Benzomorphan analogues, preparation method therefor and use thereof

Abstract

Provided in the present invention are compounds of formula X or formula X', or stereoisomers, geometric isomers, tautomers and conformational isomers thereof, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates and isotopically labeled compounds thereof, or a mixture thereof. The compounds of the present invention have dual-target effects of antagonizing NMDAR and / or inhibiting SERT, can be used for preventing and / or treating diseases associated with NMDAR and / or SERT, and can be used for preparing drugs for treating and / or preventing central nervous system diseases.

Description

Benzomorphine analogues, their preparation methods and uses

[0001] This application claims the following priority:

[0002] Application number: CN202510375622.0, application date: March 27, 2025;

[0003] Application number: CN202511410233.3, application date: September 29, 2025;

[0004] Application number: CN202610310714.5, application date: March 13, 2026. Technical Field

[0005] This invention belongs to the field of medicinal chemistry, specifically relating to a benzomorphine analogue, its preparation method, and its uses. Background Technology

[0006] Depression is a mental illness characterized primarily by persistent low mood. Compared to patients with ordinary depression, patients with treatment-resistant depression (TRD) are those whose Hamilton Depression Rating Scale score reduction is <20% after adequate treatment with two or more antidepressants at sufficient doses and for the required duration. Among patients with depressive disorders, 20%-30% do not respond well to or respond poorly to antidepressant treatment and are classified as treatment-resistant depression. Currently, the main medications for treating depression are SSRIs / SNRIs (Selective Serotonin Reuptake Inhibitors / Serotonin and Norepinephrine Reuptake Inhibitors), but these medications are ineffective for nearly one-third of patients and have a slow onset of action, even increasing the risk of suicidal tendencies. Therefore, there is a significant unmet clinical need in this area.

[0007] The N-methyl-D-aspartate receptor (NMDAR) is an important ionotropic glutamate receptor with dual ligand- and voltage-gated ion channel characteristics. Under physiological conditions, NMDAR activation promotes cell protection, preventing apoptosis and excitotoxic damage; under pathological conditions, overactivation of NMDAR, or activation by specific signals or sites, can trigger the apoptosis program. The apoptosis mechanism of NMDAR is mainly mediated by its Ca2+-β2-dimethyl-D-aspartate receptor. 2+ Influx triggers a series of pro-apoptotic cascade reactions. NMDA receptors mediate synaptic signaling and plasticity in the brain, participating in and regulating the development, learning, and memory of the nervous system. Furthermore, their dysfunction is closely related to the development of many neurological and psychiatric diseases, such as Alzheimer's disease, schizophrenia, and depression. NMDA antagonists have been approved for the treatment of Alzheimer's disease, depression, and other conditions.

[0008] The serotonin transporter (SERT) is a transmembrane transporter with a high affinity for serotonin (5-HT), capable of reuptaken from the intercellular space, thereby regulating nerve signal transduction. SERT inhibitors have led to the development of many classic antidepressants, such as fluoxetine, citalopram, and paroxetine. These drugs have a slow onset of action, typically requiring 6-8 weeks.

[0009] Racemic ketamine is a non-competitive antagonist (Ki = 0.53 μM) that binds to a site within the NMDAR pores and was initially used clinically as an anesthetic. In 2019, Johnson & Johnson's esketamine nasal spray received FDA approval for use in combination with commonly used oral antidepressants (such as fluoxetine), becoming the first rapidly acting drug for treatment-resistant and major depressive disorder. Esketamine's strong NMDAR antagonistic activity (Ki = 0.3 μM) also means that its antidepressant effect and side effects such as dissociation and addiction are mechanistically inseparable. Lanicemine, rapastinel, and AV-101, which act on other NMDAR binding sites, avoid the addictive and dissociation side effects of ketamine, but none have been successful in clinical trials. Therefore, binding to a site within the NMDAR pores is likely the main reason why ketamine exerts its rapid antidepressant effect. However, the side effects of esketamine, such as dissociation and addiction, as well as its poor oral bioavailability, greatly limit its clinical application.

[0010] In August 2022, AUVELITY, developed by Axsome Theaputic, was approved for the treatment of major depressive disorder. AUVELITY is a combination extended-release formulation of the commonly used cough suppressant dextromethorphan and the traditional antidepressant bupropion. The drug takes effect within one week and significantly improves depressive symptoms within two weeks. Similar to esketamine, dextromethorphan possesses both NMDAR antagonistic activity (Ki = 1670 nM) and SERT inhibition (Ki = 40 nM). Therefore, due to the dual-target nature of its main component, dextromethorphan, AUVELITY can exert a rapid antidepressant effect (taking effect within one week) without needing to be combined with traditional SSRIs / SNRIs, while also avoiding the dissociation and addiction side effects caused by excessive NMDAR inhibition.

[0011] When used alone, dextromethorphan faces significant first-pass metabolism issues. It is rapidly metabolized in vivo by CYP2D6 into an O-demethylated byproduct, which is then further metabolized into a highly polar compound and excreted. Bupropion, a mild to moderate CYP2D6 inhibitor, can improve the metabolism of dextromethorphan when used in combination, increasing its AUC and Cmax by more than 20. While AVEULITY addresses the metabolic issues of dextromethorphan as a combination formulation, it also introduces potential drug-drug interactions. Furthermore, due to dextromethorphan's relatively weak NMDAR antagonistic activity, its onset of action within one week is still not comparable to esketamine.

[0012] The success of AUVELITY demonstrates that further improving the NMDAR / SERT dual-target activity and pharmacometabolic properties of dextromethorphan is the right approach to discovering novel, rapid-acting antidepressants. Such drugs should not only retain the rapid onset of action of esketamine but also avoid the dissociation and addiction side effects associated with esketamine monotherapy, as well as the drug-drug interactions associated with combination formulations. Based on its safety and efficacy, this class of drugs will have access to a wider patient population and a simpler method of administration. Summary of the Invention

[0013] The purpose of this invention is to provide a benzomorphine analogue, its preparation method, and its uses.

[0014] In a first aspect, the present invention provides a compound of formula X or X', or a stereoisomer, geometric isomer, tautomer, conformational isomer, or a pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or mixture thereof:

[0015] in:

[0016] X and Y are each independently CR1 or N;

[0017] A1, A2, A3, and A4 are each independently CR a R b , O or NR c ;

[0018] R a R b and R c Each can be independently H, halogen, C 1-6 Alkyl, C 1-6 Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 alkyl-CO-, wherein the C 1-6 Alkyl, C 1-6Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO- may optionally be replaced by halogen or deuterium;

[0019] Each R1 group can be independently hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups having 1-3 heteroatoms selected from N, O, and S, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, formamido, C 1-6 Alkyl-NH-, C 1-6 Alkyl-O-, C 1-6 Deuterated alkyl-O-, C 3-6 cycloalkyl-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-, carbamoyl, C 1-6 Alkyl-NH-CO-, (C 1-6 Alkyl)2N-CO-, C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-CO-, C 3-6 Cycloalkyl-CO-NH-, amino-substituted C 1-6 Alkyl-NH-CO-, amino-substituted C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-NH-C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-NH-CO-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-CO-NH-, (C 1-20 Alkyl)2N-C 1-6 Alkyl-NH-CO-, (C 1- 20 Alkyl)2N-C 1-6 Alkyl-CO-NH-, C 1-20 Alkoxy-C 1-6 Alkyl-NH-CO-, C 1-20 Alkoxy-C 1-6 Alkyl-CO-NH-, C 6-14 Aryl-NH-C 1-6Alkyl-NH-CO-, C 6-14 Aryl-NH-C 1-6 Alkyl-CO-NH- or (3-6 membered heterocyclic group) (C 1-6 (alkyl)N-CO-; wherein R1 is optionally substituted with one, two or three halogens or oxo groups;

[0020] Alternatively, any two adjacent R1s and the carbon atoms connected to R1 together form a 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S is optionally substituted by 1, 2 or 3 methyl or halogen.

[0021] R2 and R3 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH- or 5-15 heteroaryl-NH-, wherein R2 and R3 are optionally substituted with one, two or three halogens;

[0022] Alternatively, the carbon atom bonded to R2, the carbon atom bonded to R3, and C 1-3 The alkylene groups together form a 3-6 membered carbon ring, wherein the 3-6 membered carbon ring is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkoxy;

[0023] R4 is hydrogen, deuterium, halogen, optionally substituted hydroxyl, mercapto, cyano, nitro, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-CO-O-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1- 6-alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, 5-15 membered heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-; the hydroxyl group is optionally selected from C 1-6 Alkyl and C 1-6 Alkyl-CO- substituents;

[0024] R5 represents hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 6-14 aryl-substituted C 1-6 alkyl, 5-15 membered heteroaryl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, C 3-6C with heterocyclic substitution 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0025] Alternatively, the carbon atom connected to R4, the carbon atom marked with "*", the nitrogen atom connected to R5, and R4 and R5 together form a 6-8 membered ring;

[0026] R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, hydroxyl-substituted amino, C 1-4 Alkyl, C 3- 6-cycloalkyl or C 1-4 Alkoxy-substituted amino groups;

[0027] Represents a double bond or a single bond;

[0028] m and n are each independently 0, 1, 2 or 3.

[0029] A second aspect of the present invention provides a pharmaceutical composition comprising (1) a therapeutically effective amount of a compound of formula X or X' as described in any one of claims 1-8, or a stereoisomer, geometric isomer, tautomer, conformational isomer, or a pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or a mixture thereof; and (2) a pharmaceutically acceptable carrier.

[0030] A third aspect of the invention provides applications selected from the group consisting of:

[0031] (1) The use of the compound of formula X or formula X' of the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition of the second aspect of the present invention in the preparation of NMDA receptor antagonists.

[0032] (2) The use of the compound of formula X or formula X' described in the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition described in the second aspect of the present invention in the preparation of 5-hydroxytryptamine transtransporter inhibitors.

[0033] (3) The use of the compound of formula X or formula X' described in the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotope-labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition described in the second aspect of the present invention in the preparation of drugs that regulate NMDAR / SERT dual targets;

[0034] (4) The use of the compound of formula X or formula X' described in the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the treatment and / or prevention of NMDAR-related diseases;

[0035] (5) The use of the compound of formula X or formula X' of the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition of the second aspect of the present invention in the preparation of a medicament for the treatment and / or prevention of SERT-related diseases;

[0036] (6) The use of the compound of formula X or formula X' described in the first aspect of the present invention, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the treatment and / or prevention of NMDAR / SERT dual-target related diseases.

[0037] The present invention has the following beneficial effects:

[0038] This invention provides an active ingredient that simultaneously antagonizes NMDAR activity and inhibits SERT activity (the compounds of formula I, II, III, IV, V, VI, A, and B of this invention, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof), which can be used to treat and / or prevent diseases related to NMDA receptors and / or serotonin transporters, particularly central nervous system diseases, and the active ingredient of this invention has better metabolic stability.

[0039] This invention provides an active ingredient that simultaneously antagonizes NMDAR activity and inhibits SERT activity (compounds of formulas I, II, III, IV, V, VI, A, and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof). This active ingredient exhibits significantly superior technical effects compared to single-target drugs. Preclinical studies have shown a rapid-onset antidepressant effect, and it is expected to significantly shorten the onset time of antidepressant treatment and improve the treatment response rate in clinical applications. Simultaneously, it avoids the adverse reactions associated with potent single-mechanism NMDAR antagonists, such as addiction, hallucinations, and dissociation, and has a lower risk of abuse. Attached Figure Description

[0040] Figure 1 shows the results of an in vivo study of the effects of spontaneous activity on compound 1 (5, 10 and 20 mg / kg), solvent control and clonidine (1 mg / kg) of the present invention in mice.

[0041] Figure 2 shows the results of the efficacy test of compound 1 (5, 10 and 20 mg / kg), fluoxetine (10 mg / kg), ketamine (20 mg / kg) and solvent control in a mouse model of chronic unpredictable mild stress (CUMS).

[0042] Figure 3 shows the results of the efficacy test of compound 1 (10 and 20 mg / kg), fluoxetine (10 mg / kg), esketamine (10 mg / kg), and solvent control in a mouse model of chronic social frustration stress (CSDS).

[0043] Figure 4 shows the results of compound 1 of the present invention (20, 40 and 80 mg / kg), esketamine (20 mg / kg) and solvent control in the mouse conditional position preference (CPP) test. Detailed Implementation

[0044] To enable those skilled in the art to understand the features and effects of the present invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding the present invention, and in case of conflict, the definitions in this specification shall prevail.

[0045] The theories or mechanisms described and disclosed herein, whether right or wrong, should not in any way limit the scope of the invention, that is, the contents of the invention can be implemented without being limited by any particular theory or mechanism.

[0046] In this document, the terms “contains,” “includes,” “containing,” and similar terms encompass the meanings of “basically composed of” and “composed of.” For example, when this document discloses “A contains B and C,” “A is basically composed of B and C” and “A is composed of B and C” should be considered as having been disclosed in this document.

[0047] In this document, all features defined by numerical ranges or percentage ranges, such as numerical values, quantities, contents, and concentrations, are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual numerical values ​​(including integers and fractions) within those ranges.

[0048] Unless otherwise specified, percentages refer to mass percentages and proportions refer to mass ratios in this article.

[0049] In this document, when describing embodiments or examples, it should be understood that it is not intended to limit the invention to those embodiments or examples. Rather, all alternatives, modifications, and equivalents of the methods and materials described herein are covered within the scope defined by the claims.

[0050] For the sake of brevity, not all possible combinations of the technical features in each implementation scheme or embodiment are described herein. Therefore, as long as there is no contradiction in the combination of these technical features, the technical features in each implementation scheme or embodiment can be combined arbitrarily, and all possible combinations should be considered within the scope of this specification.

[0051] The "therapeutic effective amount" of the compounds of this invention refers to the amount of the compounds of this invention that can induce a biological or medical response in an individual, or improve symptoms, slow or delay disease progression, or prevent disease, etc. The "therapeutic effective amount" can be determined by the participating physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the individual's age and related health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0052] As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. "Individual" also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the individual is a human being.

[0053] As used in this article, “inhibition” refers to the reduction or suppression of a specific patient, symptom, condition, or disease, or a significant reduction in biological activity or baseline activity of a process.

[0054] As used herein, in one embodiment, the term "treatment" refers to improving a disease or condition (i.e., halting or slowing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to improving at least one bodily parameter, which may not be perceptible to the patient. In yet another embodiment, "treatment" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both.

[0055] As used herein, “prevention” means administering one or more pharmaceutical substances, particularly the compounds of the present invention and / or their pharmaceutically acceptable salts, to an individual with a predisposition to the disease in order to prevent the individual from contracting the disease.

[0056] Unless otherwise stated, the groups in this document are defined as follows:

[0057] As used herein, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, or bromine; more preferably fluorine or chlorine.

[0058] As used in this article, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, such as C10. 1-6 Alkyl refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl or isobutyl.

[0059] As used in this article, "halogenated C" 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms, in which the hydrogen atoms are replaced by one or more identical or different halogen atoms; "halogenated C" refers to a alkyl group. 1-4 Alkyl groups follow the same pattern, such as trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, dichlorofluoromethyl, chloroethyl, bromopropyl, 2-chlorobutyl, or pentafluoroethyl, etc.

[0060] As used herein, "alkylene" refers to a group that is identical to an alkyl group but has a divalent oxidation state. Specifically, alkylene groups are those having 1 to 20 carbon atoms ("C..."). 1-20 Alkylenes ("alkylene") typically contain 1-12 carbon atoms (C1-C2). 1-12 Alkylene), preferably containing 1-6 carbon atoms (C 1-6Alkylene), more preferably containing 1-4 carbon atoms (C 1-4 Alkylenes. Examples of alkylenes include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), etc. In this document, alkylenes are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1- 6-alkyl, hydroxy-substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1- 3-alkyl substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkyl group. In a preferred embodiment, the alkylene group is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, with C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-4 Alkoxy, C 1- 4-alkyl-S-, halo-C 1-4 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-3 Alkoxy, C 6-10 Aryl, 5-6 quinone heteroaryl, C 6-10 aryl-substituted C 1-4 C-substituted with alkoxy and 5-6 heteroaryl groups 1-4Alkoxy. In a preferred embodiment, the alkylene group is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, hydroxyl, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methylcyclopropyloxy, methoxy, ethoxy, isopropoxy, isobutoxy, methylthio, cyclopropyl, cyclopropyloxy, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), difluoromethoxy, trifluoromethoxy, 1,1,1,-trifluoroethoxy, cyano, cyclopropylmethoxy, acetoxy, phenyl, pyridyl and benzyloxy.

[0061] As used in this article, "C" 1-6 "Alkoxy" refers to straight-chain or branched alkoxy groups containing 1-6 carbon atoms (e.g., C1 alkoxy, C2 alkoxy, C3 alkoxy, C4 alkoxy, C5 alkoxy, C6 alkoxy). 1-4 Alkoxy, C 1-3 "Alkoxy" follows the same pattern, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, isohexoxy, 3-methylpentoxy or n-hexoxy, etc., preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy.

[0062] As used in this article, "halogenated C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms, where the hydrogen atom is replaced by one or more identical or different halogen atoms. "Halogenated C" 1-4 The same applies to alkoxy groups, such as -OCF3, -OCH2CH2Cl, -OCHBrCH2Cl, or -OCF2CF3.

[0063] As used in this article, "oxo" means "=O", that is, the oxygen atom is connected to other atoms through a double bond.

[0064] As used in this article, "being C" 1-6 "Alkyl-substituted amino" refers to an amino group in which the hydrogen atom is replaced by one or two identical or different carbon atoms. 1-6 Alkyl substitution, such as -NHMe, -NHEt, -N(Me)Et or -NEt2, etc.

[0065] As used in this article, "C" 1-6 Alkoxy C 1-6 Alkyl or C 1-6 alkoxy-substituted C 1-6 "alkyl" refers to C 1-6 The oxygen atom of the alkoxy group and C 1-6 Alkyl linkage, such as -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2CH2OCH3.

[0066] As used in this article, "C" 1-6 "Alkoxycarbonyl" refers to C 1-6 The oxygen atom of an alkoxy group is attached to a carbonyl group, for example, -C=OOCH2CH3, -C=OOCH2CH2CH3, -C=OOCH2CH(CH3). 2 wait.

[0067] As used herein, "cycloalkyl" or "carbocyclic" refers to a saturated cyclic hydrocarbon having 3 to 13 ring carbon atoms, comprising one ring such as cyclohexyl or multiple rings such as adamantyl. Cycloalkyl compounds comprising more than one ring can be fused, spirocyclic, bridged, or combinations thereof. Preferred cycloalkyl compounds are saturated cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C..."). 3-8 Cycloalkyl groups, such as C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl, C6-cycloalkyl, C7-cycloalkyl, and C8-cycloalkyl. Examples of cycloalkyl groups include adamantyl, decahydronaphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0068] As used in this article, "hydroxyl group" refers to the -OH group.

[0069] As used in this article, "hydroxyl C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group containing 1-6 carbon atoms, with one carbon atom connected to a hydroxyl group, such as -CH2OH, -CH2CH2OH, -(CHOH)CH3, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, or -CH2CH(CH3)CH2OH, etc.

[0070] As used in this article, "C" 6-14 "Aryl" refers to a monocyclic or polycyclic aromatic cyclic group containing 6-14 ring atoms but without heteroatoms. 6-10 "Aryl" follows the same pattern, for example, phenyl and naphthyl.

[0071] As used herein, 3-10 membered cycloalkyl refers to a saturated or unsaturated monocyclic hydrocarbon group containing 3-10 carbon atoms, preferably having 3-8 or 5-8 carbon atoms, more preferably having 5-6 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, etc.

[0072] As used in this article, "C" 6-14 Aryl C 1-6 "alkyl" refers to C 6-14 Aryl and C 1-6 Alkyl linkage, such as benzyl, phenethyl, phenylpropyl, etc.

[0073] As used in this article, "C" 3-6 cycloalkyl C1-6 "alkylyl" refers to C 3-6 The cyclic carbon and C of cycloalkyl 1-6 An alkyl group is attached to an alkyl carbon, such as cyclopropylformyl, cyclopropylacetyl, cyclobutylformyl, cyclopentylformyl, etc.

[0074] As used in this article, "C" 6-14 Aryl C 1-6 "alkylyl" refers to C 6-14 Aryl and C 1-6 An alkyl group is attached to an alkyl carbon, such as benzoyl or phenylacetyl.

[0075] As used in this article, "C" 3-6 cycloalkyl C 1-6 "alkyl" refers to C 3-6 cycloalkyl and C 1-6 Alkyl linkage, such as cyclopropylmethyl, cyclobutylmethyl, etc.

[0076] As used herein, "heterocyclic" refers to a monocyclic or polycyclic group containing at least one heteroatom selected from N, O, and S as a ring member. It can be aromatic or non-aromatic, and is preferably a monocyclic group. 4-10 membered heterocycles refer to heterocyclic groups containing 4 to 10 ring atoms, such as pyridinyl, piperidinyl, morpholinyl, furanyl, thiophene, thiazolyl, imidazolyl, pyrroleyl, pyrazine, pyridazine, and pyrimidinyl.

[0077] As used herein, "heterocyclic group" refers to a saturated monocyclic or polycyclic group containing at least one heteroatom selected from N, O, and S as a ring member. 3-9 membered heterocyclic alkyl groups include azirrocyclic butyl, pyrrolidinyl, piperidinyl, azirrocyclic heptyl, morpholinyl, etc.

[0078] As used herein, "heteroaryl" or "heteroary ring" refers to a monocyclic or bicyclic aromatic ring group containing at least one heteroatom selected from N, O, or S as a ring member; 5-10-membered heteroaryls include, but are not limited to, the following groups: pyrrole, imidazolyl, pyrazolyl, 1,2,3-triazolyl, pyridinyl, pyridonel, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, etc. The heteroaryls described herein include 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 13-membered, 14-membered, and 15-membered heteroaryls.

[0079] As used herein, the terms "optional," "optionally," or "optionally" mean that the events described below may or may not occur, and the description includes both cases where the events occur and cases where they do not occur. For example, "optionally substituted alkyl" includes both "unsubstituted alkyl" and "substituted alkyl" as defined herein. "Optionally substituted with halogen" includes both cases where the alkyl is substituted with halogen and cases where it is not substituted with halogen, such as substitution with 0-3 halogens. Those skilled in the art will understand that, for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and / or inherently unstable. In this invention, an optionally substituted hydroxyl group refers to a hydroxyl group or a hydrogen atom on a hydroxyl group being replaced by another substituent.

[0080] The compounds of the present invention also include solvate forms, such as hydrates, alcohols, etc., and said solvates are also included within the scope of the present invention.

[0081] Pharmaceutically acceptable salts of the compounds of this invention refer to the conversion of the compound or its stereoisomers into a therapeutically active, non-toxic addition salt form by treating them with a suitable acid. Examples of such salts include hydrochlorides, hydrobroms, hydroiodates, sulfates or hydrogen sulfates, nitrates, phosphates or acid phosphates, perchlorates, formates, acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates, malonates, succinates, glutarate, maleates, fumarates, lactates, malates, citrates, tartrates, picrates, glutamates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, salicylates, ascorbic acid salts, camphorates, or camphorsulfonates. Conversely, treatment with an alkali can also convert the salt form into a free base form.

[0082] The term "pharmaceutically acceptable salt" as used above also includes their solvates, and these solvates are included within the scope of this invention. Examples of solvates include, for example, hydrates, alcohols, etc.

[0083] Those skilled in the art will recognize that the compounds of the present invention may contain a chiral center, thereby allowing for different isomeric forms. As used herein, "isomer" refers to different compounds having the same molecular formula but differing in the arrangement and configuration of their atoms.

[0084] "Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or two main categories: enantiomers and diastereomers.

[0085] In this embodiment, straight solid line keys are used. and straight dashed key The relative configurations of the stereocenters are indicated in this application, which include all cis, trans, syn, anti, engegen (E), and zusammen (Z) isomers and suitable mixtures thereof. For example: express A mixture of two structures; express A mixture of two structures.

[0086] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to refer to racemic mixtures. When indicating the stereochemistry of the compounds of the present invention, a single stereoisomer with known relative and absolute configurations (e.g., (1S,2S)) having two chiral centers is designated using the conventional RS system; a single stereoisomer with a known relative configuration but an unknown absolute configuration is indicated by an asterisk (e.g., (1R*,2R*)); and a racemic mixture with two letters (e.g., (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) is a racemic mixture of (1R,2S) and (1S,2R)). "Diarrhetomers" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is indicated according to the Cahn-Lingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be described by R or S. The resolved compounds with unknown absolute configurations can be designated as (+) or (-) based on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D line wavelength. Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers and diastereomers via chiral HPLC.

[0087] Geometric isomerism can occur when a compound contains a double bond or other features that give the molecule a certain degree of structural rigidity. If the compound contains a double bond, the substituent can be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration.

[0088] "Conformation isomers" are isomers that differ by rotation of one or more valence bonds.

[0089] "Tautomer" refers to an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0090] "Polymorphic" refers to a crystalline form having the same chemical structure / composition but different spatial arrangements of the molecules and / or ions forming the crystals. The compounds of this invention can be provided as amorphous solids or crystalline solids. Freeze-drying can be used to provide solid compounds of this invention.

[0091] "Solvate" refers to a physical combination of the compound of the present invention with one or more organic or inorganic solvent molecules. Such physical combination includes hydrogen bonds. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" includes solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0092] The present invention also includes all suitable isotopic variants of the compounds of the present invention or pharmaceutically acceptable salts thereof.

[0093] Isotopic variants of the compounds of the present invention or their pharmaceutically acceptable salts are defined as those in which at least one atom is replaced by an atom having the same number of atoms but a different atomic mass than that commonly found in nature. Isotopes that can be incorporated into the compounds of the present invention and their pharmaceutically acceptable salts include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 12 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18 F, 36 C1 and 125 I. Isotopic variants of the compounds described in this invention or of their pharmaceutically acceptable salts can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.

[0094] In this document, the alkyl and cycloalkyl groups are each optionally selected from halogen, hydroxyl, carboxyl, mercapto, amino, C... 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 6-14 Aryl and C 1-4 The alkoxy group is substituted with a substituent. Preferably, the alkyl and cycloalkyl groups are each optionally replaced by one, two, or three groups selected from halogens, hydroxyl groups, carboxyl groups, mercapto groups, amino groups, and C6 groups. 1-4 Substitution of alkoxy groups.

[0095] In this document, the aryl and heteroaryl groups are each optionally substituted by 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkyl group. In a preferred embodiment, the aryl and heteroaryl groups are each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, with C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-4 Alkoxy, C 1- 4-alkyl-S-, halo-C 1-4 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-3 Alkoxy C 6-10 Aryl, 5-6 quinone heteroaryl, C 6-10 aryl-substituted C 1-4 C-substituted with alkoxy and 5-6 heteroaryl groups 1-4Alkoxy. In a preferred embodiment, the aryl and heteroaryl groups are each optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, hydroxyl, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methylcyclopropyloxy, methoxy, ethoxy, isopropoxy, isobutoxy, methylthio, cyclopropyl, cyclopropyloxy, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), difluoromethoxy, trifluoromethoxy, 1,1,1,-trifluoroethoxy, cyano, cyclopropylmethoxy, acetoxy, phenyl, pyridyl and benzyloxy.

[0096] Dual-target compounds

[0097] This invention provides a compound of formula X or X', or a stereoisomer, geometric isomer, tautomer, or conformational isomer thereof, or a pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound thereof, or a mixture thereof:

[0098] in:

[0099] X and Y are each independently CR1 or N;

[0100] A1, A2, A3, and A4 are each independently CR a R b , O or NR c ;

[0101] R a R b and R c Each can be independently H, halogen, C 1-6 Alkyl, C 1-6 Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 alkyl-CO-, wherein the C 1-6 Alkyl, C 1-6 Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO- may optionally be replaced by halogen or deuterium;

[0102] Each R1 group can be independently hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups having 1-3 heteroatoms selected from N, O, and S, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, formamido, C 1-6 Alkyl-NH-, C1-6 Alkyl-O-, C 1-6 Deuterated alkyl-O-, C 3-6 cycloalkyl-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-, carbamoyl, C 1-6 Alkyl-NH-CO-, (C 1-6 Alkyl)2N-CO-, C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-CO-, C 3-6 Cycloalkyl-CO-NH-, amino-substituted C 1-6 Alkyl-NH-CO-, amino-substituted C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-NH-C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-NH-CO-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-CO-NH-, (C 1-20 Alkyl)2N-C 1-6 Alkyl-NH-CO-, (C 1- 20 Alkyl)2N-C 1-6 Alkyl-CO-NH-, C 1-20 Alkoxy-C 1-6 Alkyl-NH-CO-, C 1-20 Alkoxy-C 1-6 Alkyl-CO-NH-, C 6-14 Aryl-NH-C 1-6 Alkyl-NH-CO-, C 6-14 Aryl-NH-C 1-6 Alkyl-CO-NH- or (3-6 membered heterocyclic group) (C 1-6 (alkyl)N-CO-; wherein R1 is optionally substituted with one, two or three halogens or oxo groups;

[0103] Alternatively, any two adjacent R1s and the carbon atoms connected to R1 together form a 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S is optionally substituted by 1, 2 or 3 methyl or halogen.

