Hz,1H),7.51–7.47(m,3H),7.20–7.16(m,1 H), 6.61 (s, 1H), 4.21 (s, 2H), 3.89 (d, J = 14.9Hz, 1H), 3.80 (d, J = 15.0Hz, 2H), 3.08 (d, J = 6.4Hz, 2H), 1.33–1.29 (m, 3H).

[0615] Example 11 (Compound 11)

[0616] Step 1: Synthesis of compound 11C

[0617] Compound 11A (5.40 g, 20.1 mmol), compound 11B (5.66 g, 30.1 mmol), N,N,N',N'-tetramethylethylenediamine (3.00 mL, 20.1 mmol), and cuprous bromide (2.88 g, 20.1 mmol) were dissolved in N,N-dimethylacetamide (60 mL). The reaction mixture was stirred at 125 °C for 16 hours. After the reaction was complete, the reaction solution was poured into water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 11C (1.98 g). MS m / z (ESI) = 377.1 [M+1] + .

[0618] Step 2: Synthesis of compound 11D

[0619] Compound 11C (1.98 g, 5.26 mmol) was dissolved in N,N-dimethylformamide (60 mL). Sodium hydride (0.530 g, 13.3 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Then, iodoethane (0.850 mL, 10.6 mmol) was added, and the reaction mixture was brought to room temperature and stirred overnight. After the reaction was complete, the reaction solution was quenched with water, extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–50%) to give compound 11D (287 mg). MS m / z (ESI) = 405.2 [M+1] + .

[0620] Step 3: Synthesis of compound 11E

[0621] Compound 11D (280 mg, 0.647 mmol) was dissolved in an aqueous solution of hydrogen bromide (4 mL, 48%). The reaction mixture was stirred at 90 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was lyophilized to give compound 11E (258 mg). MS m / z (ESI) = 291.1 [M+1] + .

[0622] Step 4: Synthesis of Compound 11

[0623] Compound 11E (210 mg, 0.723 mmol), compound 1A (100 mg, 0.279 mmol), and triethylamine (0.233 mL, 1.68 mmol) were dissolved in anhydrous N,N-dimethylacetamide (4 mL). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mM NH4HCO3 / H2O); gradient: 10-90%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 11 (38.29 mg). MS m / z (ESI) = 568.2 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),10.43(s,1H),8.80(d,J=1.4Hz,1H),8 .46(d,J=1.4Hz,1H),7.52–7.40(m,4H),7.19–7.15(m,1H),6.37(d,J=9.6Hz, 1H),3.56(d,J=6.9Hz,1H),3.08–2.90(m,2H),2.89–2.70(m,4H),2.07–2.00( m, 2H), 1.87 (d, J = 12.8Hz, 2H), 1.22 (d, J = 11.4Hz, 3H), 1.16 (d, J = 7.1Hz, 3H).

[0624] Example 12 (Compound 12)

[0625] Step 1: Synthesis of compound 12C

[0626] Compound 12B (1.35 g, 6.06 mmol) was dissolved in tetrahydrofuran (10 mL). A solution of n-butyllithium in n-hexane (2.42 mL, 6.06 mmol, 2.5 N) was added dropwise to the reaction mixture under nitrogen protection at -78 °C. The reaction mixture was stirred at -78 °C for 0.5 h. Then, compound 12A (1.50 g, 5.51 mmol) was slowly added to the reaction mixture, and the reaction mixture was stirred at -78 °C for 1 h. After the reaction was complete, the reaction mixture was quenched by slowly adding ice water (20 mL), and extracted with ethyl acetate (150 mL). The organic phase was washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–50%) to give compound 12C (980 mg). MS m / z (ESI) = 299.0 [M-55]+ .

[0627] Step 2: Synthesis of compound 12D

[0628] Compound 12C (880 mg, 2.48 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection at -78 °C, lithium bis(trimethylsilylamino)amine (4.96 mL, 4.96 mmol, 1 N tetrahydrofuran solution) was added dropwise and stirred for 0.5 h. Then, a tetrahydrofuran solution of N-fluorobis(benzenesulfonamide) (1.56 g, 4.96 mmol) was added dropwise (15 mL). The reaction mixture was stirred at -78 °C for 1 h. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–50%) to give compound 12D (400 mg). MS m / z (ESI) = 317.1 [M+1–56] + .

[0629] Step 3: Synthesis of compound 12E

[0630] Compound 12D (400 mg, 1.07 mmol) was dissolved in hydrobromic acid (5 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 1.5 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to give compound 12E (300 mg, crude product), which was used directly in the next step. MS m / z (ESI) = 259.0 [M+1] + .

[0631] Step 4: Synthesis of Compound 12

[0632] Compound 12E (300 mg, crude), compound 1A (100 mg, 0.279 mmol), and triethylamine (1 mL) were dissolved in dimethylacetamide (5 mL) at room temperature. The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction solution was purified by preparative high-performance liquid chromatography (HPLC) (column: Welch-Xtimate-C18-7um-30*250nm, 10 μm; mobile phase: acetonitrile-water (10 mM FA / H2O); gradient: 34-44%; column temperature: 25 °C; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 12 (48.0 mg). MS m / z (ESI): 536.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.83(d,J=1.4Hz,1H),8.47(d,J=1.4Hz,1H),8.26(s,1H),8.05(d,J=1.8Hz,1H),7.56–7.41(m ,2H),7.24–7.12(m,1H),6.60(s,1H),3.56(q,J=6.7Hz,1H),2.92–2.58(m,4H),2.07(dd,J=26.6,16.9Hz,4H),1.21(d,J=6.9Hz,3H).

[0633] Example 13 (Compounds 107-P1 and 107-P2)

[0634] Step 1: Synthesis of Compound 107A

[0635] Compound 12C (350 mg, 0.986 mmol) was dissolved in 5 mL of an aqueous solution of 48% hydrobromic acid at room temperature. The reaction mixture was stirred at 90 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was lyophilized to give compound 107A (150 mg, crude product). MS m / z (ESI) = 241.0 [M+1] + .

[0636] Step 2: Synthesis of compound 107, compound 107-P1 and compound 107-P2

[0637] Compound 107A (100 mg, 0.415 mmol), compound 1A (149 mg, 0.415 mmol), and triethylamine (126 mg, 1.25 mmol) were dissolved in anhydrous N,N-dimethylacetamide (4 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 50-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to give compound 107 (14.51 mg). MS m / z (ESI) = 518.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ12.22(s,1H),10.35(s,1H),8.82(d,J=1.2Hz,1H),8.43(s, 1H),8.19(s,1H),7.51–7.43(m,2H),7.19–7.09(m,1H),6.51(s,1H),3.48(t,J=7.2 Hz,1H),3.18–3.10(m,1H),2.91–2.86(m,1H),2.80–2.76(m,1H),2.33–2.26(m,1H) ,1.78–1.74(m,2H),1.58–1.47(m,2H),1.42(d,J=8.0Hz,1H),1.17(d,J=8.0Hz,3H).

[0638] Compound 107 (20 mg) was resolved by SFC (ChiralPak AD column, 250×30 mm, 5 μm; 25×250 mm, 10 μm; mobile phase: methanol [0.1 NH3% (7 M methanol solution)]; gradient: 40%; column temperature: 35 °C; flow rate: 100 mL / min; wavelength: 210 nm; column pressure: 100 bar) to obtain compound 107-P1 (8.65 mg) and compound 107-P2 (8.76 mg).

[0639] Compound 107-P1: MS m / z (ESI) = 518.2 [M+1] + Supercritical fluid chromatography (SFC): retention time = 1.864 min, UV = 214 nm.

[0640] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.82(d,J=1.2Hz,1H),8.44(d,J=1.2Hz,1H ),8.21(s,1H),7.51–7.43(m,2H),7.19–7.17(m,1H),6.44(s,1H),3.49(t,J=7.2H z,1H),3.19–3.13(m,1H),2.92–2.89(m,1H),2.82–2.79(m,1H),2.49–2.43(m,1H ),2.35–2.28(m,1H),1.80–1.77(m,2H),1.60–1.52(m,2H),1.17(d,J=7.2Hz,3H).

[0641] Compound 107-P2: MS m / z (ESI) = 518.2 [M+1] +Supercritical fluid chromatography (SFC): retention time = 2.178 min, UV = 214 nm.

[0642] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.82(d,J=1.2Hz,1H),8.44(d,J=1.2Hz,1H ),8.21(s,1H),7.51–7.43(m,2H),7.19–7.17(m,1H),6.44(s,1H),3.49(t,J=7.2H z,1H),3.19–3.13(m,1H),2.92–2.89(m,1H),2.82–2.79(m,1H),2.49–2.43(m,1H ),2.35–2.28(m,1H),1.80–1.77(m,2H),1.60–1.52(m,2H),1.17(d,J=7.2Hz,3H).

[0643] Example 14 (Compounds 13-P1, 13-P2, 13-P3 and 13-P4)

[0644] Step 1: Synthesis of Components 13B-1 and Components 13B-2

[0645] Compound 1A (337 mg, 0.942 mmol), compound 13A (200 mg, 0.942 mmol) (synthetic method referred to page 32 of patent WO202357429 A1, synthesis of intermediate 4), and triethylamine (953 mg, 9.42 mmol) were dissolved in N,N-dimethylacetamide (4 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (10 mL). It was extracted with dichloromethane (10 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-20%) to obtain fraction 13B-1 (fraction 13B-1 is a pair of compounds 13B-P1 and 13B-P2 or 13B-P3 and 13B-P4) (166 mg) and fraction 13B-2 (fraction 13B-2 is a pair of compounds 13B-P1 and 13B-P2 or 13B-P3 and 13B-P4) (218 mg).

[0646] Component 13B-1: MS m / z (ESI) = 490.2 [M+1] + .

[0647] Component 13B-2: MS m / z (ESI) = 490.2 [M+1] + .

[0648] Step 2: Synthesis of components 13C-1 and 13C-2

[0649] At room temperature, fraction 13B-1 (166 mg, 0.339 mmol) was dissolved in a 4 M hydrochloric acid solution of 1,4-dioxane (4 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give fraction 13C-1 (fraction 13C-1 is a pair of compounds 13C-P1 and 13C-P2 or 13C-P3 and 13C-P4) (146 mg, crude product). MS m / z (ESI) = 390.2 [M+1] +

[0650] At room temperature, fraction 13B-2 (218 mg, 0.445 mmol) was dissolved in a 4 M hydrochloric acid solution of 1,4-dioxane (4 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give fraction 13C-2 (13C-2 is a pair of compounds 13C-P1 and 13C-P2 or 13C-P3 and 13C-P4) (181 mg, crude product). MS m / z (ESI) = 390.2 [M+1] + .

[0651] Step 3: Synthesis of Components 13-1 and Components 13-2

[0652] At room temperature, component 13C-1 (146 mg, 0.375 mmol) and N,N'-dicyclohexylcarbodiimide (154 mg, 0.750 mmol) were dissolved in anhydrous dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 15 minutes. Then, compound 1E (65.1 mg, 0.375 mmol) and 4-dimethylaminopyridine (9.16 mg, 0.0750 mmol) were added to the reaction mixture in sequence. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (15 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mmol NH4HCO3); gradient: 41-95%; column temperature: 25℃; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain fraction 13-1 (fraction 13-1 is a pair of compounds 13-P1 and 13-P2 or 13-P3 and 13-P4) (5.41 mg). MS m / z (ESI) = 545.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),10.73(s,1H),8.82(s,1H),8.47-8.43(m,1H),7.58–7.44(m,3H),7.20-7.16(m,1H),6. 55(s,1H),4.23-4.01(m,1H),3.74-3.70(m,1H),3.08-3.04(m,1H),2.53-2.51(m,2H),1.88-1.55(m,4H),1.27-1.25(m,5H).

[0653] At room temperature, component 13C-2 (181 mg, 0.465 mmol) and N,N'-dicyclohexylcarbodiimide (191 mg, 0.930 mmol) were dissolved in anhydrous dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 15 minutes, and then compound 1E (80.7 mg, 0.465 mmol) and 4-dimethylaminopyridine (11.4 mg, 0.0930 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (15 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (HPLC) (column: ASA-AZZOTA-C18; 30*150 mm, 7 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 37-95%; column temperature: 25℃; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain fraction 13-2 (fraction 13-2 is a pair of compounds 13-P1 and 13-P2 or 13-P3 and 13-P4) (3.80 mg).

[0654] MS m / z(ESI) = 545.2 [M+1] + .

[0655] 1 H NMR(400MHz,DMSO-d6)δ12.09(s,1H),10.73(s,1H),8.82(s,1H),8.49–8.43(m,1H), 7.58–7.42(m,3H),7.23–7.13(m,1H),6.55(s,1H),4.69–4.66(m,1H),4.23–4.19(m, 1H),4.04–3.98(m,1H),3.74–3.70(m,1H),3.06–2.94(m,2H),2.43–2.36(m,1H),2.1 0–2.03(m,1H),1.90–1.81(m,1H),1.72–1.66(m,1H),1.57–1.52(m,1H),1.25(s,3H).

[0656] Example 15 (Compound 23)

[0657] Step 1: Synthesis of Compound 23B

[0658] Compound 23A (1.80 g, 5.78 mmol) (synthesized according to the method described on page 59 of patent WO2020096916 for intermediate B8-C) was dissolved in a 1,4-dioxane solution (4 M, 7.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound 23B (1.90 g, crude product), which was directly used in the next reaction. 1 H NMR (400MHz, CDCl3) δ4.24–4.16(m,2H),3.32–3.27(m,1H),3.26–3.15(m,1H),2.23–1.93(m,2H),1.82–1 .78(m,1H),1.70–1.58(m,2H),1.51-1.49(m,6H)1.34–1.30(m,3H),1.26–1.22(m,1H),1.05–1.02(m,1H).

[0659] Step 2: Synthesis of compound 23D

[0660] Compound 23B (595 mg, 2.82 mmol), compound 23C (470 mg, 3.38 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.61 g, 4.22 mmol), and triethylamine (2.85 g, 28.2 mmol) were dissolved in anhydrous N,N-dimethylacetamide (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (70 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–100%) to give compound 23D (203 mg). MS m / z (ESI) = 333.2 [M+1] + .

