Morphinan compounds, preparation method therefor, and use thereof

Abstract

The present invention relates to morphinan compounds, a preparation method therefor, and the use thereof, and specifically relates to morphinan compounds represented by formula (I) and isomers, racemates, pharmaceutically acceptable salts, solvates or isotope-labelled substances thereof, a preparation method therefor, a pharmaceutical composition comprising same, and the use of same in preparing drugs for preventing and / or treating central nervous system diseases. Compared with compounds disclosed in the prior art, the compounds of the present invention have the advantages of acting on multiple targets, lower effective dose, fewer toxic and side effects, better safety and tolerance, etc., and have good overall druggability and thus possess good prospects in clinical application.

Description

Morphinan compounds, methods of making and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry. Specifically, the present application relates to a class of morphinan compounds shown in formula (I), isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopically labeled compounds thereof, methods of making the same, pharmaceutical compositions containing the same, and uses thereof in the manufacture of central nervous system disease drugs. BACKGROUND

[0002] With the rapid development of society, people's life rhythm and pressure are increasing, and mental illness has become a serious disease affecting human health, which has brought serious consequences to patients and their families. Due to the existence of factors such as easy suicide, lack of medical care, and high risk of complications, the average life expectancy of patients with mental illness is shortened. A large number of studies have shown that mental illness is related to the abnormal function of central nervous system neurotransmitters and receptors. The 5-hydroxytryptamine (5-HT) system is closely related to human mental activity, and when the 5-HT system function is disordered, it is easy to cause the occurrence of various neurological / psychiatric diseases, such as schizophrenia, depression, neuropathic pain, mania, anxiety, Parkinson's disease, etc. NMDA receptors play a key role in the transmission of neurotransmitters glutamate, and the overactivation of NMDA receptors is related to the pathogenesis of depression, schizophrenia and other neuropsychiatric diseases. Sigma-1 receptors play an important role in neuroprotection and regulation of neural plasticity, and are closely related to the onset and development of inflammation, neuropsychiatric and degenerative diseases.

[0003] NMDA receptors and 5-HT transporters are important targets for antidepressants and anxiolytics. Existing SSRIs (selective 5-HT reuptake inhibitors) can selectively inhibit 5-HT transporters, increase the concentration of 5-HT in the synaptic cleft, and thus exert antidepressant, anxiolytic and other effects. NMDA receptor inhibitors can regulate glutamate signaling pathways, which can help to quickly alleviate depressive symptoms, and have beneficial effects on senile dementia, Parkinson's disease and related dementia, epilepsy, tinnitus, brain injury, pain, etc. Sigma-1 receptor agonists are a new hope for neuropsychiatric and degenerative diseases. Therefore, compounds with multiple target activities have good research prospects.

[0004] Dextromethorphan is a non-anesthetic morphine derivative that simultaneously possesses NMDA receptor antagonistic activity, 5-HT transporter inhibition, and sigma1 agonist effects. Dextromethorphan undergoes phase I metabolism primarily in the liver, where it is demethylated by CYP2D6 to form 3-hydroxymorphine compounds. The metabolites have reduced lipid solubility, making them difficult to cross the blood-brain barrier, and most are rapidly glucuronidated and eliminated from the body quickly. Therefore, the bioavailability of dextromethorphan taken orally alone is low. Thus, finding compounds with multi-target activity that simultaneously regulates 5-HT transporters, NMDA receptors, and sigma1 receptors, along with stable metabolism and good safety profiles, is beneficial for better regulating the balance of multiple neurotransmitters such as glutamate and 5-HT in the brain, thereby improving the treatment of diseases of the central nervous system.

[0005] In view of this, the present invention is hereby proposed. Summary of the Invention

[0006] Purpose of the invention

[0007] The purpose of this invention is to provide a class of compounds that have antagonistic effects on 5-hydroxytryptamine transporters and have regulatory activity on NMDA receptors and sigma1.

[0008] One object of the present invention is to provide a morphinan compound of formula (I), or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopic label thereof.

[0009] Another object of the present invention is to provide a method for preparing morphine compounds of formula (I).

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), its isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopic labels.

[0011] Another object of the present invention is to provide the use of morphine compounds of formula (I), their isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopic labels, or the above-described pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases of the central nervous system.

[0012] Technical solution

[0013] According to one aspect of the invention, a morphinan compound represented by formula (I), or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopic label thereof, is provided.