[0104] R2 and R3 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH- or 5-15 heteroaryl-NH-, wherein R2 and R3 are optionally substituted with one, two or three halogens;

[0105] Alternatively, the carbon atom bonded to R2, the carbon atom bonded to R3, and C 1-3 The alkylene groups together form a 3-6 membered carbon ring, wherein the 3-6 membered carbon ring is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkoxy;

[0106] R4 is hydrogen, deuterium, halogen, optionally substituted hydroxyl, mercapto, cyano, nitro, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-CO-O-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1- 6-alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, 5-15 membered heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-; the hydroxyl group is optionally selected from C 1-6 Alkyl and C 1-6 Alkyl-CO- substituents;

[0107] R5 represents hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 6-14 aryl-substituted C 1-6 alkyl, 5-15 membered heteroaryl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, C 3-6 C with heterocyclic substitution 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group;

[0108] Alternatively, the carbon atom connected to R4, the carbon atom marked with "*", the nitrogen atom connected to R5, and R4 and R5 together form a 6-8 membered ring;

[0109] R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, hydroxyl-substituted amino, C 1-4 Alkyl, C 3- 6-cycloalkyl or C 1-4 Alkoxy-substituted amino groups;

[0110] Represents a double bond or a single bond;

[0111] m and n are each independently 0, 1, 2 or 3.

[0112] This invention provides compounds of formula I and formula A:

[0113] in:

[0114] X and Y can be independently represented as CH or N;

[0115] A1, A2, A3, and A4 are each independently CR a R b , O or NR c R a R b and R c Each is independent as H and C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO-;

[0116] Each R1 group can be independently hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 3- 6-cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-, carbamoyl, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-CO-, C 3-6 Cycloalkyl-CO-NH-, amino-substituted C 1-6 Alkyl-NH-CO-, amino-substituted C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-NH-C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-NH-CO-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-CO-NH-, (C 1-20Alkyl)2N-C 1-6 Alkyl-NH-CO-, (C 1-20 Alkyl)2N-C 1-6 Alkyl-CO-NH-, C 1-20 Alkoxy-C 1- 6-alkyl-NH-CO-, C 1-20 Alkoxy-C 1-6 Alkyl-CO-NH-, C 6-14 Aryl-NH-C 1-6 Alkyl-NH-CO-, C 6-14 Aryl-NH-C 1-6 Alkyl-CO-NH- or (3-6 membered heterocyclic group) (C 1-6 alkyl)N-CO-, wherein the hydroxyl group is optionally selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and C3-C8 cycloalkyl groups are substituted; or, any two adjacent R1s, the carbon atoms attached to R1s, and 1, 2, or 3 heteroatoms selected from N, O, and S form a 5-10 membered ring.

[0117] Each R2 and each R3 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, or C. 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6- 14 aryl-NH- or 5-15-membered heteroaryl-NH-; or, the carbon atom connected to R2, the carbon atom connected to R3, and the C1-C3 alkylene group together form a 3-5-membered carbon ring, wherein the C1-C3 alkylene group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1- 6-alkyl, hydroxy-substituted C 1-6Alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, C1-C3 alkyl-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted C3-C6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C3-C6 cycloalkyl substituted C 1-6 Alkoxy, C6-C14 aryl, 5-10 heteroaryl groups having 1, 2, or 3 heteroatoms selected from N, O, and S, and C6-C14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkoxy groups, R2 and R3 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1- 6-alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH- or 5-15 heteroaryl-NH-;

[0118] R4 is hydrogen, deuterium, halogen, optionally substituted hydroxyl, mercapto, cyano, nitro, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C1-6 alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, 5-15 membered heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-; the hydroxyl group is optionally selected from C1-6 Alkyl and C 1-6 Alkyl-CO- substituents;

[0119] R5 is hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C6-C14 aryl-substituted C 1-6 alkyl, 5-15 membered heteroaryl substituted C 1-6 Alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic, C3-C6 cycloalkyl-substituted C 1-6 Alkyl, C3-C6 heterocyclic substituted C 1- 6-alkyl, C2-C6 alkenyl, or C2-C6 ynyl;

[0120] Alternatively, the carbon atom connected to R4, the carbon atom marked with "*", the nitrogen atom connected to R5, and R4 and R5 together form a 6-8 membered ring;

[0121] R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, hydroxyl-substituted amino, C1-C4 alkyl, C 3-6 Cycloalkyl or C1-C4 alkoxy-substituted amino groups;

[0122] Represents a double bond or a single bond;

[0123] m and n are each independently 0, 1, 2 or 3.

[0124] In some embodiments, the present invention provides compounds of formula I and formula A:

[0125] in:

[0126] X and Y can be independently represented as CH or N;

[0127] A1, A2, A3, and A4 are each independently CR a R b , O or NR c R a R b and R c Each is independent as H and C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO-;

[0128] Each R1 group can be independently hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, amino, or C.1-6 Alkyl, C 2-6 alkenyl, C 3- 6-cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH-, 5-15 heteroaryl-NH-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-CO-, C 3-6 Cycloalkyl-CO-NH-, amino-substituted C 1-6 Alkyl-NH-CO-, amino-substituted C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-NH-C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-NH-CO-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-CO-NH-, (C 1- 20 Alkyl)2N-C 1-6 Alkyl-NH-CO-, (C 1-20 Alkyl)2N-C 1-6 Alkyl-CO-NH-, C 1-20 Alkoxy-C 1-6 Alkyl-NH-CO-, C 1-20 Alkoxy-C 1-6 Alkyl-CO-NH-, C 6-14 Aryl-NH-C 1-6 Alkyl-NH-CO-, C 6-14 Aryl-NH-C 1-6 Alkyl-CO-NH- or (3-6 membered heterocyclic group) (C 1-6 alkyl)N-CO-, wherein the hydroxyl group is optionally selected from C 1-6 Alkyl, deuterated C 1-6 Alkyl groups and C3-C8 cycloalkyl groups are substituted; or, any two adjacent R1s, the carbon atoms attached to R1s, and 1, 2, or 3 heteroatoms selected from N, O, and S form a 5-10 membered ring.

[0129] Each R2 and each R3 is independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, or C. 1- 6-alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6- 14 aryl-NH- or 5-15-membered heteroaryl-NH-; or, the carbon atom connected to R2, the carbon atom connected to R3, and the C1-C3 alkylene group together form a 3-5-membered carbon ring, wherein the C1-C3 alkylene group is optionally substituted by 1, 2, or 3 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1- 6-alkyl, hydroxy-substituted C 1-6 Alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl-O-, C1-C3 alkyl-substituted C3-C6 cycloalkyl, C1-C3 alkyl-substituted C3-C6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C3-C6 cycloalkyl substituted C 1-6 Alkoxy, C6-C 14 aryl, 5-10 heteroaryl with 1, 2 or 3 heteroatoms selected from N, O and S, C6-C 14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkoxy groups, R2 and R3 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH- or 5-15 heteroaryl-NH-;

[0130] R4 is hydrogen, deuterium, halogen, optionally substituted hydroxyl, mercapto, cyano, nitro, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, 5-15 membered heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-; the hydroxyl group is optionally selected from C 1-6 Alkyl and C 1-6 Alkyl-CO- substituents;

[0131] R5 is hydrogen, C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C6-C 14 aryl-substituted C 1-6 alkyl, 5-15 membered heteroaryl substituted C 1-6 Alkyl, C3-C6 cycloalkyl, C3-C6 heterocyclic, C3-C6 cycloalkyl-substituted C 1-6 Alkyl, C3-C6 heterocyclic substituted C 1-6 Alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;

[0132] Alternatively, the carbon atom connected to R4, the carbon atom marked with "*", the nitrogen atom connected to R5, and R4 and R5 together form a 6-8 membered ring;

[0133] R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, hydroxyl-substituted amino, C1-C4 alkyl, C 3-6 Cycloalkyl or C1-C4 alkoxy-substituted amino groups;

[0134] Represents a double bond or a single bond;

[0135] m and n are each independently 0, 1, 2 or 3.

[0136] In some implementations, R1 is H or optionally selected from C. 1-6 Alkyl, deuterated C 1-6 Alkyl and C 3-8 The hydroxyl group is substituted with a cycloalkyl substituent. Preferably, R1 is optionally selected from C1. 1-6 Alkyl, deuterated C 1-6 Alkyl and C 3-8 The hydroxyl group is substituted with a cycloalkyl substituent. Preferably, R1 is optionally selected from C1. 1-3 Alkyl, deuterated C 1-3 The hydroxyl group is substituted with an alkyl or cyclopropyl substituent. Preferably, R1 is a hydroxyl group optionally substituted with a methyl or deuterated methyl (-CD3). More preferably, R1 is a methoxy group.

[0137] In some embodiments, R1 is carbamoyl.

[0138] In some embodiments, R1 is a trideuterated methoxy group.

[0139] In some embodiments, the 5-10 membered ring is an aromatic ring or a non-aromatic ring, preferably a 5-10 membered heteroaromatic ring.

[0140] In some embodiments, the 5-10 membered ring is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1- 6-alkyl, hydroxy-substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1- 3-alkyl substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkyl group. In a preferred embodiment, the 5-10 membered ring is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of: halogen, cyano, hydroxyl, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl substituted C 1-4 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, with C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-4 Alkoxy, C 1- 4-alkyl-S-, halo-C 1-4 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-3 Alkoxy, C 6-10 Aryl, 5-6 quinone heteroaryl, C 6-10 aryl-substituted C 1-4 C-substituted with alkoxy and 5-6 heteroaryl groups 1-4 Alkyl group. In a preferred embodiment, the 5-10 membered ring is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of: fluorine, chlorine, bromine, cyano, hydroxyl, methyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methylcyclopropyloxy, methoxy, ethoxy, isopropoxy, isobutoxy, methylthio, cyclopropyl, cyclopropyloxy, carbamoyl (NH₂CO₃⁻), aminosulfonyl (NH₂SO₂⁻), difluoromethoxy, trifluoromethoxy, 1,1,1-trifluoroethoxy, cyano, cyclopropylmethoxy, acetoxy, phenyl, pyridyl, and benzyloxy. In some embodiments, the 5-10 membered ring is optionally substituted with 1 or 2 C⁻. 1-6 Alkyl substitution.

[0141] In some embodiments, any two adjacent R1 atoms, the carbon atom connected to R1, and one or two nitrogen atoms form a 5-7 membered ring; preferably, any two adjacent R1 atoms, the carbon atom connected to R1, and two nitrogen atoms form a 5-membered nitrogen-containing heteroaromatic ring.

[0142] In some implementations, each R2 and each R3 is independently selected from H, halogen, C. 1-6 Alkyl and C 1-6 Alkyl groups. Preferably, each R2 and each R3 is independently selected from H, halogens, and C. 1-6 Alkyl group. In some embodiments, each R2 and each R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, and C. 1-4 Alkyl group. In some embodiments, each R2 and each R3 is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C... 1-6 Alkyl, C 3-6 cycloalkyl, 5-15 membered heteroaryl and C 6-14 Aryl.

[0143] In some implementations, the carbon atom bonded to R2, the carbon atom bonded to R3, and C 1-3 Alkyl groups together form a 3-5 membered carbon ring, wherein the C 1-3 The alkylene group may be optionally substituted with one, two, or three halogens, preferably F; R2 and R3 are each independently hydrogen, deuterium, halogen, or C. 1-6 Alkyl and C 1-6 Alkoxy group, wherein the halogen is preferably F.

[0144] In some embodiments, R2 is hydrogen, deuterium, methyl, trideuterated methyl, F, or Cl.

[0145] In some embodiments, R3 is hydrogen, deuterium, methyl, trideuterated methyl, F, or Cl.

[0146] In some implementations, R4 is H, halogen, C 1-6 Alkyl groups or optionally selected from C 1-6 Alkyl and C 1-6 The alkyl-CO- substituent replaces the hydroxyl group. In some embodiments, R4 is hydrogen, deuterium, fluorine, hydroxyl, mercapto, cyano, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Alkyl-S- or C 1-6 Alkyl-CO2-.

[0147] In some implementations, R5 is H, C 1-6 Alkyl, C 1-6 Alkoxy, deuterated C 1-6 Alkyl or deuterated C 1-6 Alkyloxy group. In some embodiments, R5 is hydrogen, C 1-4 Alkyl, deuterated C 1-4 Alkyl, Halogenated C 1-4 Alkyl, C 1-4 alkoxy-substituted C 1- 4-alkyl, hydroxyl-substituted C1-4 Alkyl, C 6-14 aryl-substituted C 1-4 alkyl, 5-15 membered heteroaryl substituted C 1-4 Alkyl, C 3- 6 heterocyclic group, C 3-6 C with heterocyclic substitution 1-4 Alkyl, C 2-6 alkenyl or C 2-6 Alkyne group; preferably, R5 is hydrogen or C 1-4 Alkyl groups (especially methyl, ethyl, propyl, isopropyl, tert-butyl), halogenated C 1-4 Alkyl groups (especially 1,1,1-trifluoroethyl, 1-fluoroethyl), methoxyethyl, hydroxyethyl, C 3-6 Cycloalkyl-substituted methyl groups (especially cyclopropylmethyl, cyclobutylmethyl, and glycidyl oxybutanemethyl), C 3-6 C with heterocyclic substitution 1-4 Alkyl (especially methyl groups substituted with epoxide), benzyl, C 3-6 Cycloalkyl groups (especially cyclopropyl groups).

[0148] In some embodiments, R5 is selected from methyl, trideuterated methyl, or hydrogen.

[0149] In some embodiments, the carbon atom bonded to R4, the carbon atom marked with an asterisk (*), the nitrogen atom bonded to R5, and R4 and R5 together form a 6-8 membered ring; in addition to the nitrogen atom bonded to R5, the 6-8 membered ring also includes 0, 1, or 2 heteroatoms selected from N, O, and S. Preferably, in addition to the nitrogen atom bonded to R5, the 6-8 membered ring also includes 0 or 1 N or O atom. In some embodiments, the 6-8 membered ring also includes one oxygen atom, which is preferably directly bonded to the carbon atom bonded to R4.

[0150] In some implementations, R6 and R7 are each independently hydrogen or deuterium.

[0151] In some implementations, A1, A2, A3, and A4 are each independently a CR. a R b Or O; or A1, A2, A3, and A4 can each be independently CR. a R b or NR c In some implementations, one of A1, A2, A3, and A4 is 0 or NR. c The rest are CR a R b In some implementations, A1 is NR. c A2, A3, and A4 are all CR a R b In some implementations, A4 is CR.a R b One of A1, A2, and A3 is 0, and the rest are CR. a R b In some implementations, R a and R b All are H. In some implementations, R c C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO-.

[0152] In some implementations, X is CH and Y is N; or X is N and Y is CH; or both X and Y are CH. Preferably, both X and Y are CH.

[0153] In some embodiments, the compound of formula I has the structure shown in formula B:

[0154] in:

[0155] The ring C is a 5-10 membered heteroaromatic ring having 1, 2, or 3 heteroatoms selected from N, O, and S; the ring C is optionally surrounded by 1, 2, or 3 heteroatoms selected from hydroxyl, amino, nitro, deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 3-8 Substituents of cycloalkyl groups;

[0156] The definitions of X, Y, m, n, R4, R5, R6, R7, R2, and R3 are as described in any of the embodiments herein.

[0157] In some embodiments, ring C is a 5-10 membered heteroaromatic ring having 1, 2, or 3 N atoms, preferably a 5-7 membered heteroaromatic ring having 1, 2, or 3 N atoms. In some embodiments, ring C is a 5-7 membered heteroaromatic ring having 2 N atoms, preferably a 5 membered heteroaromatic ring having 2 N atoms.

[0158] In some implementations, ring C is not replaced or is replaced by 1, 2 or 3 Cs. 1-6 Alkyl groups are substituted.

[0159] In some embodiments, the compound of formula I has the structure shown in formula I-1:

[0160] Wherein, X, Y, m, n, R1, R2, R3, R4, R5, R6 and R7 are as defined in any embodiment of this document.

[0161] In some embodiments, the compound of formula I has the structure shown in formula II:

[0162] The definitions of R1, R2, R3, R4, R5, R6, R7, X, Y, m, and n are as described in any of the embodiments herein.

[0163] Preferably, in Formula II, R4 and NR5 have the same orientation in terms of spatial conformation.

[0164] In some embodiments, the compound of formula I has the structure shown in formula III:

[0165] The definitions of R1, R2, R3, R4, R5, X, Y, m, and n are as described in any of the embodiments herein.

[0166] Preferably, in Formula III, R1 is hydrogen (H), deuterium (D), methoxy (-OCH3), trideuterated methoxy (-OCD3), hydroxyl (OH), carbamoyl (NH2CO-) or ethoxy (-OCH2CH3).

[0167] Preferably, in Formula III, R2 is hydrogen (H), deuterium (D), methyl (CH3), trideuterated methyl (CD3), F, or Cl.

[0168] Preferably, in Formula III, R3 is hydrogen (H), deuterium (D), methyl (CH3), trideuterated methyl (CD3), F, or Cl.

[0169] Preferably, in Formula III, R4 is a hydroxyl group (OH), F, an acetoxy group (OAc), or H.

[0170] Preferably, in Formula III, R5 is hydrogen (H), methyl (CH3), or trideuterated methyl (CD3).

[0171] Preferably, in Formula III, R4 and NR5 have the same orientation in terms of spatial conformation.

[0172] In some embodiments, the compound of formula X has the structure shown in formula X-1:

[0173] Among them, R1 is selected from 5-membered heteroaryl, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 The alkyl group is selected from deuterated alkyl-O-, cyclopropyl-O-, or carbamoyl; wherein R1 is optionally substituted with one, two, or three halogens; R2 and R3 are each independently selected from hydrogen or methyl; or the carbon atom connected to R2, the carbon atom connected to R3, and the methylene group together form a 3-membered carbon ring; R4 is selected from hydrogen, hydroxyl, or methoxy; R5 is selected from hydrogen, deuterium, methyl, or trideuterated methyl. Represents a double bond or a single bond; when R5 is selected from methyl and R1 is selected from methoxy, R2 is not methyl; n = 0 or 1; m = 0 or 1.

[0174] Preferably, in formula X-1, the carbon atom connected to R2, the carbon atom connected to R3, and the methylene group together form a 3-membered carbon ring.

[0175] Preferably, in formula X-1, R1 is selected from methyl, methoxy, trideuterated methoxy, carbamoyl or 5-membered heteroaryl; R2 and R3 are each independently selected from hydrogen or methyl; R4 is selected from hydroxyl; R5 is selected from methyl or trideuterated methyl; m = 1, n = 1.

[0176] Preferably, in formula X-1, the 5-membered heteroaryl group is selected from:

[0177] Preferably, in formula X-1, R1 is selected from methyl, methoxy, trideuteroxy, carbamoyl, ... R2 and R3 are each independently selected from hydrogen or methyl; R4 is selected from hydroxyl; R5 is selected from methyl or trideuterated methyl; m=1, n=1.

[0178] In some embodiments, the compound of formula X has the structure shown in formula X-2:

[0179] Among them, R1 is selected from 5-membered heteroaryl, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Deuterated alkyl-O- or carbamoyl; wherein R1 is optionally substituted with one, two or three halogens; R2 and R3 are each independently selected from hydrogen or methyl; R5 is selected from hydrogen, deuterium, methyl or trideuterated methyl.

[0180] Preferably, in formula X-2, the 5-membered heteroaryl group is selected from:

[0181] Preferably, in formula X-2, R1 is selected from... Methoxy, trideuteroxy, or carbamoyl; R2 and R3 are each independently selected from hydrogen; R5 is selected from hydrogen, deuterium, methyl, or trideuteroxymethyl; n = 1; m = 1.

[0182] In some embodiments, the compound of formula X' has the structure shown in formula X'-1:

[0183] A1 is selected from CR a R b , O or NR C , where R a Independently selected from H and R bIndependently selected from methyl, R c Selected independently from C 1-3 Alkyl-CO- or C 1-3 Alkyl-SO2-; R1 is selected from C 1-3 Alkyl-O-, C 1-3 Deuterated alkyl-O-; R4 is selected from hydrogen, hydroxyl, or methoxy; R5 is selected from hydrogen, deuterium, methyl, or trideuterated methyl; It represents a double bond or a single bond.

[0184] Preferably, in formula X'-1, A1 is selected from >N-CO-CH3 or >CH-CH3; R4 is selected from hydrogen or hydroxyl; and R5 is selected from methyl.

[0185] In some embodiments, the compound of formula I has the structure shown in formula IV:

[0186] The definitions of R1, R2, R3, R5, m, and n are as described in any of the embodiments described in this paper.

[0187] Preferably, in Formula IV, OH and NR5 have the same orientation in terms of spatial conformation.

[0188] In some implementations, R5 in Formula IV is H, CH3, or CD3.

[0189] In some embodiments, the compound of formula I has the structure shown in formula V:

[0190] The definitions of R1, R3, R5, m, and n are as described in any of the embodiments described in this paper.

[0191] In some embodiments, the compound of formula I has the structure shown in formula VI:

[0192] The definitions of R1, R3, R5, m, and n are as described in any of the embodiments described in this paper.

[0193] In some implementations, in Formula VI, R5 is H, CH3, or CD3.

[0194] In some embodiments, compound A has the structure shown in formula A-1:

[0195] Wherein, A1, A2, A3, A4, R1, R4, R5, R6, R7, X and Y are as defined in any of the embodiments herein.

[0196] In some embodiments, compound B has the structure shown in formula B-1:

[0197] Among them, rings C, m, n, R2, R3, R4, R5, R6, R7, X, and Y are as defined in any of the embodiments herein.

[0198] The present invention also has some embodiments derived from any combination of the above-mentioned embodiments.

[0199] In some embodiments, the compound of formula I or formula A is selected from:

[0200] The present invention also provides stereoisomers, geometric isomers, tautomers, conformational isomers of compounds of formula X, X', I, II, III, IV, V, VI, A, and B, as well as pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof.

[0201] Pharmaceutical Composition

[0202] This invention provides an active ingredient that can simultaneously antagonize NMDAR and inhibit SERT, and this active ingredient can be used to treat and / or prevent related central nervous system diseases, diabetes, tumors, and other diseases.

[0203] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the following compounds selected from the present invention: compound I, compound II, compound III, compound IV, compound V, compound VI, compound A, and compound B, including their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers.

[0204] In this article, "medicinal carrier" refers to, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or livestock use.

[0205] The present invention provides a pharmaceutical formulation, which includes, but is not limited to: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., lipid-soluble or oil-soluble injections), etc. The above dosage forms include (1) compounds of formula X, formula X', formula I, formula II, formula III, formula IV, formula V, formula VI, formula A, and formula B of the present invention, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotope-labeled compounds, or one or more of the above mixtures; or (2) pharmaceutical compositions.

[0206] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, comprising mixing one or more of the following compounds of the present invention: a stereoisomer, geometric isomer, tautomer, conformational isomer, pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or mixture thereof, with a pharmaceutically acceptable carrier.

[0207] In some embodiments, the pharmaceutical composition further includes existing NMDAR antagonists and / or SERT inhibitors.

[0208] use

[0209] The compounds of this invention have dual-target effects of antagonizing NMDAR and / or inhibiting SERT, and can be used to prevent and / or treat diseases associated with NMDAR and / or SERT, particularly central nervous system diseases. Therefore, this invention provides for applications selected from the group consisting of:

[0210] (1) The use of one or more of the following pharmaceutical compositions of the present invention in the preparation of NMDA receptor antagonists: compounds of formula X, formula X', formula I, formula II, formula III, formula IV, formula V, formula VI, formula A, and formula B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof and / or the pharmaceutical compositions of the present invention.

[0211] (2) The use of one or more of the following compounds of the present invention, namely, X', I, II, III, IV, V, VI, A and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the pharmaceutical compositions of the present invention, in the preparation of 5-hydroxytryptamine transtransporter inhibitors;

[0212] (3) The use of one or more of the following compounds of the present invention, namely, X', I, II, III, IV, V, VI, A and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotope-labeled compounds, or mixtures thereof, and / or the pharmaceutical compositions of the present invention, in the preparation of drugs that regulate NMDAR / SERT dual targets;

[0213] (4) The use of one or more of the following compounds of the present invention, namely, X', I, II, III, IV, V, VI, A and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotope-labeled compounds, or mixtures thereof, and / or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the treatment and / or prevention of NMDAR-related diseases;

[0214] (5) The use of one or more of the following compounds of the present invention, namely, X', I, II, III, IV, V, VI, A and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotope-labeled compounds, or mixtures thereof, and / or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the treatment and / or prevention of SERT-related diseases;

[0215] (6) The use of one or more of the following compounds of the present invention, namely, X', I, II, III, IV, V, VI, A and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotope-labeled compounds, or mixtures thereof, and / or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the treatment and / or prevention of NMDAR / SERT dual-target related diseases.

[0216] The NMDAR-related diseases are those that can be prevented, treated, and / or alleviated by antagonizing NMDAR activity. In some embodiments, the NMDAR-related diseases are central nervous system diseases.

[0217] The SERT-related diseases are those that can be prevented, treated, and / or alleviated by inhibiting SERT activity. In some embodiments, the SERT-related diseases are central nervous system diseases.

[0218] In some implementations, NMDAR / SERT dual-target diseases are central nervous system diseases.

[0219] In some implementations, the central nervous system diseases are selected from: cerebral ischemia; stroke; cerebral infarction; traumatic brain injury; anti-NMDA receptor encephalitis; epilepsy; amyotrophic lateral sclerosis (ALS); schizophrenia; refractory, intractable, or chronic schizophrenia; affective disorders; mental disorders; mood disorders; type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; treatment-resistant depression; dysphoric disorder; cyclothymic disorder; panic attacks; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; hysteria; anorexia nervosa; sleep disorders; adjustment disorder; cognitive impairment; autism; neuropathic pain; mania; Parkinson's disease; Huntington's disease; Alzheimer's disease; various dementias; memory impairment; ADHD; attention deficit / hyperactivity disorder; tic disorders; and other neurological events or neurodegenerations caused by NMDA receptor activation. In some embodiments, the neuropathic pain is selected from peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain.

[0220] In some embodiments, the central nervous system disorders are selected from: Type I bipolar disorder; Type II bipolar disorder; depression; endogenous depression; major depressive disorder; treatment-resistant depression; dysphoric disorder; cyclothymic disorder; panic attacks; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; Parkinson's disease; peripheral diabetic neuropathy; postherpetic neuralgia; and complex regional pain syndrome. Preferably, the central nervous system disorders are selected from: depression; major depressive disorder; treatment-resistant depression; Type I bipolar disorder; Type II bipolar disorder; and anxiety disorder.

[0221] The present invention also provides the use of compounds of formula I, II, III, IV, V, VI, A, and B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotopically labeled compounds, or mixtures thereof in the treatment and / or improvement of depression (such as major depressive disorder, treatment-resistant depression), Alzheimer's disease-related symptoms (such as agitation, anxiety, agitation, aggression, depression, hallucinations, memory loss, paranoia, and delusions), Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and pain.

[0222] The present invention also provides a method for treating and / or preventing NMDAR and / or SERT-related diseases, the method comprising administering to a subject in need one or more of the following compounds: compound X, compound X', compound I, compound II, compound III, compound IV, compound V, compound VI, compound A, and compound B, their stereoisomers, geometric isomers, tautomers, conformational isomers, pharmaceutically acceptable salts, isotopically labeled compounds, or mixtures thereof, and / or pharmaceutical compositions of the present invention.

[0223] The solvent used in this invention is commercially available.

[0224] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names.

[0225] The following abbreviations were used in the examples:

[0226] PhNTf2 represents N-phenyltrifluoromethylsulfonamide; DMF represents N,N-dimethylformamide; AcOEt represents ethyl acetate; THF represents tetrahydrofuran; DCM represents dichloromethane; DIEA represents N,N-diisopropylethylamine; Pd(PPh3)4 represents tetratetraphenylphosphine palladium; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; XPhos represents 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; TEA represents triethylamine; Grubbs I catalyst is a ruthenium carbene complex catalyst, CAS: 172222-30-9; Grubbs II catalyst is a catalyst made by combining Grubbs... The tricyclohexylphosphine ligand in catalyst I is replaced with a disubstituted dihydroimidazolium ligand, CAS: 246047-72-3; Pd(PPh3)2Cl2 represents bis(triphenylphosphine)palladium dichloride; tBuBrettPhos represents 2-(di-tert-butylphosphine)-3,6-dimethoxy-2'-4'-6'tri-1-propyl-1,1'-bisphenyl, CAS: 1160861-53-9; PdCl2(dppf) represents 1,1-bis(diphenylphosphine)ferrocenepalladium chloride; XPhos-Pd-G2 is an organometallic complex, CAS: 1310584-14-5; NMP represents N-methylpyrrolidone; Select F is a selective fluorine reagent, CAS: 140681-55-6; NBS represents N-bromosuccinimide; DEA represents diethylamine.

[0227] In some implementations, the NMDAR-related diseases and SERT-related diseases are as described in any of the embodiments herein.