[0661] Step 3: Synthesis of compound 23E

[0662] Compound 23D (20 mg, 0.060 mmol) was dissolved in MeOH (1 mL) at room temperature. 1 M lithium hydroxide aqueous solution (0.2 mL, 0.2 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the pH of the reaction mixture was adjusted to 5–6 with 1 M dilute hydrochloric acid, and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 23E (18 mg). MS m / z (ESI) = 305.2 [M+1] + .

[0663] Step 4: Synthesis of Compound 23

[0664] At room temperature, compound 23E (18.0 mg, 0.131 mmol) and compound 23F (synthetic method referred to step 1 on page 38 of patent WO2022073905A1) (20.0 mg, 0.0900 mmol) were dissolved in pyridine (2 mL). The reaction solution was cooled to 0 °C, and phosphorus oxychloride (0.082 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (5 mL × 3), and the combined organic phases were washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 37-95%; column temperature: 25℃; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 23 (0.9 mg). MS m / z (ESI) = 510.2 [M+1] + .

[0665] Example 16 (Compound 197)

[0666] Step 1: Synthesis of Compound 197B

[0667] At room temperature, compound 1E (114 mg, 0.657 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (166 mg, 0.438 mmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (0.217 mL, 1.31 mmol) and compound 197A (100 mg, 0.438 mmol) were added to the reaction mixture (the synthesis method is described on page 28 of patent CN117624194, which describes the synthesis of intermediate M11-7). The reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–25%) to give compound 197B (110 mg). MS m / z (ESI) = 384.2 [M+1] + .

[0668] Step 2: Synthesis of compound 197C

[0669] Compound 197B (100 mg, 0.261 mmol) was dissolved in TFA (3 mL) at room temperature, and the reaction mixture was stirred at 75 °C for 2 hours. After the reaction was complete, the reaction solution was directly concentrated under reduced pressure to obtain compound 197C (70 mg, crude product), which was directly used in the next reaction. MS m / z (ESI) = 266.0 [M+1] + .

[0670] Step 3: Synthesis of Compound 197

[0671] Compound 197C (70 mg, crude), compound 1A (synthetic method according to the synthesis method of intermediate 2 on page 38 of patent WO2022073905A1) (94.4 mg, 0.263 mmol), and triethylamine (26.7 mg, 0.263 mmol) were dissolved in anhydrous N,N-dimethylacetamide (3 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was purified by preparative high performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 50-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 197 (2.88 mg). MS m / z (ESI) = 543.2 [M+1] + .

[0672] Example 17 (Compound 214)

[0673] Step 1: Synthesis of compound 214B

[0674] Compound 214A (5.00 g, 21.9 mmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (50 mL) and chloroform (3.53 mL) at -78 °C. Under a nitrogen atmosphere, a 1 M solution of lithium bis(trimethylsilylamino)nethylene in tetrahydrofuran (43.9 mL, 43.9 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 4 hours and then allowed to rise naturally to room temperature overnight with stirring. After the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–10%) to give compound 214B (4.15 g). MS m / z (ESI) = 263.0 [M-56] + .

[0675] Step 2: Synthesis of compound 214C

[0676] Compound 214B (4.00 g, 12.5 mmol) and 4-bromo-3-hydroxypyridine (2.18 g, 12.5 mmol) were dissolved in methanol (40 mL). DBU (2.86 g, 18.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with water (400 mL), extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–20%) to give compound 214C (300 mg). MS m / z (ESI) = 416.8 [M+1] + .

[0677] Step 3: Synthesis of compound 214D

[0678] Compound 214C (300 mg, 0.722 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at -78 °C. Under a nitrogen atmosphere, a 2.5 M solution of n-butyllithium in tetrahydrofuran (0.578 mL, 1.45 mmol) was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 4 hours. After the reaction was complete, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–20%) to give compound 214D (40.0 mg). MS m / z (ESI) = 305.1 [M+1] + .

[0679] Step 4: Synthesis of compound 214E

[0680] Compound 214D (40.0 mg, 0.125 mmol) was dissolved in dichloromethane (2 mL) at 0 °C. m-chloroperoxybenzoic acid (32.3 mg, 0.187 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated sodium bicarbonate aqueous solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 214E (42.0 mg). MS m / z (ESI) = 321.1 [M+1] + .

[0681] Step 5: Synthesis of compound 214F

[0682] Compound 214E (42.0 mg, 0.125 mmol) was dissolved in 2 mL of 4 M hydrochloric acid containing 1,4-dioxane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was added to 5 mL of ethyl acetate, sonicated, and filtered. The filter cake was collected to give compound 214F (12.0 mg). MS m / z (ESI) = 221.0 [M+1] + .

[0683] Step 6: Synthesis of Compound 214

[0684] Compound 214F (12 mg, 0.054 mmol), compound 1A (32.5 mg, 0.0915 mmol), and triethylamine (27.5 mg, 0.275 mmol) were dissolved in anhydrous N,N-dimethylacetamide (2 mL) at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was purified by preparative high-performance liquid chromatography (HPLC) (column: Agela-Durashell-C18; 25 × 250 mm, 10 μm; mobile phase: acetonitrile-water (10 mmol NH4HCO3); gradient: 50-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 214 (0.58 mg). MS m / z (ESI) = 498.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.83(d,J=1.6Hz,1H),8.61(s,1H),8.46(d,J=1.2Hz,1H),7.98(dd,J=6.4Hz,1.6Hz,1H),7.69(d,J=6.8Hz,1H),7 .54–7.44(m,2H),7.21–7.17(m,1H),3.60(q,J=6.8Hz,1H),2.95–2.92(m,1H ),2.86–2.83(m,1H),2.00–1.89(m,4H),1.78–1.75(m,2H),1.22(d,J=6.8Hz 3H).

[0685] Example 18 (Compound 212)

[0686] Step 1: Synthesis of compound 212B

[0687] Sodium borohydride (1.9 g, 50.225 mmol) was slowly added to ethanol (200 mL) containing compound 212A (10 g, 45.362 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 0.5 hours. After the reaction was complete, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (500 mL × 2), and the combined organic phases were washed with saturated brine (100 mL × 2). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0-4 / 1) to give compound 212B (9.6 g). MS m / z (ESI) = 221.8 [M+1] + .

[0688] Step 2: Synthesis of compound 212C

[0689] At 0 °C, phosphorus tribromide (13.9 g, 51.350 mmol) was slowly added to dichloromethane (300 mL) containing compound 212B (9.6 g, 43.153 mmol). The reaction mixture was allowed to rise naturally to room temperature and stirred overnight. After the reaction was complete, the reaction solution was quenched with water (100 mL), extracted with ethyl acetate (500 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0-5 / 1) to give compound 212C (11.1 g). MS m / z (ESI) = 283.8 [M+1] + .

[0690] Step 3: Synthesis of compound 212E

[0691] Under nitrogen protection at 0°C, sodium hydride (74 mg, 1.850 mmol, purity: 60%) was slowly added to N,N-dimethylformamide (8 mL) containing compound 212D (400 mg, 1.543 mmol). The reaction mixture was stirred at 0°C for 20 minutes. Then, compound 212C (440 mg, 1.542 mmol) was added to the reaction mixture. The reaction mixture was allowed to rise naturally to room temperature and stirred for 3 hours. After the reaction was complete, the reaction mixture was quenched with water (50 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (50 mL × 4). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0-5 / 1) to give compound 212E (300 mg). MS m / z (ESI) = 407.0 [M-55] + .

[0692] Step 4: Synthesis of compound 212F

[0693] Under nitrogen protection at -78°C, a tetrahydrofuran solution of 2.5M n-butyllithium (0.95 mL, 2.375 mmol) was slowly added dropwise to a tetrahydrofuran solution of compound 212E (1 g, 2.156 mmol). The reaction mixture was stirred at -78°C for 3 hours and then allowed to rise naturally to room temperature and stirred overnight. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (50 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: ASA-AZZOTA—C18-7μm-30*150 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-65%; column temperature: 25℃; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 212F (170 mg). MS m / z (ESI) = 353.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ8.63(s,1H),7.77(s,1H),5.03(s,2H),3.87–3.78(m ,2H),3.12–2.98(m,2H),1.95–1.88(m,2H),1.73–1.64(m,2H),1.41(s,9H).

[0694] Step 5: Synthesis of compound 212G

[0695] At room temperature, 10% palladium on carbon (85 mg) was slowly added to a 5 mL ethanol solution of compound 212F (170 mg, 0.482 mmol). The reaction mixture was stirred for 5 hours at room temperature under a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 212G (150 mg). MS m / z (ESI) = 321.0 [M+1] + .

[0696] Step 6: Synthesis of compound 212H

[0697] At room temperature, 200 mg of Desmartin oxidant (0.472 mmol) was slowly added to a 5 mL solution of compound 212G (100 mg, 0.312 mmol) in dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with 5 mL of 10% sodium thiosulfate solution and 5 mL of saturated sodium bicarbonate solution was added. The mixture was then extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0-10 / 1) to give compound 212H (45 mg). MS m / z (ESI) = 319.2 [M+1] + .

[0698] Step 7: Synthesis of compound 212I

[0699] At room temperature, m-chloroperoxybenzoic acid (105 mg, 0.608 mmol) was slowly added to a dichloromethane (4 mL) solution of compound 212H (130 mg, 0.305 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was quenched with 10% sodium thiosulfate solution (2 mL) and the pH was adjusted to 7–8 by adding saturated sodium bicarbonate solution (2 mL). The mixture was extracted with ethyl acetate (100 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0 / 1–10 / 1) to give compound 212I (130 mg). MS m / z (ESI) = 335.1 [M+1] + .

[0700] Step 8: Synthesis of compound 212J

[0701] At room temperature, trifluoroacetic acid (0.3 mL, 3.918 mmol) was added to a solution of compound 212I (75 mg, 0.224 mmol) in dichloromethane (1.5 mL), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give crude compound 212J (60 mg). MS m / z (ESI) = 235.0 [M+1] + .

[0702] Step 9: Synthesis of Compound 212

[0703] Compound 212J (50 mg, 0.149 mmol) was dissolved in anhydrous N,N-dimethylacetamide (2 mL) at room temperature. Triethylamine (75 mg, 0.741 mmol) and compound 1A (80 mg, 0.223 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 90 °C for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (HPLC) (column: Puningtech-Pntulips-C18-10 μm-30*250 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-90%; column temperature: 25 °C; flow rate: 35 mL / min; wavelength: 220 nm / 254; column pressure: 80 bar) to obtain compound 212 (13.62 mg). MS m / z (ESI) = 512.2 [M+1] + .

[0704] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),8.82(d,J=1.2Hz,1H),8.45(d,J=1.2Hz,1H) ,8.34(d,J=2.0Hz,1H),8.21(dd,J=6.4,1.6Hz,1H),7.79(d,J=6.8Hz,1H),7.51–7 .43(m,2H),7.20–7.14(m,1H),4.88(s,2H),3.51(q,J=6.8Hz,1H),2.78–2.72(m,1 H), 2.70–2.61 (m, 2H), 2.47–2.42 (m, 1H), 1.98–1.85 (m, 4H), 1.20 (d, J = 7.2Hz, 3H).

[0705] Example 19 (Compound 224)

[0706] Step 1: Synthesis of compound 224B:

[0707] Compound 224A (450 mg, 1.2 mmol) (synthetic method according to step 3 on page 33 of patent US20250206734A1) was dissolved in dichloromethane (12.5 mL) under ice bath conditions. Triethylamine (0.5 mL, 3.6 mmol) and trifluoromethanesulfonic anhydride (2.5 mL, 14.9 mmol) were added dropwise to the reaction solution. The reaction mixture was naturally heated to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 224B (600 mg). This was used directly in the next reaction. MS m / z (ESI) = 489.0 [M+1] + .

[0708] Step 2: Synthesis of compound 224:

[0709] Compound 224B (27 mg) was dissolved in 1,2-dichloroethane (2 mL) at room temperature. N,N-diisopropylethylamine (21.4 mg, 0.17 mmol) and compound 212J (13.0 mg, 0.05 mmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred overnight at 40 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 25 × 150 mm, 5 μm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 46-76%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm) to obtain compound 224 (0.91 mg). MS m / z (ESI): 573.2 [M+1] + .

[0710] Example 20 (Compound 205)

[0711] Step 1: Synthesis of compound 205A:

[0712] Compound 212G (300 mg, 0.94 mmol) was dissolved in dichloromethane (10 mL). Triethylamine (0.33 mL, 0.94 mmol) and methanesulfonyl chloride (129 mg, 1.12 mmol) were added sequentially under ice bath conditions. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed sequentially with water (20 mL × 2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 205A (350 mg). MS m / z (ESI): 399.2 [M+1] + .

[0713] Step 2: Synthesis of compound 205B:

[0714] Compound 205A (350 mg, 0.88 mmol) was dissolved in methanol (15 mL). Palladium on carbon (100 mg, 10%) was added to the reaction solution, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filter cake was washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 3%-6%) to obtain compound 205B (110 mg). MS m / z (ESI): 305.2 [M+1] + .

[0715] Step 3: Synthesis of compound 205C:

[0716] Compound 205B (100 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (100 mg, 0.49 mmol, 85% purity) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched in saturated sodium thiosulfate solution (30 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed successively with water (30 mL × 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-3%) to give compound 205C (100 mg). MS m / z (ESI): 321.2 [M+1] + .

[0717] Step 4: Synthesis of compound 205D:

[0718] Compound 205C (90.0 mg, 0.24 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (149 mg, 1.31 mmol) was slowly added under ice bath conditions. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give compound 205D (60.0 mg, crude product). The crude product was used directly in the next step without purification. MS m / z (ESI): 221.1 [M+1] + .

[0719] Step 5: Synthesis of compound 205:

[0720] Compound 205D (50.0 mg, 0.23 mmol) was dissolved in N,N-dimethylacetamide (5 mL) at room temperature, followed by the sequential addition of triethylamine (115 mg, 1.14 mmol) and compound 1A (89.4 mg, 0.25 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and purified by preparative high-performance liquid chromatography (HPLC) (column: YMC-Triart-C18; 30 × 150 mm, 7 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 10–16%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 60 bar) to obtain compound 205 (5.0 mg). MS m / z (ESI): 498.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.82(s,1H),8.46–8.42(m,1H),8.03(s,1H),8.00(d,J=6.8Hz,1H),7.53–7.41(m,2H),7.21 –7.12(m,2H),4.62(s,2H),3.49(q,J=6.7Hz,1H),2.64–2.53(m,6H),1.78–1.67(m,2H),1.67–1.52(m,2H),1.19(d,J=6.8Hz,3H).