[0014] in:

[0015] X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 3-8 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C10aryl, or wherein Y and Y1are each independently selected from O, NH, NR6, or S, Y2is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6is independently selected from substituted or unsubstituted C1-C30alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl or 5-10 membered heteroaryl, or, two R6and the atom to which they are attached form a substituted or unsubstituted 3-8 membered ring containing 1-3 heteroatoms selected from N, O and S; and said substituents, when present, are R7;

[0016] Preferably, X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 4-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C10aryl, or wherein Y and Y1are each independently selected from O, NH, NR6, or S, Y2is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6is independently selected from substituted or unsubstituted C1-C20alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl or 5-10 membered heteroaryl, or, two R6and the atom to which they are attached form a substituted or unsubstituted 4-6 membered ring containing 1-3 heteroatoms selected from N, O and S; and said substituents, when present, are R7;

[0017] More preferably, X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted phenyl, or wherein Y and Y1are each independently selected from O, NH, NR6, or S, Y2is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6is independently selected from substituted or unsubstituted C1-C18alkyl, or, two R6and the atom to which they are attached form a substituted or unsubstituted 5-6 membered heterocyclic ring containing 1-4 heteroatoms selected from N, S, O, and, when substituted, the substituents are R7;

[0018] R1is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C1-C30alkanoyl, substituted or unsubstituted C3-C10cycloalkanoyl, substituted or unsubstituted 3-10 membered non-aromatic heterocyclylacyl, substituted or unsubstituted C1-C30alkoxycarbonyl, substituted or unsubstituted C3-C6cycloalkoxycarbonyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered arylacyl or heteroarylacyl, -COO(substituted or unsubstituted C6-C20aryl), -COO(substituted or unsubstituted 5-20 membered heteroaryl), -C(R8)2O-(CO)-(substituted or unsubstituted C1-C30alkyl or substituted or unsubstituted C3-C30cycloalkyl), -C(R8)2O-(CO)O-(substituted or unsubstituted C1-C30alkyl or substituted or unsubstituted C3-C30cycloalkyl), -C(R8)2O-(CO)-(substituted or unsubstituted C6-C20aryl), -C(R8)2O-(CO)-(substituted or unsubstituted 5-20 membered heteroaryl), the residue of an amino acid after removal of the hydroxyl group of the carboxyl group, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; wherein R8is H or C1-C6alkyl; and, when substituted, the substituents are R7;

[0019] R1is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C1-C30alkanoyl, substituted or unsubstituted C3-C8cycloalkanoyl, substituted or unsubstituted 3-10 membered non-aromatic heterocyclylcarbonyl, substituted or unsubstituted C1-C30alkoxycarbonyl, substituted or unsubstituted C3-C6cycloalkoxycarbonyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-10 membered arylacyl or heteroarylacyl, -COO(substituted or unsubstituted C6-C8aryl), -COO(substituted or unsubstituted 5-8 membered heteroaryl), -C(R8)2O-(CO)-(substituted or unsubstituted C1-C30alkyl), -C(R8)2O-(CO)O-(substituted or unsubstituted C1-C30alkyl), -C(R8)2O-(CO)-(substituted or unsubstituted C6-C10aryl), -C(R8)2O-(CO)-(substituted or unsubstituted 5-7 membered heteroaryl), a residue of an amino acid after removal of the hydroxyl group from the carboxyl group, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; wherein R8is H or C1-C3alkyl; and the substituents, when present, are R7;

[0020] R2, R3, R4are each independently selected from hydrogen, substituted or unsubstituted C1-C10alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C6-C10aryl or 5-10 membered heteroaryl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C2-C10alkynyl, substituted or unsubstituted C1-C10alkoxy, substituted or unsubstituted C3-C6cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted by one or two C1-C6alkyl groups, amino substituted by one or two C3-C6cycloalkyl groups, mercapto, substituted or unsubstituted C1-C6alkylthio, substituted or unsubstituted C3-C6cycloalkylthio, halogen; and the substituents, when present, are R7;

[0021] or

[0022] X and R3, R2and R3, or X and R4together with the C atoms of the phenyl ring to which they are attached form a 4-10 membered ring containing 0-3 heteroatoms selected from N, O and S, which 4-10 membered ring can be aromatic or non-aromatic,