[0228] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0229] Synthesis of intermediates

[0230] Synthesis of intermediate A

[0231] Step 1: Dissolve compound A-1 (200 g, 1.14 mol) in anhydrous toluene (1 L) under nitrogen protection and stir. Slowly add tetrahydropyrrole (121.08 g, 1.70 mol) at room temperature. After the addition is complete, heat the reaction solution to 130 °C and reflux for 2 hours until no more water is produced. Cool the reaction solution to room temperature and slowly add allyl bromide (274.61 g, 2.27 mol). Continue heating the reaction solution to 125 °C for 4 hours. After cooling the reaction solution again, add water (500 mL). Continue heating the reaction solution to 110 °C and stir for 2 hours. Cool the reaction solution to room temperature and extract with EtOAc (500 mL * 2). Combine the organic phases and wash successively with 0.5 M hydrochloric acid (500 mL) and saturated brine (500 mL), dry to anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound A-2. LCMS: MS m / z(ESI)[M+H] + =217.2.

[0232] Step 2: Compound A-2 (60 g, 277.42 mmol) was dissolved in THF (600 mL), and NaH (22.19 g, 554.85 mmol) was added in portions at 0 °C. The reaction mixture was stirred in an ice-water bath for 1 hour, and then 2-bromo-N,N-dimethylethylamine hydrobromide (64.62 g, 277.42 mmol) was added in portions. The reaction mixture was then stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with EtOAc (300 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–10% DCM / MeOH (0.5% NH3·H2O)) to obtain compound A-3. LCMS: MS m / z (ESI) [M+H] + =288.2.

[0233] Step 3: Compound A-3 (60 g, 208.77 mmol) was dissolved in 1.2 L of THF. The mixture was stirred at room temperature, and a solution of pyridine tribromoonium salt (86.80 g, 271.40 mmol) in 300 mL of THF was slowly added dropwise. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. A solid precipitated from the reaction mixture. The reaction mixture was filtered, and the filter cake was added to 500 mL of isopropanol, stirred for 10 minutes, filtered again, and dried under reduced pressure to obtain compound A-4. LCMS: MS m / z (ESI) [M+H] + =366.1.

[0234] Step 4: Compound A-4 (200 g, 313.06 mmol) was dissolved in methanol (1.0 L), and ammonia (391.83 g, 3.13 mol) was slowly added with stirring at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and evaporated to dryness. The crude product was purified by silica gel column chromatography (0–15% DCM / MeOH (0.5% ammonia), flow rate: 100 mL / min) to obtain compound A-5. LCMS: MS m / z (ESI) [M+H] + =286.3; 1 H NMR (400MHz, CDCl3) δ7.22(d,J=8.4Hz,1H),6.85(dd,J=8.4,2.4Hz,1H),6.73(d,J=2.4Hz,1H),5. 79-5.65(m,1H),5.20(dd,J=17.2,1.2Hz,1H),5.12(d,J=10.4Hz,1H),4.45(d,J=5.2Hz,1H),4.28 (d,J=11.2Hz,1H),3.95(d,J=19.6Hz,1H),3.79(s,6H),3.61-3.50(m,4H),3.39-3.26(m,1H),2.9 1(dd,J=14.4,6.4Hz,1H),2.76(dd,J=14.4,6.8Hz,1H),2.67-2.51(m,1H),1.93(d,J=13.2Hz,1H).

[0235] Step 5: Compound A-5 (14.5 g, 50.63 mmol) was added to diphenyl ether (200 mL). The reaction mixture was heated to an external temperature of 190 °C for approximately 1.5 hours. The reaction solution dissolved, became clear, and deepened in color. Heating was then stopped. The reaction solution was cooled to 30 °C. The reaction solution was purified by silica gel column chromatography (0–5% MeOH / DCM, flow rate: 100 mL / min) to obtain intermediate A. LCMS: MS m / z (ESI) [M+H] + =272.2; 1H NMR (400MHz, CDCl3) δ7.06 (d, J=8.4Hz, 1H), 6.76 (dd, J=8.4, 2.4Hz, 1H), 6.71 (d, J=2.4Hz, 1H), 5.89-5.73 (m,1H),5.14(dd,J=17.2,1.6Hz,1H),5.04(d,J=10.4Hz,1H),3.79(s,3H),3.47(d,J=17.6Hz,1H),3.35(d, J=5.6Hz,1H),3.10(dd,J=17.6,6.0Hz,1H),2.88(dd,J=15.2,6.0Hz,1H),2.72(td,J=12.4,2.4Hz,1H),2.6 2(dd,J=14.8,7.6Hz,1H),2.58-2.51(m,1H),2.46(s,3H),2.29(td,J=12.8,4.8Hz,1H),1.71-1.63(m,1H).

[0236] Synthesis of intermediate B

[0237] Intermediate A (500 mg, 1.84 mmol) was dissolved in dichloroethane (10 mL). Under nitrogen protection, potassium carbonate (2.04 g, 14.7 mmol) and ethyl chloroformate (1.00 g, 9.22 mmol) were added, and the mixture was stirred at 80 °C for 10 hours. After the reaction was complete, water (10 mL) was added to quench the reaction. The mixture was extracted three times with ethyl acetate (10 mL), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10–20) to obtain intermediate B. LC-MS: MS m / z (ESI) [M+H] + =330.0.

[0238] Synthesis of intermediate C

[0239] Step 1: Intermediate B (370 mg, 1.12 mmol) was dissolved in anhydrous THF (5 mL). Allyl magnesium bromide (THF, 1 M, 2.25 mL) was added dropwise under nitrogen protection at 0 °C. The reaction mixture was slowly heated to room temperature and stirred for 10 hours. After the reaction was complete, the solution was quenched in ice water (10 mL). The mixture was extracted three times with ethyl acetate (10 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10–20) to obtain compound C-1. LC-MS: MS m / z (ESI) [M+H] + =372.1.

[0240] Step 2: Compound C-1 (260 mg, 700 μmol) was dissolved in anhydrous DCM (5 mL). Under nitrogen protection, Grubbs II catalyst (59.4 mg, 70.0 μmol) was added, and the reaction mixture was heated to 40 °C and stirred for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 10–30) to obtain intermediate C. LCMS: MS m / z (ESI) [M+H] + =344.0.

[0241] Synthesis of intermediate D

[0242] Step 1: Intermediate C (150 mg, 436.8 μmol) and iodomethane (93.0 mg, 655 μmol) were dissolved in anhydrous THF (1 mL). Sodium hydroxide (26.2 mg, 655 μmol, 60% purity) was added under nitrogen protection at 0 °C. The reaction mixture was heated to room temperature and stirred for 2 hours. After the reaction was complete, water (1 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (1 mL x 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE = 0–30%) to obtain compound D-1. LCMS: MS m / z (ESI) [M+H] + =358.2.

[0243] Step 2: Compound D-1 (110 mg, 307 μmol) was dissolved in anhydrous methanol (1 mL). Wet palladium on carbon (20 mg, 10% purity) was added under nitrogen protection. The reaction mixture was stirred for 2 hours under a hydrogen atmosphere (15 psi). After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure to obtain intermediate D. LCMS: MS m / z (ESI) [M+H] + =360.3.

[0244] Synthesis of intermediate E

[0245] Intermediate B (1.2 g, 3.64 mmol) was dissolved in anhydrous toluene (20 mL), and palladium dichloride (139.74 mg, 364.31 μmol) was added. The reaction mixture was stirred at 110 °C for 16 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure and evaporated to dryness. The crude product was purified by silica gel column chromatography (silica, n-hexane / tetrahydrofuran = 100 / 0 to 90 / 10) to give intermediate E. LC-MS: MS m / z (ESI) [M+H] + =329.9; 1H NMR (400MHz, CD3OD) δ = 7.12 (d, J = 8.4Hz, 1H), 6.85 (dd, J = 8.4, 2.8Hz, 1H), 6.66 (d ,J=2.8Hz,1H),5.88-5.74(m,2H),4.76–4.66(m,1H),4.23-4.11(m,2H),4.10-4. 00(m,1H),3.77-3.75(m,3H),3.46-3.37(m,1H),3.32-3.26(m,1H),3.04-2.89(m ,1H),2.27–2.13(m,1H),2.10-2.02(m,1H),1.92-1.89(m,3H),1.35–1.20(m,3H).

[0246] Synthesis of intermediates F and H

[0247] Step 1: Intermediate A (700 mg, 2.58 mmol) and ammonium acetate (1.99 g, 25.80 mmol) were dissolved in anhydrous THF (14 mL), and tetraisopropyl titanium dioxide (IV) (1.47 g, 5.16 mmol) was added. The reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to 25 °C, and sodium cyanoborohydride (324.22 mg, 5.16 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 hours. Water (1 mL) was added to the reaction mixture, and the pH was adjusted to 10 with triethylamine. The mixture was filtered and concentrated under reduced pressure to obtain compound F-1. LCMS: MS m / z (ESI) [M+H] + =273.0.

[0248] Step 2: Compound F-1 (702 mg, 2.58 mmol) was dissolved in methanol (14 mL), and triethylamine (1.30 g, 12.89 mmol) and BOC anhydride (843.71 mg, 3.87 mmol) were added. The mixture was stirred at 65 °C for 16 hours. 4-Dimethylaminopyridine (157.43 mg, 1.29 mmol) was added to the reaction solution, and the mixture was stirred at 65 °C for 6 hours. The reaction solution was diluted with water (10 mL), extracted with DCM (10 mL x 3), and the organic phase was concentrated and evaporated to dryness. The crude product was purified by silica gel column chromatography (0–8–12–36% tetrahydrofuran / petroleum ether) to obtain intermediates F and H.

[0249] Intermediate F:LCMS:MS m / z(ESI)[M+H] +=373.1;1H NMR (400MHz, DMSO-d6) δ = 7.03 (d, J = 8.4Hz, 1H), 6.78 (d, J = 2.4Hz, 1H), 6.74 (dd, J = 8.4, 2.4Hz, 1H), 6.02-5.84 (m, 2H), 5.20-5.09 (m, 2H), 3.71 (s, 3H) ),3.70–3.60(m,1H),3.00–2.89(m,1H),2.88-2.83(m,1H),2.66-2.56(m, 3H),2.31-2.21(m,4H),1.91-1.81(m,2H),1.34(s,9H),1.14-1.09(m,1H).

[0250] Intermediate H: LCMS:MS m / z(ESI)[M+H] + =373.1;1H NMR (400MHz, DMSO-d6) δ = 7.02 (d, J = 8.4Hz, 1H), 6.78 (d, J = 2.4Hz, 1H), 6.70 (dd, J = 8.4, 2.4Hz, 1 H),6.46(d,J=9.6Hz,1H),5.72-5.58(m,1H),5.09-4.87(m,2H),3.78(d,J=9.2Hz,1H),3.70(s,3 H),3.06(d,J=18.0Hz,1H),2.93–2.84(m,1H),2.70-2.58(m,2H),2.45–2.34(m,1H),2.33–2.26 (m,1H),2.25(s,3H),2.06-1.95(m,1H),1.93-1.83(m,1H),1.41(s,9H),1.03(d,J=12.4Hz,1H).

[0251] Synthesis of intermediate G

[0252] Step 1: Intermediate H (500 mg, 1.34 mmol) was dissolved in anhydrous THF (10 mL), and boranetetrahydrofuran (1 M, 4.03 mL) was added dropwise under nitrogen protection at -10 °C. The reaction mixture was stirred at -10 °C for 2.5 hours. Next, sodium hydroxide aqueous solution (1 M, 5.37 mL) and hydrogen peroxide (340 mg, 3.00 mmol, 30% purity) were added dropwise to the reaction solution. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound G-1. LCMS: MS m / z (ESI) [M+H] + =391.2; 1H NMR(400MHz, DMSO-d6)δ=7.04(d,J=8.8Hz,1H),6.77–6.65(m,2H),6.30(d,J= 9.6Hz,1H),4.38-4.28(m,1H),3.84–3.76(m,1H),3.75-3.67(m,4H),3.43-3.3 5(m,1H),3.31-3.26(m,1H),3.11–3.02(m,1H),2.93–2.84(m,1H),2.77-2.62 (m,2H),2.32-2.21(m,4H),1.91-1.80(m,2H),1.42(s,9H),1.03-0.95(m,2H).

[0253] Step 2: Compound G-1 (300 mg, 768.22 μmol) and pyridine (303.83 mg, 3.84 mmol) were dissolved in anhydrous DCM (6 mL). A solution of methanesulfonic anhydride (160.58 mg, 921.86 μmol) in DCM (1.5 mL) was added dropwise under nitrogen protection at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL), extracted with DCM (5 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound G-2. LCMS: MS m / z (ESI) [M+H] + =469.1.

[0254] Step 3: Compound G-2 (359 mg, 766.10 μmol) was dissolved in anhydrous N,N-dimethylformamide (6 mL), and sodium hydride (61.28 mg, 1.53 mmol) was added under nitrogen at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (10 mL) at 0 °C, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound G-3. LCMS: MS m / z (ESI) [M+H] + =373.1.

[0255] Step 4: Compound G-3 (163 mg, 437.58 μmol) was dissolved in anhydrous DCM (2 mL), and hydrochloric acid / dioxane (2 M, 2.19 mL) was added at 25 °C. The reaction mixture was stirred at 25 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure and evaporated to dryness to obtain intermediate G (hydrochloride). LCMS: MS m / z (ESI) [M+H] + =273.0.

[0256] Synthesis of Intermediate I

[0257] Step 1: Compound I-1' (5.00 g, 13.7 mmol) and cesium carbonate (9.80 g, 30.1 mmol) were dissolved in anhydrous DMF (50 mL), and PhNTf2 (5.86 g, 16.4 mmol) was added. The reaction mixture was stirred at 70 °C for 10 hours. After the reaction was complete, the solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate I-1. MS m / z (ESI) [M+H] + =462.1.

[0258] Step 2: Compound I-2 (5.50 g, 11.9 mmol) and TEA (6.03 g, 59.6 mmol) were dissolved in anhydrous DMF (50 mL). Under N2 protection, palladium acetate (268 mg, 1.19 mmol), 1,3-bis(diphenylphosphine)propane (983 mg, 2.38 mmol), and formic acid (2.00 g, 41.7 mmol) were added. The reaction was carried out under N2 protection and stirred at 80 °C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound I-3. MS m / z (ESI) [M+H] + =314.2.

[0259] Step 3: Compound I-3 (4.60 g, 14.7 mmol) and K₂CO₃ (16.2 g, 117 mmol) were dissolved in anhydrous dichloroethane (40 mL), and ethyl chloroformate (6.04 g, 55.7 mmol) was added. The reaction was stirred at 80 °C for 12 hours. After the reaction was complete, water (50 mL) was added to quench the reaction, and the mixture was extracted three times with EtOAc (50 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound I-4. MS m / z (ESI) [M+H] + =372.1.

[0260] Step 4: Compound I-4 (1.30 g, 3.50 mmol) was dissolved in anhydrous dioxane (30 mL), and concentrated hydrochloric acid (12 M, 8.75 mL) was added. The reaction mixture was stirred at 80 °C for 3 hours. After the reaction was complete, saturated NaHCO3 aqueous solution was added dropwise to adjust the pH to neutral. The mixture was extracted with EtOAc (50 mL × 3), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound I-5. MS m / z (ESI) [M+H] + =358.1.

[0261] Step 5: Compound I-5 (1.00 g, 2.80 mmol) was dissolved in anhydrous THF (20 mL). NaBH4 (340 mg, 8.99 mmol) was added in portions under N2 protection, and the reaction was stirred at 25 °C for 2 hours. After the reaction was complete, water (50 mL) was added dropwise to quench the reaction. The mixture was extracted three times with EtOAc (50 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound I-6. MS m / z (ESI) [M+H] + =362.2.

[0262] Step 6: Compound I-6 (100 mg, 277 μmol) and triphenylphosphine (290 mg, 1.11 mmol) were dissolved in anhydrous toluene (1 mL), and imidazole (75.3 mg, 1.11 mmol) and elemental iodine (281 mg, 1.11 mmol) were added. The reaction mixture was stirred at 80 °C for 2 hours under N2 protection. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate I. MS m / z (ESI) [M+H] + =328.3; 1 H NMR (400MHz, CD3OD) δ7.04(d,J=8.4Hz,1H),6.89(d,J=2.4Hz,1H),6.76(dd,J=8.4,2.4Hz,1 H),5.68-5.58(m,1H),5.54-5.45(m,1H),4.52–4.41(m,1H),4.22–4.08(m,2H),3.95–3.84( m,1H),3.77(s,3H),3.38–3.27(m,1H),2.88(dd,J=17.6,5.6Hz,1H),2.79-2.62(m,2H),2.1 4-1.95(m,3H),1.80-1.71(m,1H),1.70–1.60(m,1H),1.52–1.42(m,1H),1.31-1.24(m,3H).

[0263] Compound Synthesis

[0264] Example 1: Synthesis of Compounds 1 and 105

[0265] Step 1: Intermediate A (1.4 g, 5.16 mmol) was dissolved in THF (20 mL), and allyl magnesium bromide (THF, 1 M, 10.3 mL) was added at 0 °C. The mixture was stirred at 25 °C for 10 hours. After the reaction was complete, the reaction solution was slowly quenched in portions by pouring it into ice water (20 mL). Saturated ammonium chloride aqueous solution (10 mL) and saturated saline solution (10 mL) were added. The mixture was extracted separately with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give compound 1-1. LCMS: MS m / z (ESI) [M+H] + =314.1.

[0266] Step 2: Compound 1-1 (1.6 g, 5.10 mmol) was dissolved in anhydrous DCM (100 mL), and Grubbs II catalyst (433 mg, 510 μmol) was added. The mixture was stirred at 40 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [water (0.225% formic acid-acetonitrile]; B%: 0%-30%, 12 min) to obtain compound 1-2 (formate) and compound 1-2' (formate).

[0267] Compounds 1-2 (formate salts): LCMS: MS m / z (ESI) [M+H] + =286.0; 1 H NMR (400MHz, CD3OD) δ8.45 (s, 1H), 7.09 (d, J = 8.4Hz, 1H), 6.88-6.72 (m, 2H) ,5.89-5.75(m,1H),5.74–5.62(m,1H),3.77(s,3H),3.45–3.31(m,2H),3.18 -3.07(m,1H),3.06-2.89(m,2H),2.79(s,3H),2.71-2.53(m,2H),2.50–2.37 (m,1H),2.26-2.15(m,1H),2.15-2.05(m,1H),1.36(dd,J=14.0,2.4Hz,1H).

[0268] Compounds 1-2' (formate): LCMS: MS m / z (ESI) [M+H] + =286.0; 1H NMR (400MHz, CD3OD) δ8.57(s,1H),7.16(d,J=8.4Hz,1H),6.92(d,J=2.4Hz,1H),6.84(d d,J=8.4,2.4Hz,1H),5.79-5.68(m,1H),5.48-5.36(m,1H),3.78(s,3H),3.51(d,J=6.0H z,1H),3.44-3.34(m,2H),3.05(dd,J=12.4,4.8Hz,1H),2.88(s,3H),2.84-2.67(m,2H) ,2.51-2.33(m,2H),2.30-2.18(m,1H),2.10-2.01(m,1H),1.40(dd,J=14.0,2.4Hz,1H).

[0269] Step 3: Compounds 1-2' (formate, 1.6 g, 5.10 mmol) were purified by preparative SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); mobile phase: [A: carbon dioxide - B: methanol (0.1% ammonia)]; B%: 35%, isobaric elution mode) to obtain compound 1 (formate) and compound 105 (formate).

[0270] Chiral analysis methods:

[0271] Column type: Chiralpak IG-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.2% MNH3); Gradient: 5%-40% of B in 3 min, then 5% of B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi.

[0272] Compound 1 (formate): Retention time = 1.429 min, 98.22% ee, LCMS: MS m / z (ESI) [M+H] + =286.0; 1H NMR(400MHz,CD3OD)δ8.56(brs,1H),7.12(d,J=8.0Hz,1H),6.89(s,1H),6.81( d,J=7.6Hz,1H),5.80–5.60(m,1H),5.50–5.31(m,1H),3.76(s,3H),3.46–3.35( m,1H),3.32-3.20(m,2H),3.03-2.90(m,1H),2.88-2.72(m,4H),2.70–2.55(m,1 H),2.49-2.28(m,2H),2.27-2.15(m,1H),2.08-1.90(m,1H),1.42–1.30(m,1H).

[0273] Compound 105 (formate): Retention time = 1.552, 99.78% ee, LCMS: MS m / z (ESI) [M+H] + =285.9; 1 H NMR (400MHz, CD3OD) δ7.02(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H),6.71(dd ,J=8.4,2.8Hz,1H),5.71–5.58(m,1H),5.44–5.34(m,1H),3.73(s,3H),3.20 (d,J=18.4Hz,1H),2.92-2.80(m,1H),2.80-2.76(m,1H),2.68–2.57(m,1H), 2.44-2.33(m,5H),2.20-2.02(m,3H),1.94–1.81(m,1H),1.20-1.06(m,1H).

[0274] Example 2: Synthesis of compounds 34 and 109

[0275] Step 1: Intermediate A (700 mg, 2.58 mmol) was dissolved in anhydrous THF (8 mL). Vinyl magnesium bromide tetrahydrofuran solution (1 M, 10.32 mL) was added dropwise under nitrogen protection at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with ammonium chloride aqueous solution (10 mL) at 0 °C, and extracted three times with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0–5% methanol / DCM) to obtain compound 34-1. LCMS: MS m / z (ESI) [M+H] + =300.0; 1H NMR (400MHz, DMSO-d6) δ = 6.98 (d, J = 8.4Hz, 1H), 6.86 (dd, J = 17.6, 10.8Hz, 1H), 6.78 (d, J = 2.4Hz, 1H), 6.65 (dd, J = 8.4,2.4Hz,1H),6.17–6.00(m,1H),5.45(dd,J=17.6,2.4Hz,1H),5.23(dd,J=10.8,2.4Hz,1H),5.01(dd,J=17.6, 2.4Hz,1H),4.93-4.83(m,1H),4.32(s,1H),3.68(s,3H),2.93-2.84(m,1H),2.82-2.73(m,1H),2.70–2.65(m,1H) ,2.64-2.55(m,2H),2.38–2.29(m,1H),2.25(s,3H),2.03-1.91(m,1H),1.89–1.78(m,1H),1.09(d,J=12.0Hz,1H).

[0276] Step 2: Compound 34-1 (495 mg, 1.65 mmol) and Grubbs I (408.17 mg, 495.98 μmol) were dissolved in anhydrous toluene (15 mL). The reaction solution was stirred at 80 °C under nitrogen protection for 16 hours. The reaction solution was quenched with water (0.5 mL), concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 25%-45%, 11 min) to obtain compound 109 and compound 34.

[0277] Compound 109: LCMS: MS m / z (ESI) [M+H] + =271.9; 1 H NMR (400MHz, CD3OD) δ = 7.07 (d, J = 8.4Hz, 1H), 6.71 (dd, J = 8.4, 2.8Hz, 1H), 6.66 (d,J=2.8Hz,1H),6.22–6.16(m,1H),6.15-6.10(m,1H),3.78(s,3H),3.24(d,J= 6.0Hz,1H),3.11-3.03(m,1H),3.00-2.89(m,2H),2.46-2.41(m,1H),2.40(s,3 H),2.35-2.28(m,1H),2.27-2.17(m,1H),2.03-1.92(m,1H),1.45–1.35(m,1H).

[0278] Compound 34: LCMS:MS m / z (ESI) [M+H] + =272.0; 1 H NMR (400MHz, CD3OD) δ = 7.06 (d, J = 8.4Hz, 1H), 6.84 (d, J = 2.4Hz, 1H), 6.69 (dd, J = 8.4, 2.4Hz, 1H), 6.51–6.42 (m, 1H), 5.98-5.89 (m, 1H), 3. 78(s,3H),3.24-3.14(m,2H),3.11-3.01(m,1H),2.96-2.86(m,1H),2 .44(s,3H),2.36-2.23(m,2H),2.16-2.03(m,1H),1.70-1.60(m,2H).

[0279] Example 3: Synthesis of compounds 49 and 112

[0280] Step 1: Intermediate E (500 mg, 1.52 mmol) was dissolved in anhydrous THF (10 mL), and allyl magnesium bromide (THF, 1 M, 1.97 mL) was added at 0 °C. The mixture was stirred at 25 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was quenched by dropwise addition of saturated NH4Cl (1 mL) at 0 °C. The reaction mixture was concentrated and evaporated to dryness. The crude product was purified by silica gel column chromatography (silica, n-hexane / tetrahydrofuran = 100 / 0 to 90 / 10) to give compound 49-1. LCMS: MS m / z (ESI) [M+H] + =372.1.

[0281] Step 2: Compound 49-1 (220 mg, 592.24 μmol) was dissolved in anhydrous THF (4 mL), and lithium aluminum hydride (2.5 M, 473.79 μL) was added at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. Water (0.1 mL), 15% sodium hydroxide solution (0.1 mL), and water (0.3 mL) were added dropwise to the reaction mixture at 0 °C. After drying with anhydrous sodium sulfate and filtering, the filtrate was evaporated to dryness to obtain compound 49-2. LCMS: MS m / z (ESI) [M+H] + =314.0.

[0282] Step 3: Compound 49-2 (220 mg, 592.24 μmol) was dissolved in anhydrous toluene (4 mL), and Grubbs II (136.51 mg, 160.80 μmol) was added. The reaction mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by preparative HPLC (column: WePure Biotech XP C18 150*40 mm*7 μm; mobile phase: [A: water (ammonia)-B: acetonitrile]; B%: 25%-45%, 10 min) to obtain compounds 112 and 49.

[0283] Compound 112: LCMS:MS m / z (ESI) [M+H] + =272.1; 1 H NMR (400MHz, CD3OD) δ = 7.07 (d, J = 8.4Hz, 1H), 6.71 (dd, J = 8.4, 2.8Hz, 1H), 6 .66(d,J=2.8Hz,1H),6.22–6.16(m,1H),6.15-6.10(m,1H),3.78(s,3H),3.2 4(d,J=6.0Hz,1H),3.12-3.03(m,1H),2.99-2.90(m,2H),2.46-2.39(m,4H), 2.35-2.28(m,1H),2.26-2.18(m,1H),2.02-1.92(m,1H),1.45-1.37(m,1H).

[0284] Compound 49: LCMS:MS m / z (ESI) [M+H] + =272.1; 1 H NMR (400MHz, CD3OD) δ = 7.06 (d, J = 8.4Hz, 1H), 6.84 (d, J = 2.8Hz, 1H), 6.69 (dd, J = 8.4, 2.8Hz, 1H), 6.52–6.45 (m, 1H), 5.97–5.90 (m, 1H), 3. 78(s,3H),3.24-3.16(m,2H),3.10-3.02(m,1H),2.96-2.87(m,1H),2 .44(s,3H),2.35-2.27(m,2H),2.16-2.05(m,1H),1.72-1.62(m,2H).

[0285] Example 4: Synthesis of compounds 120 and 121

[0286] Intermediate D (30 mg, 83.46 μmol) was dissolved in THF (1 mL), and lithium aluminum hydride (THF, 2.5 M, 500.75 μL) was added under a nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 2 hours. Water (0.05 mL), 15% sodium hydroxide (0.05 mL), and water (0.15 mL) were added to the reaction solution at 0 °C. The reaction solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 55%-75%, 10 min) to obtain compounds 120 and 121.

[0287] Compound 121: LCMS:MS m / z (ESI) [M+H] + =302.2; 1 H NMR (400MHz, CD3OD): δ=7.09 (d, J=8.4Hz, 1H), 6.83 (d, J=2.4Hz, 1H), 6.78 (dd, J=8. 4,2.4Hz,1H),3.76(s,3H),3.37(d,J=5.6Hz,1H),3.26(s,3H),2.80(dd,J=19.2,6. 0Hz,1H),2.61(dd,J=12.4,3.2Hz,1H),2.54(s,3H),2.40-2.20(m,2H),2.06-1.97( m,2H),1.81–1.72(m,1H),1.62-1.48(m,2H),1.45-1.25(m,4H),1.08-1.00(m,1H).

[0288] Compound 120: LCMS:MS m / z (ESI) [M+H] + =302.2; 1 H NMR (400MHz, CD3OD): δ = 6.96 (d, J = 8.4Hz, 1H), 6.71 (d, J = 2.4Hz, 1H), 6.65 (d d,J=8.4,2.4Hz,1H),3.73(s,3H),3.11(s,3H),3.05-2.94(m,2H),2.64(dd, J=17.6,6.0Hz,1H),2.58–2.47(m,1H),2.40-2.32(m,5H),2.17–2.06(m,1H) ,2.00-1.91(m,2H),1.80-1.67(m,3H),1.63-1.47(m,2H),0.98-0.90(m,1H).

[0289] Example 5: Synthesis of Compound 59

[0290] Step 1: Intermediate A (400 mg, 1.47 mmol) was dissolved in anhydrous THF (7 mL). 3-Butenylmagnesium bromide (THF, 1 M, 4.42 mL) was slowly added under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was quenched with saturated ammonium chloride (20 mL) at 0 °C, extracted with ethyl acetate (5 mL * 3), and the organic phase was washed with brine (20 mL * 3). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until evaporated to dryness. The crude product was purified by silica gel column chromatography (silica, dichloromethane / methanol = 100 / 0 to 95 / 5) to give compound 59-1. LCMS: MS m / z (ESI) [M+H] + =328.2.