[0721] Example 21 (Compound 229)

[0722] Compound 212J (29.5 mg, 0.13 mmol) was dissolved in N,N-dimethylacetamide (1 mL) at room temperature. Triethylamine (25.5 mg, 0.13 mmol) and compound 229A (30 mg, 0.09 mmol) were added sequentially to the reaction mixture (synthetic method follows the method for intermediate B-6-a on page 141 of patent WO202566935A1). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 25 × 150 mm, 5 μm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 45-75%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm) to obtain compound 229 (4.09 mg). MS m / z (ESI): 511.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.34(s,1H),8.21(d,J=6.8Hz,1H),8. 18–8.08(m,2H),7.79(d,J=6.8Hz,1H),7.54–7.45(m,2H),7.35–7.25(m,1H), 7.16–7.09(m,1H),4.88(s,2H),3.48(d,J=7.1Hz,1H),2.82–2.70(m,1H),2. 71–2.60(m,2H),2.47–2.41(m,1H),2.02–1.79(m,4H),1.20(d,J=6.8Hz,3H).

[0723] Example 22 (Compound 320)

[0724] Step 1: Synthesis of compound 320C:

[0725] Compound 320A (5.00 g, 12.5 mmol) was dissolved in N,N-dimethylformamide (50 mL) at room temperature. Cesium carbonate (12.3 g, 37.7 mmol) and compound 320B (2.63 g, 15.1 mmol) were added to the reaction solution, and the reaction mixture was stirred at 70 °C for 4 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (20 mL). It was extracted with ethyl acetate (20 mL × 2), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA / PE = 0%–40%) to give compound 320C (2.50 g). MS m / z (ESI): 389.0 [M+1-56] + .

[0726] Step 2: Synthesis of compound 320D:

[0727] Compound 320C (2.25 g, 5.07 mmol) was dissolved in THF (60 mL) under nitrogen protection at -78 °C. 1.6 M n-butyllithium (4.44 mL, 7.10 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at -78 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with saturated ammonium chloride solution (200 mL) and stirred for 30 minutes. The mixture was extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (EA / PE = 0%–50%) to give compound 320D (200 mg). MS m / z (ESI): 319.1 [M+1] + .

[0728] Step 3: Synthesis of compound 320E:

[0729] Compound 320D (300 mg, 0.942 mmol) was dissolved in dichloromethane (6 mL) at 0 °C. M-chloroperoxybenzoic acid (573 mg, 2.82 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane (10 mL), washed with saturated sodium carbonate solution (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 320E (250 mg). MS m / z (ESI) = 335.1 [M+1] + .

[0730] Step 4: Synthesis of compound 320F:

[0731] Compound 320E (250 mg, 0.748 mmol) was dissolved in dichloromethane (0.8 mL) at room temperature. Trifluoroacetic acid (0.2 mL) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 0.5 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium carbonate aqueous solution (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residual silica was purified by column chromatography (ethyl acetate / petroleum ether = 0%–80%) to give compound 320F (140 mg). MS m / z (ESI) = 235.0 [M+1] + .

[0732] Step 5: Synthesis of Compound 320:

[0733] Triethylamine (0.039 mL, 0.279 mmol) was added to a solution of compound 224B (68.0 mg, 0.139 mmol) and compound 320F (32.6 mg, 0.139 mmol) in dichloromethane (0.2 mL) at 0 °C. The reaction mixture was stirred overnight at 40 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex-Luna-C18-10 μm-25*150 mm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 10-95%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to give compound 320 (15.5 mg). LCMS m / z (ESI) = 573.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.35(s,1H),9.19(d,J=2.8Hz,1H),8.21(d,J=1.6Hz,1H),8.03(s,1H),7.93-7.83(m,2H),7.66-7.52(m,3 H),7.33-7.18(m,1H),4.99-4.92(m,1H),4.37(s,2H),2.99-2.80(m,2H),2.72-2.59(m,2H),1.89-1.72(m,2H),1.63-1.49(m,2H).

[0734] Example 23 (Compound 328)

[0735] Step 1: Synthesis of compound 328C:

[0736] Compounds 328A (25.0 g, 96.8 mmol) and 328B (21.5 g, 106 mmol) were dissolved in N,N-dimethylformamide (300 mL) at room temperature. 1-Butylphosphine anhydride (139 g, 194 mmol) and triethylamine (53.8 mL, 387 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed sequentially with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–3%) to give compound 328C (27.6 g). MS m / z (ESI) = 342.0 [M⁻¹⁰⁰⁺¹] + .

[0737] Step 2: Synthesis of compound 328D:

[0738] Compound 328C (20.9 g, 47.3 mmol) was dissolved in tetrahydrofuran (210 mL) at room temperature. Sodium hydride (2.84 g, 70.9 mmol, 60%) was slowly added in portions under ice bath conditions. The reaction mixture was stirred at 0 °C for 0.5 h. Iodomethane (7.35 mL, 118 mmol) was added to the reaction mixture, and the reaction mixture was brought to room temperature and stirred for 2 h. After the reaction was complete, the reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed successively with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–70%) to give compound 328D (11.9 g). MS m / z (ESI) = 400.0 [M-56+1] + .

[0739] Step 3: Synthesis of compound 328E:

[0740] Compound 328D (2.90 g, 6.36 mmol) was dissolved in tetrahydrofuran (90 mL) at room temperature. 2.5 M n-butyllithium (2.92 mL, 7.31 mmol) was slowly added dropwise to the reaction mixture at -78 °C. The reaction mixture was stirred at -78 °C under a nitrogen atmosphere for 2 hours. After the reaction was complete, the reaction mixture was quenched in saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed successively with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0%–30%) to give compound 328E (250 mg). MS m / z (ESI) = 346.2 [M+1] + .

[0741] Step 4: Synthesis of compound 328F:

[0742] Compound 328E (620 mg, 1.80 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Under ice bath conditions, m-chloroperoxybenzoic acid (729 mg, 3.59 mmol) was added in portions to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted in dichloromethane (100 mL), quenched with saturated sodium thiosulfate solution (50 mL), and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed successively with water (40 mL × 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 50%–100%) to give compound 328F (280 mg). MS m / z (ESI) = 362.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=1.6Hz,1H),8.51(dd,J=2.0,6.8Hz,1H),7.89(d,J=6.8Hz,1H),3 .83(d,J=12.8Hz,2H),3.1-3.3(m,2H),3.08(s,3H),2.0-2.2(m,2H),1.9-2.0(m,2H),1.44(s,9H).

[0743] Step 5: Synthesis of compound 328G:

[0744] Compound 328F (260 mg, 0.72 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Trifluoroacetic acid (1.50 mL, 19.6 mmol) was added under ice bath conditions, and the reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex-Luna-C18; 25 × 150 mm, 10 μm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 5-35%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 60 bar) to obtain compound 328G (150 mg). MS m / z (ESI): 262.1 [M+1] + .

[0745] Step 6: Synthesis of Compound 328:

[0746] At room temperature, compound 224B (100 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), followed by the addition of triethylamine (0.06 mL, 0.41 mmol) and compound 328G (64.2 mg, 0.25 mmol). The reaction mixture was stirred overnight at 40 °C. After the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed successively with water (10 mL × 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (HPLC) (column: ASA-AZZOTA-C18; 30×250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 54-64%; column temperature: 25℃; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 60 bar) to give compound 328 (21.2 mg). MS m / z (ESI): 600.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.37 (s, 1H), 9.21 (d, J = 2.8Hz, 1H), 8.48 (d, J = 1.6Hz, 1 H),8.41(dd,J=1.6,6.4Hz,1H),8.07(s,1H),7.91(d,J=2.4Hz,1H),7.73(d,J=6 .8Hz,1H),7.7-7.5(m,2H),7.3-7.2(m,1H),5.05-4.99(m,1H),3.3-3.2(m,1H), 3.2-3.1(m,2H),3.08(s,3H),3.0-2.9(m,1H),2.3-2.1(m,2H),2.0-1.8(m,2H).

[0747] Example 24 (Compound 342)

[0748] Step 1: Synthesis of compound 342B:

[0749] At 0 °C, thionyl chloride (31.7 mL, 437.5 mmol) was added dropwise to methanol (150 mL) and stirred for 15 minutes. Then, compound 342A (15 g, 109.4 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was quenched with saturated sodium bicarbonate solution (200 mL). The residue was extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 342B (14 g, crude product). MS m / z (ESI): 152.1 [M+1]+ . 1 H NMR (400MHz, DMSO-d6) δ8.91 (s, 1H), 8.58 (d, J = 4.8Hz, 1H), 7.38 (d, J = 4.8Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H).

[0750] Step 2: Synthesis of compound 342C:

[0751] Compound 342B (5 g, 33.0 mmol) was dissolved in tetrahydrofuran (80 mL) at 0 °C. A solution of 3M methylmagnesium bromide (33.1 mL, 99.2 mmol) in tetrahydrofuran was slowly added dropwise to the reaction mixture. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the reaction mixture was quenched with methanol (40 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30%–40%) to give compound 342C (4.8 g). MS m / z (ESI) = 152.1 [M+1] + .

[0752] Step 3: Synthesis of compound 342E:

[0753] Compound 342C (4.8 g, 31.7 mmol) was dissolved in tetrahydrofuran (80 mL) at -78 °C. A 2.5 M solution of n-butyllithium (27.9 mL, 69.8 mmol) in tetrahydrofuran was slowly added dropwise to the reaction mixture while stirring for 1 hour. Then, compound 342D (1.52 mL, 31.7 mmol) was added to the reaction mixture. The reaction mixture was then brought to room temperature and stirred for 2 hours. After the reaction was complete, the reaction mixture was quenched with methanol (40 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1%–10%) to give compound 342E (3.8 g). MS m / z (ESI): 341.2 [M+1] + .

[0754] Step 4: Synthesis of compound 342F:

[0755] Compound 342E (3 g, 8.81 mmol) was dissolved in toluene (30 mL) at room temperature. Phosphoric acid (6.09 g, 52.9 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at 100 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 342F (2.4 g, crude product). MS m / z (ESI): 323.2 [M+1] + .

[0756] Step 5: Synthesis of compound 342H:

[0757] Compound 342F (1.1 g, 3.41 mmol) and triethylamine (1.42 mL, 10.2 mmol) were dissolved in toluene (11 mL) at 0 °C. Compound 342G (2.44 g, 17.1 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 100 °C for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL) and stirred at 70 °C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The mixture was extracted with ethyl acetate (200 mL × 2), and the aqueous phase was concentrated under reduced pressure to give compound 342H (1.5 g, crude product). MS m / z (ESI): 233.1 [M+1] + .

[0758] Step 6: Synthesis of compound 342I:

[0759] Compound 342H (1.5 g, 6.46 mmol) was dissolved in methanol (10 mL) at 0 °C. Boc anhydride (1.41 g, 6.46 mmol) was added to the reaction solution, and the reaction mixture was stirred at 70 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (200 mL). It was extracted with dichloromethane (200 mL × 2), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 30%–50%) to give compound 342I (800 mg). MS m / z (ESI): 333.2 [M+1] + .

[0760] Step 7: Synthesis of compound 342J:

[0761] Compound 342I (800 mg, 2.41 mmol) and selenium dioxide (801 mg, 7.219 mmol) were dissolved in 1,4-dioxane (8 mL) at room temperature. The reaction mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (50 mL). It was extracted with dichloromethane (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 342J (330 mg, crude product). MS m / z (ESI): 347.2 [M+1] + .

[0762] Step 8: Synthesis of compound 342K:

[0763] Compound 342J (250 mg, 0.722 mmol) was dissolved in dichloromethane (2 mL) at room temperature. m-chloroperoxybenzoic acid (161 mg, 0.794 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with water (50 mL), extracted with dichloromethane (50 mL × 2), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 342K (210 mg, crude product). MS m / z (ESI): 363.3 [M+1] + .

[0764] Step 9: Synthesis of compound 342L:

[0765] Compound 342K (80 mg, 0.221 mmol) was dissolved in dichloromethane (1 mL) at room temperature. Trifluoroacetic acid (0.4 mL, 5.224 mmol) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was adjusted to a weakly alkaline pH by adding saturated sodium bicarbonate solution, then diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 342L (50 mg, crude product). MS m / z (ESI): 263.1 [M+1] + .

[0766] Step 10: Synthesis of Compound 342:

[0767] Compound 342L (70 mg, 0.267 mmol) and compound 224B (130 mg, 0.267 mmol) were dissolved in dichloromethane (1 mL) at room temperature. Triethylamine (0.074 mL, 0.534 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was diluted with water (40 mL), extracted with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Nouryon-Kromasil-C18-10 μm-25 × 150 mm; mobile phase: acetonitrile-water (0.1% FA); gradient: 62-72%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to obtain compound 342 (5.8 mg). MS m / z(ESI): 601.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ9.37 (s, 1H), 9.20 (d, J = 3.0Hz, 1H), 8.52 (d, J = 1.6Hz, 1H),8.20(dd,J=1.6,6.8Hz,1H),8.06(s,1H),7.90(d,J=3.0Hz,1H),7.73(d, J=6.8Hz,1H),7.67-7.55(m,2H),7.30-7.23(m,1H),5.04-4.92(m,1H),3.00- 2.85(m,4H),1.95-1.86(m,2H),1.83-1.72(m,2H),1.52(s,3H),1.48(s,3H).

[0768] Example 25 (Compound 319)

[0769] At room temperature, compound 229A (59.9 mg, 0.168 mmol) (synthetic method referred to the synthesis method of intermediate B-6-a on page 141 of patent WO202566935A1) and triethylamine (0.085 mL, 0.610 mmol) were dissolved in N,N-dimethylacetamide (0.5 mL), and compound 342L (40 mg, 0.152 mmol) was added to the above reaction solution. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (40 mL). It was extracted with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Nouryon-Kromasil-C18-10 μm-25 × 150 mm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 36-66%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm; column pressure: 80 bar) to give compound 319. MS m / z (ESI): 539.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.14(s,1H),8.58(d,J=1.6Hz,1H),8.23(dd,J=1.6,6.8Hz, 1H),8.15(d,J=2.8Hz,1H),8.13-8.09(m,1H),7.78(d,J=6.8Hz,1H),7.55-7.47(m,2H ),7.30(m,1H),7.12(m,1H),3.44(q,J=6.8Hz,1H),2.75-2.66(m,2H),2.62(m,2H),1 .99-1.89(m,2H),1.87-1.79(m,2H),1.62(s,3H),1.60(s,3H),1.20(d,J=6.8Hz,3H).