[0023] said 4-10 membered ring is optionally substituted with one or more R5, each R5is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, oxo, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, C1-C6alkanoyl, C3-C6cycloalkanoyl, carbamoyl, carbamoyl substituted with one or two C1-C6alkyl or C3-C6cycloalkyl, amino substituted with one or two C1-C6alkyl or C3-C6cycloalkyl, amino substituted with one or two C1-C6alkanoyl or C3-C6cycloalkanoyl, C1-C6alkoxycarbonyl, C3-C6cycloalkoxycarbonyl, 3-10 membered heterocycloalkyl, C6-14aryl, or 5-10 membered heteroaryl;

[0024] Preferably, R2, R3, R4are each independently selected from hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl or 5-10 membered heteroaryl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C2-C10alkynyl, substituted or unsubstituted C1-C10alkoxy, substituted or unsubstituted C3-C6cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted with one or two C1-C6alkyl, amino substituted with one or two C3-C6cycloalkyl, thiol, substituted or unsubstituted C1-C6alkylthio, substituted or unsubstituted C3-C6cycloalkylthio, halogen; when substituted, the substituents are R7;

[0025] or

[0026] X and R3, R2 and R3, or X and R4, together with the C atoms on the phenyl ring to which they are attached, form a 5-6 membered ring selected from:

[0027] wherein Z1, Z2, Z3are independently selected from C, N, O, S, NR5, CR5, C(R5)2; provided that at least one of Z1, Z2and Z3is a heteroatom;

[0028] each R5is independently selected from hydrogen, halogen, hydroxy, amino (-NH2), cyano, carboxy, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkanoyl, carbamoyl (-CONH2), carbamoyl substituted with C1-C6alkyl, amino substituted with one or two C1-C6alkyl, amino substituted with one or two C1-C6alkanoyl, C1-C6alkoxycarbonyl, 4-8 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl.

[0029] More preferably, R2, R3, R4 are each independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl or 5-10 membered heteroaryl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted by one or two C1-C6 alkyl groups, amino substituted by one or two C3-C6 cycloalkyl groups, mercapto, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C3-C6 cycloalkylthio, halogen; in the substituted case, the substituents are R7;

[0030] or

[0031] X and R3, R2 and R3, or X and R4 and the C atoms of the phenyl ring to which they are attached together form a 5-6 membered ring,

[0032] said 5-6 membered ring is selected from:

[0033] wherein the direction of the heterocyclic ring connection can vary, i.e., may also mean may also mean and so on,

[0034] wherein R5 is independently selected from hydrogen, halogen, amino, cyano, hydroxy, carboxy, carbamoyl (-CONH2), carbamoyl substituted by C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, amino substituted by one or two C1-C6 alkyl groups, amino substituted by one or two C1-C6 alkanoyl groups, C1-C6 alkanoyl, C1-C6 alkoxycarbonyl, C3-C6 cycloalkyl, 4-8 membered heterocycloalkyl, C6-10 aryl or 5-10 membered heteroaryl,

[0035] Preferably, each R5 is independently selected from hydrogen, amino, hydroxy, carboxy, C1-C3 alkyl (in particular methyl, ethyl, isopropyl), halo C1-C3 alkyl (in particular trifluoromethyl), C1-C3 alkoxy (in particular methoxy, ethoxy), C1-C3 alkanoyl (in particular formyl), carbamoyl (-CONH2), formamido, methylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl (in particular methoxycarbonyl, ethoxycarbonyl), C3-C5 cycloalkyl (in particular cyclopropyl), phenyl, pyridyl, pyrrolidinyl, piperidinyl or morpholinyl;

[0036] R7is one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9) substituents each independently selected from deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo (=0), C1-C6alkyl, C3-C6cycloalkyl, 3-8 membered heterocyclyl containing 1-3 heteroatoms unsubstituted or substituted with oxo or C1-C6alkyl, C6-C20aryl unsubstituted or substituted with C1-C6alkoxy, 5-20 membered heteroaryl unsubstituted or substituted with oxo or C1-C6alkyl, 3-8 membered heterocyclyl C1-C6alkyl unsubstituted or substituted with oxo or C1-C6alkyl, 5-20 membered heteroaryl C1-C6alkyl unsubstituted or substituted with oxo or C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyloxy, C1-C6alkylthio, C3-C6cycloalkylthio, amino substituted with one or two C1-C6alkyl groups, and amino substituted with one or two C3-C6cycloalkyl groups, -NHCO-(C1-C6alkyl or C3-C6cycloalkyl), -N(C1-C6alkyl or C3-C6cycloalkyl)CO-(C1-C6alkyl or C3-C6cycloalkyl), -CHO, -CO(C1-C6alkyl or C3-C6cycloalkyl), -COOH, -COO(C1-C6alkyl or C3-C6cycloalkyl), -CONH(C1-C6alkyl or C3-C6cycloalkyl), -CON(C1-C6alkyl or C3-C6cycloalkyl)2.