[0291] Step 2: Compound 59-1 (25.0 mg, 76.35 μmol) was dissolved in DCM (1 mL), and Grubbs II (12.96 mg, 15.27 μmol) was added. The reaction solution was stirred at 40 °C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (formic acid)-acetonitrile]; B%: 0%-30%, 10 min) to obtain compound 59 (formate). LCMS: MS m / z (ESI) [M+H] + =300.2; 1 H NMR (400MHz, CD3OD) δ = 8.47 (brs, 1H, FA), 7.12 (d, J = 8.4Hz, 1H), 7.05 (d, J = 2.0Hz, 1H), 6 .84-6.76(m,1H),6.16-6.01(m,1H),5.90-5.77(m,1H),3.81-3.75(m,3H),3.48-3.36(m ,1H),3.25–3.18(m,1H),3.13(d,J=18.8Hz,1H),3.00-2.90(m,2H),2.80(s,3H),2.79-2 .72(m,2H),2.52-2.40(m,3H),2.09-1.92(m,1H),1.63–1.50(m,1H),1.35–1.24(m,1H).

[0292] Example 6: Synthesis of Compound 35

[0293] Step 1: Intermediate A (350 mg, 1.29 mmol) was dissolved in anhydrous THF (1 mL). Under nitrogen protection at 0 °C, isopropenyl magnesium bromide tetrahydrofuran solution (1 M, 7.00 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 0.5 hours. The reaction mixture was quenched at 0 °C with ammonium chloride aqueous solution (10 mL), extracted with ethyl acetate (10 mL x 2), and the aqueous phase was further extracted with DCM (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (0–10% methanol / dichloromethane) to give compound 35-1. LCMS: MS m / z (ESI) [M+H] + =314.0.

[0294] Step 2: Compound 35-1 (447 mg, 1.43 mmol) and Grubbs II (242.15 mg, 285.23 μmol) were dissolved in anhydrous toluene (15 mL). The reaction mixture was stirred at 80 °C under nitrogen protection for 16 hours. The reaction mixture was quenched with water (1 mL), concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (0–3–9–25% methanol / dichloromethane). Compound 35 was then purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150 × 40 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 33%–53%, 10 min). LCMS: MS m / z (ESI) [M+H] + =286.0; 1 H NMR (400MHz, CD3OD) δ = 7.06 (d, J = 8.4Hz, 1H), 6.69 (dd, J = 8.4, 2.8Hz, 1H), 6.6 3(d,J=2.8Hz,1H),5.68-5.64(m,1H),3.77(s,3H),3.16(d,J=6.0Hz,1H),3.1 1-3.04(m,1H),2.93-2.85(m,1H),2.84–2.74(m,1H),2.39(s,3H),2.34-2.22 (m,2H),2.21–2.10(m,1H),2.02-1.91(m,1H),1.87(s,3H),1.44-1.36(m,1H).

[0295] Example 7: Synthesis of Compound 55

[0296] Step 1: Intermediate E (500 mg, 1.52 mmol) was dissolved in anhydrous THF (8 mL), and 2-methylallyl magnesium bromide (THF, 0.5 M, 4.71 mL) was added under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with brine (20 mL * 3). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until dry. The crude product was purified by silica gel column chromatography (silica, industrial hexane / tetrahydrofuran = 100 / 0 to 85 / 15) to give compound 55-1. LCMS: MS m / z (ESI) [M + H] + =386.0.

[0297] Step 2: Compound 55-1 (331 mg, 858.64 μmol) was dissolved in anhydrous THF (4 mL). Lithium aluminum hydride (THF, 2.5 M, 686.91 μL) was added under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched at 0 °C by adding water (0.1 mL), 15% sodium hydroxide (0.1 mL), and water (0.3 mL). The reaction solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 55-2. LCMS: MS m / z (ESI) [M+H] + =328.0.

[0298] Step 3: Compound 55-2 (255 mg, 778.72 μmol) was dissolved in toluene (3 mL), and Grubbs II (146.39 mg, 233.62 μmol) was added. The mixture was stirred at 100 °C for 2 hours. The reaction solution was concentrated and evaporated to dryness. The crude product was purified by preparative HPLC (column: 41-Welch Xtimate C18 150*40 mm, 7 μm; mobile phase: [A: water (0.225 formic acid)-B: acetonitrile]; B%: 8%-28%, 10 min) to obtain compound 55 (formate). LCMS: MS m / z (ESI) [M+H] + =286.1; 1 H NMR (400MHz, CD3OD) δ=8.56(brs,1H,FA),7.12(d,J=8.8Hz,1H),6.85(d,J=2.4Hz,1H),6.75(dd,J=8.4,2.4Hz,1H),6.10(s,1H),3.82-3.72(m,4H),3 .38-3.30(m,1H),3.25-3.10(m,2H),2.98(d,J=12.0Hz,1H),2.90(s,3H), 2.71-2.57(m,1H),2.27(d,J=16.0Hz,1H),1.89(s,3H),1.85-1.76(m,2H).

[0299] Example 8: Synthesis of compounds 127, 127-A, 127-B, and 128

[0300] Step 1: Intermediate A (600 mg, 2.21 mmol) was dissolved in EtOH (20 mL), and NaBH4 (190 mg, 5.02 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 2 hours and quenched with 2 M dilute hydrochloric acid. The reaction mixture was adjusted to pH 7 with ammonia and then concentrated under reduced pressure and evaporated to dryness to obtain compound 127-1. LCMS: MS m / z (ESI) [M+H] + =274.1.

[0301] Step 2: Compound 127-1 (300 mg, 1.10 mmol) was dissolved in THF (10 mL), and boranetetrahydrofuran (1 M, 4.39 mL) was slowly added at -10 °C. The reaction mixture was stirred at -10 °C for 5 hours. NaOH (1 M, 4.39 mL) was slowly added dropwise to quench the reaction, followed by H2O2 (150.00 mg, 1.32 mmol). The reaction mixture was stirred at room temperature for 1 hour, then HCl (10 mL) was added, and the temperature was raised to 75 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness. The residue was neutralized with ammonia (5 mL) and diluted with NaHCO3 (10 mL), followed by EtOAc (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, DCM:MeOH = 100:0 to 10:1 (1% ammonia)) to give compound 127-2. LC-MS: MS m / z (ESI) [M+H] + =292.2.

[0302] Step 3: Compound 127-2 (170 mg, 583.42 μmol) was dissolved in DCM (5 mL), cooled to 0 °C, and pyridine (230.74 mg, 2.92 mmol) was added, followed by a DCM (0.5 mL) solution of methanesulfonic anhydride (121.96 mg, 700.11 μmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), washed with saturated brine (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 127-3. LCMS: MS m / z (ESI) [M+H] + =370.2.

[0303] Step 4: Compound 127-3 (215 mg, 581.91 μmol) was dissolved in DMF (4 mL), and NaH (47 mg, 1.18 mmol) was slowly added in portions with stirring at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (0.2 mL) and filtered. The filtrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 25%-65%, 12.0 min) to obtain compounds 128 and 127.

[0304] Compound 128: LCMS:MS m / z (ESI) [M+H] + =274.1;1H NMR (400MHz, CDCl3) δ7.03(d,J=8.0Hz,1H),6.80-6.70(m,2H),4.18(dd,J=11.2,5.2Hz,1H),3.80(s,3H),3.58-3.42(m,2H),3.29-3.10(m,2H),2.8 3-2.60(m,2H),2.59-2.49(m,1H),2.49-2.34(m,3H),2.32-2.24(m,1H),2 .23-2.03(m,2H),1.80-1.67(m,1H),1.52-1.44(m,1H),1.10-0.98(m,1H).

[0305] Compound 127: LCMS:MS m / z (ESI) [M+H] + =274.1;1H NMR (400MHz, CDCl3) δ7.07(d,J=8.4Hz,1H),6.81(d,J=2.8Hz,1H),6.72(dd,J=8.4,2.8Hz,1H),3.92(dd,J=11.2,4.8Hz,1H),3.80(s,3H),3.68-3 .50(m,2H),3.21-3.10(m,1H),3.04-2.91(m,1H),2.88-2.77(m,1H),2.5 2-2.35(m,5H),2.17-2.04(m,1H),1.84-1.66(m,3H),1.43-1.35(m,2H).

[0306] Step 5: Compound 127 (20 mg, 73.16 μmol) was purified by preparative SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [A: carbon dioxide - B: methanol (0.1% ammonia)]; B%: 20%, isobaric elution mode) to obtain compound 127-A and compound 127-B.

[0307] Compound 127-B: LCMS:MS m / z (ESI) [M+H] + =274.1; 1 H NMR(400MHz, CDCl3)7.07(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H),6.72(dd,J=8.4, 2.4Hz,1H),3.93(dd,J=11.2,4.8Hz,1H),3.80(s,3H),3.68-3.53(m,2H),3.15(t,J =4.4Hz,1H),3.04-2.94(m,1H),2.89-2.77(m,1H),2.51-2.36(m,5H),2.15-2.05( m,1H),1.82-1.75(m,1H),1.74-1.69(m,1H),1.62-1.54(m,1H),1.45-1.36(m,2H).

[0308] Compound 127-A: LCMS:MS m / z (ESI) [M+H] + =274.1; 1 H NMR (400MHz, CDCl3) δ7.07(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H),6.72(dd,J=8.4,2.4Hz,1H ),3.93(dd,J=11.2,4.8Hz,1H),3.80(s,3H),3.66-3.55(m,2H),3.15(t,J=4.4Hz,1H),3.03-2 .93(m,1H),2.86-2.75(m,1H),2.55-2.45(m,1H),2.44(s,3H),2.38(dd,J=12.0,3.2Hz,1H),2 .15-2.04(m,1H),1.81-1.74(m,1H),1.73-1.65(m,1H),1.61-1.53(m,1H),1.45-1.36(m,2H).

[0309] Example 9: Synthesis of Compound 140

[0310] Intermediate G (hydrochloride) (60 mg, 194.27 μmol) and triethylamine (98.29 mg, 971.35 μmol) were dissolved in anhydrous DCM (1.5 mL), and a DCM solution of acetyl chloride (15.25 mg, 194.27 μmol) (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 30%-70%, 11 min) to give compound 140. LCMS: MS m / z (ESI) [M+H] + =315.2; 1 H NMR (400MHz, CD3OD) δ=7.11(d,J=8.0Hz,1H),6.85-6.77(m,2H),4.06-3.93(m,3H),3.78(s,3H),3.56-3.46(m,1H),3.33–3.24(m,1H),3.06(dd,J =18.4,5.6Hz,1H),2.88-2.80(m,1H),2.61(s,3H),2.53-2.34(m,3H),2. 25(s,3H),2.02-1.89(m,2H),1.79-1.68(m,1H),1.40(d,J=11.0Hz,1H).

[0311] Example 10: Synthesis of Compound 124

[0312] Step 1: Intermediate F (397 mg, 1.07 mmol) was dissolved in anhydrous THF (8 mL), and boranetetrahydrofuran (1 M, 3.20 mL) was added dropwise under nitrogen protection at -10 °C. The reaction mixture was stirred at -10 °C for 2.5 hours. Next, sodium hydroxide aqueous solution (1 M, 4.26 mL) and hydrogen peroxide (269.96 mg, 2.38 mmol) were added dropwise to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound 124-1. LCMS: MS m / z (ESI) [M+H] + =391.1.

[0313] Step 2: Compound 124-1 (305 mg, 781.02 μmol) and pyridine (308.89 mg, 3.91 mmol) were dissolved in anhydrous DCM (3 mL). A solution of methanesulfonic anhydride (163.26 mg, 937.22 μmol) in DCM (0.6 mL) was added dropwise under nitrogen protection at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with water (5 mL), extracted with DCM (5 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound 124-2. LCMS: MS m / z (ESI) [M+H] + =469.4.

[0314] Step 3: Compound 124-2 (365 mg, 778.91 μmol) was dissolved in anhydrous N,N-dimethylformamide (6 mL), and sodium hydride (62.31 mg, 1.56 mmol) was added under nitrogen at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (5 mL) at 0 °C, extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound 124-3. LCMS: MS m / z (ESI) [M+H] + =373.4.

[0315] Step 4: Compound 124-3 (1290 mg, 778.52 μmol) was dissolved in anhydrous DCM (3 mL), and hydrochloric acid / dioxane (2 M, 3.89 mL) was added at 25 °C. The reaction solution was stirred at 25 °C for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 124-4. LCMS: MS m / z (ESI) [M+H] + =273.0.

[0316] Step 5: Compound 124-4 (106 mg, 389.16 μmol) and triethylamine (196.89 mg, 1.95 mmol) were dissolved in anhydrous DCM (1.5 mL), and a DCM solution of acetyl chloride (30.55 mg, 389.16 μmol) (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 16%-56%, 11 min) to obtain crude compound 124. The crude compound 124 (40 mg) was further subjected to preparative HPLC (column: 52-Welch Xtimate C18 150×30 mm, 5 μm; mobile phase: [A: water (0.225% formic acid) - B: acetonitrile]; B%: 10%-40%, 10 min) to give compound 124. LC-MS: MS m / z (ESI) [M+H] + =315.0; 1 H NMR (400MHz, CD3OD) δ=8.44(s,1H,FA),7.21(d,J=8.4Hz,1H),6.99(d,J=2.4Hz,1H),6.89(dd,J=8.4,2.4Hz,1H),4.24(brs,1H),4.18(brs,1H),3.82 (s,3H),3.60-3.46(m,1H),3.28-3.19(m,1H),3.16-3.05(m,2H),2.90(s, 3H),2.77-2.53(m,3H),2.13(s,3H),2.08-1.95(m,2H),1.78-1.55(m,3H).

[0317] Example 11: Synthesis of Compound 141

[0318] Intermediate G (hydrochloride) (60 mg, 194.27 μmol) and triethylamine (98.29 mg, 971.35 μmol) were dissolved in anhydrous DCM (1.5 mL), and a DCM solution of methanesulfonic anhydride (37.22 mg, 213.70 μmol) (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 43%-63%, 10 min) to obtain compound 141. LCMS: MS m / z (ESI) [M+H] + =351.1; 1 H NMR (400MHz, CD3OD) δ = 7.08 (d, J = 8.4Hz, 1H), 6.86-6.76 (m, 2H), 4.26-4.07 (m, 2H), 3.78 (s, 3H), 3.31-3.25 (m, 2H), 3.04 (s, 3H), 2.97-2.85 (m, 1H),2.75-2.54(m,3H),2.48-2.37(m,4H),2.32–2.20(m,1H),2.13-1.9 9(m,1H),1.87-1.79(m,1H),1.74-1.61(m,1H),1.11(d,J=12.8Hz,1H).

[0319] Example 12: Synthesis of Compound 125

[0320] Compound 124-4 (102 mg, 374.47 μmol) and triethylamine (189.46 mg, 1.87 mmol) were dissolved in anhydrous DCM (1.5 mL), and a DCM solution of methanesulfonic anhydride (71.75 mg, 411.92 μmol) (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was quenched with water (0.5 mL), concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 19%-59%, 11 min) to obtain compound 125. LCMS: MS m / z (ESI) [M+H] + =351.4; 1H NMR (400MHz, CD3OD) δ = 7.10 (d, J = 8.4Hz, 1H), 6.83 (s, 1H), 6.78 (d, J = 8.4Hz, 1H), 3 .78(s,3H),3.64(brs,1H),3.40(d,J=2.4Hz,1H),3.28-3.19(m,1H),3.17-3.04(m, 2H),3.03(brs,1H),2.97(s,3H),2.60–2.48(m,1H),2.47-2.42(m,4H),2.16–2.05 (m,1H),1.93–1.78(m,2H),1.70–1.60m,1H),1.60–1.51(m,1H),1.50-1.44(m,1H).

[0321] Example 13: Synthesis of compounds 19 and 126

[0322] A mixture of compounds 1-2 and 1-2' (150 mg, 526 μmol) was dissolved in anhydrous methanol (5 mL). Wet palladium on carbon (20 mg, 10% purity) was added under nitrogen protection. The reaction mixture was stirred for 12 hours under a hydrogen atmosphere (15 psi). After the reaction was complete, the mixture was filtered through diatomaceous earth and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.225% formic acid-acetonitrile); B%: 0%-35%, 12 min) to obtain compounds 126 (formate) and 19 (formate).

[0323] Compound 126 (formate): LCMS: MS m / z (ESI) [M+H] + =288.1; 1 H NMR(400MHz,CD3OD)δ8.51(s,1H,FA),7.09(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H), 6.78(dd,J=8.4,2.4Hz,1H),3.76(s,3H),3.44-3.32(m,2H),3.14(d,J=18.2Hz,1H) ,3.10-3.04(m,1H),2.87(s,3H),2.66–2.55(m,2H),2.44–2.30(m,1H),2.16-1.99( m,2H),1.95-1.82(m,1H),1.81-1.62(m,3H),1.58–1.45(m,1H),1.31-1.19(m,1H).

[0324] Compound 19 (formate): LCMS: MS m / z (ESI) [M+H] + =288.2; 1 H NMR (400MHz, CD3OD) δ8.57(s,1H,FA),7.19(d,J=8.4Hz,1H),6.90(d,J=2.4Hz,1H),6.86(dd,J =8.4,2.4Hz,1H),3.80(s,3H),3.40–3.30(m,2H),3.28-3.15(m,1H),3.05(dd,J=12.8,4.4Hz, 1H),2.86(s,3H),2.70–2.55(m,1H),2.46–2.30(m,1H),2.19-2.09(m,1H),2.07-1.95(m,1H), 1.93-1.78(m,1H),1.62-1.52(m,3H),1.52–1.42(m,1H),1.42-1.28(m,1H),1.28–1.18(m,1H).

[0325] Example 14: Synthesis of compounds 122 and 123

[0326] Intermediate D (50 mg, 139.10 μmol) was dissolved in ethylene glycol (1 mL), and potassium hydroxide (156.08 mg, 2.78 mmol) was added. The mixture was stirred at 50 °C for 12 hours. The reaction solution was concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [water (0.225% formic acid-acetonitrile]; B%: 15%-35%, 10 min) to give compounds 123 (formate) and 122 (formate).

[0327] Compound 123 (formate): LCMS: MS m / z (ESI) [M+H] + =288.1; 1 H NMR (400MHz, CD3OD) δ = 8.53 (s, 1H, FA), 7.06 (d, J = 8.4Hz, 1H), 6.86-6.70 (m, 2H), 3.94–3.81 (m, 1H), 3.76 (s, 3H), 3.31-3.25 (m, 1H), 3.17(s,3H),3.12–3.00(m,1H),2.98-2.86(m,1H),2.78-2.56(m,2H),2.13-1.89(m,4H),1.80-1.53(m,4H),1.27(d,J=12.4Hz,1H).

[0328] Compound 122 (formate): LCMS: MS m / z (ESI) [M+H] + =288.2; 1 H NMR (400MHz, CD3OD) δ = 8.55 (s, 1H, FA), 7.15 (d, J = 8.4Hz, 1H), 6.97-6.74 ( m,2H),3.96-3.84(m,1H),3.78(s,3H),3.33(s,3H),3.25-3.06(m,2H),3.0 3-2.91(m,1H),2.76-2.60(m,1H),2.43-2.31(m,1H),2.13-1.98(m,2H),1 .96-1.63(m,2H),1.62-1.43(m,3H),1.42-1.27(m,2H),1.25-1.12(m,1H).

[0329] Example 15: Synthesis of Compound 103

[0330] Step 1: Compound 1 (1 g, 3.50 mmol) and potassium carbonate (4.84 g, 35.04 mmol) were dissolved in anhydrous dichloroethane (20 mL). Ethyl chloroformate (2 M, 815.34 μL) was added at 25 °C, and the reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was quenched at 0 °C with 100 mL of sodium carbonate aqueous solution, extracted three times with DCM (100 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (0–10% tetrahydrofuran / petroleum ether) to obtain compound 103-1. LCMS: MS m / z (ESI) [M+H] + =344.0; 1 H NMR (400MHz, CD3OD) δ7.04(d,J=8.4Hz,1H),6.89(d,J=2.4Hz,1H),6.77(dd,J=8.4,2.4 Hz,1H),5.71-5.62(m,1H),5.47-5.36(m,1H),4.44–4.32(m,1H),4.20–4.10(m,2H),3. 94–3.86(m,1H),3.77(s,3H),3.40(dd,J=18.4,6.8Hz,1H),2.92-2.82(m,1H),2.73-2. 63(m,2H),2.44-2.35(m,1H),2.22-2.11(m,2H),2.02-1.93(m,1H),1.33-1.26(m,4H).

[0331] Step 2: Compound 103-1 (690 mg, 2.01 mmol) was dissolved in anhydrous ethylene glycol (8 mL) and anhydrous tetrahydrofuran (3 mL), and potassium hydroxide (2.25 g, 40.18 mmol) was added at 25 °C. The reaction mixture was stirred at 80 °C for 24 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B%: 10%-30%, 10 min) to obtain compound 103 (formate). LCMS: MS m / z (ESI) [M+H] + =272.2; 1 H NMR (400MHz, CD3OD) δ8.56 (s, 1H), 7.13 (d, J = 8.4Hz, 1H), 6.93 (d, J = 2.4Hz, 1H), 6.88-6.8 0(m,1H),5.79-5.67(m,1H),5.47-5.38(m,1H),3.78(s,3H),3.61(d,J=7.2Hz,1H),3.54-3 .46(m,1H),3.15(d,J=19.2Hz,1H),3.06(dd,J=13.2,4.4Hz,1H),2.86-2.73(m,2H),2.51 -2.43(m,1H),2.42-2.35(m,1H),2.28-2.17(m,1H),2.08-1.96(m,1H),1.42–1.32(m,1H).

[0332] Example 16: Synthesis of compounds 18, 151, 152, and 153

[0333] Step 1: Intermediate C (280 mg, 815.34 μmol) was dissolved in anhydrous DCM (6 mL). Boron tribromide (2 M, 815.34 μL) was added under nitrogen protection at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (5 mL) at 0 °C, the pH was adjusted to 8 with sodium bicarbonate, and the mixture was extracted three times with DCM (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 18-1. LCMS: MS m / z (ESI) [M+H] + =329.9.

[0334] Step 2: 18-1 (240 mg, 728.62 μmol) and cesium carbonate (949.59 mg, 2.91 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. Deuterated iodomethane (211.24 mg, 1.46 mmol) was added dropwise at 25 °C, and the reaction mixture was stirred at 50 °C under nitrogen protection for 5 h. The reaction mixture was quenched with water (10 mL), extracted three times with ethyl acetate (10 mL), and concentrated under reduced pressure to obtain compound 18-2. LCMS: MS m / z (ESI) [M+H] + =347.2; 1 H NMR (400MHz, CD3OD) δ=7.08-6.98(m,1H),6.91-6.79(m,1H),6.79-6.72(m,1H),5.89-5.38(m,2H),4.42-4.25(m,1H ),4.22-4.10(m,2H),3.95-3.78(m,1H),3.50–3.35(m,1H),2.73-2.47(m,4H),2.16-1.97(m,2H),1.38-1.11(m,5H).

[0335] Step 3: LiAlD4 (90.38 mg, 2.38 mmol) was dissolved in anhydrous tetrahydrofuran (3 mL), and 18-2 (275 mg, 793.80 μmol) was added dropwise under nitrogen protection at 0 °C. The reaction solution was stirred for 16 hours under nitrogen protection at 50 °C. The reaction solution was quenched at 0 °C with water (0.1 mL), 15% sodium hydroxide aqueous solution (0.1 mL), and water (0.3 mL). The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.04% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 35%-55%, 10 min) to obtain compounds 18-2A and 18-2B.

[0336] 18-2A:LCMS:MS m / z(ESI)[M+H] + =292.0; 1H NMR (400MHz, CD3OD) δ = 7.08 (d, J = 8.4Hz, 1H), 6.86 (d, J = 2.4Hz, 1H), 6.76 (dd, J = 8.4, 2.4Hz, 1H), 5.72-5.64 (m, 1H), 5.47-5.37 (m, 1H) ,3.30-3.24(m,1H),3.09-2.99(m,2H),2.76-2.60(m,2H),2.47-2.32(m,2H),2.26-2.13(m,2H),2.01-1.91(m,1H),1.29-1.21(m,1H).

[0337] 18-2B:LCMS:MS m / z(ESI)[M+H] + =292.0; 1 H NMR (400MHz, CD3OD) δ = 7.01 (d, J = 8.4Hz, 1H), 6.75 (d, J = 2.4Hz, 1H), 6.70 (dd ,J=8.4,2.4Hz,1H),5.82-5.74(m,1H),5.73-5.64(m,1H),3.39-3.34(m,1H) ,3.08-2.90(m,2H),2.78–2.70(m,1H),2.67-2.57(m,1H),2.53-2.42(m,1H) ,2.40-2.30(m,1H),2.21-1.99(m,2H),1.99–1.89(m,1H),1.15–1.05(m,1H).

[0338] Step 4: Compound 18-2A (550 mg, 1.89 mmol) was chirally separated into compounds 18 and 151 by preparative SFC (column: Daicel ChiralPak IG (250*30 mm, 10 μm); mobile phase: [A: carbon dioxide-B: ethanol (0.1% ammonia)]; B%: 35%, isobaric elution mode). Chiral analysis was used to determine the ee values ​​of compound 18 (RT = 2.949, 98.70% ee) and compound 151 (RT = 3.288, 99.84% ee). (Column: Chiralpak IG-3100 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: ethanol (0.2% MNH3); Gradient: from 5% to 40% of B in 3 min, then 5% of B for 1 min; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi).

[0339] Compound 18: LCMS: MS m / z (ESI) [M+H]+ =292.0; 1 H NMR (400MHz, CD3OD) δ = 7.04 (d, J = 8.4Hz, 1H), 6.83 (d, J = 2.4Hz, 1H), 6.72 (dd, J = 8.4, 2.4Hz, 1H), 5.72-5.60 (m, 1H), 5.47-5.33 (m, 1H), 3.26-3. 16(m,1H),2.94-2.82(m,1H),2.82-2.75(m,1H),2.70-2.60(m,1H),2.4 5-2.34(m,2H),2.22-2.02(m,3H),1.95-1.84(m,1H),1.21-1.10(m,1H).

[0340] Compound 151: LCMS:MS m / z (ESI) [M+H] + =292.0; 1 H NMR (400MHz, CD3OD) δ = 7.04 (d, J = 8.4Hz, 1H), 6.83 (d, J = 2.4Hz, 1H), 6.72 (dd, J = 8.4, 2.4Hz, 1H), 5.72-5.61 (m, 1H), 5.47-5.33 (m, 1H), 3.26-3. 15(m,1H),2.94-2.82(m,1H),2.82-2.75(m,1H),2.70-2.60(m,1H),2.4 5-2.34(m,2H),2.22-2.02(m,3H),1.95-1.85(m,1H),1.21-1.11(m,1H).

[0341] Step 5: Compound 18-2B (3g) was chirally separated into compounds 152 and 153 using a preparative SFC (column: DAICEL CHIRALPAK IG (250mm*50mm, 10μm); mobile phase: [A: CO2 – B: methanol (0.1% ammonia)]; B%: 50%, isobaric elution mode). Chiral analysis determined the ee values ​​(column: Chiralpak IG-3100×4.6mm ID, 3μm; mobile phase: A: CO2, B: ethanol (0.2% MNH3); gradient: from 5% to 40% of B in 3 min, then 5% of B for 1 min; flow rate: 2.8 mL / min; column temperature: 35℃; ABPR: 1500 psi).

[0342] Compound 152:1 H NMR (400MHz, CD3OD) δ=7.01(d,J=8.4Hz,1H),6.75(s,1H),6.70(dd,J=8.4,2.0Hz,1H),5.82-5.64(m,2H),3.40-3.33(m,1H),3.08-2.99(m,1H),2.9 8-2.90(m,1H),2.77-2.71(m,1H),2.69-2.57(m,1H),2.53-2.42(m,1H),2 .40-2.30(m,1H),2.21-1.99(m,2H),1.99-1.89(m,1H),1.15-1.04(m,1H).

[0343] Compound 153: LCMS: MS m / z (ESI) [M+H] + =292.0; 1 H NMR (400MHz, CD3OD) δ = 7.01 (d, J = 8.4Hz, 1H), 6.75 (d, J = 2.4Hz, 1H), 6.70 (dd ,J=8.4,2.4Hz,1H),5.82-5.64(m,2H),3.39-3.34(m,1H),3.08-3.00(m,1H) ,2.99-2.90(m,1H),2.78–2.70(m,1H),2.67-2.57(m,1H),2.53-2.42(m,1H) ,2.40-2.30(m,1H),2.21-1.99(m,2H),1.99–1.89(m,1H),1.15–1.05(m,1H).