[0770] Example 26 (Compound 273)

[0771] Step 1: Synthesis of compound 205D:

[0772] Compound 205C (420 mg, 1.311 mmol) was dissolved in dichloromethane (4 mL) at room temperature. Trifluoroacetic acid (3 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) (column: Xbridge-C18; 19 × 150 mm, 5 μm; mobile phase: acetonitrile-water (10 mmol ammonium bicarbonate); gradient: 10-20%; column temperature: 25 °C; flow rate: 30 mL / min; wavelength: 220 nm) to obtain compound 205D (250 mg). MS m / z (ESI): 221.1 [M+1] + .

[0773] Step 2: Synthesis of Compound 273:

[0774] Compound 224B (100 mg, 0.205 mmol) was dissolved in dichloromethane (2 mL) at room temperature. Triethylamine (0.06 mL, 0.41 mmol) and compound 205D (45.11 mg, 0.205 mmol) were added sequentially to the reaction mixture, which was stirred overnight at 40 °C. After the reaction was complete, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 15 / 1) to give compound 273 (2.0 mg). MS m / z (ESI): 559.2 [M+1] + .

[0775] Example 27 (Compound 347)

[0776] Compound 205D (50 mg, 0.227 mmol) was dissolved in N,N-dimethylacetamide (1 mL) at room temperature. Triethylamine (0.13 mL, 0.91 mmol) and compound 229A (81.07 mg, 0.227 mmol) were added sequentially to the reaction mixture, which was stirred overnight at 60 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (10 mL). It was extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (20 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 347 (12.3 mg). MS m / z (ESI): 497.2. [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ10.15(s,1H),8.20-8.11(m,2H),8.08-7.99(m,2H),7.56-7.48(m,2H),7.36-7.27(m,1H),7.24-7.18(m,1H),7.17 -7.10(m,1H),4.64(s,2H),3.56-3.45(m,1H),2.79-2.61(m,4H),2.56 -2.55(m,1H),1.85-1.72(m,2H),1.70-1.52(m,2H),1.34-1.14(m,4H).

[0777] Example 28 (Compound 273, Compound 273-P1 and Compound 273-P2)

[0778] Step 1: Synthesis of compound 224B:

[0779] Compound 224A (45.0 g, 126 mmol) and triethylamine (35.0 mL, 253 mmol) were dissolved in dichloromethane (1 L). Trifluoromethanesulfonic anhydride (31.9 mL, 189 mmol) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered through silica gel, and the filter cake was washed with dichloromethane (800 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–5%) to give compound 224B (49.5 g). MS m / z (ESI): 489.0 [M+1] + .1 H NMR(400MHz, CDCl3) δ9.16(d,J=0.6Hz,1H),9.12(d,J=2.9Hz,1H),8.24(s,1H), 7.43–7.40(m,1H),7.31–7.23(m,1H),7.12–6.98(m,2H),6.21(q,J=5.8Hz,1H).

[0780] Step 2: Synthesis of compound 273B:

[0781] Compound 273A (10.0 g, 58.1 mmol) was dissolved in tetrahydrofuran (100 mL) at -78 °C. A 2 mol / L solution of diisopropylaminolithium in tetrahydrofuran (34.8 mL, 69.6 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 0.5 h. Then, a tetrahydrofuran solution of compound 214A (13.9 g, 69.8 mmol) was added to the reaction mixture, and the reaction mixture was stirred at -78 °C for 2 h. After the reaction was complete, the reaction mixture was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–10%) to give compound 273B (15.8 g). MS m / z (ESI): 371.2 [M+1] + .

[0782] Step 3: Synthesis of compound 273C:

[0783] Compound 273B (14.0 g, 37.7 mmol) was dissolved in tetrahydrofuran (20 mL) at -78 °C. A 2.5 mol / L tetrahydrofuran solution of n-butyllithium (30.2 mL, 75.4 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at -78 °C for 0.5 h. Then, N,N-dimethylformamide (58.6 mL, 754.2 mmol) was added dropwise to the reaction mixture, and the mixture was stirred at -78 °C for 1 h. After the reaction was complete, the reaction mixture was quenched with water (300 mL), extracted with ethyl acetate (150 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was added to a mixed solvent of petroleum ether (30 mL) and ethyl acetate (90 mL) and stirred overnight. The residue was filtered, and the filter cake was dried under vacuum to give compound 273C (5.5 g). MS m / z (ESI): 321.2 [M+1] + .

[0784] Step 4: Synthesis of compound 273D:

[0785] Compound 273C (5.5 g, 17.2 mmol) was dissolved in methanol (80 mL) under ice bath conditions. Sodium borohydride (3.25 g, 85.8 mmol) was added to the reaction solution in portions, and the reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, the reaction solution was quenched with water (300 mL), extracted with dichloromethane (300 mL × 2), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 273D (5.3 g). MS m / z (ESI): 323.2 [M+1] + .

[0786] Step 5: Synthesis of compound 205B:

[0787] Compound 273D (2.0 g, 6.2 mmol) was dissolved in toluene (20 mL) at room temperature. N,N-diisopropylethylamine (800.0 mg, 6.2 mmol) and cyanomethylenetri-n-butylphosphine (3.0 g, 12.4 mmol, CAS: 157141-27-0) were added sequentially to the reaction mixture. The reaction mixture was stirred overnight at 110 °C under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated ammonium chloride solution (40 mL), and extracted with ethyl acetate (35 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a 4 / 1 solution of petroleum ether / ethyl acetate (40 mL) and washed with 20 mL of saturated citric acid solution (20 mL × 2). The combined aqueous phases were then washed with a 3 / 1 solution of petroleum ether / ethyl acetate (30 mL). The pH of the aqueous phase was adjusted to weakly alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL), and the resulting ethyl acetate phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (tetrahydrofuran / dichloromethane = 0%–10%) to give compound 205B (1.47 g). MS m / z (ESI): 305.2 [M+1] + .

[0788] Step 6: Synthesis of compound 205C:

[0789] Compound 205B (1.47 g, 4.82 mmol) was dissolved in dichloromethane (20 mL) under ice bath conditions. m-chloroperoxybenzoic acid (4.90 g, 24.1 mmol) was added in portions to the reaction mixture, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, sodium thiosulfate (100 mL) was added to quench the reaction mixture, and the mixture was stirred for 10 minutes. The pH was then adjusted to weakly alkaline by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (60 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 205C (1.10 g, crude product). The crude product was used directly in the next step without purification. MS m / z (ESI): 321.2 [M+1] + .

[0790] Step 7: Synthesis of compound 205D:

[0791] Compound 205C (800 mg, 2.50 mmol) was dissolved in ethyl acetate (10 mL) at room temperature. A solution of ethyl acetate containing hydrochloric acid (4 M, 1.87 mL, 7.48 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was filtered, and the filter cake was dried under vacuum to obtain the hydrochloride salt of compound 205D (453.0 mg). 1 H NMR (400MHz, DMSO-d6) δ9.24(brs,2H),8.72(d,J=2.1Hz,1H),8.62(dd,J=6.6,2.1Hz,1H),7.67(d ,J=6.6Hz,1H),4.82(s,2H),3.16–3.06(m,2H),3.06–2.93(m,2H),2.89(s,2H),1.93–1.77(m,4H).

[0792] Step 8: Synthesis of compound 273, compound 273-P1 and compound 273-P2:

[0793] Compound 224B (1.08 g, 4.92 mmol) was dissolved in acetonitrile (50 mL) at room temperature. Triethylamine (0.91 mL, 6.55 mmol) and the hydrochloride salt of compound 205D (1.60 g, 3.28 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred overnight at 70 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (200 mL), and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed sequentially with water (100 mL × 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) (column: Waters-Xbridge-C18; 19×250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-60%; column temperature: 25℃; flow rate: 20 mL / min; wavelength: 254 nm; column pressure: 60 bar) to give compound 273 (175.7 mg). MS m / z (ESI): 559.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.19 (d, J = 2.8Hz, 1H), 8.03 (s, 1H), 7.9 9–7.93(m,2H),7.89(d,J=2.4Hz,1H),7.66–7.53(m,2H),7.29–7.23(m,1H), 7.14(d,J=6.4Hz,1H),4.96(q,J=9.2Hz,1H),4.53–4.43(m,2H),2.90–2.83( m,1H),2.83–2.73(m,2H),2.53(s,2H),2.38–2.30(m,1H),1.73–1.52(m,4H).

[0794] Compound 273 (175 mg) was resolved by supercritical fluid chiral chromatography (equipment: Waters-SFC-150, column: ChiralPak AS, 250×25 mm, 10 μm; mobile phase: methanol [0.2% NH3 (7M methanol solution)]; gradient: 40%; column temperature: 40 °C; flow rate: 120 mL / min; wavelength: 214 nm; column pressure: 100 bar) to obtain compounds 273-P1 (63.5 mg) and 273-P2 (57.0 mg).

[0795] Compound 273-P1:

[0796] MS m / z(ESI) = 559.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 1.708 min, UV = 214 nm.

[0797] 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.19 (d, J = 3.2Hz, 1H), 8.03 (s, 1H), 7.9 9–7.93(m,2H),7.89(d,J=2.4Hz,1H),7.66–7.53(m,2H),7.29–7.23(m,1H), 7.14(d,J=6.4Hz,1H),4.96(q,J=9.2Hz,1H),4.53–4.43(m,2H),2.90–2.83( m,1H),2.83–2.73(m,2H),2.53(s,2H),2.38–2.30(m,1H),1.73–1.52(m,4H).

[0798] Compound 273-P2:

[0799] MS m / z(ESI) = 559.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.465 min, UV = 214 nm.

[0800] 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.19 (d, J = 2.8Hz, 1H), 8.03 (s, 1H), 7.9 9–7.93(m,2H),7.89(d,J=2.4Hz,1H),7.66–7.53(m,2H),7.30–7.23(m,1H), 7.14(d,J=6.4Hz,1H),4.96(q,J=8.8Hz,1H),4.54–4.41(m,2H),2.91–2.83( m,1H),2.83–2.73(m,2H),2.53(s,2H),2.36–2.30(m,1H),1.73–1.51(m,4H).

[0801] Example 29 (Compound 205-P1 and Compound 205-P2)

[0802] The scaled-up batch of compound 205 (550 mg) was purified by supercritical fluid chiral chromatography (equipment: Waters_SFC150; column: ChiralPak AS25×250mm, 10µm; column temperature: 35℃; mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH): ACN=40 / 60; flow rate: 100 mL / min; column pressure: 100 bar; wavelength: 262 nm; cycle time: 12 min; sample solution: 550 mg dissolved in 16 mL methanol / dichloromethane; injection volume: 4 mL) to obtain compounds 205-P1 (233.8 mg) and 205-P2 (225.2 mg).

[0803] Compound 205-P1:

[0804] MS m / z(ESI) = 498.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.349 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.82(d,J=1.5Hz,1H),8.44(d,J=1.5Hz,1H),8.03(s,1H),8.00(dd,J=6.6,2.1Hz,1H),7.54–7.40(m, 2H),7.22–7.12(m,2H),4.62(s,2H),3.49(q,J=7.0Hz,1H),2.66–2.51(m,6H),1.78–1.67(m,2H),1.67–1.52(m,2H),1.19(d,J=6.9Hz,3H).

[0805] Compound 205-P2:

[0806] MS m / z(ESI) = 498.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 3.057 min, UV = 214 nm. 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.82(d,J=1.5Hz,1H),8.44(d,J=1.5Hz,1H),8.03(s,1H),8.00(dd,J=6.5,2.0Hz,1H),7.53–7.40(m, 2H),7.22–7.12(m,2H),4.62(s,2H),3.49(q,J=7.0Hz,1H),2.66–2.51(m,6H),1.78–1.67(m,2H),1.67–1.51(m,2H),1.19(d,J=7.0Hz,3H).

[0807] Example 30 (Compound 364, Compound 364-P1 and Compound 364-P2)

[0808] Step 1: Synthesis of Compound 364B

[0809] Compound 364A (1.00 g, 5.08 mmol) was dissolved in tetrahydrofuran (20 mL) at 0 °C. Sodium hydride (0.22 g, 5.58 mmol, purity: 60%) was added to the reaction solution, and the reaction mixture was stirred at 0 °C for 30 min. Then, benzenesulfonyl chloride (1.08 g, 6.09 mmol) was added to the reaction solution, and the reaction mixture was allowed to rise naturally to room temperature and stirred for 1 h. After the reaction was complete, the reaction mixture was quenched with water (20 mL), extracted with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (25 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 15%–20%) to give compound 364B (1.40 g). MS m / z (ESI): 336.9 [M+1] + . 1 H NMR(400MHz, DMSO-d6)δ8.32–8.28(m,1H),8.25(d,J=3.6Hz,1H),8.09–8.04(m,2H),7. 79–7.73(m,1H),7.67–7.62(m,2H),7.57(d,J=8.8Hz,1H),7.00(dd,J=3.6,0.8Hz,1H).

[0810] Step 2: Synthesis of compound 364C

[0811] Compound 364B (1.45 g, 4.30 mmol) was dissolved in 1,4-dioxane (30 mL) at room temperature. Tert-butyl carbamate (0.76 g, 6.45 mmol), methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (0.39 g, 0.43 mmol, CAS: 1470372-59-8), and cesium carbonate (4.20 g, 12.90 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 100 °C for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 15%–20%) to give compound 364C (1.58 g). MS m / z (ESI): 374.1 [M+1] + .