[0344] Example 17: Synthesis of Compound 16

[0345] Step 1: Compound 103-1 (280 mg, 815.34 μmol) was dissolved in anhydrous DCM (6 mL). Boron tribromide (2 M, 815.34 μL) was added under nitrogen protection at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched with water (5 mL) at 0 °C, the pH was adjusted to 8 with sodium bicarbonate, and the mixture was extracted three times with DCM (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16-2. LCMS: MS m / z (ESI) [M+H] + =329.9.

[0346] Step 2: Compound 16-2 (240 mg, 728.62 μmol) and cesium carbonate (949.59 mg, 2.91 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 25 °C for 0.5 h. Deuterated iodomethane (211.24 mg, 1.46 mmol) was added dropwise at 25 °C, and the reaction mixture was stirred at 50 °C under nitrogen protection for 5 h. The reaction mixture was quenched with water (10 mL), extracted three times with ethyl acetate (10 mL), and concentrated under reduced pressure to obtain compound 16-3. LCMS: MS m / z (ESI) [M+H] + =347.2;1H NMR (400MHz, CD3OD) δ=7.08-6.98(m,1H),6.91-6.79(m,1H),6.79-6.72(m,1H),5.89-5.38(m,2H),4.42-4.25(m,1H ),4.22-4.10(m,2H),3.95-3.78(m,1H),3.50–3.35(m,1H),2.73-2.47(m,4H),2.16-1.97(m,2H),1.38-1.11(m,5H).

[0347] Step 3: Compound 16-3 (100 mg, 288.65 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Under nitrogen protection and in an ice-water bath, a solution of lithium aluminum hydride tetrahydrofuran (2.5 M, 346 μL) was added, and the reaction was stirred at 50 °C for 10 hours. After the reaction was complete, water (1 mL) was added to quench the reaction. After filtration, the mixture was purified by preparative HPLC (column: 52-Welch Ultimate C18 150 × 30 mm, 5 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; B%: 36%-76%, 10.0 min) to obtain compound 16. LCMS: MS m / z (ESI) [M+H] + =289.0; 1H NMR (400MHz, CD3OD) δ7.02(d,J=8.4Hz,1H),6.81(d,J=2.4Hz,1H),6.71(dd,J=8 .4,2.4Hz,1H),5.69-5.57(m,1H),5.45-5.31(m,1H),3.20(d,J=18.4Hz,1H),2. 92-2.82(m,1H),2.82-2.75(m,1H),2.64(dd,J=17.2,5.6Hz,1H),2.44-2.32(m, 5H),2.20-2.12(m,2H),2.11-2.03(m,1H),1.93-1.83(m,1H),1.20–1.09(m,1H).

[0348] Example 18: Synthesis of Compound 143

[0349] Compound 16-3 (1.00 g, 2.89 mmol) was dissolved in ethylene glycol (10 mL) and anhydrous tetrahydrofuran (4 mL), and potassium hydroxide (3.24 g, 57.7 mmol) was added. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was complete, the mixture was filtered and purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30 mm*5 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - acetonitrile]; elution gradient: 12%-62%, 12.0 min) to obtain compound 143. LCMS: MS m / z (ESI) [M+H] + =275.2;1H NMR (400MHz, CD3OD) δ7.04(d,J=8.4Hz,1H),6.84(d,J=2.4Hz,1H),6.74(dd,J=8.4,2.4Hz,1H),5.71-5.58(m,1H),5.45–5.34(m,1H),3.39-3.3 2(m,1H),3.05-2.97(m,2H),2.72-2.59(m,2H),2.59-2.50(m,1H),2.45 -2.35(m,1H),2.19-2.07(m,2H),1.91–1.80(m,1H),1.13–1.03(m,1H).

[0350] Example 19: Synthesis of Compound 145

[0351] Step 1: Compound 145-0 (900 mg, 3.34 mmol) and 2-methyl-2-butene (1.17 g, 16.7 mmol) were dissolved in anhydrous DCM (10 mL). Under nitrogen protection at -78 °C, a boron tribromide dichloromethane solution (2 M, 3.34 mL) was added. The reaction mixture was slowly heated to 25 °C and stirred for 5 hours. After the reaction was complete, ammonia was added to quench the reaction, and the pH was adjusted to 8-9. The mixture was extracted three times with DCM (10 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 145-1. LCMS: MS m / z (ESI) [M+H] + =256.3

[0352] Step 2: Compound 145-1 (300 mg, 1.17 mmol) and triethylamine (238 mg, 2.35 mmol) were dissolved in anhydrous DCM (3 mL), and PhNTf2 (504 mg, 1.41 mmol) was added. The reaction mixture was stirred at 25 °C for 10 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 145-2. LCMS: MS m / z (ESI) [M+H] + =388.0

[0353] Step 3: Compound 145-2 (500 mg, 1.29 mmol) and zinc cyanide (360 mg, 3.07 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), and tetrakis(triphenylphosphine)palladium (149 mg, 129 μmol) was added. The reaction was carried out under nitrogen protection at 100 °C with stirring for 10 hours. After the reaction was complete, water (5 mL) was added for dilution, and the mixture was extracted three times with ethyl acetate (5 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 145-3. LCMS: MS m / z (ESI) [M+H] + =265.2.

[0354] Step 4: Compound 145-3 (310 mg, 1.17 mmol) was dissolved in ethanol (1.5 mL) and water (1.5 mL). Potassium hydroxide (329 mg, 5.86 mmol) was added under an ice-water bath, and the reaction was stirred at 80 °C for 1 hour. After the reaction was complete, the mixture was filtered, and the filtrate was purified by preparative HPLC (column: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: A: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 5%-35%, 10.0 min) to obtain compound 145.

[0355] LCMS: MS m / z(ESI)[M+H] + =283.2; 1H NMR (400MHz, DMSO-d6) δ7.88(brs,1H),7.79(s,1H),7.60(d,J=8.0Hz,1H),7.22(br s,1H),7.17(d,J=8.0Hz,1H),5.64–5.54(m,1H),5.46-5.37(m,1H),3.08-2.91(m,2H ),2.90–2.83(m,1H),2.82-2.70(m,1H),2.34-2.30(m,1H),2.28(s,3H),2.10-1.99 (m,2H),1.97-1.83(m,2H),1.78-1.66(m,1H),1.62-1.49(m,1H),1.36–1.25(m,1H).

[0356] Example 20: Synthesis of Compound 156

[0357] Step 1: Intermediate I (430 mg, 1.31 mmol) and 2-methyl-2-butene (461 mg, 6.57 mmol) were dissolved in anhydrous DCM (5 mL). Under N2 protection at -78 °C, a 2 M, 985 μL solution of boron tribromide in DCM was added. The reaction mixture was stirred at 25 °C for 5 hours. After the reaction was complete, saturated NaHCO3 solution was added to quench the reaction until no more bubbles were generated. The mixture was extracted three times with DCM (5 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 156-1. MS m / z (ESI) [M+H] + =314.2.

[0358] Step 2: Compound 156-1 (200 mg, 638 μmol) and TEA (129 mg, 1.28 mmol) were dissolved in anhydrous DCM (3 mL), and PhNTf2 (228 mg, 638 μmol) was added. The reaction mixture was stirred at 25 °C for 10 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 156-2. MS m / z (ESI) [M+H] + =446.2.

[0359] Step 3: Compound 156-2 (0.30 g, 673 μmol) was dissolved in anhydrous dioxane (5 mL). Under a nitrogen atmosphere, aziridine (69.3 mg, 741 μmol), Pd2(dba)3 (61.7 mg, 67.3 μmol), XPhos (96.3 mg, 202 μmol), and cesium carbonate (329 mg, 1.00 mmol) were added. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 0 to 94 / 6) to obtain compound 156-3. MS m / z (ESI) [M+H] + =353.3.

[0360] Step 4: Compound 156-3 (170 mg, 482 μmol) was dissolved in anhydrous THF (2 mL). Under a nitrogen atmosphere and at 0 °C, a 2.5 M, 0.58 mL THF solution of LiAlH4 was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched at 0 °C with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 0%-25%) to obtain the formate salt of compound 156. MS m / z (ESI) [M+H] + =295.1; 1 H NMR (400MHz, CD3OD) δ = 8.51 (s, 1H), 7.04 (d, J = 8.0Hz, 1H), 6.49-6.35 (m, 2H), 5. 72-5.44(m,2H),3.86-3.76(m,4H),3.73-3.67(m,1H),3.28-3.21(m,1H),3.19- 3.09(m,2H),3.00-2.93(m,1H),2.93(s,3H),2.88-2.78(m,1H),2.41-2.28(m,3 H),2.17-2.02(m,2H),2.00-1.90(m,1H),1.84-1.76(m,1H),1.74-1.66(m,1H).

[0361] Example 21: Synthesis of Compound 157

[0362] Compound 145-2 (100 mg, 0.26 mmol), 2-azacyclobutanone (27.52 mg, 0.39 mmol), CuI (100.00 mg, 0.94 mmol), and cesium carbonate (252.30 mg, 0.77 mmol) were dissolved in anhydrous dioxane (2 mL), substituted with N2 three times, and reacted at 110 °C for 16 hours. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: 41-Welch Ultimate C18 150 × 40 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 25%-45%) to obtain compound 157. MS m / z (ESI) [M+H] + =309.2; 1 H NMR (400MHz, CDCl3) δ = 7.34 (d, J = 1.6Hz, 1H), 7.14-7.05 (m, 2H), 5.71-5.60 (m, 1H),5.55-5.45(m,1H),3.68-3.53(m,2H),3.13-2.97(m,4H),2.90-2.74(m,2H) ,2.50(dd,J=12.2,3.2Hz,1H),2.44(s,3H),2.28-2.19(m,1H),2.18-2.08(m,2 H),2.00-1.90(m,1H),1.89-1.79(m,1H),1.79-1.67(m,1H),1.55-1.44(m,1H).

[0363] Example 22: Synthesis of Compound 158

[0364] Step 1: Compound 156-2 (0.50 g, 1.12 mmol), tert-butyl carbamate (0.20 g, 1.68 mmol), Pd2(dba)3 (0.10 g, 112 μmol), cesium carbonate (1.46 g, 4.49 mmol), and XPhos (0.53 g, 112 μmol) were dissolved in anhydrous 1,4-dioxane (10 mL). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The organic phases were combined, washed with saturated brine (60 mL × 1), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness to obtain compound 158-1. MS m / z (ESI) [M+H] + =413.2.

[0365] Step 2: Compound 158-1 (0.66 g, 1.60 mmol) was dissolved in anhydrous THF (15 mL). A 2.5 M, 3.5 mL solution of LiAlH4 in THF was slowly added dropwise under a N2 atmosphere at 0 °C. The reaction mixture was stirred for 1 hour at 25 °C under N2 protection. The reaction solution was then quenched with water (0.5 mL), 15% NaOH aqueous solution (0.5 mL), and water (1.5 mL) under N2 protection at 0 °C. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 158-2. MS m / z (ESI) [M+H] + =355.2.

[0366] Step 3: Compound 158-2 (0.21 g, 0.60 mmol) was dissolved in 1,4-dioxane hydrogen chloride solution (2 M, 10 mL). The reaction solution was stirred at 25 °C for 2 hours. The reaction solution was concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150×40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia) + 10 mM ammonium bicarbonate - B: acetonitrile]; gradient: 10%-50% B) and then purified by SFC (column: 101-DAICEL CHIRALPAK IM 250×30 mm, 10 μm; mobile phase: [A: CO2 - B: ethanol (0.1% ammonia)]; B%: 55%) to obtain compound 158. MS m / z (ESI) [M+H] + =255.2; 1 H NMR (400MHz, CD3CN) δ = 6.82 (d, J = 8.0 Hz, 1H), 6.59 ( d, J = 2.4 Hz, 1H), 6.42 ( dd, J = 8.0, 2 .4Hz,1H),5.63-5.57(m,1H),5.52-5.44(m,1H),4.10-3.57(m,2H),2.92(d,J=18.4Hz, 1H),2.88-2.81(m,1H),2.75(dd,J=18.0,5.6Hz,1H),2.61(dd,J=18.4,6.0Hz,1H),2. 31(s,3H),2.11-1.99(m,3H),1.76-1.65(m,2H),1.40-1.31(m,1H),1.31-1.22(m,2H).

[0367] Example 23: Synthesis of Compound 159

[0368] Compound 158 (0.27 g, 1.06 mmol) was dissolved in anhydrous DCM (5 mL), and chloroacetyl (0.13 g, 1.59 mmol, 113 μL) and TEA (295 μL) were added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150 × 40 mm, 7 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; gradient: 8% - 48% B) to obtain compound 159. MS m / z (ESI) [M+H] + =297.2; 1 H NMR (400MHz, DMSO-d6) δ = 9.76 (s, 1H), 7.43-7.35 (m, 2H), 7.01 (d, J = 8.0Hz, 1H), 5.69-5.38 (m, 2H), 2.94 (d, J = 18.8Hz, 1H), 2.87-2.80 (m, 1H) ,2.76-2.58(m,2H),2.35-2.28(m,1H),2.27(s,3H),2.07-2.00(m,2H) ,1.99(s,3H),1.97-1.84(m,2H),1.76-1.54(m,2H),1.33-1.22(m,1H).

[0369] Example 24: Synthesis of Compound 160

[0370] Step 1: Compound 156-2 (200 mg, 449 μmol) was dissolved in anhydrous dioxane (2 mL). Under a nitrogen atmosphere, trimethylcycloboroxane (67.6 mg, 539 μmol), Pd(PPh3)4 (25.9 mg, 22.5 μmol), and potassium phosphate (143 mg, 674 μmol) were added. The reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 90 / 10) to give compound 160-1. MS m / z (ESI) [M+H] + =312.1; 1H NMR (400MHz, CD3OD) δ=7.15(s,1H),7.02-6.92(m,2H),5.70-5.41(m,2H),4.45(brs,1H),4.22-4.03(m,2H),3.87(dd,J=13.6,4.8Hz,1H),3.40-3.3 0(m,1H),2.92(dd,J=17.6,5.6Hz,1H),2.78-2.59(m,2H),2.28(s,3H),2. 12-1.92(m,3H),1.76-1.57(m,2H),1.52-1.41(m,1H),1.31-1.22(m,3H).

[0371] Step 2: Compound 160-1 (120 mg, 385 μmol) was dissolved in anhydrous THF (2 mL). Under a nitrogen atmosphere and at 0 °C, a 2.5 M, 0.46 mL THF solution of LiAlH4 was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched at 0 °C with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 13%-43%) to obtain compound 160. MS m / z (ESI) [M+H] + =254.0; 1 H NMR (400MHz, CD3OD) δ = 7.10 (s, 1H), 7.02-6.96 (m, 1H), 6.94-6.89 (m, 1H), 5.68-5 .52(m,1H),5.51-5.41(m,1H),3.07(d,J=18.8Hz,1H),3.02-2.96(m,1H),2.95-2 .79(m,2H),2.46(dd,J=11.6,3.6Hz,1H),2.41(s,3H),2.26(s,3H),2.21-2.11(m ,2H),2.10-2.00(m,1H),2.00-1.88(m,1H),1.85-1.68(m,2H),1.47-1.39(m,1H).

[0372] Example 25: Synthesis of Compound 161

[0373] Procedure: A mixture of formic acid (12.1 mg, 0.25 mmol) and acetic anhydride (16.1 mg, 0.16 mmol, 14.8 μL) was heated to 60 °C. After 30 minutes, the mixture was cooled to 0 °C. Compound 158 (20 mg, 78.6 μmol) was dissolved in anhydrous THF (0.5 mL) and anhydrous toluene (0.5 mL) and slowly added dropwise to the mixture. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; gradient: 18%-58% B) to obtain compound 161. MS m / z (ESI) [M+H] + =283.2; 1 H NMR (400MHz, DMSO-d6) δ = 9.99 (s, 1H), 8.19 (d, J = 2.0Hz, 1H), 7.47 (d, J = 2.0Hz, 1H), 7.3 5(dd,J=8.0,2.0Hz,1H),7.09-7.00(m,1H),5.61-5.55(m,1H),5.48-5.40(m,1H),2.94 (d,J=18.8Hz,1H),2.84(dd,J=6.0,3.2Hz,1H),2.74-2.60(m,2H),2.34-2.30(m,1H),2 .27(s,3H),2.07-1.98(m,2H),1.97-1.85(m,2H),1.75-1.53(m,2H),1.36-1.24(m,1H).

[0374] Example 26: Synthesis of Compound 162

[0375] Step 1: Compound 145-3 (200 mg, 0.45 mmol) and KOH (509.35 mg, 9.08 mmol) were dissolved in ethanol (2 mL) and water (2 mL). The reaction was carried out at 80 °C for 8 hours. The reaction solution was concentrated under reduced pressure to remove ethanol, and then water (10 mL) was added. The solution was extracted with EtOAc (5 mL × 3) to remove some impurities. The aqueous phase was purified by reversed-phase column chromatography (mobile phase: water (0.1% formic acid-acetonitrile) to obtain compound 162-1. MS m / z (ESI) [M+H] + =284.1.

[0376] Step 2: Compound 162-1 (45 mg, 0.16 mmol), methylamine hydrochloride (32.17 mg, 0.48 mmol), DIEA (102.62 mg, 0.79 mmol), and HATU (72.46 mg, 0.19 mmol) were dissolved in DCM (0.5 mL) and reacted at 25 °C for 2 hours. Water (5 mL) was added to the reaction solution, and the mixture was extracted three times with DCM (3 mL). The mixed organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to obtain the crude product. Compound 162-1 was purified by preparative HPLC (column: 40-Welch Ultimate C18 150 × 30 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 18%-58%). MS m / z (ESI) [M+H] + =297.2; 1 H NMR (400MHz, CD3OD) δ = 7.82 (d, J = 1.2Hz, 1H), 7.59 (dd, J = 8.0, 1.6Hz, 1H), 7.24 (d, J = 8. 0Hz,1H),5.72-5.57(m,1H),5.52-5.40(m,1H),3.23-3.12(m,1H),3.10-2.93(m,3H),2 .92(s,3H),2.52(dd,J=12.4,3.2Hz,1H),2.44(s,3H),2.28–2.19(m,1H),2.18-2.07(m ,2H),2.06-1.96(m,1H),1.93-1.78(m,1H),1.77-1.64(m,1H),1.50(d,J=13.2Hz,1H).

[0377] Example 27: Synthesis of Compound 163

[0378] Compound 162-1 (45 mg, 0.16 mmol), dimethylamine hydrochloride (38.85 mg, 0.48 mmol), DIEA (102.62 mg, 0.79 mmol), and HATU (72.46 mg, 0.19 mmol) were dissolved in DCM (0.5 mL) and reacted at 25 °C for 2 hours. Water (5 mL) was added to the reaction mixture, and the mixture was extracted three times with DCM (3 mL). The mixed organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to obtain the crude product. Compound 163 was purified by preparative HPLC (column: 40-Welch Ultimate C18 150 × 30 mm, 7 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 22%-62%). MS m / z (ESI) [M+H] + =311.2; 1 H NMR (400MHz, CD3OD) δ = 7.38 (d, J = 1.2Hz, 1H), 7.28-7.13 (m, 2H), 5.67-5.57 (m, 1H), 5.51-5.41(m,1H),3.21-3.14(m,1H),3.08(s,3H),3.04(dd,J=6.4,3.2Hz,1H),2.9 7(s,3H),2.96-2.85(m,2H),2.50(dd,J=12.0,3.2Hz,1H),2.43(s,3H),2.24-2.08( m,3H),2.06-1.96(m,1H),1.90-1.77(m,1H),1.77-1.65(m,1H),1.53-1.43(m,1H).

[0379] Example 28: Synthesis of Compound 165

[0380] Step 1: Under a nitrogen atmosphere and at 0°C, intermediate I (500 mg, 1.53 mmol) was dissolved in anhydrous THF (5 mL), followed by the addition of a 1 M, 4.58 mL THF solution of LiAlD4. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched at 0°C with water (0.5 mL), 15% NaOH aqueous solution (0.5 mL), and water (1.5 mL). After drying with anhydrous Na2SO4, filtration, and concentration under reduced pressure, crude compound 165-1 was obtained directly. MS m / z (ESI) [M+H] + =273.2.

[0381] Step 2: Compound 165-1 (400 mg, crude product) was dissolved in anhydrous DCM (4 mL). 2-Methyl-2-butene (515 mg, 7.34 mmol) and a 2 M, 1.62 mL solution of boron tribromide in DCM were added at -78 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 5 hours. The reaction mixture was quenched with saturated NaHCO3 solution, extracted with DCM (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (DCM / methanol = 100 / 0 to 90 / 10) to obtain compound 165-2. MS m / z (ESI) [M+H] + =259.1.

[0382] Step 3: Compound 165-2 (370 mg, 1.43 mmol) was dissolved in anhydrous DCM (5 mL), followed by the addition of TEA (435 mg, 4.30 mmol) and PhNTf2 (767 mg, 2.15 mmol). The reaction mixture was stirred at 25 °C for 10 hours. The reaction mixture was diluted with 5 mL of water, extracted with DCM (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 0 / 100) to obtain compound 165-3. MS m / z (ESI) [M+H] + =391.5.

[0383] Step 4: Under a nitrogen atmosphere, compound 165-3 (500 mg, 1.30 mmol) was dissolved in anhydrous DMF (5 mL), followed by the addition of zinc cyanide (902 mg, 7.68 mmol) and Pd(PPh3)4 (148 mg, 128 μmol). The reaction mixture was stirred at 100 °C for 10 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 solution, extracted with EtOAc (5 mL × 3), and the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 0 / 100) to obtain compound 165-4. MS m / z (ESI) [M+H] + =268.1.

[0384] Step 5: Compound 165-4 (100 mg, 374 μmol) was dissolved in anhydrous ethanol (1 mL) and water (0.5 mL), and then KOH (210 mg, 3.74 mmol) was added. The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was quenched and neutralized with 2 M hydrochloric acid, concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 0%-20%) to obtain the formate salt of compound 165. MS m / z (ESI) [M+H] + =286.1; 1 H NMR (400MHz, CD3OD) δ=8.54(s,1H),7.94(d,J=1.2Hz,1H),7.74(dd,J=8.0,1 .6Hz,1H),7.33(d,J=8.0Hz,1H),5.74-5.63(m,1H),5.54-5.41(m,1H),3.80 -3.68(m,1H),3.47-3.33(m,2H),3.20-3.03(m,2H),2.76-2.65(m,1H),2.52 -2.41(m,1H),2.21(d,J=18.4Hz,1H),2.15-1.98(m,2H),1.81-1.62(m,2H).

[0385] Example 29: Synthesis of Compound 169

[0386] Compound 145-2 (500 mg, 1.29 mmol), 2-pyrrolidone (164.75 mg, 1.94 mmol), CuI (500 mg, 4.70 mmol), and cesium carbonate (1.26 g, 3.87 mmol) were dissolved in anhydrous dioxane (10 mL), purged three times with N2, and reacted at 110 °C for 16 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by preparative HPLC (column: 52-Welch Ultimate C18 150 × 40 mm, 5 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 20%-60%) to obtain compound 169. MS m / z (ESI) [M+H] + =323.2; 1H NMR (400MHz, CDCl3) δ = 7.59 (d, J = 2.4Hz, 1H), 7.33 (dd, J = 8.0, 2.4Hz, 1H), 7.10 (d, J = 8.0Hz, 1H), 5.68– 5.58(m,1H),5.54-5.42(m,1H),3.94-3.75(m,2H),3.06(d,J=18.6Hz,1H),3.02-2.94(m,1H),2.90-2. 71(m,2H),2.59(t,J=8.0Hz,2H),2.49-2.37(m,4H),2.23-2.17(m,1H),2.16-2.12(m,2H),2.11-2.07( m,1H),2.03-1.91(m,1H),1.86-1.81(m,1H),1.80-1.77(m,1H),1.75-1.67(m,1H),1.55-1.43(m,1H).

[0387] Example 30: Synthesis of Compound 166

[0388] Compound 145-2 (100 mg, 258 μmol) was dissolved in anhydrous dioxane (2 mL). Pyrazole (21.1 mg, 310 μmol), Pd2(dba)3 (23.6 mg, 25.8 μmol), tBuBrettPhos (12.5 mg, 25.8 μmol), and potassium phosphate (110 mg, 516 μmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30mm, 5μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 10%-40%) to give the formate salt of compound 166. MS m / z (ESI) [M+H] + =306.2; 1H NMR (400MHz, CD3OD) δ=8.56(brs,1H),8.21(d,J=2.4Hz,1H),7.75(d,J=1.6Hz,1H),7.71(d,J=1 .2Hz,1H),7.58(dd,J=8.4,2.0Hz,1H),7.35(d,J=8.4Hz,1H),6.52(t,J=2.0Hz,1H),5.76-5.61( m,1H),5.57-5.44(m,1H),3.74(brs,1H),3.43-3.32(m,2H),3.19-3.00(m,2H),2.92(s,3H),2.8 2-2.70(m,1H),2.53-2.40(m,1H),2.21(d,J=18.0Hz,1H),2.15-1.98(m,2H),1.83-1.69(m,2H).

[0389] Example 31: Synthesis of Compound 167

[0390] Compound 145-2 (100 mg, 258 μmol) was dissolved in anhydrous toluene (1 mL) and dioxane (0.2 mL). Imidazole (21.1 mg, 310 μmol), Pd2(dba)3 (23.6 mg, 25.8 μmol), tBuBrettPhos (12.5 mg, 25.8 μmol), and potassium phosphate (110 mg, 516 μmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30mm, 5μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 10%-40%) to give the formate salt of compound 167. MS m / z (ESI) [M+H] + =306.1; 1H NMR (400MHz, CD3OD) δ = 8.42 (brs, 1H), 8.18 (brs, 1H), 7.63-7.52 (m, 2H), 7.47-7. 37(m,2H),7.18(brs,1H),5.74–5.65(m,1H),5.56-5.46(m,1H),3.90-3.76(m,1H) ,3.52-3.33(m,2H),3.24(d,J=10.4Hz,1H),3.09(dd,J=18.0,5.2Hz,1H),2.99(s ,3H),2.90-2.75(m,1H),2.56-2.45(m,1H),2.29-2.01(m,3H),1.90-1.70(m,2H).

[0391] Example 32: Synthesis of Compound 168

[0392] Compound 145-2 (100 mg, 0.26 mmol), 1-H-pyrazole-3-boronic acid pinacol ester (100.17 mg, 0.52 mmol), PdCl2 (dppf) (37.77 mg, 0.052 mmol), and cesium carbonate (210.25 mg, 0.65 mmol) were dissolved in anhydrous dioxane (2 mL) and water (0.5 mL), and the mixture was substituted with N2 three times. The reaction was carried out at 90 °C for 12 hours. The reaction solution was subjected to reduced pressure distillation to remove the solvent, and water (15 mL) was added. The mixture was extracted three times with EtOAc (10 mL × 3). The mixed organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative HPLC (column: 41-Welch Ultimate C18 150 × 40 mm, 7 μm; mobile phase: [water (0.225% formic acid) - B: acetonitrile]; B%: 0%-40%) to obtain the formate salt of compound 168. MS m / z (ESI) [M+H] + =306.2; 1H NMR (400MHz, CD3OD) δ = 8.55 (s, 1H), 7.81 (d, J = 1.2Hz, 1H), 7.72-7.55 (m, 2H), 7.2 8(d,J=8.0Hz,1H),6.66(d,J=2.4Hz,1H),5.77-5.63(m,1H),5.55-5.42(m,1H),3. 80-3.66(m,1H),3.43-3.32(m,1H),3.31-3.23(m,1H),3.20-3.06(m,2H),2.92(s ,3H),2.85-2.70(m,1H),2.50-2.40(m,1H),2.27-1.97(m,3H),1.85-1.67(m,2H).

[0393] Example 33: Synthesis of Compound 171

[0394] Compound 145-2 (200 mg, 516 μmol) was dissolved in anhydrous toluene (3 mL). Under a nitrogen atmosphere, 2-tributyltin-thiazolium (386 mg, 1.03 mmol), Pd(PPh3)2Cl2 (36.2 mg, 51.6 μmol), and lithium chloride (98.5 mg, 2.32 mmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid) - B: acetonitrile]; B%: 0%-25%) to obtain the formate salt of compound 171. MS m / z(ESI)[M+H] + =323.1; 1H NMR (400MHz, CD3OD) δ=8.53(s,1H),8.00(d,J=1.6Hz,1H),7.86(d,J=3.2Hz,1H),7.77(dd,J= 8.0,1.6Hz,1H),7.60(d,J=3.2Hz,1H),7.35(d,J=8.0Hz,1H),5.78-5.65(m,1H),5.57-5.47(m ,1H),3.69(brs,1H),3.38-3.33(m,2H),3.17-3.03(m,2H),2.89(s,3H),2.80-2.66(m,1H),2 .47-2.37(m,1H),2.30-2.19(m,1H),2.18-2.08(m,1H),2.08-1.98(m,1H),1.83-1.69(m,2H).