[0812] Step 3: Synthesis of compound 364D

[0813] Compound 364C (1.58 g, 4.23 mmol) was dissolved in a mixed solvent of tetrahydrofuran (10 mL), methanol (6 mL), and water (6 mL) at room temperature. Sodium hydroxide (0.34 g, 8.46 mmol) was added to the reaction solution, and the reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (30 mL). It was extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 25%–30%) to give compound 364D (0.70 g). MS m / z (ESI): 234.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.35(s,1H),7.73(d,J=8.8Hz,1H),7.59–7.53(m,2H),6.42–6.34(m,1H),1.49(s,9H).

[0814] Step 4: Synthesis of compound 364E

[0815] Compound 364D (0.70 g, 3.00 mmol) was dissolved in 1,4-dioxane (20 mL) at room temperature. Cuprous iodide (0.17 g, 0.90 mmol), N,N-dimethylglycine (90.0 mg, 0.90 mmol), 2,4-difluoroiodobenzene (0.72 g, 3.00 mmol), and cesium carbonate (1.96 g, 6.00 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 15%–20%) to give compound 364E (110.0 mg). MS m / z (ESI): 346.1 [M+1] + .

[0816] Step 5: Synthesis of compound 364F

[0817] Compound 364E (92.0 mg, 0.27 mmol) was dissolved in dichloromethane (4 mL) at 0 °C. Trifluoroacetic acid (607.5 mg, 5.33 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved by adding dichloromethane (5 mL) and water (5 mL), and then the pH was adjusted to alkaline by adding saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (15 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give compound 364F (59.0 mg). MS m / z (ESI): 246.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ7.69–7.56(m,2H),7.53–7.48(m,1H),7.34–7.26(m,2H),6.44–6.38(m,2H),5.59(s,2H).

[0818] Step 6: Synthesis of Compound 364G

[0819] Compound 364F (43.0 mg, 0.18 mmol) was dissolved in dichloromethane (3 mL) at 0 °C. N,N'-dicyclohexylcarbodiimide (54.3 mg, 0.26 mmol, CAS: 538-75-0), 2-bromopropionic acid (40.2 mg, 0.26 mmol), and silver nitrate (6.0 mg, 0.035 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (20 mL), extracted with dichloromethane (10 mL × 3), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–20%) to give compound 364G (53.0 mg). MS m / z (ESI): 380.0 [M+1] + .

[0820] Step 7: Synthesis of Compound 364, Compound 364-P1 and Compound 364-P2

[0821] Compound 205B (135.6 mg, 0.62 mmol) was dissolved in N,N-dimethylacetamide (6 mL) at room temperature. Compound 364G (180.0 mg, 0.47 mmol) and triethylamine (0.20 mL, 1.42 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred at 70 °C for 1 hour. After the reaction was complete, the reaction mixture was cooled to room temperature and diluted with water (30 mL). It was extracted with ethyl acetate (45 mL × 2). The combined organic phases were washed sequentially with water (30 mL × 2) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–8%) to give compound 364 (141 mg). MS m / z (ESI) = 520.2 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 8.06-8.02 (m, 2H), 8.01 (dd, J = 6.4, 1.6Hz, 1H), 7.83 (dd,J=3.2,0.4Hz,1H),7.77-7.71(m,1H),7.71-7.67(m,1H),7.65-7.60(m,1H),7.36-7.30 (m,1H),7.19(d,J=6.8Hz,1H),6.72(d,J=2.8Hz,1H),4.63(s,2H),3.45(q,J=6.4Hz,1H),2 .65(s,2H),2.63-2.52(m,4H),1.81-1.71(m,2H),1.71-1.59(m,2H),1.21(d,J=7.2Hz,3H).

[0822] Compound 364 (130 mg) was purified by supercritical fluid chiral chromatography (equipment: WATERS 150 preparative SFC (SFC-01); column: Chiral Pak AS, 250 × 25 mm ID, 5 μm; column temperature: 35 °C; mobile phase: CO2 / MeOH [(0.2% NH3 (7 M in MeOH)]: ACN = 55 / 45; flow rate: 100 mL / min; column pressure: 100 bar; wavelength: 255 nm; cycle time: 17 min; sample solution: 130 mg dissolved in 6 mL methanol; injection volume: 5 mL) to obtain compounds 364-P1 (45.1 mg) and 364-P2 (42.9 mg).

[0823] Compound 364-P1:

[0824] MS m / z(ESI) = 520.2[M+1] + Supercritical fluid chromatography (SFC): retention time = 1.805 min, UV = 214 nm. 1H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 8.07-8.02 (m, 2H), 8.01 (dd, J = 6.4, 1.6Hz, 1H), 7.83 (dd,J=3.2,0.4Hz,1H),7.77-7.71(m,1H),7.71-7.67(m,1H),7.67-7.60(m,1H),7.37-7.29 (m,1H),7.19(d,J=6.4Hz,1H),6.72(d,J=3.2Hz,1H),4.63(s,2H),3.45(q,J=6.8Hz,1H),2 .65(s,2H),2.63-2.51(m,4H),1.80-1.72(m,2H),1.72-1.59(m,2H),1.21(d,J=6.8Hz,3H).

[0825] Compound 364-P2:

[0826] MS m / z(ESI) = 520.2[M+1] + Supercritical fluid chromatography (SFC): retention time = 2.387 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 8.06-8.02 (m, 2H), 8.00 (dd, J = 6.4, 1.2Hz, 1H), 7.83 (dd,J=3.2,0.4Hz,1H),7.77-7.71(m,1H),7.71-7.67(m,1H),7.67-7.60(m,1H),7.37-7.30 (m,1H),7.19(d,J=6.8Hz,1H),6.72(d,J=3.2Hz,1H),4.63(s,2H),3.45(q,J=6.8Hz,1H),2 .65(s,2H),2.64-2.52(m,4H),1.80-1.72(m,2H),1.72-1.59(m,2H),1.21(d,J=6.8Hz,3H).

[0827] Example 31 (Compounds 347-P1 and 347-P2)

[0828] The amplified batch of compound 347 (67 mg, 0.135 mmol) was purified by supercritical fluid chiral chromatography (equipment: SFC-150 (Waters); column: AS25*250 mm, 10 μm (Daicel); column temperature: room temperature; mobile phase: CO2 / MeOH [(0.2% NH3 (7 M in MeOH)]: ACN = 65 / 35; flow rate: 100 mL / min; column pressure: 100 bar; wavelength: 214 nm; cycle time: 10.67 min; sample solution: 60 mg dissolved in 25 mL methanol / dichloromethane; injection volume: 4 mL) to obtain compounds 347-P1 (20.1 mg) and 347-P2 (20.31 mg).

[0829] Compound 347-P1:

[0830] MS m / z(ESI): 497.1 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.873 min, UV = 214 nm. 1 H NMR (400MHz, DMSO-d6) δ = 10.15 (s, 1H), 8.20-8.08 (m, 2H), 8.07-7.98 (m, 2H), 7.57-7.42 (m, 2H), 7.36-7.27 (m, 1H), 7.20 (d, J = 6.4Hz, 1H), 7.17-7 .09(m,1H),4.64(s,2H),3.60-3.43(m,1H),2.64(s,4H),2.56-2.54(m,1 H),1.83-1.71(m,2H),1.69-1.54(m,2H),1.32-1.24(m,1H),1.20(s,3H).

[0831] Compound 347-P2:

[0832] MS m / z (ESI): 497.1 [M+1]+. Supercritical fluid chromatography (SFC): retention time = 3.842 min, UV = 214 nm. 1H NMR (400MHz, DMSO-d6) δ=10.13(s,1H),8.20-8.08(m,2H),8.07-7.98(m,2H),7.57-7.42(m,2H),7.36-7.27(m,1H),7.20(d,J=6.4Hz,1H),7.17-7 .09(m,1H),4.64(s,2H),3.60-3.43(m,1H),2.64(s,4H),2.56-2.54(m,1 H),1.83-1.71(m,2H),1.69-1.54(m,2H),1.32-1.24(m,1H),1.20(s,3H).

[0833] Example 32 (Compound 360)

[0834] Step 1: Synthesis of Compound 360C

[0835] At 0°C, compound 360A (300.0 mg, 1.05 mmol) (synthetic method according to step 2 on page 32 of patent US20250206734A1) was dissolved in N,N-dimethylformamide (3.0 mL). Compound 360B (260.4 mg, 2.10 mmol, CAS: 65864-64-4) was added to the reaction solution and stirred for 0.5 hours. Then, cesium fluoride (637 mg, 4.19 mmol) was added to the reaction solution, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was quenched with water (10 mL), extracted with dichloromethane (15 mL × 4), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–4%) to give compound 360C (100 mg). MS m / z(ESI): 339.0 [M+1] + . 1 HNMR(400MHz,DMSO-d6)δ9.31(s,1H),9.16(d,J=2.8Hz,1H),8.05(s,1H),7.89(d,J=2.8Hz,1H),7 .65-7.52(m,2H),7.28-7.22(m,1H),6.48(d,J=6.0Hz,1H),6.38-6.16(m,1H),5.08-4.98(m,1H).

[0836] Step 2: Synthesis of Compound 360D

[0837] Compound 360C (140 mg, 0.41 mmol) and triethylamine (0.12 mL, 0.83 mmol) were dissolved in dichloromethane (3.0 mL) at 0 °C. Trifluoromethanesulfonic anhydride (175 mg, 0.62 mmol) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was filtered through silica gel, and the filter cake was washed with dichloromethane (80 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%–10%) to give compound 360D (92 mg). MS m / z (ESI): 471.0 [M+1] + .

[0838] Step 3: Synthesis of Compound 360

[0839] Compound 205D (51.7 mg, 0.24 mmol) was dissolved in acetonitrile (2.0 mL) at room temperature. Lithium trifluoromethanesulfonate (39.7 mg, 0.25 mmol), compound 360D (92.0 mg, 0.20 mmol), and N,N-diisopropylethylamine (50.6 mg, 0.39 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was purified by preparative high-performance liquid chromatography (HPLC) (column: ASA-AZZOTA-C18; 30 × 250 mm, 10 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 31-41%; column temperature: 25 °C; flow rate: 35 mL / min; wavelength: 220 nm; column pressure: 60 bar) to obtain 360 (2.8 mg). MS m / z (ESI): 541.2 [M+1] + .

[0840] Example 33 (Compounds 212-P1 and 212-P2)

[0841] Compound 212 (7.0 mg) was purified by supercritical fluid chiral chromatography (equipment: WATERS150 preparative SFC (SFC-01); column: ChiralPak AS, 250×25mm ID, 5μm; column temperature: 35℃; mobile phase: CO2 / [MeOH (0.2% NH3 (7M in MeOH)); flow rate: 100 mL / min; column pressure: 100 bar; wavelength: 240 nm; sample solution: 7 mg dissolved in 4.3 mL methanol / dichloromethane; injection volume: 2.1 mL) to obtain compounds 212-P1 (0.94 mg) and 212-P2 (2.16 mg).

[0842] Compound 212-P1: MS m / z (ESI): 512.2 [M+1]+ Supercritical fluid chromatography (SFC): retention time = 2.132 min, UV = 214 nm.

[0843] Compound 212-P2: MS m / z (ESI): 512.2 [M+1] + Supercritical fluid chromatography (SFC): retention time = 2.640 min, UV = 214 nm.

[0844] Referring to the synthesis method in the above embodiments, the following compounds were synthesized:

[0845] Example 42 (Compounds 359, 359-P1, and 359-P2)

[0846] Step 1: Synthesis of Compound 359B

[0847] At room temperature, compound 359A (8 g, 36.7 mmol) (synthetic method according to step 1 on page 30 of patent US20250206734A1) was dissolved in tetrahydrofuran (40 mL). 2M dilute hydrochloric acid (40 mL, 80.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred overnight at 60 °C. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with water (200 mL). Extraction was performed with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 359B (5 g). 1 H NMR (400MHz, CDCl3) δ9.89 (s, 1H), 6.89-6.71 (m, 3H), 4.64 (s, 2H).

[0848] Step 2: Synthesis of compound 359D

[0849] Compound 359C (50.0 g, 241.53 mmol) was dissolved in acetonitrile (500 mL) at room temperature. Triethylamine (50.2 mL, 362.3 mmol) and 2,4-dimethoxybenzylamine (48.5 g, 289.8 mmol) were added sequentially to the reaction solution, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was slowly quenched in water (1 L), extracted with ethyl acetate (1 L × 3), and the combined organic phases were washed successively with water (1 L × 3) and saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by slurrying (ethyl acetate / petroleum ether = 1 / 3) to give compound 359D (77 g). MS m / z (ESI) = 338.0 [M+1] +.

[0850] Step 3: Synthesis of compound 359E

[0851] Compound 359D (108.4 g, 320.9 mmol) was dissolved in tetrahydrofuran (1100 mL) at 0 °C. A toluene solution of diisobutylaluminum hydride (641.9 mL, 1.5 M) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 0 °C for 3 hours. After the reaction was complete, the reaction mixture was quenched with a saturated sodium potassium tartrate aqueous solution (1 L), extracted with ethyl acetate (1.5 L × 3), and the combined organic phases were washed with saturated brine (2 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by pulping (ethyl acetate / petroleum ether = 1 / 3) to give compound 359E (89.5 g). MS m / z (ESI) = 310.0 [M+1] + .

[0852] Step 4: Synthesis of compound 359F

[0853] Compound 359E (100 g, 322.8 mmol) was dissolved in dichloromethane (1000 mL) at 0 °C. Dys-Martin oxidant (273.9 g, 645.7 mmol) was added fractionally to the reaction mixture, and the reaction mixture was stirred at 0 °C for 3 hours. After the reaction was complete, the reaction mixture was quenched at 0 °C with saturated sodium bicarbonate aqueous solution (1 L), extracted with ethyl acetate (1.5 L × 3), and the combined organic phases were washed with saturated brine (1 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane = 0%–10%) to give compound 359F (57 g). MS m / z (ESI) = 308.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.11(s,1H),8.69(t,J=6.00Hz,1H),8.00(dd,J=7.88,0.88Hz,1H),7.73(dd,J=7.68,1.6 8Hz, 1H), 6.62 (d, J = 2.36Hz, 1H), 6.50 (dd, J = 8.32, 2.36Hz, 1H), 4.45 (d, J = 6.12Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H).