[0395] Example 34: Synthesis of Compound 172

[0396] Procedure: Compound 145-2 (200 mg, 516 μmol) was dissolved in anhydrous toluene (3 mL). Under a nitrogen atmosphere, 4-(tributyltin)thiazole (386 mg, 1.03 mmol) and Pd(dppf)Cl2 (37.8 mg, 51.6 μmol) were added. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was cooled to room temperature, diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 13%-33%) to obtain the formate salt of compound 172. MS m / z (ESI) [M+H] + =323.1; 1H NMR (400MHz, CD3OD) δ = 9.06 (d, J = 2.0Hz, 1H), 8.50 (s, 1H), 8.00 (d, J = 1.6Hz, 1H), 7.88 (d, J = 2 .0Hz,1H),7.78(dd,J=8.0,1.6Hz,1H),7.31(d,J=8.0Hz,1H),5.77-5.64(m,1H),5.60-5.45(m ,1H),3.73(brs,1H),3.42-2.33(m,2H),3.22-3.09(m,2H),2.94(s,3H),2.86-2.75(m,1H),2 .45-2.35(m,1H),2.27-2.18(m,1H),2.16-2.07(m,1H),2.06-1.96(m,1H),1.87-1.72(m,2H).

[0397] Example 35: Synthesis of Compound 173

[0398] Step 1: Compound 145-2 (1.1 g, 2.84 mmol), bis(pinnatrol)boronic acid ester (865.21 mg, 3.41 mmol), PdCl2 (dppf) (62.33 mg, 0.085 mmol), and potassium acetate (835.97 mg, 8.52 mmol) were dissolved in anhydrous dioxane (10 mL), substituted with N2 three times, and reacted at 80 °C for 16 hours. The reaction solution was subjected to vacuum distillation to remove dioxane, water (20 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (industrial hexane / THF = 99 / 1 to 30 / 70) to obtain 173-1. MS m / z (ESI) [M+H] + =365.8.

[0399] Step 2: Compound 173-1 (300 mg, 0.82 mmol), compound 173-1A (202.05 mg, 1.23 mmol), PdCl2 (dppf) (60.09 mg, 0.082 mmol), and K2CO3 (226.99 mg, 1.64 mmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL), and the mixture was replaced with N2 three times. The reaction was carried out at 90 °C for 16 hours. The reaction solution was subjected to vacuum distillation to remove dioxane, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: 41-Welch Ultimate C18 150×40 mm, 7 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 4%-34%) to obtain the formate salt of compound 173. MS m / z (ESI) [M+H] + =323.2; 1 H NMR (400MHz, CD3OD) δ = 8.96 (d, J = 4.4Hz, 1H), 8.57 (brs, 1H), 8.04 (s, 1H), 7.93- 7.71(m,2H),7.34(d,J=8.0Hz,1H),5.75-5.63(m,1H),5.55-5.45(m,1H),3.75( brs,1H),3.48-3.32(m,2H),3.20-3.10(m,2H),2.94(s,3H),2.85-2.74(m,1H), 2.52-2.40(m,1H),2.22(d,J=17.6Hz,1H),2.17-1.97(m,2H),1.86-1.68(m,2H).

[0400] Example 36: Synthesis of Compound 174

[0401] Procedure: Compound 145-2 (200 mg, 516 μmol) was dissolved in anhydrous toluene (3 mL). 2-(tri-n-butyltinyl)oxazole (370 mg, 1.03 mmol) and Pd(PPh3)4 (59.7 mg, 51.6 μmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 0%-25%) to obtain the formate salt of compound 174. MS m / z (ESI) [M+H] + =307.2; 1 H NMR (400MHz, CD3OD) δ=8.51(s,1H),8.07(d,J=1.6Hz,1H),7.98(s,1H),7.88(dd,J=8.0 ,1.6Hz,1H),7.39(d,J=8.0Hz,1H),7.30(d,J=0.8Hz,1H),5.76-5.66(m,1H),5.57-5.4 3(m,1H),3.82-3.68(m,1H),3.48-3.34(m,2H),3.20-3.05(m,2H),2.93(s,3H),2.82-2 .68(m,1H),2.50-2.38(m,1H),2.30-2.20(m,1H),2.17-1.99(m,2H),1.83-1.72(m,2H).

[0402] Example 37: Synthesis of Compound 175

[0403] Procedure: Compound 173-1 (200 mg, 472 μmol) was dissolved in anhydrous dioxane (1.5 mL), NMP (0.5 mL), and water (0.5 mL). Compound 175-1 (174 mg, 945 μmol), XPhos-Pd-G2 (37.2 mg, 47.2 μmol), and cesium carbonate (462 mg, 1.42 mmol) were added under a nitrogen atmosphere. The reaction mixture was stirred at 90 °C for 12 hours. The reaction mixture was diluted with 5 mL of water, extracted with EtOAc (5 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under rotary evaporation. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30mm, 5μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 0%-35%) to give the formate salt of compound 175. MS m / z (ESI) [M+H] + =307.1; 1 H NMR (400MHz, CD3OD) δ=8.52(s,1H),8.33(s,1H),8.26(s,1H),7.83(s,1H),7.63(d,J= 8.0Hz,1H),7.29(d,J=8.0Hz,1H),5.74-5.64(m,1H),5.55-5.45(m,1H),3.76(brs,1H) ),3.45-3.33(m,2H),3.20-3.09(m,2H),2.95(s,3H),2.85-2.75(m,1H),2.47-2.40(m ,1H),2.21(d,J=18.4Hz,1H),2.16-2.06(m,1H),2.06-1.98(m,1H),1.83-1.73(m,2H).

[0404] Example 38: Synthesis of compounds 176 and 177

[0405] Step 1: Under a nitrogen atmosphere, intermediate I (5.00 g, 15.3 mmol) was dissolved in anhydrous acetonitrile (50 mL), and then Select F (10.8 g, 30.5 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 87 / 13) to give compound 176-1 (a mixture of fluorinated compounds at positions 2 and 4). MS m / z (ESI) [M+H] +=346.1

[0406] Step 2: Under a nitrogen atmosphere and at 0°C, compound 176-1 (mixture, 3.20 g, 9.26 mmol) was dissolved in anhydrous THF (30 mL), followed by the addition of a 2.5 M, 7.41 mL THF solution of LiAlH4. The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was quenched at 0°C with water (1 mL), 15% NaOH aqueous solution (1 mL), and water (3 mL). After drying with anhydrous Na2SO4, filtration, and concentration under reduced pressure, the crude product compound 176-2 (mixture) was directly obtained. MS m / z (ESI) [M+H] + =288.1.

[0407] Step 3: Compound 176-2 (mixture, 2.60 g) was dissolved in anhydrous DCM (30.0 mL). 2-Methyl-2-butene (6.35 g, 90.5 mmol) and a 2 M, 18.1 mL solution of boron tribromide in DCM were added at -78 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 5 hours. The reaction mixture was quenched with saturated NaHCO3 solution, extracted with DCM (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to directly obtain the crude product compound 176-3 (mixture). MS m / z (ESI) [M+H] + =274.1.

[0408] Step 4: Compound 176-3 (mixture, 2.47 g) was dissolved in anhydrous DCM (30 mL), then TEA (2.74 g, 27.1 mmol) and PhNTf2 (4.84 g, 13.6 mmol) were added. The reaction mixture was stirred at 25 °C for 10 hours. The reaction mixture was diluted with 50 mL of water, extracted with DCM (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was subjected to silica gel column chromatography (petroleum ether / THF = 100 / 0 to 60 / 40) to give compound 176-4 (mixture). MS m / z (ESI) [M+H] + =406.1.

[0409] Step 5: Under a nitrogen atmosphere, compound 176-4 (mixture, 3.00 g) was dissolved in anhydrous DMF (30 mL), followed by the addition of zinc cyanide (5.21 g, 44.4 mmol) and Pd(PPh3)4 (855 mg, 740 μmol). The reaction mixture was stirred at 100 °C for 10 hours. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 solution (20 mL), extracted with EtOAc (50 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 0 / 100) to give compound 176-5 (mixture). MS m / z (ESI) [M+H] + =283.0.

[0410] Step 6: Compound 176-5 (mixture, 260 mg) was dissolved in anhydrous ethanol (2 mL) and water (2 mL), and then KOH (517 mg, 9.21 mmol) was added. The reaction solution was stirred at 80 °C for 1 hour. The reaction solution was quenched and neutralized with 2 M hydrochloric acid, concentrated under reduced pressure, and the concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 5%-25%) to obtain compound 176-6 (mixture). MS m / z (ESI) [M+H] + =301.1.

[0411] Step 7: Compound 176-6 (mixture, 100 mg) was purified by preparative SFC (column: Daicel ChiralPak AD (250×30 mm, 10 μm); mobile phase: [A: CO2–B: isopropanol (0.1% ammonia)]; B%: 25%, isobaric elution mode) to obtain compound 176 and compound 177.

[0412] SFC analysis conditions: (Column: Chiralpak AD-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: isopropanol (0.2% 7M NH3 / methanol solution); Gradient: 5%-40% B for 3 minutes, followed by 5% B for 1 minute; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi).

[0413] Compound 176: Retention time = 2.774 min, MS m / z (ESI) [M+H] + =301.1; 1H NMR (400MHz, CD3OD) δ=7.56(t,J=7.6Hz,1H),7.12(d,J=8.0Hz,1H),5.78-5.63(m,1H),5.55–5.45(m,1H),3.40(dd,J=17.6,6.0Hz,1H),3.33- 3.27(m,1H),3.18(brs,2H),2.80(d,J=12.4Hz,1H),2.61(s,3H),2.41 -2.30(m,1H),2.30-2.18(m,1H),2.18-2.05(m,2H),1.94-1.74(m,3H).

[0414] Compound 177: Retention time = 3.116 min, MS m / z (ESI) [M+H] + =301.1; 1 H NMR (400MHz, CD3OD) δ = 7.84 (d, J = 7.6Hz, 1H), 7.06 (d, J = 12.0Hz, 1H), 5.73-5.61 (m, 1H),5.56-5.43(m,1H),3.39(brs,1H),3.28-3.11(m,2H),2.98(dd,J=18.0,5.6Hz,1 H),2.89-2.78(m,1H),2.67(s,3H),2.49-2.37(m,1H),2.35-2.25(m,1H),2.23-2.13 (m,1H),2.12-2.02(m,1H),1.97-1.85(m,1H),1.76-1.66(m,1H),1.66-1.56(m,1H).

[0415] Example 40: Synthesis of Compound 179

[0416] Compound 106 (200.0 mg, 0.70 mmol) was dissolved in pyridine (5 mL), and SOCl2 (250.13 mg, 2.1 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated NaHCO3 (5 mL) in an ice bath, concentrated under reduced pressure, and evaporated to dryness. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (formic acid) - B: acetonitrile]; B%: 0%-40%) to obtain compound 179. MS m / z (ESI) [M+H] + =304.2; 1H NMR (400MHz, CD3OD) δ = 7.03 (d, J = 8.8Hz, 1H), 6.76-6.70 (m, 2H), 5.84-5.64 (m, 2H), 3.77-3.74 (m, 3H), 3.73-3.63 (m, 1H), 3. 17-3.09(m,3H),2.68-2.55(m,2H),2.53-2.46(m,1H),2.43(s,3H),2.40-2.34(m,1H),2.27-2.10(m,2H),1.24-1.16(m,1H).

[0417] Example 41: Synthesis of Compound 206

[0418] Step 1: 3-Methoxypropylene (265.73 mg, 3.69 mmol) was added to a mixed solution of THF (10 mL) and hexamethylphosphoric acid diamine (0.5 mL), and a THF solution of sec-butyllithium (1.3 M, 2.83 mL) was added dropwise at -40 °C. After addition, the mixture was stirred at this temperature for 30 min, and then a THF solution of compound 206-1 (500 mg, 1.84 mmol) in 2 mL was added dropwise at -40 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched by adding ammonium chloride solution (30 mL) at 0 °C, then diluted with water (50 mL), and extracted with industrial hexane (30 mL × 3). The organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM / methanol = 0 / 100 to 1 / 5) to obtain compound 206-2. MS m / z(ESI)[M+H] + =344.1.

[0419] Step 2: Compound 206-2 (300 mg, 873.47 μmol) was dissolved in toluene (20 mL), and tetrafluoro-p-benzoquinone (15.73 mg, 87.35 μmol) and Grubbs II catalyst (54.73 mg, 87.35 μmol) were added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction was quenched with dilute hydrochloric acid (1 N, 50 mL), then diluted with water (50 mL), and extracted with EtOAc (50 mL × 3). The aqueous phase was collected, and ammonia (5 mL) was added to adjust the pH to 10. Extraction was then performed again with EtOAc (50 mL × 3). The organic layer was washed with brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM / methanol = 100 / 0 to 1 / 5) to obtain compound 206. MS m / z (ESI) [M+H] + =316.2.

[0420] Step 3: Compound 206 (40 mg) was subjected to preparative SFC (column: DAICEL CHIRALPAK IG (250×30 mm, 10 μm); mobile phase: [A: CO2–B: ethanol (0.1% ammonia)]; B%: 45%, isobaric elution mode) chiral separation and preparative HPLC (column: 52-Welch Xtimate C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid-B: acetonitrile]; B%: 0%–40%) to obtain compounds 206-A and 206-B.

[0421] SFC analysis method: (Column: Chiralpak IG-3 100×4.6mm ID, 3μm; Mobile phase: 40% of ethanol (0.2% M NH3) in CO2; Flow rate: 2.8mL / min; Column temperature: 35℃; ABPR: 1500psi).

[0422] 206-A: Retention time = 1.032 minutes, MS m / z (ESI) [M+H] + =316.2; 1 H NMR (400MHz, CDCl3) δ==6.99(d,J=8.4Hz,1H),6.77-6.75(m,1H),6.71-6.67( m,1H),5.88-5.84(m,1H),5.75-5.70(m,1H),3.76(s,3H),3.62(brs,1H),3.2 6(s,3H),3.20-3.13(m,1H),3.10-3.01(m,2H),2.69-2.62(m,1H),2.43(s,3H ),2.42–2.37(m,2H),2.32-2.25(m,2H),2.12-2.04(m,1H),1.30–1.19(m,1H).

[0423] 206-B: Retention time = 1.427 minutes, MS m / z (ESI) [M+H] + =316.2; 1H NMR (400MHz, CDCl3) δ = 8.53 (brs, 1H), 6.99 (d, J = 8.4Hz, 1H), 6.77-6.75 (m, 1 H),6.71-6.67(m,1H),5.88-5.84(m,1H),5.75-5.70(m,1H),3.78(s,3H),3. 69(brs,1H),3.47-3.34(m,2H),3.26(s,3H),3.10-3.00(m,2H),2.69-2.62( m,3H),2.43(s,3H),2.50-2.38(m,2H),2.37-2.22(m,1H),1.35-1.26(m,1H).

[0424] Example 42: Synthesis of Compound 192

[0425] Step 1: Compound 156-1 (500 mg, 1.60 mmol), potassium cyclopropyltrifluoroborate (590.22 mg, 3.99 mmol), copper acetate (72.45 mg, 398.86 μmol), 1,10-phenanthroline (71.88 mg, 398.86 μmol), and K₂CO₃ (661.50 mg, 4.79 mmol) were dissolved in toluene (6 mL) and water (2 mL). The mixture was purged three times with oxygen and reacted at 70 °C for 16 hours under an oxygen atmosphere. Water (30 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (30 mL × 3). The mixed organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (industrial hexane / THF = 99 / 1 to 95 / 5) to obtain compound 192-1. MS m / z (ESI) [M+H] + =353.9.

[0426] Step 2: Compound 192-1 (190 mg) was dissolved in THF (3 mL), substituted with N2 three times, and a LiAlH4 THF solution (2.5 M, 645.06 μL) was slowly added dropwise at 0 °C. The reaction was carried out at 25 °C for 2 hours. The reaction solution was quenched with water, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: 40-WePure Biotech XP tC18 150×30 mm, 7 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 14%-44%) to obtain the formate salt of compound 192. MS m / z (ESI) [M+H] + =296.2; 1H NMR (400MHz, CDCl3) δ = 8.55 (s, 1H), 7.07 (d, J = 8.0Hz, 1H), 7.00-6.84 (m, 2H ),5.67-5.43(m,2H),3.74-3.64(m,1H),3.63-3.53(m,1H),3.28-3.18(m,1 H),3.17-3.00(m,2H),2.88-2.79(m,1H),2.78(s,3H),2.67-2.51(m,2H),2 .27-1.99(m,3H),1.80-1.67(m,1H),1.64-1.54(m,1H),0.80-0.67(m,4H).

[0427] Example 43: Synthesis of Compound 188

[0428] Step 1: Dissolve 156-1 (400 mg, 1.28 mmol), isopropane bromo (470.95 mg, 3.83 mmol), and K₂CO₃ (882.00 mg, 6.38 mmol) in DMF (5 mL). React at 60 °C for 12 hours. Add water (30 mL) to the reaction solution and extract with EtOAc (30 mL × 3). Combine the organic phases, wash with saturated brine, dry to anhydrous Na₂SO₄, filter, and evaporate to dryness to obtain the crude product. Purify the crude product by silica gel column chromatography (industrial hexane / THF = 99 / 1 to 95 / 5) to obtain compound 188-1. MS m / z (ESI) [M+H] + =356.0.

[0429] Step 2: Compound 188-1 (200 mg, 562.64 μmol) was dissolved in THF (4 mL), substituted with N2 three times, and a LiAlH4 THF solution (2.5 M, 675.16 μL) was slowly added dropwise at 0 °C. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was quenched with water, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: 52-Welch Ultimate C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid) - B: acetonitrile]; B%: 7%-47%) to obtain the formate salt of compound 188. MS m / z (ESI) [M+H] + =298.0; 1H NMR (400MHz, CDCl3) δ = 8.55 (s, 1H), 7.04 (d, J = 8.4Hz, 1H), 6.82 (d, J = 2.4Hz, 1 H),6.74(dd,J=8.4,2.4Hz,2H),5.65-5.45(m,2H),4.57-4.42(m,1H),3.65-3. 53(m,1H),3.27-2.98(m,3H),2.89-2.78(m,1H),2.77(s,3H),2.66-2.52(m,2H ),2.25-1.97(m,3H),1.80-1.67(m,1H),1.63-1.53(m,1H),1.36-1.27(m,6H).

[0430] Example 44: Synthesis of Compound 187

[0431] Step 1: Compound 156-1 (300 mg, 957 μmol) and K₂CO₃ (397 mg, 2.87 mmol) were dissolved in anhydrous DMF (3 mL), and 1-bromo-2-fluoroethane (243 mg, 1.91 mmol) was added. The reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 187-1 (crude product). MS m / z (ESI) [M+H] + =360.0.

[0432] Step 2: Compound 187-1 (200 mg, crude product) was dissolved in anhydrous THF (2 mL). A 2.5 M, 668 μL solution of LiAlH4 in THF was added under N2 protection in an ice-water bath. The reaction was stirred at 25 °C for 2 hours. After the reaction was complete, water (1 mL) was added to quench the reaction. Compound 187 was purified by preparative HPLC (column: 41-WePure Biotech XP tC18 150 × 40 mm, 7 μm; mobile phase: [A: H2O (0.05% NH3H2O ​​+ 10 mM NH4HCO3) - B: ACN]; elution gradient: 27% - 67% B). MS m / z (ESI) [M+H] + =302.2; 1H NMR (400MHz, CD3OD) δ7.05(d,J=8.4Hz,1H),6.88(d,J=2.4Hz,1H),6.75(dd,J=8.4,2.4Hz,1H),5. 67-5.57(m,1H),5.53-5.42(m,1H),4.77-4.72(m,1H),4.66-4.60(m,1H),4.23-4.17(m,1H),4.16- 4.08(m,1H),3.12-3.00(m,2H),2.92-2.78(m,2H),2.56-2.46(m,1H),2.44(s,3H),2.27-2.20(m,1 H),2.20-2.14(m,1H),2.13-2.03(m,1H),2.03-1.92(m,1H),1.85-1.70(m,2H),1.53-1.43(m,1H).

[0433] Example 45: Synthesis of Compound 190

[0434] Step 1: Compound 156-1 (0.40 g, 1.28 mmol) was dissolved in anhydrous acetonitrile (3 mL) and water (3 mL). KOH (1.43 g, 25.5 mmol) and diethyl bromofluoromethylphosphonate (0.68 g, 2.55 mmol) were slowly added at -78 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with EtOAc (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 93 / 7) to give compound 190-1. MS m / z (ESI) [M+H] + =363.9; 1H NMR (400MHz, CD3OD) δ = 7.09 (d, J = 8.4Hz, 1H), 7.06 (d, J = 2.4Hz, 1H), 6.92 (dd, J = 8.0, 2.4Hz, 1H),6.48(t,J=74.4Hz,1H),5.69-5.57(m,1H),5.55-5.47(m,1H),4.63-4.39(m,1H),4.26- 4.09(m,2H),4.05-3.80(m,1H),3.40-3.23(m,1H),2.83-2.72(m,2H),2.71-2.55(m,1H),2. 12-2.06(m,2H),2.05-2.00(m,1H),1.73-1.61(m,2H),1.38-1.31(m,1H),1.30-1.22(m,3H).

[0435] Step 2: Compound 190-1 (0.20 g, 550 μmol) was dissolved in anhydrous THF (3 mL). A 2.5 M, 660 μL solution of LiAlH4 in THF was slowly added dropwise at 0 °C under a N2 atmosphere. The reaction mixture was stirred for 2 hours at 25 °C under N2 protection. The reaction mixture was then quenched with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL) at 0 °C under N2 protection. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 5%-35%) to obtain the formate salt of compound 190. MS m / z (ESI) [M+H] + =305.9; 1 H NMR (400MHz, CD3OD) δ = 8.53 (s, 1H), 7.25 (d, J = 8.4Hz, 1H), 7.14 (d, J = 2.4Hz, 1H), 7.02 (d d,J=8.4,2.4Hz,1H),6.77(t,J=74.4Hz,1H),5.73-5.62(m,1H),5.58-5.45(m,1H),3.68 (brs,1H),3.30-3.24(m,2H),3.15-3.04(m,1H),2.98-2.90(m,1H),2.88(s,3H),2.77-2 .63(m,1H),2.46-2.35(m,1H),2.24-2.04(m,2H),2.04-1.93(m,1H),1.80-1.65(m,2H).

[0436] Example 46: Synthesis of Compound 191

[0437] Step 1: Compound 156-1 (0.35 g, 1.12 mmol) and CsF (0.85 g, 5.58 mmol) were dissolved in anhydrous toluene (5 mL). Under a nitrogen atmosphere, (trifluoromethyl)trimethylsilane (0.79 g, 5.58 mmol), 2-fluoropyridine (0.54 g, 5.58 mmol), silver trifluoromethanesulfonate (1.43 g, 5.58 mmol), and Select F (0.79 g, 2.23 mmol) were slowly added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 94 / 6) to give compound 191-1. MS m / z(ESI)[M+H] + =382.0.

[0438] Step 2: Compound 191-1 (0.10 g, 262 μmol) was dissolved in anhydrous THF (2 mL). A 2.5 M, 315 μL solution of LiAlH4 in THF was slowly added dropwise under a N2 atmosphere at 0 °C. The reaction mixture was stirred for 2 hours under N2 protection at 25 °C. The reaction mixture was then quenched with water (0.05 mL), 15% NaOH aqueous solution (0.05 mL), and water (0.15 mL) under N2 protection at 0 °C. The mixture was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 10%-40%) to obtain the formate salt of compound 191. MS m / z (ESI) [M+H] + =323.9; 1H NMR (400MHz, CD3OD) δ = 7.23 (d, J = 8.4Hz, 1H), 7.18 (s, 1H), 7.08-6.98 (m, 1H), 5.71-5. 56(m,1H),5.54-5.38(m,1H),3.22-3.08(m,2H),3.00-2.90(m,1H),2.84(dd,J=17.6,6 .0Hz,1H),2.57(dd,J=12.4,4.4Hz,1H),2.48(s,3H),2.27-2.18(m,2H),2.18-2.09(m ,1H),2.08-1.95(m,1H),1.92-1.79(m,1H),1.78-1.62(m,1H),1.49(d,J=12.4Hz,1H).

[0439] Example 47: Synthesis of Compound 193

[0440] Step 1: To a 1 mL solution of compound 156-1 (51 mg, 162.74 μmol) in acetonitrile, K₂CO₃ (112.46 mg, 813.68 μmol) and fluoroiodomethane (33.83 mg, 211.56 μmol) were added, and the reaction was stirred overnight at room temperature. The mixture was quenched with water (1 mL), extracted three times with EtOAc (1 mL), and concentrated under reduced pressure to obtain crude compound 193-1, which was used directly in the next step without purification. MS m / z (ESI) [M+H] + =346.3.

[0441] Step 2: Under an ice-water bath, a THF solution of LiAlH4 (12.31 mg, 324.26 μmol, 2.5 M, 129.72 μL) was added to a THF solution of compound 193-1 (56 mg, crude) in 2 mL of water. The reaction was stirred for 3 hours under a N2 atmosphere. The mixture was quenched at 0°C with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150×30 mm, 5 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium bicarbonate) - B: acetonitrile]; B%: 40%-70%) to obtain compound 193. MS m / z (ESI) [M+H] + =288.3; 1H NMR (400MHz, CD3OD) δ = 7.10 (d, 8.4Hz, 1H), 7.00 (d, J = 2.4Hz, 1H), 6.87 (dd, J = 8 .4,2.4Hz,1H),5.75-5.73(m,1H),5.63-5.59(m,2H),5.49-5.47(m,1H),3.11-3 .06(m,1H),3.01-2.98(m,1H),2.88-2.80(m,2H),2.49-2.45(m,1H),2.41(s,3 H),2.19-2.15(m,2H),2.13-2.07(s,2H),1.84-1.70(m,2H),1.48-1.43(m,1H).

[0442] Example 48: Synthesis of Compound 197

[0443] Step 1: Compound I-3 (2.00 g, 5.38 mmol) was dissolved in anhydrous THF (20 mL). Ethyl magnesium bromide (THF, 2 M, 1.46 mL) was slowly added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with saturated ammonium chloride, extracted with EtOAc (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The crude product was subjected to silica gel column chromatography (petroleum ether / THF = 100 / 0 to 84 / 16) to give compound 197-1. MS m / z (ESI) [M+H] + =401.8.

[0444] Step 2: Compound 197-1 (1.35 g, 3.36 mmol) was dissolved in anhydrous dioxane (25 mL). Concentrated hydrochloric acid (12 M, 8.41 mL, 101 mmol) was slowly added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, quenched with 2 M NaOH aqueous solution, extracted with EtOAc (50 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness to obtain the crude product compound 197-2. MS m / z (ESI) [M+H] + =405.8.

[0445] Step 3: Compound 197-2 (1.30 g, crude product) was dissolved in anhydrous methanol (20 mL). NaBH4 (242 mg, 6.41 mmol) was slowly added at 25 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 1 hour. The reaction solution was quenched with saturated ammonium chloride, extracted with EtOAc (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness to obtain the crude product compound 197-3. MS m / z (ESI) [M+H] + =407.9.

[0446] Step 4: Compound 197-3 (0.90 g, crude product) was dissolved in anhydrous pyridine (10 mL). Methanesulfonyl chloride (1.20 g, 10.5 mmol) was slowly added at 0 °C under a N2 atmosphere. The reaction mixture was stirred at 25 °C for 16 hours. The reaction solution was quenched with saturated NaHCO3 aqueous solution, extracted with EtOAc (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, concentrated, and evaporated to dryness to obtain the crude product compound 197-4. MS m / z (ESI) [M+H] + =485.9.

[0447] Step 5: Compound 197-4 (0.65 g, 1.34 mmol) was dissolved in anhydrous DMF (10 mL). NaI (2.00 g, 13.4 mmol) and zinc powder (0.87 g, 13.4 mmol) were slowly added under a nitrogen atmosphere. The reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth filter to remove the zinc powder, washed with water, and extracted with EtOAc (20 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to dryness. The crude product was purified by silica gel column chromatography (petroleum ether / THF = 100 / 0 to 95 / 5) to obtain compound 197-5. MS m / z (ESI) [M+H] + =356.1.

[0448] Step 6: Compound 197-5 (120 mg, 338 μmol) was dissolved in anhydrous THF (2 mL). Under a nitrogen atmosphere and at 0 °C, a 2.5 M, 270 μL solution of LiAlH4 in THF was added. The reaction mixture was stirred at 50 °C for 16 hours. The reaction mixture was quenched at 0 °C with water (0.1 mL), 15% NaOH aqueous solution (0.1 mL), and water (0.3 mL). The solution was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [water (0.225% formic acid)-B: acetonitrile]; B%: 5%-35%) to obtain compound 197. MS m / z (ESI) [M+H] + =298.1; 1 H NMR (400MHz, CD3OD) δ = 6.99 (d, J = 8.4Hz, 1H), 6.83 (d, J = 2.4Hz, 1H), 6.70 (dd, J = 8.4, 2.4 Hz,1H),5.54-5.37(m,2H),3.80-3.69(m,4H),3.20(t,J=4.0Hz,1H),3.03(d,J=18.0Hz,1 H),2.79-2.69(m,1H),2.67-2.59(m,1H),2.58-2.42(m,6H),2.25-2.15(m,1H),2.03-1.9 4(m,1H),1.85-1.75(m,1H),1.48-1.36(m,3H),1.36-1.26(m,1H),0.96(t,J=7.2Hz,3H).