[0854] Step 5: Synthesis of compound 359G

[0855] Compound 359F (90.5 g, 293.9 mmol) was dissolved in trifluoroethanol (900 mL) at room temperature. Trimethylchlorosilane (47.9 g, 440.9 mmol) was added to the reaction solution, and the reaction mixture was stirred at 60 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with saturated sodium bicarbonate aqueous solution (500 mL). The mixture was extracted with dichloromethane (1.5 L × 3), and the combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%–5%) to give compound 359G (12.5 g). MS m / z (ESI) = 158.0 [M+1] + .

[0856] Step 6: Synthesis of compound 359H

[0857] Compounds 359G (600 mg, 3.80 mmol) and 359B (786 mg, 4.57 mmol) were dissolved in ethanol (12 mL) at room temperature. Potassium carbonate (631 mg, 4.57 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 70 °C for 5.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1%–20%) to give compound 359H (600 mg). MS m / z (ESI) = 294.0 [M+1] + .

[0858] Step 7: Synthesis of compound 359J

[0859] Compound 359H (350 mg, 1.19 mmol) was dissolved in a mixed solvent of water (1 mL) and 1,4-dioxane (10 mL) at room temperature. Cesium carbonate (1.16 g, 3.57 mmol), XPhos Pd G2 (93.7 mg, 0.12 mmol, CAS: 1310584-14-5), and compound 359I (0.3 mL, 1.78 mmol) were added sequentially to the reaction solution. The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (30 mL). It was extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1%–20%) to give compound 359J (300 mg). MS m / z(ESI) = 286.0 [M+1] + .

[0860] Step 8: Synthesis of compound 359K

[0861] Compound 359J (500 mg, 1.75 mmol) was dissolved in a mixed solvent of water (5 mL) and tetrahydrofuran (15 mL) at 0 °C. Sodium periodate (1.87 g, 8.76 mmol) and potassium osmium tetroxide dihydrate (29 mg, 0.088 mmol) were added sequentially to the reaction solution, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated sodium sulfite solution (30 mL), extracted with ethyl acetate (30 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10%–30%) to give compound 359K (400 mg). MS m / z (ESI) = 288.0 [M+1] + .

[0862] Step 9: Synthesis of compound 359L

[0863] Compound 359K (400 mg, 1.39 mmol) was dissolved in tetrahydrofuran (8 mL) at 0 °C. (Trifluoromethyl)trimethylsilane (396 mg, 2.78 mmol, CAS: 81290-20-2) was added to the reaction mixture, followed by dropwise addition of a 1 M tetrabutylammonium fluoride solution (2.78 mL, 2.78 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (20 mL), extracted with ethyl acetate (20 mL × 2), and the combined organic phases were washed with saturated brine (30 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (tetrahydrofuran / petroleum ether = 0%–40%) to give compound 359L (200 mg). MS m / z (ESI) = 358.0 [M+1] + .

[0864] Step 10: Synthesis of Compound 359M

[0865] At 0 °C, 359 L (100 mg, 0.28 mmol) of compound was dissolved in dichloromethane (2 mL). Triethylamine (77 μL, 0.56 mmol) and trifluoromethanesulfonic anhydride (71 μL, 0.42 mmol) were added sequentially to the reaction mixture. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction mixture was used directly for the next reaction without further treatment. MS m / z (ESI) = 490.0 [M+1] + .

[0866] Step 11: Synthesis of compounds 359, 359-P1 and 359-P2

[0867] At room temperature, compound 205D (108 mg, 0.491 mmol) was dissolved in acetonitrile (2 mL), and lithium trifluoromethanesulfonate (76.5 mg, 0.491 mmol), compound 359M (the mixture obtained in the previous step) and N,N-diisopropylethylamine (79.2 mg, 0.613 mmol) were added to the reaction solution in sequence. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 1). The mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (HPLC) (column: Waters-SunFire-C18-10μm-30*250mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-70%; column temperature: 25℃; flow rate: 35 mL / min; wavelength: 220 nm) to give compound 359 (48.37 mg). MS m / z (ESI) = 560.2 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ9.39 (d, J=2.8Hz, 1H), 8.39 (s, 1H), 8.04-7.94 (m, 3H), 7.71-7.61 (m, 2H), 7.35-7.26 (m, 1H), 7.14 (d, J= 7.3Hz, 1H), 5.38 (q, J = 9.0Hz, 1H), 4.59-4.41 (m, 2H), 2.97-2.74 (m, 3H), 2.55 (s, 2H), 2.41 (t, J = 9.9Hz, 1H), 1.77-1.54 (m, 4H).

[0868] Compound 359 (35 mg) was separated into compounds 359-P1 (7.12 mg) and 359-P2 (7.75 mg) by supercritical fluid chiral chromatography (equipment: WATERS150 preparative SFC (SFC-01); column: ChiralPak OJ, 250×30 mm ID, 5 μm; column temperature: 35 °C; mobile phase: CO2 / [MeOH (0.2% NH3 (7 M in MeOH): ACN = 80 / 20; flow rate: 100 mL / min; column pressure: 100 bar; wavelength: 221 nm; sample solution: 35 mg dissolved in 8 mL methanol; injection volume: 6 mL)).

[0869] Compound 359-P1:

[0870] MS m / z(ESI) = 560.2[M+1] +Supercritical fluid chromatography (SFC): retention time = 1.412 min, UV = 214 nm.

[0871] 1 H NMR (400MHz, DMSO-d6) δ9.38(d,J=2.8Hz,1H),8.39(s,1H),8.00-7.98(m,1H),7.98-7.96(m,2H),7.68-7.62(m,2H),7.32-7.26(m,1H),7.14(d, J=7.2Hz,1H),5.37(q,J=9.2Hz,1H),4.53-4.45(m,2H),2.95-2.89(m,1H ),2.85-2.76(m,2H),2.55(s,2H),2.43-2.37(m,1H),1.73-1.59(m,4H).

[0872] Compound 359-P2:

[0873] MS m / z(ESI) = 560.2[M+1] + Supercritical fluid chromatography (SFC): retention time = 1.977 min, UV = 214 nm.

[0874] 1 H NMR (400MHz, DMSO-d6) δ9.38(d,J=2.8Hz,1H),8.39(s,1H),8.00-7.98(m,1H),7.98-7.95(m,2H),7.68-7.62(m,2H),7.32-7.26(m,1H),7.14(d, J=7.2Hz,1H),5.38(q,J=9.2Hz,1H),4.53-4.44(m,2H),2.94-2.88(m,1H ),2.85-2.74(m,2H),2.55(s,2H),2.43-2.38(m,1H),1.73-1.57(m,4H).

[0875] According to the synthesis method of the present invention, the corresponding raw materials can be selected and the compounds in Table A and Table B can be prepared by referring to the method of the above specific embodiments.

[0876] Comparative Example 1

[0877] Comparative Example 1 was synthesized according to the synthesis steps of Example 4 in US20250206734A1, with an MS m / z (ESI) of 499.2 [M+1]. + .

[0878] Biological test cases

[0879] Test Example 1: Determination of the inhibitory activity of the compound against the MRGPRX2 receptor (IP1)

[0880] This study used HEK293T cells stably expressing the MRGPRX2 receptor (MRGPRX2-HEK293T). MRGPRX2 receptor activation led to an increase in intracellular IP1 levels. Intracellular IP1 levels were detected using the HTRF IP-One Gq detection kit (CisBio, 62IPAPEC) and read out by EnVision (PerkinElmer, 2009-0030). By detecting changes in intracellular IP1 levels, the inhibitory effect of the test compound on the MRGPRX2 receptor was observed.

[0881] The experimental method is briefly described below:

[0882] MRGPRX2-HEK293T cells were digested and dispersed from the cell culture flask, and seeded into 384-well plates at a concentration of 7500 cells / well. Serially diluted compounds were added to the 384-well plates, followed by vortexing to mix, and incubation at 37°C for 15 minutes. Cortistatin-14 (MCE, HY-P1932) was then added to the 384-well plates to a final concentration of EC10. 90 The plate was then incubated at 37°C for 60 minutes. 5 μL / well of IP1-d2 working solution and 5 μL / well of IP1-Tb working solution were added sequentially to the 384-well plate, vortexed to mix, and then incubated at room temperature for 60 minutes. After incubation, the readings at 665 nm and 615 nm were detected using EnVision, and the ratio between the two was calculated.

[0883] Calculate the inhibitory activity of the compound against MRGPRX2 using the following formula:

[0884] Inhibition rate (%) = 100 × (Ratio) cpd -Ratio LC ) / (Ratio HC -Ratio LC )

[0885] Ratio HC Contains the highest concentration of reference inhibitor and EC. 90 The ratio of cortistatin-14 concentration in cell pores

[0886] Ratio LC Includes EC 90 The ratio of cortistatin-14 concentration in cell pores

[0887] Inhibition curves were generated using inhibition rate and compound concentration, and IC50 was calculated.50 Some test results are shown in Table I below. Where A: IC 50 ≤100nM; B: 100nM <IC 50 ≤500nM; C: 500nM <IC 50 ≤1000nM; D: IC 50 >1000nM.

[0888] Table I

[0889] In conclusion, the compounds of the present invention, such as those in the examples, exhibit excellent inhibitory activity against MRGPRX2, particularly, for example, compounds 273-P1, 364-P1, and 347-P1, which show IP1 inhibitory activity of 1C. 50 The value is less than 10 nM.

[0890] Test Example 2: Determination of the inhibitory activity of the compound on the MRGPRX2 receptor (calcium flow)

[0891] This study used HEK293T cells stably expressing the MRGPRX2 receptor (MRGPRX2-HEK293T). MRGPRX2 receptor activation led to an increase in intracellular calcium ion levels. Intracellular calcium ions and Screen Quest... TM The calcium-sensitive dye in the Fluo-8 No Wash Calcium Assay Kit (AAT Bioquest, 36316) binds to the analyte, significantly enhancing its fluorescence intensity. This signal can be detected using a Molecular Device (Tetra). By detecting changes in fluorescence intensity, the inhibitory effect of the analyte on the MRGPRX2 receptor can be observed.

[0892] The experimental method is briefly described below:

[0893] MRGPRX2-HEK293T cells were digested and dispersed from the cell culture flasks, resuspended in DMEM medium (Gibco, 10569-010) containing 5% FBS (HyClone, SV30208.02), 100 U / mL Penicillin-Streptomycin (Invitrogen, 15140), and 20 mM HEPES (Gibco, 15630-080), and seeded at a concentration of 20,000 cells / well in 384-well plates. The plates were then incubated overnight at 37°C with 5% CO2. The next day, 20 μL / well of dye solution was added to each well of the 384-well plate, and the mixture was vortexed and incubated at 25°C for 1 hour. Then, 10 μL / well of serially diluted compound was added to each well of the 384-well plate, and fluorescence intensity changes were recorded over 160 seconds using a fluorescence imaging plate reader. Next, the 384-well plate was incubated at 25°C for another 30 minutes. Then, 10 μL / well of cortistatin-14 (MCE, HY-P1932) was added to each 384-well plate, bringing the final concentration to EC50. 90 The fluorescence intensity changes were recorded over 160 seconds using a fluorescence imaging plate reader.

[0894] The inhibitory activity of the compound against MRGPRX2 was calculated using the following formula: Inhibition rate (%) = (1 - (RFU) compound -RFU low control ) / (RFU high control -RFU low control ))*100

[0895] RFU low control Fluorescence values ​​containing only cell pores

[0896] RFU high control Includes EC 90 Fluorescence values ​​of cortistatin-14 concentrations in cell wells

[0897] Inhibition curves were generated using inhibition rate and compound concentration, and IC50 was calculated. 50 Some test results are shown in Table II below. Where A: IC 50 ≤100nM; B: 100nM <IC 50 ≤500nM; C: 500nM <IC 50 ≤1000nM; D: IC 50 >1000nM.

[0898] Table II

[0899] In conclusion, the compounds of the present invention, such as the compounds in the examples, exhibit excellent inhibitory activity against MRGPRX2.

[0900] Test Example 3: LAD2 Degranulation Experiment

[0901] This study used LAD2 cells as a model, activated the MRGPRX2 receptor with Cortistatin-14 (MCE, HY-P1932), promoted LAD2 cell degranulation, and released β-Hexosaminidase. The proportion of LAD2 cells degranulated was quantitatively analyzed using a kit (tribioscience, TBS2105). By detecting changes in the proportion of LAD2 cells degranulated, the inhibitory effect of the test compound on the MRGPRX2 receptor was reflected. The experimental methods are briefly described below:

[0902] Before the experiment, LAD2 cells were cultured overnight at 37°C in SCF-free medium (R&D, 255-SC-200 / CF) containing 1% GlutaMAX (Invitrogen, 35050-061) in StemPro-34 (Gibco, 10639-011)) and incubated. The next day, the cells were washed twice with HEPES buffer (Solarbio, H1070), and after adjusting the cell density, they were seeded at a density of 20,000 cells / well in 96-well plates (Corning, 3799). Serially diluted test compounds were added to the cells, mixed, and incubated at 37°C for 1 hour. Subsequently, 0.5 μM Cortistatin-14 was added to the cells, mixed, and incubated at 37°C for 1 hour. After incubation, the cell supernatant was collected by centrifugation, and the cells were lysed with 0.1% Triton X-100 (Sigma, 648463). Following the kit instructions, the cell supernatant and cell lysis buffer were mixed separately with the substrate and incubated at 37°C in the dark for 1 hour. Finally, the reaction was terminated with Stop Reagent, and the OD400 nm reading was recorded. The proportion of β-Hexosaminidase in the cell supernatant to the total β-Hexosaminidase in the supernatant and cell lysis buffer was defined as the LAD2 degranulation ratio, and the inhibitory activity of the compound against LAD2 degranulation was calculated using the following formula:

[0903] Inhibition rate (%)=100×(high control-compound) / (high control-low control)

[0904] High control: The proportion of LAD2 particles degranulated after Cortistatin-14 treatment.

[0905] Low control: The proportion of LAD2 particles removed after 0.1% DMSO treatment.

[0906] Compound: The proportion of LAD2 particles degranulated after treatment with the test compound and Cortistatin-14.

[0907] Inhibition curves were generated using inhibition rate and compound concentration, and IC50 was calculated. 50， Some test results are shown in Table III below.

[0908] A: IC 50 ≤10nM; B: 10nM <IC 50 ≤100nM; C: 100nM <IC 50 ≤1000nM; D: 1000nM <IC 50 .