[0449] Example 49: Synthesis of Compound 199

[0450] Step 1: Compound 156-1 (500 mg, 1.66 mmol), 2-iodo-1,1-difluoroethane (1.53 g, 7.98 mmol), and K₂CO₃ (1.10 g, 7.98 mmol) were dissolved in DMF (6 mL). The reaction mixture was reacted at 80 °C for 12 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (25 mL × 3). The mixed organic phase was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by silica gel column chromatography (industrial hexane / THF = 99 / 1 to 95 / 5) to obtain compound 199-1. MS m / z (ESI) [M+H] + =378.2.

[0451] Step 2: Compound 199-1 (150 mg, 0.40 mmol) was dissolved in THF (3 mL), substituted with N2 three times, and lithium aluminum hydride (2.5 M, 0.48 mL) was slowly added dropwise at 0 °C. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was quenched with water, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: 40-Welch Ultimate C18 150 × 30 mm, 7 μm; mobile phase: [water (0.225% formic acid) - B: acetonitrile]; B%: 2%-32%) to obtain the formate salt of compound 199. MS m / z (ESI) [M+H] + =320.1; 1 H NMR (400MHz, CDCl3) δ = 8.63 (s, 1H), 7.08 (d, J = 8.4Hz, 1H), 6.88 (d, J = 2.4Hz, 1H), 6.73 ( dd,J=8.4,2.4Hz,1H),6.28-5.87(m,1H),5.72-5.40(m,2H),4.22-4.09(m,2H),3.29(b rs,1H),3.11-2.91(m,2H),2.87-2.70(m,2H),2.62(s,3H),2.51-2.40(m,1H),2.40-2. 30(m,1H),2.22-2.11(m,1H),2.07-1.95(m,2H),1.80-1.65(m,1H),1.58-1.47(m,1H).

[0452] Example 50: Synthesis of Compound 200

[0453] Procedure: Compound 199-1 (150 mg, 0.4 mmol) was dissolved in THF (3 mL), substituted with N2 three times, and a LiAlD4 THF solution (2.5 M, 1.19 mL) was slowly added dropwise at 0 °C. The reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was quenched with water, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: 40-Welch Xtimate C18 150 × 30 mm, 7 μm; mobile phase: [water (0.225% formic acid) - B: acetonitrile]; B%: 2%-32%) to obtain the formate salt of compound 200. MS m / z (ESI) [M+H] + =323.1; 1H NMR (400MHz, CDCl3) δ = 8.63 (s, 1H), 7.08 (d, J = 8.4Hz, 1H), 6.88 (d, J = 2.4Hz, 1H), 6. 73(dd,J=8.4,2.4Hz,1H),6.28-5.87(m,1H),5.72-5.40(m,2H),4.22-4.09(m,2H), 3.29(brs,1H),3.11-2.91(m,2H),2.87-2.70(m,2H),2.51-2.40(m,1H),2.40-2.30 (m,1H),2.22-2.11(m,1H),2.07-1.95(m,2H),1.80-1.65(m,1H),1.58-1.47(m,1H).

[0454] Example 51: Synthesis of compounds 104 and 209

[0455] Step 1: Compound 1-2' (200 mg, 700.82 μmol) was dissolved in DCM (10 mL), and boron tribromide (2 M, 525.62 μL) was added dropwise at 0 °C. The mixture was stirred in an ice bath for 2 hours. Ammonia (1 mL) was slowly added dropwise to the reaction mixture in an ice bath to adjust the pH to 8. The mixture was diluted with water, extracted with ethyl acetate (10 mL × 4), and the combined organic phases were washed with saturated sodium chloride (10 mL × 2), followed by drying with anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and evaporated to dryness. The crude product was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [A: water (0.05% ammonia + 10 mM ammonium carbonate) - B: acetonitrile]; B%: 16%-46%) to obtain compound 104-1. LCMS: MS m / z (ESI) [M+H] + =272.2; 1 H NMR (400MHz, CD3OD) δ = 6.95 (d, J = 8.0Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 6.60 (dd, J = 8.4, 2.4Hz, 1H), 5.76-5.60 (m, 1H), 5.49-5.29 (m, 1H), 3.26- 3.16(m,1H),3.01-2.91(m,2H),2.69-2.54(m,2H),2.51(s,3H),2.42- 2.28(m,2H),2.24-2.09(m,2H),1.96-1.85(m,1H),1.26-1.08(m,1H).

[0456] Step 2: The crude product was purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: [A: CO2-B: ethanol (0.1% ammonia)]; B%: 45%) to obtain compound 104 and compound 209.

[0457] SFC analysis method: (Column: Chiralcel OJ-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 3.5 min and hold 40% for 1.0 min, then 5% of B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi).

[0458] Compound 209: Retention time = 3.287 min. LCMS: MS m / z (ESI) [M+H] + =272.2; 1 H NMR (400MHz, CD3OD) δ = 6.94 (d, J = 8.0Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 6.59 (dd, J = 8 .4,2.4Hz,1H),5.73-5.56(m,1H),5.52-5.35(m,1H),3.18(d,J=18.0Hz,1H),2.9 0-2.76(m,2H),2.66-2.55(m,1H),2.45-2.40(m,1H),2.39(s,3H),2.39-2.32(m, 1H),2.23-2.13(m,2H),2.12-2.01(m,1H),1.96-1.82(m,1H),1.18-1.12(m,1H).

[0459] Compound 104: Retention time = 4.228 min. LC-MS: MS m / z (ESI) [M+H] + =272.2; 1H NMR (400MHz, CD3OD) δ = 6.94 (d, J = 8.0Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 6.59 (dd, J = 8 .4,2.4Hz,1H),5.73-5.56(m,1H),5.52-5.35(m,1H),3.18(d,J=18.0Hz,1H),2.9 0-2.76(m,2H),2.66-2.55(m,1H),2.45-2.40(m,1H),2.39(s,3H),2.39-2.32(m, 1H),2.23-2.13(m,2H),2.12-2.01(m,1H),1.96-1.82(m,1H),1.18-1.12(m,1H).

[0460] Example 52: Synthesis of Compound 178

[0461] KOH was dissolved in acetonitrile (5 mL) and water (5 mL), cooled to -20 °C, and compound 104 (200 mg, 737.05 μmol) and diethyl bromofluoromethylphosphonate (393.59 mg, 1.47 mmol) were added sequentially. The reaction solution was reacted at 25 °C for 12 hours, diluted with water, and extracted with EtOAc (10 mL × 4). The organic phases were combined and washed with saturated sodium chloride (10 mL × 2), followed by drying with anhydrous Na₂SO₄. The mixture was filtered, concentrated under reduced pressure, and evaporated to dryness. The crude product was purified by preparative HPLC (column: 55-Boston Prime C18 150 × 30 mm, 5 μm; mobile phase: [A: water (0.225% formic acid)-B: acetonitrile]; B%: 0%-30%) to obtain the formate salt of compound 178. MS m / z (ESI) [M+H] + =322.1; 1 H NMR (400MHz, CD3OD) δ = 8.53 (s, 1H), 7.25 (d, J = 8.4Hz, 1H), 7.14 (s, 1H), 7.03 (d, J=8.4Hz,1H),6.77(t,J=74.0Hz,1H),5.79-5.61(m,1H),5.50-5.34(m,1H),3.50 -3.46(m,1H),3.45-3.33(m,2H),3.08-2.96(m,1H),2.85(s,3H),2.80-2.63(m, 2H),2.52-2.31(m,2H),2.26-2.13(m,1H),2.11-2.00(m,1H),1.48-1.31(m,1H).

[0462] Example 53: Synthesis of Compound 4 and Compound 210

[0463] Step 1: Compound A-1 (15.0 g, 85.1 mmol) was dissolved in toluene (300 mL), tetrahydropyrrole (9.08 g, 127.7 mmol) was added, and water was separated using a water separator. The reaction was stirred at 110 °C for 2 hours. After cooling to room temperature, 3-bromo-2-methylpropene (23.0 g, 170 mmol) was added. The reaction was stirred at 110 °C for 12 hours. After cooling to room temperature again, 40 mL of water was added, and the reaction was stirred at 95 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with 500 mL of water, extracted with EtOAc (500 mL × 2), the organic phase was washed with saturated brine (500 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (THF / petroleum ether = 0–5%) to give compound 4-1. MS m / z (ESI) [M+H] + =231.1; 1 H NMR (400MHz, DMSO-d6) δ = 7.15 (d, J = 8.0Hz, 1H), 6.78-6.71 (m, 2H), 4.80-4.42 (m, 2H), 3.72-3.68 (m, 3H), 3.6 4(t,J=7.2Hz,1H),3.10-2.92(m,2H),2.65-2.55(m,1H),2.49-2.47(m,1H),2.47-2.40(m,2H),1.71(s,3H).

[0464] Step 2: Compound 4-1 (5.5 g, 23.88 mmol) was dissolved in THF (50 mL). NaH (1.91 g, 47.78 mmol, 60% purity) was slowly added under N2 flow at 0 °C. The reaction was carried out under N2 atmosphere and stirred at 0 °C for 30 minutes. Then, 2-bromomethyldimethylamine hydrobromide (5.56 g, 23.88 mmol) was slowly added at 0 °C. The reaction was carried out under 25 °C and stirred for 8 hours. After the reaction was complete, the reaction solution was slowly poured into a saturated ammonium chloride ice-water solution (200 mL). It was diluted with 500 mL of water, extracted with EtOAc (200 mL × 3), washed with saturated brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (THF / petroleum ether = 0–30%) to obtain compound 4-2. MS m / z (ESI) [M+H] + =302.2.

[0465] Step 3: Compound 4-2 (5.5 g, 18.25 mmol) was dissolved in THF (100 mL), and pyridinium tribromide (6.13 g, 19.16 mmol) was slowly added. The reaction was stirred at 25 °C for 8 hours in the dark. After the reaction was completed, the solution was concentrated under reduced pressure and evaporated to dryness to obtain compound 4-3 (crude product). It was directly subjected to MS m / z (ESI) [M+H] without purification. + =380.1.

[0466] Step 4: Compound 4-3 (20.0 g, crude product) was dissolved in methanol (200 mL), and ammonia (65.82 g, 525.88 mmol, 28% purity) was added. The reaction was stirred at 25 °C for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure and evaporated to dryness. The crude product was purified by silica gel column chromatography (DCM / methanol = 8%) to obtain compound 4-4. MS m / z (ESI) [M+H] + =300.0.

[0467] Step 5: Compound 4-4 (0.6 g, 7.63 mmol) was dissolved in THF (50 mL). Allyl magnesium bromide (THF, 1 M, 15.25 mL, 15.25 mmol) was slowly added under N2 flow at 0 °C. The reaction was stirred at 25 °C for 5 hours under N2 atmosphere. After the reaction was complete, propionic acid (5 mL) was added at 0 °C to quench the reaction. A solid precipitated, which was filtered, washed with THF (50 mL × 2), and collected. Compound 4-5 was obtained. MS m / z (ESI) [M + H] + =342.2; 1 H NMR(400MHz, DMSO-d6)δ=7.18-7.09(m,2H),6.85(dd,J=8.4,2.4Hz,1H),6.14-6.00(m,1H ),5.89(s,1H),5.23-5.13(m,2H),4.97-4.80(m,2H),3.72(s,3H),3.55-3.46(m,1H),3.45 (s,3H),3.30-3.20(m,1H),3.19-3.13(m,1H),3.12(s,3H),2.85-2.78(m,1H),2.74-2.61( m,2H),2.58-2.53(m,1H),2.41(s,1H),2.14-2.03(m,1H),1.86(s,3H),1.42-1.32(m,1H).

[0468] Step 6: Compounds 4-5 (0.6 g, 1.75 mmol) were dissolved in diphenyl sulfide (20 mL), and the reaction was stirred at 180 °C for 2 hours. After the reaction was complete, the reaction solution was cooled to room temperature, and 10 mL of dilute hydrochloric acid (1 M) was added to adjust the pH to 3. The solution was then diluted with 50 mL of water and extracted with EtOAc (50 mL × 2). The aqueous phase was then adjusted to pH 10 with NaOH aqueous solution (20%, 5 mL) and extracted with EtOAc (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure until evaporated to dryness. Compounds 4-6 were obtained and used directly in the next step without purification. MS m / z (ESI) [M+H] + =328.1; 1 H NMR (400MHz, DMSO-d6) δ = 7.06-7.02 (m, 2H), 6.71 (dd, J = 8.4, 2.4Hz, 1H), 6.00 -5.84(m,1H),5.09-4.93(m,2H),4.91-4.78(m,2H),4.19(d,J=1.6Hz,1H),3.7 0-3.65(m,3H),3.04-2.94(m,1H),2.73-2.62(m,2H),2.61-2.56(m,2H),2.35 -2.26(m,2H),2.25(s,3H),1.89(s,3H),1.86-1.73(m,2H),1.13-1.01(m,1H).

[0469] Step 7: Dissolve compound 4-6 (0.50 g, 76.35 μmol) in toluene (5 mL), add Grubbs II catalyst (64.82 mg, 22.90 μmol) and tetrafluorop-benzoquinone (27.49 mg, 152.69 μmol). Stir the reaction at 80 °C for 2 hours under a N2 atmosphere. After the reaction is complete, cool the reaction solution to room temperature, add 2 mL of dilute hydrochloric acid (adjust pH to 3 with 1 M, add 10 mL of water) to dilute, wash with EtOAc (1 mL × 2), adjust the pH of the aqueous phase to 10 with ammonia, extract with EtOAc (10 mL × 3), wash the organic phase with saturated brine (10 mL), dry with anhydrous Na2SO4, concentrate under reduced pressure and evaporate to dryness. The crude product was purified by preparative HPLC (column: Phenomenex Gemini-NX 150×40mm×7μm; mobile phase: [A: water (ammonia + ammonium bicarbonate) - B: acetonitrile]; B%: 30%-70%) to obtain compounds 4-7. MS m / z (ESI) [M+H + =300.2.

[0470] Step 8: Compounds 4-7 (0.12 g, 400.0 μmol) were purified by preparative SFC (column: DAICEL CHIRALPAK AY-H (250 mm × 30 mm, 10 μm); mobile phase: [CO2-ethanol (0.1% ammonia)]; B%: 20%) to obtain compounds 4 and 210.

[0471] SFC analysis method: (DAICEL CHIRALPAK AY-3 100×4.6mm ID, 3μm; mobile phase: A: CO2, B: ethanol (0.05% DEA); gradient: from 5% to 40% of B in 3.0 min and hold 40% for 1.0 min, then 5% of B for 1.0 min; flow rate: 2.8 mL / min; column temperature: 35℃; ABPR: 1500 psi).

[0472] Compound 4: Retention time = 1.843 min, 99.10% ee, MS m / z (ESI) [M+H] + =300.1; 1 H NMR (400MHz, DMSO-d6) δ = 7.01 (d, J = 8.4Hz, 1H), 6.72 (d, J = 2.4Hz, 1H), 6.68 (dd ,J=8.4,2.4Hz,1H),5.00(brs,1H),4.35(s,1H),3.68(s,3H),3.07(d,J=18.4H z,1H),2.82-2.73(m,1H),2.69(d,J=6.4Hz,1H),2.40-2.33(m,1H),2.32-2.18 (m,5H),2.00-1.88(m,3H),1.80-1.69(m,1H),1.62(s,3H),1.07-0.97(m,1H).

[0473] Compound 210: Retention time = 2.350 min, 99.93% ee, MS m / z (ESI) [M+H] + =300.1; 1H NMR (400MHz, DMSO-d6) δ = 7.01 (d, J = 8.4Hz, 1H), 6.72 (d, J = 2.4Hz, 1H), 6.68 (dd, J =8.4,2.4Hz,1H),5.01(brs,1H),4.39(s,1H),3.68(s,3H),3.07(d,J=18.4Hz,1H ),2.82-2.65(m,2H),2.40-2.31(m,2H),2.30(s,3H),2.29-2.18(m,1H),2.03-1. 94(m,2H),1.94-1.88(m,1H),1.80-1.69(m,1H),1.62(s,3H),1.07-0.97(m,1H).

[0474] Biological testing

[0475] Test Example 1: 5-Serotonin Transporter Receptor Inhibitory Activity Test

[0476] HEPES (Sigma, Cat: H3375-100G)

[0477] HBSS (Gibco, Cat: 14065-056)

[0478] Bovine Serum Albumin(ABCONE,Cat:A23088-100G)

[0479] Poly-D-Lysine(Gibco,Cat:A3890401)

[0480] Neurotransmitter transporter uptake assay kit(Molecular devices,Cat:R8174)

[0481] Incubator (Thermo, 240)

[0482] Automated multimode microplate reader(TECAN Spark)

[0483] 384-well plate (Agilent, Cat: 204628-100)

[0484] In HEK-293 cells overexpressing human SERT, the inhibitory effect of the test compound on human SERT transporters was detected using a Neurotransmitter transporter uptake assay kit (Molecular devices). The assay was performed according to the kit instructions, with duloxetine used as a positive control. The specific procedures are as follows:

[0485] a) Seed HEK-293-hSERT cells at 20,000 cells / well into 384-well plates coated with poly-L-lysine (0.1 mg / mL), and then transfer the 384-well plates to an incubator and incubate overnight at 37°C.

[0486] b) The next day, test solutions of loxetine and the compound of the present invention were prepared using experimental buffer (HBSS solution containing 0.1% BSA and 20mM HEPES). The initial concentration of both was 100μM, diluted 5 times, with 12 concentration points and double replicates.

[0487] c) Remove the 384-well plate containing HEK-293-hSERT cells from the incubator, remove the culture medium from the wells, and add 25 μL of the test compound solution to each well; incubate at 37°C for 30 min.

[0488] d) Add 25 μL of dye to each well and incubate at 37°C for 30 min;

[0489] e) Read the fluorescence values ​​on TECAN Spark and analyze the data using Graphpad Prism software. The results are shown in Table 1.

[0490] Table 1. SERT inhibitory activity of the compounds of the present invention

[0491] The data above show that the compounds in the embodiments of the present invention have stronger SERT inhibitory activity compared with dextromethorphan, and are expected to have better preventive or therapeutic effects on SERT-related central nervous system diseases.

[0492] Test Example 2: NMDA Receptor Antagonistic Activity Assay

[0493] The effects of compounds on NMDA receptor (N-methyl-D-aspartate receptor, NR1 / 2B) channel currents were tested using the electrophysiological whole-cell manual patch-clamp method.

[0494] Extracellular fluid formulation: 140mM NaCl, 4mM KCl, 2mM CaCl2·2H2O, 10mM HEPES, 5mM D-Glucose, pH adjusted to 7.4 with NaOH;

[0495] Intracellular fluid formulation: 10mM NaCl, 110mM CsMes, 2mM MgCl2·6H2O, 10mM HEPES, 10mM EGTA, 2mM Na2-ATP, 0.2mM Na2-GTP, and CsOH to adjust pH to 7.2.

[0496] Specific operations:

[0497] a. Cell preparation

[0498] Cell culture: HEK-293 cell lines stably expressing NR1 / NR2B receptors were cultured in DMEM medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 100 μg / mL Zeocin and 200 μg / mL Hygromycin B at 37°C and 5% carbon dioxide.

[0499] Cell passage: Remove the old culture medium and wash once with PBS, then add 0.25% Trypsin-EDTA solution and incubate at 37°C. When the cells detach from the bottom of the dish, add approximately complete culture medium to stop digestion. Transfer the cell suspension to sterile centrifuge tubes, centrifuge at 1000 rpm for 5 min to collect cells, and seed each cell culture dish with 2.5 × 10⁶ cells. 5 cells.

[0500] NR1 / NR2B receptor expression: Before patch-clamp assay, cells were separated with 0.25% Trypsin-EDTA, and 8 × 10⁸ cells were used. 3 Cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). Tetracycline was added for induction, along with 1 mM D-AP5. After 18 hours, the cells were tested.

[0501] b. Compound preparation

[0502] On the day of testing, the stock solution of the compound of this invention was diluted with DMSO to an intermediate concentration, and then diluted with extracellular fluid to obtain the final concentration to be tested. The DMSO content in the final test concentration did not exceed 0.2%.

[0503] c. Electrophysiological recording process

[0504] The current induced by 100 μM glutamic acid (containing 10 μM glycine) was recorded at room temperature using whole-cell patch-clamp technique. The glass microelectrode was fabricated from a glass electrode blank (BF150-86-10, Sutter) using a stretching apparatus. After instillation of the electrode fluid, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was connected to the patch-clamp amplifier by inserting it into the amplifier probe. Clamping voltage and data recording were controlled and recorded via computer using PatchMaster (HEKA) software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, cells were clamped at -70 mV. A rapid drug delivery system was used to administer 100 μM glutamic acid (containing 10 μM glycine) via gravity to induce channel currents. Once the current stabilized, 100 μM glutamic acid (containing 10 μM glycine) containing the compound was administered to observe changes in current amplitude. The compound was continuously administered from low to high concentrations, with a final administration of 100 μM glutamic acid (containing 10 μM glycine). Each test concentration of the compound was administered for at least 20 seconds, and at least two cells (n≥2) were tested for each concentration.

[0505] d. Data processing

[0506] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of channel current (current amplitude induced by 100 μM Glutamic acid (containing 100 μM Glycine) at -70 mV) by different compound concentrations was calculated using the following formula:

[0507] Inhibition%=[1-(I / Io)]×100%;

[0508] Wherein, Inhibition% represents the percentage of NMDA channel current inhibited by the compound, and I and Io represent the current amplitude induced by 100 μM Glutamic acid (containing 100 μM Glycine) before and after drug administration.

[0509] The IC50 of the compound was calculated using GraphPad Prism 8 software by fitting the following equation: Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*Hil1Slope))

[0510] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively. The test results are shown in Table 2.

[0511] Table 2 NMDA receptor antagonistic activity of the compounds of the present invention

[0512] The data above show that the compounds in the embodiments of the present invention have NMDA receptor antagonistic activity and are expected to have preventive or therapeutic effects on NMDA receptor-related central nervous system diseases.

[0513] Test Example 3: Liver Microsomal Experiment

[0514] Reference standards and reagents: NADPH, magnesium chloride, testosterone, phosphate buffer, etc. were provided by Dalian Meilun Biotechnology Co., Ltd., etc.

[0515] Liver microsomes: Liver microsomes were provided by BD Gentest.

[0516] The experimental procedure is as follows.

[0517] a) With cofactor (NADPH): 25 μL of 10 mM NADPH was added to the incubation solution. The final concentrations of microsomes and NADPH were 0.5 mg / mL and 1 mM, respectively. b) Without cofactor (NADPH): 25 μL of 100 mM phosphate buffer was added to the incubation solution. The final concentration of microsomes was 0.5 mg / mL. The mixture was preheated at 37°C for 10 minutes.

[0518] The reaction was initiated by adding 2.5 μL of a 100 μM solution of either the control or test compound. Verapamil was used as a positive control in this study. The final concentration of the test or control compound was 1 μM. The incubation solution was incubated in a water bath at 37 °C.

[0519] A 30 μL sample was taken from the reaction solution and subjected to LC-MS / MS at 0, 5, 15, 30, 45, and 60 minutes. The reaction was stopped by adding 5 volumes of cold acetonitrile and internal standards (200 nmol of labetalol, 100 nmol of ketorolac, and 100 nmol of thiobutamol). The sample was centrifuged at 3,220 g for 40 minutes. 100 μL of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0520] All calculations were performed using Microsoft Excel.

[0521] Peak area was determined using extracted ion chromatograms. The slope value k was determined by linear regression of the natural logarithm of the remaining percentage of parent drug against the incubation time curve.

[0522] The in vitro half-life (t1 / 2) is determined based on the slope value: T 1 / 2 = -0.693 / k.

[0523] The conversion of in vitro half-life (minutes) to in vitro intrinsic clearance (in vitro CLint, in mL / min / mg) was performed using the following formula (average of repeated assays):

[0524] The amplified CL was calculated using the following equation. int (mL / min / kg), predicted liver clearance rate CL H (mL / min / kg) and liver extraction rate (ER): were determined using the following equations:

[0525] Predicted liver clearance rate CL H =(QH×Scale-up CLint×fub) / (QH+Scale-up CL int ×fub).

[0526] Species: Human, cynomolgus monkey, beagle dog, SD rat, mouse.

[0527] Microsomal concentration: 0.5 mg / mL.

[0528] Coenzyme: NADPH 1.00mM.

[0529] Test concentrations: analyte: 1.00 μM, verapamil: 1.00 μM.

[0530] Time: 0, 5, 15, 30, 45, 60 min.

[0531] Incubation conditions: The final volume of the system is 100 μL, and the incubation is carried out at 37 °C. At the end of the incubation, 2 times the volume of acetonitrile is added to terminate the reaction.

[0532] Negative control: without coenzyme, incubated for 0, 30 and 60 min, under the same operating conditions as the experimental group.

[0533] Double parallel, n=2; Excel summary.

[0534] The experimental results are shown in Table 3 below.

[0535] Table 3. Liver microsomal stability data of the compounds of the present invention. NC: Not calculated; not metabolized during the test period. ND: Not measured.

[0536] The data above show that the compounds in the embodiments of the present invention have stronger stability in liver microparticle metabolism in various genera compared with dextromethorphan.

[0537] Test Example 4: Human Hepatocyte Experiment

[0538] Controls and reagents: Williams' E medium, DPBS, GlutaMAX (100x), HEPES, Human-insulin, etc. were provided by Gibco, Isotonic percoll was provided by Cytiva, and FBS and Dexamethasone were provided by Sigma.

[0539] Hepatocytes: Human hepatocytes were provided by BioIVT.

[0540] Experimental steps:

[0541] 1) Transfer 198 μL of hepatocytes into each well of a 96-well uncoated plate. Place the plate in an incubator and allow the hepatocytes to heat for 10 minutes.

[0542] 2) Pipette 2 μL of the 100 μM test compound or positive control into the corresponding well of the 96-well uncoated plate to begin the reaction. Place the plate back into the incubator to set the designed time points.

[0543] 3) Transfer the contents of the well to 25 μL aliquots at transfer times of 0.5, 15, 30, 60, 90, and 120 minutes. Then, terminate the reaction by mixing the aliquots with 6 volumes (300 μL) of acetonitrile containing internal standards IS (100 nM alprazolam, 200 nM caffeine, 200 nM labetalol, and 100 nM tolbutamide). Vortex for 5 minutes. Centrifuge the sample at 3,220 g for 45 minutes. Dilute 100 μL of the supernatant with 100 μL of ultrapure water and use the mixture for LC / MS / MS analysis. All incubations were performed in duplicate.

[0544] Data processing and analysis: All calculations were performed using Microsoft Excel. Peak areas were determined based on the extracted ion chromatograms. The in vitro half-life (t0.05) of the parent compound was determined through regression analysis of the percentage disappearance of the parent compound versus time curves. 1 / 2 ).

[0545] In vitro half-life (in vitro t) 1 / 2 Determined by the slope value: T 1 / 2 = -0.693 / k.

[0546] The in vitro t-values ​​were calculated using the following formula (average of repeated measurements). 1 / 2 (in minutes) converted to in vitro intrinsic clearance rate (in vitro CL) int At μL / min / 1×10 6 (based on individual cells):

[0547] V = incubation volume (0.2 mL);

[0548] N = number of hepatocytes per well (0.1 × 10⁻⁶) 6 (cells).

[0549] Amplify CL int (mL / min / kg), predicting liver CL H The calculation of (mL / min / kg) and liver extraction ratio (ER) was performed using the following formula:

[0550] Amplify CL int =(0.693 / T) 1 / 2 )×(1 / (hepatocyte concentration (0.5×10⁶ cells / mL)))×2544.3;

[0551] Predicting liver CL H = (21×Scale-up CL) int ×fub) / (21+Scale-up CL int ×fub);

[0552] ER = Predictive liver CL H / QH;

[0553] Where fub is the fraction of unbound drug in the plasma, assumed to be 1.

[0554] The experimental results are shown in Table 4 below.

[0555] Table 4. Hepatocyte stability data of the compounds of the present invention.

[0556] The data above show that the compounds in the embodiments of the present invention have more significant metabolic stability in hepatocytes of various species compared with dextromethorphan.

[0557] Test Example 5: Dextromethorphan and Compound 1ICR Mouse Box-Based Dosing Experiment

[0558] The in vivo metabolic experiment method for ICR mice is described below.

[0559] Animals: Male ICR mice. They were divided into an intravenous (IV) group and a gavage (PO) group, and were fasted for 12 hours before administration.

[0560] Drugs: The positive compound dextromethorphan is dissolved in water and administered intravenously (iv) at a dose of 5 mg / kg; orally (po) at a dose of 20 mg / kg. Compound 1 of this invention is dissolved in water and administered intravenously (iv) at a dose of 5 mg / kg; orally (po) at a dose of 20 mg / kg. The two compound administration solutions are mixed together for administration.

[0561] Sample collection and bioanalysis:

[0562] Blood samples were collected from mice at 0, 0.25, 0.5, 1, 2, 4, 8, and 24 hours (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0563] The desired series of working solution concentrations are obtained by diluting the analyte stock solution in aqueous solution with 50% acetonitrile.