[0909] Table III

[0910] In conclusion, the compounds of the present invention, such as those in the examples, exhibit excellent inhibitory activity against MRGPRX2, and in particular, for example, the inhibitory activity against LAD2 of compound 273-P1 is IC50. 50 The value is less than 2nM.

[0911] Test Example 4: Pharmacokinetic Test of the Compounds of the Invention in Mice

[0912] 1. Experimental Objective

[0913] Using C57BL / 6J mice as test animals, the drug concentration in plasma at different time points after intravenous injection and gavage administration of the compound of the present invention was determined by LC / MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in mice.

[0914] 2. Experimental Design

[0915] 2.1 Experimental drugs and animals;

[0916] Compounds of the present invention

[0917] C57BL / 6J mice, male, 17.41-21.56g, were purchased from Vital River Laboratory Animal Technology Co., Ltd.

[0918] 2.2 Drug Preparation

[0919] Intravenous injection group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a 5% DMSO / 40% PEG400 / 55% saline solution with a final concentration of 0.2 mg / mL.

[0920] Oral gavage group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a 5% DMSO / 40% PEG400 / 55% saline solution with a final concentration of 0.3 mg / mL.

[0921] 2.3 Administration

[0922] Six C57BL / 6J mice were used, divided into two groups of three. After fasting overnight, the mice were administered the drugs via intravenous injection and gavage, respectively. The mice were fed 4 hours after administration. The dosages of each compound are shown in Table IV below:

[0923] Table IV

[0924] 3. Operation

[0925] Blood samples of 30 μL were collected via the submandibular vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after gavage administration. The blood samples were anticoagulated with EDTA-K2. Plasma was separated by centrifugation within 60 minutes of collection (centrifugation conditions: 6800g, 6 minutes, 2–8°C). Collected plasma was stored at –80°C before analysis.

[0926] The levels of different compounds in mouse plasma after intravenous injection and gavage administration were determined by LC-MS / MS.

[0927] 4. Pharmacokinetic Parameter Results

[0928] Oral bioavailability is the percentage of AUC (area under the curve) after oral administration of an equal amount of drug and the AUC (area under the curve) after intravenous administration of an equal amount of drug. The formula for calculation is as follows: In the formula, AUC represents the area under the blood drug concentration-time curve, the subscripts ig and iv represent oral gavage preparation and intravenous injection preparation, respectively, and D represents the dosage.

[0929] The pharmacokinetic parameters of the compounds of the present invention in mice are shown in Table V below.

[0930] Table V

[0931] Note: N / A indicates no relevant results.

[0932] Conclusion: The compounds of this invention exhibit good pharmacokinetic absorption, high bioavailability, and better pharmacokinetic properties.

[0933] Test Example 5: Rat Pharmacokinetic Test of the Compounds of the Invention

[0934] 1. Experimental Objective

[0935] Using SD rats as test animals, the drug concentration in plasma at different time points after intravenous injection and gavage administration of the compound of the present invention was determined by LC / MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in rats.

[0936] 2. Experimental Design

[0937] 2.1 Experimental drugs and animals;

[0938] Compounds of the present invention

[0939] Male SD rats were purchased from Vital River Laboratory Animal Technology Co., Ltd.

[0940] 2.2 Drug Preparation

[0941] Intravenous injection group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a final concentration of 0.2 mg / mL of 3% DMSO + 10% PEG400 + 87% saline solution or 5% DMSO + 40% PEG400 + 55% saline solution.

[0942] Oral gavage group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a final concentration of 0.3 mg / mL of 3% DMSO + 10% PEG400 + 87% saline solution or 5% DMSO + 40% PEG400 + 55% saline solution.

[0943] 2.3 Administration

[0944] Nine SD rats were used, divided into three groups of three. After fasting overnight, the drugs were administered intravenously or by gavage. Rats were fed four hours after administration. The dosages of each compound are shown in Table VI below.

[0945] Table VI

[0946] 3. Operation

[0947] Blood samples were collected via the jugular vein or other suitable vein at 0.15 mL each time, anticoagulated with EDTA-K2, at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after gavage administration. Plasma was separated by centrifugation within 60 minutes of collection (centrifugation conditions: 6800 g, 6 minutes, 2–8 °C). Collected plasma was stored at –80 °C before analysis.

[0948] The levels of the target compounds in rat plasma after intravenous injection and gavage administration were determined by LC-MS / MS.

[0949] 4. Pharmacokinetic Parameter Results

[0950] Oral bioavailability is the percentage of AUC (area under the curve) after oral administration of an equal amount of drug and the AUC (area under the curve) after intravenous administration of an equal amount of drug. The formula for calculation is as follows: In the formula, AUC represents the area under the blood drug concentration-time curve, the subscripts ig and iv represent oral gavage preparation and intravenous injection preparation, respectively, and D represents the dosage.

[0951] The pharmacokinetic parameters of the compounds of the present invention in rats are shown in Table VII below.

[0952] Table VII

[0953] Note: N / A indicates no relevant results.

[0954] Conclusion: The compounds of this invention exhibit good pharmacokinetic absorption, high bioavailability, and better pharmacokinetic properties.

[0955] Test Example 6: Canine Pharmacokinetics of the Compounds of the Invention

[0956] 1. Experimental Objective

[0957] Using Beagle dogs as test animals, the drug concentration in plasma at different time points after intravenous injection and gavage administration of the compound of the present invention was determined by LC / MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in Beagle dogs.

[0958] 2. Experimental Design

[0959] 2.1 Experimental drugs and animals;

[0960] Compounds of the present invention

[0961] Beagle dog, male, Beijing Mars Biotechnology Co., Ltd.

[0962] 2.2 Drug Preparation

[0963] Intravenous injection group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a 3% DMSO + 10% PEG400 + 87% saline solution with a final concentration of 0.25 mg / mL.

[0964] Oral gavage group: Weigh an appropriate amount of drug, add an appropriate amount of DMSO to dissolve it, then add an appropriate amount of PEG400 and saline to prepare a final concentration of 0.2 mg / mL of 3% DMSO + 10% PEG400 + 87% saline solution.

[0965] 2.3 Administration

[0966] Beagle dogs were administered the drugs via intravenous injection and gavage after fasting overnight. They were fed 4 hours after administration. The dosages of each compound are shown in Table VIII below:

[0967] Table VIII

[0968] 3. Operation

[0969] Blood samples were collected via the jugular vein or other suitable vein at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous administration, and at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after gavage administration. Each sample was 1 mL and anticoagulated with EDTA-K2. Plasma was separated by centrifugation within 60 minutes of collection (centrifugation conditions: 2200 g, 10 min, 2–8 °C). Collected plasma was stored at –80 °C before analysis.

[0970] The levels of the target compounds in canine plasma after intravenous injection and gavage administration of different compounds were determined by LC-MS / MS.

[0971] 4. Pharmacokinetic Parameter Results

[0972] Oral bioavailability is the percentage of AUC (area under the curve) after oral administration of an equal amount of drug and the AUC (area under the curve) after intravenous administration of an equal amount of drug. The formula for calculation is as follows: In the formula, AUC represents the area under the blood drug concentration-time curve, the subscripts ig and iv represent oral gavage preparation and intravenous injection preparation, respectively, and D represents the dosage.

[0973] Conclusion: The compounds of this invention exhibit good pharmacokinetic absorption, high bioavailability, and better pharmacokinetic properties.

[0974] Test Example 7: Liver Microsomal Stability Test of the Compounds of the Invention

[0975] At 37°C, 1 μM of the analyte compound was incubated with liver microsomes (0.5 mg / mL) from mice, rats, dogs, monkeys, and humans using an NADPH regeneration system for 15, 30, 45, and 60 minutes. The concentration of the analyte compound in the resulting samples was then determined using LC-MS / MS. The half-life (T5) of the compound in the liver microsome solutions from mice, rats, dogs, monkeys, and humans was calculated by assigning the remaining percentage of the compound at each time point. 1 / 2 ) and inherent clearance rate (CLint(mic)).

[0976] Conclusion: The compounds of the present invention, such as those in the examples, have good stability in mouse, rat, dog, monkey, and human liver microsomes.

[0977] Test Example 8: Hepatocyte stability test of the compound of the present invention

[0978] At 37°C, 1 μM of the test compound reacted with mouse, rat, dog, monkey, and human hepatocytes (0.5 × 10⁻⁶ cells). 6 After incubation at 15, 30, 60, 90, and 120 minutes (samples / mL), the concentration of the analyte in the resulting samples was determined by LC-MS / MS. The half-life (T5) of the analyte in mouse, rat, dog, monkey, and human hepatocyte suspensions was calculated by assigning the remaining percentage of the analyte at each time point. 1 / 2 ) and inherent clearance rate (CLint(hep)).

[0979] Conclusion: The compounds of the present invention, such as those in the examples, exhibit good stability in mouse, rat, dog, monkey, and human hepatocytes.

[0980] Test Example 9: Caco-2 Permeability Test of the Compounds of the Present Invention

[0981] The experiment used monolayers of Caco-2 cells, incubated in 96-well Transwell plates in duplicate. A transport buffer solution (HEPES, 10 mM HEPES, pH 7.4 ± 0.05) containing either the compound of the present invention (5 μM) or the control compounds digoxin (5 μM), minoxidil (5 μM), and atenolol (5 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. The integrity of the monolayer cells after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0982] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good permeability.

[0983] Test Example 10: Plasma Protein Binding Test of the Compounds of the Invention

[0984] The compound was dissolved in DMSO to a final concentration of 10 mM to obtain stock solution I. An appropriate amount of stock solution I was transferred and diluted with DMSO to obtain a 200 μM diluted stock solution II. 1.5 μL of stock solution II was transferred into a 1.5 mL Eppendorf tube, and 298.5 μL of blank plasma was added. The mixture was stirred to obtain a 1 μM plasma sample 2 (DMSO content 0.5%), which was used to determine the plasma protein binding rate at this concentration.

[0985] Add 120 μL of plasma sample to the dialysis chamber using the HTD apparatus and dialyze with an equal volume of dialysis buffer (PBS). This experiment requires duplicate assays. Seal the dialysis plates and place them in an incubator containing 5% carbon dioxide at 37°C, incubating with shaking at approximately 150 rpm for 6 hours. After dialysis, open the seal and aspirate 20 μL from each of the buffer and plasma chambers of the four dialysis plates, transferring them to the buffer sample plate and plasma sample plate, respectively. Add 80 μL of blank plasma to the buffer sample plate and an equal volume of PBS to the plasma sample plate. Add 480 μL of quenching solution (acetonitrile containing internal standards including 200 nM labetalol, 100 nM tolbutamide, and 100 nM ketoprofen) to precipitate proteins. Vortex for 15 minutes. Centrifuge the buffer and plasma sample plates at 3220 g for 30 minutes at 4°C. Transfer 100 μL of the supernatant from the buffer and plasma sample plates to a new plate and dilute with 100 μL of water. After thorough mixing, analyze the sample using liquid chromatography-mass spectrometry (LC / MS-MS), determining the peak area ratios of total drug (plasma chamber) and free drug (buffer chamber) to the internal standard, and calculating the free percentage (f...). u plasma %)

[0986] Test Example 11: Cardiomyocyte safety experiment of the compound of the present invention

[0987] This study used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (HELP, 4111) as a model to examine the effects of test compounds on parameters such as FPDc (corrected field potential duration), thereby reflecting the safety of the test compounds for cardiomyocytes. The experimental methods are briefly described below:

[0988] Add 5 μL of 50 μg / mL fibronectin (Sigma, F0895) to the center of each well in a CytoView MEA 96-well plate (Axion BioSystems, M768-tMEA-96W) and incubate at 37°C with 5% CO2 for at least 1 hour. Collect hiPSC-CMs cells and seed them into 96-well plates at a density of 20,000 cells / well, then incubate overnight at 37°C. On day 2 post-seeding, remove two-thirds of the culture medium from each well of the 96-well plate and replenish with maintenance medium (HELP, 3001), then replace half the maintenance medium every 2 days thereafter. On day 6 post-seeding, dilute the test compound with maintenance medium and incubate at 37°C for later use. After removing half of the maintenance medium from each well of the 96-well plate, add an equal volume of the diluted compound to each well. One hour after treatment, Spike Amplitude (SA), Beat Period (BP), and Field Potential Durations (FPD) data were collected using the Axion Maestro Pro MEA recording system. The changes in SA, BP, and FPDc caused by the compound were calculated to determine whether the compound posed a safety risk to cardiomyocytes.

[0989] Conclusion: The compounds of this invention have good safety for cardiomyocytes.

[0990] Test Example 12: Evans Blue Efficacy Experiment of the Compounds of the Present Invention

[0991] The aim of this study was to investigate the inhibitory effect of a novel small molecule MRGPRX2 antagonist on mast cell degranulation in a Cortistatin-14-induced Evans blue exudation model.

[0992] Experimental methods:

[0993] Nine-week-old male humanized MRGPRX2 mice were selected for the pharmacological experiment. After grouping, the mice were administered either the solvent or the compound orally. Two hours later, all animals were anesthetized by intravenous injection of 1% Evans Blue solution (Sigma, E2129) via the tail vein. Ten minutes after the intravenous injection, the mice were anesthetized by inhalation of isoflurane (Qingdao Aubofang Pharmaceutical Technology Co., Ltd., 20250907). The control group mice were injected with PBS (Corning, 21-040-CV) into the back of both the left and right ears. The other groups of mice were injected intradermally with PBS into the back of the left ear and with Cortistatin-14 (MCE, HY-P1932) into the back of the right ear. Ten minutes after the intradermal injections, the animals were euthanized. The left and right ears of the mice were collected, neatly arranged on white paper, and photographed. Each ear was immersed in 1 mL of formamide solution (Sinopharm Chemical Reagent Co., Ltd., 30091218) for Evans blue extraction, and the absorbance at 620 nm was measured using a microplate reader (TECAN, Infinite 200M). The reduction in Evans blue concentration was used to evaluate the inhibitory effect of the compound on MRGPRX2.

[0994] Conclusion: The compound of the present invention exhibits good inhibitory effect on MRGPRX2 in the Evans blue exudation model.