[0564] Add 3 μL of working solution (5, 10, 20, 50, 100, 500, 1000, 5000, 10000 ng / mL) to 30 μL of blank plasma to obtain calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 1000, 500, 1000 ng / mL), for a total volume of 33 μL. Prepare four plasma quality control samples at concentrations of 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL, independent of the samples used in the calibration curve. These standard samples were prepared on the day of analysis in the same manner as the calibration standards.

[0565] 33 μL of standard, 33 μL of quality control sample, and 33 μL of unknown sample (30 μL mouse plasma and 3 μL blank solution) were added separately to 200 μL of acetonitrile mixture containing bismuth (IS) to precipitate proteins. After centrifugation at 4000 rpm for 15 min at 4 °C, the supernatant was diluted 3-fold with water. 10 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis, and pharmacokinetic parameters were calculated.

[0566] The experimental results are shown in Table 5 below.

[0567] Table 5. Pharmacokinetic results of the compounds in mice.

[0568] The data above show that the compound of the present invention has a better exposure level than dextromethorphan in mice.

[0569] Test Example 6: Rats undergoing cassette administration of dextromethorphan and compound 1

[0570] Animals: Male SD rats. They were divided into an intravenous (IV) group and a gavage (PO) group. The IV group was fasted for 12 hours before administration, while the IV group was not fasted.

[0571] Drugs: The positive compound dextromethorphan was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 2 mg / kg; orally (po) at a dose of 10 mg / kg. Compound 1 of this invention was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 2 mg / kg; orally (po) at a dose of 10 mg / kg. The two compound administration solutions were mixed together for administration.

[0572] Sample collection and bioanalysis:

[0573] Blood samples were collected from the rats in the gavage administration group at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0574] Blood samples were collected from rats in the intravenous administration group at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0575] The desired series of working solution concentrations were obtained by diluting the analyte stock solution with acetonitrile:water (50:50, v / v).

[0576] Add 5 μL of working solution (10, 20, 40, 100, 400, 2400, 8000, 32000, 40000 ng / mL) to 95 μL of blank plasma to obtain calibration standards ranging from 0.5 to 2000 ng / mL (0.5, 1, 2, 5, 20, 120, 400, 1600, 2000 ng / mL), for a total volume of 100 μL. Prepare two plasma quality control samples at concentrations of 3 ng / mL, 600 ng / mL, 1500 ng / mL, and 15000 ng / mL, independent of the samples used in the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0577] 10 μL of standard, 10 μL of quality control sample, and 10 μL of unknown sample were each added to 200 μL of acetonitrile to precipitate proteins, along with 20 μL of internal standard. After centrifugation at 3900 rpm for 10 min at 4 °C, the supernatant was diluted twice with water. 1 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis, and pharmacokinetic parameters were calculated.

[0578] The experimental results are shown in Table 6 below.

[0579] Table 6. Pharmacokinetic results of the compounds in rats.

[0580] The data above show that the compound of the present invention has a better exposure level than dextromethorphan in rats.

[0581] Test Example 7: Dextromethorphan and Compound 1 Beagle Dog Box Dosing Experiment

[0582] Animals: Male beagle dogs. They were divided into an intravenous (IV) group and a gavage (PO) group, and were fasted for 12 hours before administration, except for the IV group which was not fed.

[0583] Drugs: The positive compound dextromethorphan was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 1 mg / kg; orally (po) at a dose of 5 mg / kg. Compound 1 in this invention was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 1 mg / kg; orally (po) at a dose of 5 mg / kg. The two compound solutions were administered together.

[0584] Sample collection and bioanalysis:

[0585] Blood samples were collected from the beagle dogs administered the drug via gavage at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0586] Blood samples were collected from the beagle dogs in the intravenous administration group at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0587] The desired series of working solution concentrations were obtained by diluting the analyte stock solution with acetonitrile:water (50:50, v / v).

[0588] Add 5 μL of working solution (10, 20, 40, 100, 400, 2400, 8000, 32000, 40000 ng / mL) to 95 μL of blank plasma to obtain calibration standards ranging from 0.5 to 2000 ng / mL (0.5, 1, 2, 5, 20, 120, 400, 1600, 2000 ng / mL), for a total volume of 100 μL. Prepare two plasma quality control samples at concentrations of 3 ng / mL, 600 ng / mL, 1500 ng / mL, and 15000 ng / mL, independent of the samples used in the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0589] 10 μL of standard, 10 μL of quality control sample, and 10 μL of unknown sample were each added to 200 μL of acetonitrile to precipitate proteins, along with 20 μL of internal standard. After centrifugation at 3900 rpm for 10 min at 4 °C, the supernatant was diluted twice with water. 1 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis, and pharmacokinetic parameters were calculated.

[0590] The experimental results are shown in Table 7 below.

[0591] Table 7. Pharmacokinetic results of the compounds in beagle dogs.

[0592] The data above show that the compound of the present invention has significantly higher bioavailability than dextromethorphan in beagle dogs.

[0593] Test Example 8: Dextromethorphan and Compound 1 Box-type Dosing Experiment in Crab-eating Macaques

[0594] Animals: Male cynomolgus monkeys. They were divided into an intravenous (IV) group and a gavage (PO) group. The IV group was fasted for 12 hours before administration, while the IV group was not fasted.

[0595] Drugs: The positive compound dextromethorphan was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 1 mg / kg; orally (po) at a dose of 5 mg / kg. Compound 1 in this invention was dissolved in a solvent (DMSO / EtOH / PEG300 / 0.9% NaCl (5 / 5 / 40 / 50, v / v / v / v)) and administered intravenously (iv) at a dose of 1 mg / kg; orally (po) at a dose of 5 mg / kg. The two compound solutions were administered together.

[0596] Sample collection and bioanalysis:

[0597] Blood samples were collected from the cynomolgus monkeys administered the drug via gavage at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0598] Blood samples were collected from the intravenous administration group of cynomolgus monkeys at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (n=3 at each time point) and placed into EP tubes containing the anticoagulant K2EDTA.

[0599] The desired series of working solution concentrations were obtained by diluting the analyte stock solution with acetonitrile:water (50:50, v / v).

[0600] Add 5 μL of working solution (10, 20, 40, 100, 400, 2400, 8000, 32000, 40000 ng / mL) to 95 μL of blank plasma to obtain calibration standards ranging from 0.5 to 2000 ng / mL (0.5, 1, 2, 5, 20, 120, 400, 1600, 2000 ng / mL), for a total volume of 100 μL. Prepare two plasma quality control samples at concentrations of 3 ng / mL, 600 ng / mL, 1500 ng / mL, and 15000 ng / mL, independent of the samples used in the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0601] 10 μL of standard, 10 μL of quality control sample, and 10 μL of unknown sample were each added to 200 μL of acetonitrile to precipitate proteins, along with 20 μL of internal standard. After centrifugation at 3900 rpm for 10 min at 4 °C, the supernatant was diluted twice with water. 1 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis, and pharmacokinetic parameters were calculated.

[0602] The experimental results are shown in Table 8 below.

[0603] Table 8. Pharmacokinetic results of the compounds in cynomolgus monkeys.

[0604] The data above show that the compound of the present invention has significantly higher bioavailability than dextromethorphan in cynomolgus monkeys.

[0605] Test Example 9: Forced Swim Test

[0606] Drug: The compound of the present invention is dissolved in 5% DMSO, then mixed with 5% solubil HS15, and then 90% physiological saline is added to prepare a solution of appropriate concentration. It should be prepared and used immediately.

[0607] Animals: Male C57BL / 6J mice, 8 weeks old, weighing approximately 20-22g. Animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Mice in each group were administered either the solvent formulation or the test drug via gavage.

[0608] Experimental Procedure: Forced swimming tests were performed on mice 0.5 hours after drug administration. The forced swimming test used a transparent cylinder with a diameter of 10 cm and a height of 25 cm, filled with sterilized water at 24±1℃ at a depth not less than 20 cm above the cylinder height. Mice were placed in the experimental room for 1 hour to acclimatize before the experiment. At the start of the experiment, the mice were placed in the device for 6 minutes. The entire process was recorded by a camera; only the last 4 minutes of immobility were counted when analyzing the data.

[0609] The experimental results are shown in Table 9 below.

[0610] Table 9. Effective doses of the compounds in the mouse FST experiment.

[0611] The data above show that the compounds in the embodiments of the present invention can exert a significant antidepressant effect at a lower dose compared with dextromethorphan.

[0612] Test Example 10: Acute Toxicity Test of Single-Dose Administration in Mice

[0613] Drug: The compound of the present invention is dissolved in 5% DMSO, then mixed with 5% solubil HS15, and then 90% physiological saline is added to prepare a solution of appropriate concentration. It should be prepared and used immediately.

[0614] Animals: Male C57BL / 6J mice, 8 weeks old, weighing approximately 20-22g. Animals were randomly divided into a blank control group and each test drug group. Mice in each group were administered the solvent formulation or the test drug via gavage.

[0615] Experimental procedure: After administration, relevant clinical observations were conducted.

[0616] The experimental results are shown in Table 10 below.

[0617] Table 10 Maximum tolerated doses of compounds in acute toxicity experiments in mice.

[0618] Conclusion: The compounds in the embodiments of this invention have a larger safety window than the positive compound dextromethorphan.

[0619] Test Example 11: In vivo test of the effect on spontaneous activity in mice

[0620] Methods: Mice were placed in a spontaneous activity box, and their activities were recorded for 60 minutes using a video acquisition system. The video was processed and analyzed using Noldus EthoVision XT software to calculate the distance the mice moved within 60 minutes, thereby evaluating the effect of the test compound on the spontaneous activity of mice.

[0621] Drug: The compound of this invention is dissolved in 5% EtOH, then mixed with +5% Solutol HS-15, and then 90% physiological saline is added to prepare a solution of appropriate concentration. It should be prepared and used immediately.

[0622] Animals: Male C57BL / 6J mice, 6–8 weeks old. Mice were randomly divided into groups of 10 each and administered orally by gavage the solvent control, different doses of compound 1 (5 mg / kg, 10 mg / kg, 20 mg / kg), or the positive control drug clonidine (1 mg / kg).

[0623] Experimental results: As shown in Figure 1, compared with the solvent control group, the activity distance of mice in the clonidine group was significantly reduced, and the total activity distance of mice was not significantly changed by each dose group of the test compound 1 (5mg / kg, 10mg / kg, 20mg / kg).

[0624] Conclusion: Single oral gavage administration of compound 1 at doses of 5 mg / kg, 10 mg / kg, and 20 mg / kg had no significant effect on spontaneous activity in mice, and no significant central nervous system inhibitory or excitatory effects were observed, supporting its good behavioral safety profile within this dose range.

[0625] Test Example 12: Pharmacological Efficacy Trial of a Chronic Unpredictable Mild Stress (CUMS) Model

[0626] Methods: This study evaluated the antidepressant effect of a compound on a mouse model of chronic unpredictable mild stress (CUMS). Mice in the model group were exposed to unpredictable mild stress for 29 consecutive days. Stress factors included overnight lighting, transient food or water deprivation, a 45° tilted cage, damp bedding, and isolated or crowded living conditions. After modeling, the animals were grouped according to their sucrose preference level and body weight. The test compound was administered as a single dose, and its antidepressant effect was assessed using a sucrose preference test.

[0627] Drug: The compound of this invention is dissolved in 5% EtOH, then mixed with +5% Solutol HS-15, and then 90% physiological saline is added to prepare a solution of appropriate concentration. It should be prepared and used immediately.

[0628] Animals: Male C57BL / 6J mice, 7 weeks old. CUMS model mice were randomly divided into groups of 12 each, and were administered solvent control, compound 1 (5 mg / kg, 10 mg / kg, 20 mg / kg), fluoxetine (10 mg / kg), and ketamine (20 mg / kg), respectively. Except for ketamine, which was administered intraperitoneally, the others were administered orally by gavage.

[0629] Experimental results: As shown in Figure 2, one day after administration, compared with the model control group, a single oral gavage administration of 10 mg / kg, 20 mg / kg of compound 1 and 20 mg / kg of ketamine significantly improved the sucrose preference of CUMS model mice, while no significant improvement in sucrose preference was observed with 5 mg / kg of compound 1 and 10 mg / kg of fluoxetine.

[0630] Conclusion: In a mouse model of chronic unpredictable mild stress depression, a single oral gavage administration of compound 1 at 10 mg / kg and 20 mg / kg significantly improved the anhedonic depressive-like behavior of the model mice, exhibiting a rapid onset antidepressant effect superior to fluoxetine and comparable to ketamine, suggesting that compound 1 has a rapid onset oral antidepressant effect.

[0631] Test Example 13: Pharmacological Trial of a Chronic Social Frustration Stress (CSDS) Model

[0632] Methods: This study evaluated the antidepressant effect of a compound on a chronic social frustration stress (CSDS) model mouse. Mice in the model group were challenged daily by selected CD1 mice for 10 minutes. After the challenge, they were separated from the aggressive mice by perforated partitions and kept in the same cage to continuously expose them to social stress for 11 consecutive days, with different CD1 mice introduced each day. After model establishment, behavioral changes in the model were assessed using a social interaction (SI) test, and susceptible mice were selected for inclusion in the model based on the SI ratio. The test compound was administered as a single dose, and its antidepressant effect was evaluated using the social interaction test.

[0633] Drug: The compound of this invention is dissolved in 5% EtOH, then mixed with +5% Solutol HS-15, and then 90% physiological saline is added to prepare a solution of appropriate concentration. It should be prepared and used immediately.

[0634] Animals: Male C57BL / 6J mice, 6–8 weeks old. Susceptible mice after CSDS modeling were randomly divided into groups of 10 each. The groups were administered solvent control, compound 1 (10 mg / kg, 20 mg / kg), fluoxetine (10 mg / kg), and esketamine (10 mg / kg), respectively. Except for esketamine, which was administered intraperitoneally, the others were administered orally by gavage.

[0635] Experimental results: As shown in Figure 3, 0.5 hours after a single administration, compared with the model control group, 10 mg / kg compound 1 increased the social interaction ratio of susceptible mice, but the difference was not statistically significant; compared with the model control group, 20 mg / kg compound 1 and esketamine significantly increased the social interaction ratio of susceptible mice, while 10 mg / kg fluoxetine did not show any effect on improving the social interaction ratio.

[0636] Conclusion: In a mouse model of chronic social frustration and depression, a single oral gavage dose of 20 mg / kg of compound 1 significantly improved the depressive-like behavior of social frustration in the model mice, exhibiting a rapid onset antidepressant effect superior to fluoxetine and comparable to esketamine, suggesting that compound 1 has a rapid onset oral antidepressant effect.

[0637] Test Example 14: Conditional Place Preference (CPP) Test

[0638] Methods: This test included three phases: acclimatization, conditioning, and testing. During the acclimatization phase, mice were placed in a CPP (Conditional Place Preferred) box once daily for three consecutive days, with CPP scores measured on Day 1. The conditioning phase lasted six days, with mice receiving either drug-free or drug-containing box training twice daily (morning and afternoon). During drug-free box training, mice were given either a solvent or injectable saline solution and placed in the box for approximately 45 minutes. During drug-containing box training, mice were given either a solvent, Compound 1, or esketamine for approximately 45 minutes. During the testing phase, one day after the last training session, the time mice spent in both the drug-containing and drug-free boxes within 15 minutes was measured, and the Conditioned Place Preferred Score (CPP Score) was calculated using the formula: (T... post-drug -T pre- drug )-(T post-vehicle -T pre-vehicle The purpose of this test is to observe the degree of preference of mice for a specific environment after repeatedly associating reward stimuli with non-reward stimuli (specific environment) in order to evaluate whether the compound has the potential to induce conditioned place preference in mice.

[0639] Drug: The compounds of this invention are prepared into solutions of appropriate concentrations using 5% Solutol HS-15 and 90% physiological saline, and should be used immediately after preparation.

[0640] Animals: Male C57BL / 6J mice, 8 weeks old. Mice were randomly divided into groups and administered solvent control, compound 1 (20 mg / kg, 40 mg / kg, 80 mg / kg), or esketamine (20 mg / kg), respectively. Except for esketamine, which was administered intraperitoneally, the others were administered orally by gavage.

[0641] Experimental results: As shown in Figure 4, in the CPP test, compared with the control group, 20 mg / kg esketamine significantly increased the conditional position preference score, while compound 1 at 20 mg / kg, 40 mg / kg and 80 mg / kg did not cause an increase in conditional position preference score.

[0642] Conclusion: In the conditional position preference test, none of the doses of compound 1 induced the CPP effect in mice, suggesting that it does not have a reward effect or addictive potential.

[0643] Test Example 15: Natural Withdrawal Test in ICR Mice

[0644] Methods: This test was conducted in ICR mice with a 28-day repeated administration and a 28-day recovery period. The solvent or compound was administered orally via gavage once daily for 28 consecutive days. Natural withdrawal was evaluated from Day 29 to Day 35. This test assessed the potential of the compound to induce withdrawal responses in mice by observing spontaneous withdrawal-related behavioral changes after drug withdrawal.

[0645] Drug: The compounds of this invention are prepared into solutions of appropriate concentrations using 5% Solutol HS-15 and 90% physiological saline, and should be used immediately after preparation.

[0646] Animals: Male and female ICR mice, 7–9 weeks old. Mice were randomly divided into groups of 6 females and 6 males, and were administered the solvent control, compound 1 (10 mg / kg / day, 30 mg / kg / day, and 80 mg / kg / day) orally by gavage, respectively.

[0647] Experimental results: Compared with the solvent control group, no significant changes in natural withdrawal reactions of male and female animals in the compound 1 administration groups (10 mg / kg / day, 30 mg / kg / day, 80 mg / kg / day), including body weight, abnormal body position, high irritability, tremor, teeth clicking, restlessness, ptosis, tearing, diarrhea, salivation, and weight loss (compared to the body weight at the last administration), were observed.

[0648] Conclusion: In the natural withdrawal test in mice, compound 1 did not induce withdrawal response in mice, suggesting that it does not have a reward effect or addictive potential.

[0649] Based on the experimental results of the above embodiments, the compounds of the present invention simultaneously possess dual-target inhibitory activities against SERT and NMDAR. In various animal models, the compounds produced significant antidepressant effects shortly after a single dose, achieving marked efficacy at low doses; simultaneously, no obvious addiction or withdrawal reactions were observed, nor did they cause significant central excitation or inhibition effects. Compared with single SERT inhibitors or single NMDAR antagonists, the compounds of the present invention exhibit significant advantages in terms of onset speed and safety, achieving a combination of non-addictiveness and rapid onset, thus demonstrating the overall technical effect brought about by dual-target synergy.

Claims

1. A compound of formula X or X', or a stereoisomer, geometric isomer, tautomer, conformational isomer, or a pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or a mixture thereof: in: X and Y are each independently CR1 or N; A1, A2, A3, and A4 are each independently CR a R b , O or NR c ; R a R b and R c Each can be independently H, halogen, C 1-6 Alkyl, C 1-6 Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 alkyl-CO-, wherein the C 1-6 Alkyl, C 1-6 Alkyl-O, C 1-6 Alkyl-SO2- or C 1-6 Alkyl-CO- may optionally be replaced by halogen or deuterium; Each R1 group can be independently hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, nitro, amino, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2- 6-acetylinyl, C 3-6 Cycloalkyl groups, 3-6 membered heterocycloalkyl groups having 1-3 heteroatoms selected from N, O, and S, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, formamido, C 1-6 Alkyl-NH-, C 1-6 Alkyl-O-, C 1-6 Deuterated alkyl-O-, C 3-6 cycloalkyl-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-, carbamoyl, C 1-6 Alkyl-NH-CO-, (C 1-6 Alkyl)2N-CO-, C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-CO-, C 3-6 Cycloalkyl-CO-NH-, amino-substituted C 1-6 Alkyl-NH-CO-, amino-substituted C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-NH-C 1-6 Alkyl-CO-NH-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-NH-CO-, C 3-6 cycloalkyl-NH-C 1-6 Alkyl-CO-NH-, (C 1-20 Alkyl)2N-C 1-6 Alkyl-NH-CO-, (C 1- 20 (alkyl)2N-C 1-6 Alkyl-CO-NH-, C 1-20 Alkoxy-C 1-6 Alkyl-NH-CO-, C 1-20 Alkoxy-C 1-6 Alkyl-CO-NH-, C 6-14 Aryl-NH-C 1-6 Alkyl-NH-CO-, C 6-14 Aryl-NH-C 1-6 Alkyl-CO-NH- or (3-6 membered heterocyclic group) (C 1-6 (alkyl)N-CO-; wherein R1 is optionally substituted with one, two or three halogens or oxo groups; Alternatively, any two adjacent R1s and the carbon atoms connected to R1 together form a 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein the 5-10 membered ring containing 1, 2 or 3 heteroatoms selected from N, O and S is optionally substituted by 1, 2 or 3 methyl or halogen. R2 and R3 are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, mercapto, cyano, nitro, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1-6 Alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, C 6-14 Aryl-O-, 5-15 heteroaryl-O-, C 6-14 aryl-NH- or 5-15 heteroaryl-NH-, wherein R2 and R3 are optionally substituted with one, two or three halogens; Alternatively, the carbon atom bonded to R2, the carbon atom bonded to R3, and C 1-3 The alkylene groups together form a 3-6 membered carbon ring, wherein the 3-6 membered carbon ring is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, carbamoyl (NH2CO-), aminosulfonyl (NH2SO2-), C 1-6 Alkyl, Halogenated C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-O-, C 1-3 Alkyl-substituted C 3-6 cycloalkyl, C 1-3 Alkyl-substituted C 3-6 cycloalkyl-O-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, Halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, C 6-14 aryl, 5-10 heteroaryl groups having 1, 2 or 3 heteroatoms selected from N, O and S, C 6-14 aryl-substituted C 1-6 C-substituted with alkoxy and 5-10 heteroaryl groups 1-6 Alkoxy; R4 is hydrogen, deuterium, halogen, optionally substituted hydroxyl, mercapto, cyano, nitro, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 6-14 aryl, 5-15 membered heteroaryl with 1-3 heteroatoms selected from N, O and S, C 1-6 Alkyl-NH-, C 1-6 Alkoxy, C 1-6 Alkyl-S-, C 1-6 Alkyl-CO-O-, C 1-6 Alkyl-NH-CO-, C 1-6 Alkyl-CO-NH-, C 1- 6-alkyl-NH-CO2-, C 1-6 Alkyl-CO-NH-O-, 5-15 membered heteroaryl-O-, C 6-14 aryl-NH-, 5-15-membered heteroaryl-NH-; the hydroxyl group is optionally selected from C 1-6 Alkyl and C 1-6 Alkyl-CO- substituents; R5 represents hydrogen, deuterium, and C. 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 alkoxy-substituted C 1-6 Alkyl, hydroxyl substituted C 1-6 Alkyl, C 6-14 aryl-substituted C 1-6 alkyl, 5-15 membered heteroaryl substituted C 1-6 Alkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic group, C 3-6 Cycloalkyl-substituted C 1-6 Alkyl, C 3-6 C with heterocyclic substitution 1-6 Alkyl, C 2-6 alkenyl or C 2-6 alkynyl group; Alternatively, the carbon atom connected to R4, the carbon atom marked with "*", the nitrogen atom connected to R5, and R4 and R5 together form a 6-8 membered ring; R6 and R7 are each independently hydrogen, deuterium, halogen, hydroxyl, mercapto, amino, hydroxyl-substituted amino, C 1-4 Alkyl, C 3- 6-cycloalkyl or C 1-4 Alkoxy-substituted amino groups; Represents a double bond or a single bond; m and n are each independently 0, 1, 2 or 3.

2. The compound of claim 1, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that, The compound of formula X has the structure shown in formula X-1: Among them, R1 is selected from 5-membered heteroaryl, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Deuterated alkyl-O-, cyclopropyl-O-, carbamoyl; wherein R1 is optionally substituted with one, two or three halogens; R2 and R3 are each independently selected from hydrogen and methyl groups; Alternatively, the carbon atom connected to R2, the carbon atom connected to R3, and the methylene group together form a 3-membered carbon ring; R4 is selected from hydrogen, hydroxyl, or methoxy; R5 is selected from hydrogen, deuterium, methyl, or trideuterium methyl; Represents a double bond or a single bond; When R5 is selected from methyl and R1 is selected from methoxy, R2 is not methyl; n = 0 or 1; m = 0 or 1.

3. The compound of claim 1, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that, The compound of formula X' has the structure shown in formula X'-1: A1 is selected from CR a R b , O or NR C , where R a Independently selected from H and R b Independently selected from methyl, R c Selected independently from C 1-3 Alkyl-CO- or C 1-3 Alkyl-SO2-; R1 is selected from C 1-3 Alkyl-O-, C 1-3 Deuterated alkyl-O-; R4 is selected from hydrogen, hydroxyl, or methoxy; R5 is selected from hydrogen, deuterium, methyl, or trideuterium methyl; It represents a double bond or a single bond.

4. The compound of formula X-1 as claimed in claim 2, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that... , R1 is selected from methyl, methoxy, trideuteroxy, carbamoyl or 5-membered heteroaryl; R2 and R3 are each independently selected from hydrogen or methyl; R4 is selected from hydroxyl groups; R5 is selected from methyl or trideuterated methyl; m = 1; n = 1.

5. The compound of formula X-1 as claimed in claim 4, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, wherein the 5-membered heteroaromatic ring is selected from:

6. The compound of formula X'-1 as claimed in claim 3, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that, As stated, A1 is selected from >N-CO-CH3 or >CH-CH3; R4 is selected from hydrogen or hydroxyl groups; R5 is selected from methyl.

7. The compound of formula X as claimed in claim 1, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that, The compound of formula X has the structure shown in formula X-2: Among them, R1 is selected from 5-membered heteroaryl, C 1-3 Alkyl, C 1-3 Alkyl-O-, C 1-3 Deuterated alkyl-O- or carbamoyl; wherein R1 is optionally substituted with one, two or three halogens; R2 and R3 are each independently selected from hydrogen or methyl; R5 is selected from hydrogen, deuterium, methyl, or trideuterated methyl.

8. The compounds of formula X and X' as claimed in claim 1, or their stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, characterized in that, The compounds of formula X and formula X' are selected from:

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises (1) a therapeutically effective amount of any one of claims 1-8 of the compound of formula X or X', or a stereoisomer, geometric isomer, tautomer, conformational isomer, or a pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or a mixture thereof; and (2) a pharmaceutically acceptable carrier.

10. Choose from the following group of applications: (1) The use of any compound of formula X or formula X' according to any one of claims 1-8, or a stereoisomer, geometric isomer, tautomer, conformational isomer, or pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or mixture thereof, and / or the use of the pharmaceutical composition according to claim 9 in the preparation of an NMDA receptor antagonist. (2) The use of any compound of formula X or formula X' according to any one of claims 1-8, or a stereoisomer, geometric isomer, tautomer, conformational isomer, or pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or mixture thereof, and / or the use of the pharmaceutical composition according to claim 9 in the preparation of a 5-hydroxytryptamine transtransporter inhibitor. (3) The use of any compound of formula X or formula X' according to any one of claims 1-8, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition according to claim 9 in the preparation of a drug that modulates the NMDAR / SERT dual-target; (4) The use of the compound of formula X or formula X' of any one of claims 1-8, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the use of the pharmaceutical composition of claim 9 in the preparation of a medicament for the treatment and / or prevention of NMDAR-related diseases; (5) The use of any compound of formula X or formula X' according to any one of claims 1-8, or a stereoisomer, geometric isomer, tautomer, conformational isomer, or pharmaceutically acceptable salt, prodrug, hydrate, polymorph, solvate, isotopically labeled compound, or mixture thereof, and / or the use of the pharmaceutical composition according to claim 9 in the preparation of a medicament for the treatment and / or prevention of SERT-related diseases; (6) The use of the compound of formula X or formula X' of any one of claims 1-8, or its stereoisomers, geometric isomers, tautomers, conformational isomers, or pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, solvates, isotopically labeled compounds, or mixtures thereof, and / or the pharmaceutical composition of claim 9 in the preparation of a medicament for the treatment and / or prevention of NMDAR / SERT dual-target-related diseases.

11. The application as described in claim 10, characterized in that: The NMDAR-related diseases are central nervous system diseases; The SERT-related diseases are central nervous system diseases; The diseases associated with the NMDAR / SERT dual targets are central nervous system diseases.

12. The application as described in claim 11, characterized in that, The central nervous system diseases mentioned are selected from: cerebral ischemia; stroke; cerebral infarction; traumatic brain injury; anti-NMDA receptor encephalitis; epilepsy; amyotrophic lateral sclerosis; schizophrenia; refractory, difficult-to-manage, or chronic schizophrenia; affective disorders; mental disorders; mood disorders; type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; treatment-resistant depression; dysphoric disorder; cyclothymic disorder; panic attacks; Panic disorder; social phobia; Obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; hysteria; anorexia nervosa; sleep disorder; adjustment disorder; cognitive impairment; autism; neuropathic pain; bipolar disorder; Parkinson's disease; Huntington's disease; Alzheimer's disease; various dementias; memory impairment; ADHD; attention deficit / hyperactivity disorder; tic disorders; and other neurological events or neurodegenerations caused by NMDA receptor activation.

Images