Claims

1. A compound of general formula (I”), its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts thereof, in, Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-S(=O)(=NR c )-(CR a R b ) p -、-O-(CR a R b ) p -、-S-(CR a R b ) p -、-(CR a R b ) p -、-NR a R b -、-C(=O)-、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-C(=NR c ), -CR a =CR b -、-C(=O)O-、-CR a =N-, -3-18-membered heterocyclic-, -3-12-membered carbocyclic- and -5-6-membered heteroaryl-; Y either does not exist or is -CR1R2-; Ring A is selected from 3-18-membered heterocyclic groups, 5-15-membered heteroaryl groups, and 6-14-membered aryl groups; Ring B is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, and 5-15 membered heteroaryl groups; and ring B is not a [missing information - likely a specific type of cyclic group]. Optionally, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups, wherein the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e Replaced; The ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups; R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; Each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, -C 1-6 Alkylene-OC 1-6 Alkyl, C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted; Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic or 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted; Each R M It does not exist or is selected independently from hydrogen, halogen, deuterium, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ; Or any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted; Each R A Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, 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, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced; Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Deuterated alkoxy group, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced; M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-; Each R a R b R c R d Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 Alkynyl and amino; the alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further surrounded by 1-5 R groups. x Replaced; Optional, R a and R b Together with the atoms attached to it, they form C 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted; Each R e Each is independently selected from hydrogen, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, amino, =O, =CR a R b =NR c The alkyl, haloalkyl, alkoxy, or haloalkoxy groups may optionally be further oxidized by 1-5 R groups. x Replaced; Each R x Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group; p and q are each independent integers between 0 and 3; k is 0 or 1; m, n, and s are each an independent integer between 0 and 5.

2. The compound according to claim 1, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts thereof, having the structure shown in general formula (I), in, X does not exist or is selected from -C(=O)-(CR) a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-O-(CR a R b ) p -、-S-(CR a R b ) p -、-CR a R b -、-NR a R b -; Y either does not exist or is -CR1R2-; Ring A is selected from 3-18 membered heterocyclic groups or 5-15 membered heteroaryl groups; Ring B is selected from 3-12 membered carbon cyclic groups or 3-18 membered heterocyclic groups; The ring C is selected from 3-12 membered carbocyclic groups, 3-18 membered heterocyclic groups, 6-18 membered aryl groups, or 5-15 membered heteroaryl groups; R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ; Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, 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, =CR a R b -MC 3-8 Carbocyclic group, -M- (4-8 membered heterocyclic group), wherein the hydroxyl, amino, alkyl, alkenyl, alkoxy, carbocyclic, or heterocyclic group is optionally further surrounded by 1-5 R groups. x Replaced; Each R B Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, -(CR) a R b ) p -S(=O)2R c 、-(CR a R b ) p -S(=O)NR c R d 、-(CR a R b ) p -S(=O)(=NH)R c 、-(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -P(=O)R c R d 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, =CR a R b -MC 3-12 Carbocyclic, -M-(3-12-membered heterocyclic), -M-(6-12-membered aryl), -M-(5-12-membered heteroaryl), wherein the hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced; M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-; Each R a R b R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; Each R x Each is independently selected from halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOC 1-3 Alkyl, -N(C) 1-3 alkyl)2、-NH(C 1-3 Alkyl groups, -SF5, -SCF3, =CR a R b C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group; p is an integer between 0 and 3; m, n, and s are each an independent integer between 0 and 5.

3. The compound according to claim 1 or 2, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts thereof, having a structure represented by general formula (IIG) or general formula (II), in, Z is selected from -C(=O)-, -O-(CR) a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -C(=O)O-, S(=O)2, 5-6 heteroaryl, CR a =CR b and -C(=NR) c )-; Each R M It does not exist or is selected independently from hydrogen, halogen, deuterium, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、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, =CR a R b ; Or any two R M Together with the atoms attached to it, they form C 3-10 Carbocyclic or 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic group and 3 to 10-membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted; R B1 For hydrogen or M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-; Ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl and 5-12-membered heteroaryl; k is 0 or 1; m, n, and s are each an independent integer from 1 to 5; t is an integer between 0 and 5; u and v are each independently 0, 1, or 2; the remaining groups are as defined in claim 1.

4. The compound according to any one of claims 1-3, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein, Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-S(=O)-(CR a R b ) p -、-S(=O)2-(CR a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、C(=O)O、CR a =N, -3-10 heterocyclic-, -3-10 carbocyclic- and 5-6 heteroaryl; Y either does not exist or is -CR1R2-; Ring A is selected from 3-10-membered heterocyclic groups, 5-10-membered heteroaryl groups, and 6-10-membered aryl groups; Ring B is selected from 5-12 membered carbocyclic groups, 5-12 membered heterocyclic groups, and 5-12 membered heteroaryl groups; As an option, an R on ring A A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-8 Carbocyclic or 5- to 8-membered heterocyclic groups; The ring C is selected from 6-14 aryl, 5-12 heteroaryl, and 3-15 heterocyclic groups; R y Selected from hydrogen, halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups; Each R1 and R2 is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; Each R M It does not exist or is selected independently from hydrogen, halogen, hydroxyl, =O, -(CR) a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, =CR a R b ; Each R A Each is independently selected from hydrogen, halogen, hydroxyl, =O, cyano, amino, 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, =CR a R b ; Each R B Each independently selected from -MC 3-8 Carbocyclic, -M-(4-8 membered heterocyclic), -M-(6-12 membered aryl), -M-(5-10 membered heteroaryl), wherein the carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally further surrounded by 1-5 R groups. x Replaced; M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-; Each R a R b Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Halogenated alkyl; the alkyl group, or halogenated alkyl group, may optionally be further divided by 1-5 R groups. x Replaced; Each R c R d Each is independently selected from hydrogen, halogen, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkoxy group; the alkyl, haloalkyl, or alkoxy group may optionally be further surrounded by 1-5 R groups. x Replaced; Each R x Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, =O, =S, =NH, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamine group; p and q are each independent integers between 0 and 2; m, n, and s are each an independent integer from 1 to 4.

5. The compound according to claim 3, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein, Selected from (For example, )、 (For example, )、 Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-S(=O)(=NR c )-, -S(=O)2-, C(=O)O, CR a =N, -3-6 heterocyclic-, -5-9 spirocyclic-, -3-6 carbocyclic-, 5-6 heteroaryl; Z is selected from -C(=O)-, -O-(CR) a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b -, -C(=O)O-, S(=O)2, 5-6 heteroaryl, CR a =CR b and -C(=NR) c )-; R A1 R A2 and R A3 Whether the groups are the same or different, they are each independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups; Y does not exist or is -CR1R2- Each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, -C 1-3 Alkylene-OC 1-3 Alkyl and C 3-6 Carbocyclic group, the C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy and C 3-6 The carbocyclic group is optionally selected from deuterium, halogen, hydroxyl, and C. 1-6 One or more substituents in the alkyl group are substituted; Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic or 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 The alkyl group is substituted by one or more substituents; the ring C is selected from 6-10 aryl, 5-15 heteroaryl, and 10-15 heterocyclic groups; R A1 R A2 and R A3 Whether the groups are the same or different, they are each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl groups and C 1-6 Halogenated alkoxy groups.

6. The compound according to any one of claims 1-5, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein, Ring B is selected from 5-7-membered heterocyclic groups, 6-10-membered benzodicycloalkyl groups, 6-10-membered benzodicycloalkyl groups, 6-10-membered benzodiaryl groups, 6-10-membered spirobicycloalkyl groups, 6-10-membered spirodicycloalkyl groups, 6-10-membered bridged bicycloalkyl groups, and 5-6-membered azaaryl groups; preferably, ring B is selected from the following structures: Preferably, ring B is selected from the following structures: The asterisk (*) is attached to the X group.

7. The compound according to any one of claims 1-6, its stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt, wherein... for The ring C is a 5-15 membered heteroaryl or a 10-15 membered heterocyclic group; R B1 For hydrogen or M does not exist or is selected from -CR a R b -, -O-, -C(=O), -NHC(=O)-, -C(=O)NH-; Ring D is selected from C 3-12 Carbocyclic, 3-12-membered heterocyclic, 6-12-membered aryl, and 5-12-membered heteroaryl; preferably, ring D is phenyl; Each R B Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkoxy groups and C 1-6 Deuterated alkoxy groups; t is an integer between 0 and 5; n is an integer from 1 to 5; R x As defined in claim 1; Preferably, Selected from 8. The compound according to any one of claims 1-7, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, having the structures shown in formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), (III-1), (III-2), (III-3), (IV-1), and (IV-2): in, t is an integer from 0 to 5, and the definitions of the other groups are as described in any one of claims 1-7; Preferably, an R A With an R on ring B M They are connected together, thus forming C with their respective connected atoms and the X group. 5-10 Carbocyclic or 5- to 10-membered heterocyclic groups, wherein the C 5-10 The carbocyclic group and the 5- to 10-membered heterocyclic group are optionally separated by one or more R e What it replaced.

9. The compound according to any one of claims 1-8, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein, Each X either does not exist or is independently selected from -C(=O)-(CR). a R b ) p -、-C(=O)-、-O-(CR a R b ) p -、-(CR a R b ) p -、-(CR a R b ) p -NR c -、-(CR a R b ) p -C(=O)-NR c -、-C(=CR a R b )-、-S(=O)(=NR c -, -S(=O)-, -S(=O)2-, -oxocyclobutyl-, -5-7-membered spirocyclic-, -cyclopropyl-, -cyclobutyl; Y either does not exist or is -CR1R2-; R y Selected from F, Cl, Br, methyl, ethyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, and trifluoroisopropyl; Each R1 and R2 is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, cyclopropyl, vinyl, ethynyl, propynyl, -CH=CF2, CD3, CF2D, CF2Cl, CF2OCH3; Optionally, R1 and R2 together with the atoms they are attached to form C 3-6 Carbocyclic groups and 3-6 membered heterocyclic groups, wherein the C 3-6 The carbocyclic group and 3-6 membered heterocyclic groups are optionally selected from deuterium, halogen, hydroxyl and C. 1-6 One or more substituents in the alkyl group are substituted; Each R M Not present or independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, -(CR a R b ) p -OR c 、-(CR a R b ) p -NR c R d 、-(CR a R b ) p -SR c 、-(CR a R b ) p -CN、=CR a R b ; Each R A Each is independently selected from hydrogen, F, Cl, Br, hydroxyl, =O, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy, =CR a R b ; Each R B Each is independently selected from -M-(phenyl) or -M-(5-6-membered heteroaryl), wherein the phenyl or heteroaryl group is optionally further surrounded by 1-5 R groups. x The substituted group; among which, the 5-6 membered heteroaryl group is, for example, pyridinyl, pyrimidinyl, pyrazinyl, 1,3-oxazinyl, 1,3-thiazinyl, or triazinyl; M does not exist or is selected from -CR a R b -、-O-; Each R a R b R c R d Each is independently selected from hydrogen, F, Cl, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, and trifluoroisopropoxy. Each R x Each group is independently selected from F, Cl, Br, hydroxyl, cyano, amino, nitro, =O, =S, =NH, -NHCOCH3, -NHCOCH2CH3, -N(CH3)2, -NH(CH3), -SF5, -SCF3, =CR a R b Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoropropoxy, trifluoroisopropoxy; p and q are each independent integers between 0 and 2; m, n, and s are each an independent integer from 1 to 4.

10. The compound according to claim 3, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, having the structure shown in formula (II-7), (II-8), (II-9), or (II-10): R M1 R M2 R M3 and R M4 Each is independently selected from hydrogen, halogen, hydroxyl, =O, 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, =CR a R b ; Optionally, R M1 and R M2 R M3 and R M4 R M1 and R M3 Any group of atoms connected to it together forms C. 3-8 Carbocyclic or 3-8 membered heterocyclic groups, wherein the C 3-8 The carbocyclic group and 3-8 membered heterocyclic groups are optionally selected from deuterium, halogens, and C. 1-6 One or more substituents in the alkyl group are substituted; The remaining groups are as defined in claim 3.

11. The compound, its stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt according to any one of claims 3-10, wherein, Selected from (For example, )、 (For example, )、 Each of the groups is defined as described in any one of claims 3-10.

12. The compound of claim 10, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, wherein... for (For example, ); Each R a R b Each is independently selected from hydrogen, halogen, deuterium, hydroxyl, and C. 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; Y is -CR1R2-; each R1 and R2 is independently selected from hydrogen, deuterium, halogen, and C. 1-3 Alkyl and C 1-3 Halogenated alkyl groups; Selected from The remaining groups are as defined in any one of claims 3-10.

13. The compound, stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, wherein the compound is selected from the group consisting of the compounds in Table A or Table B.

14. A pharmaceutical composition or pharmaceutical preparation comprising the compound of any one of claims 1-13, its stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers.

15. The pharmaceutical composition or pharmaceutical preparation according to claim 14, comprising 0.1-1500 mg of the compound according to any one of claims 1-13, its stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers.

16. Use of the compound, stereoisomer, tautomer, racemate, nitride, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition or pharmaceutical preparation of any one of claims 1-13, in the preparation of a medicament for the treatment / prevention of MRGPRX2-related diseases.

17. The use according to claim 16, wherein the MRGPRX2-related disease is selected from autoimmune diseases; preferably, the MRGPRX2-related disease is selected from chronic spontaneous urticaria, chronic induced urticaria, mast cell hyperplasia, atopic dermatitis, cystitis, migraine, asthma, Crohn's disease, ulcerative colitis and rheumatoid arthritis.

18. 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 1-13, its stereoisomers, tautomers, racemates, nitrides, or pharmaceutically acceptable salts, or the pharmaceutical composition or pharmaceutical preparation of any one of claims 14-15, wherein the therapeutically effective amount is preferably 0.1-1500 mg, and the disease is selected from autoimmune diseases; preferably, the disease is selected from chronic spontaneous urticaria, chronic induced urticaria, mast cell hyperplasia, atopic dermatitis, cystitis, migraine, asthma, Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

19. A method for preparing a compound of formula (IIG), A compound of general formula (IIG-a) or a salt thereof reacts with a compound of general formula (IIG-b) or a salt thereof in the presence of a base to give a compound of general formula (IIG) or a pharmaceutically usable salt thereof. R Z It is a leaving group such as halogen (e.g., Cl, Br or I), trifluoromethanesulfonate (OTf), methanesulfonate (OMs); The remaining groups are as defined in claim 3.

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