[0037] According to one embodiment of the application, the morphinan compound is selected from:

[0038] wherein M1, M2, M3and M4are each independently selected from C, S, O, N, C=0, M5is C or N, and M1to M5are not simultaneously C atoms; denotes a single or double bond, preferably the is thiazole, thiophene, furan, imidazole.

[0039] N is an integer from 0 to 3, for example 0, 1, 2, 3 or 4;

[0040] Z is selected from halogens, cyano, cyanomethyl, nitro, amino (-NH2), C1-C6 alkyl-substituted amino groups, mercapto groups, C1-C6 alkylthio groups, deuterated or unsubstituted C1-C6 alkyl groups, fluorinated C1-C6 alkyl groups, deuterated or unsubstituted C3-C6 cycloalkyl groups, fluorinated C3-C6 cycloalkyl groups, hydroxyl groups, deuterated or unsubstituted C1-C6 alkoxy groups, deuterated or unsubstituted C3- C6 cycloalkoxy, substituted or unsubstituted C6-C10 aryl or 5-10 heteroaryl; when substituted, the substituent is R7; preferably, Z is selected from halogen, cyano, deuterated or unsubstituted C1-C3 alkyl, fluorinated C1-C6 alkyl, deuterated or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl or 5-6 heteroaryl; when substituted, the substituent is R7;

[0041] The definitions of R1 to R7 are the same as those in the above text;

[0042] X1 is a deuterated or unsubstituted C1-C6 alkoxy group, preferably a methoxy group with 0 to 3 deuterated substituted hydroxyl groups, an ethoxy group with 0 to 5 deuterated substituted ethoxyl groups, a propoxy group with 0 to 7 deuterated substituted n-propoxyl groups, or an isopropoxy group with 0 to 7 deuterated substituted ethoxyl groups.

[0043] Preferably, R1 is selected from: hydrogen, methyl, methyl with 1 to 3 deuterated branches, ethyl, ethyl with 1 to 5 deuterated branches, n-propyl, n-propyl with 1 to 7 deuterated branches, isopropyl, isopropyl with 1 to 7 deuterated branches, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, formyl, acetyl, propionyl, butyryl, isopropionyl, isobutyryl, tert-butyryl, benzoyl, p-toluyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyryl, isopropoxycarbonyl alkyl, isobutyryloxycarbonyl, tert-butyryloxycarbonyl, trichloroethoxycarbonyl, dodecanealkyloxycarbonyl, hexadecanealkyloxycarbonyl, phenoxycarbonyl, p-methoxyphenoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzyl, p-methoxybenzyl, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, pentanoyloxymethyl, lauroyloxymethyl, palmitoyloxymethyl, 1-(pyridin-3-yl)acyloxymethyl, methoxymethyl, 2-aminoacetyl, 2-amino-3-methylbutyryl, 2-aminophenylpropionyl, pyrrole-2-acyl, 2-amino-4-carboxypropionyl, 2-amino-3-(1-H-imidazol-4-yl)propionyl, 2-amino-3-hydroxybutyryl

[0044] According to one embodiment of the present invention, the morphine compound is most preferably selected from the following compounds or combinations thereof:

[0045] More preferably, the morphinan compounds of the present application are selected from the following compounds: A-1, A-2, A-63, A-120, A-121, A-123, A-130, A-131, A-153, A-154, A-156, A-158, A-163, A-168, A-173, A-174, A-176 to A-424.

[0046] The compounds of the present application have NMDA receptor, monoamine transporter and sigma 1 multi-target effects, and can be used for the treatment of various central nervous system diseases, especially depression, bipolar disorder, schizophrenia, anxiety, phobia, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, hyperactivity, pain, alcohol-induced neuropathy or behavioral abnormalities, etc.

[0047] According to a second aspect of the present application, a preparation method of a morphinan compound represented by formula (I) is provided, and the preparation method can be carried out by the following method.

[0048] Reaction formula:

[0049] (1) X1 in the compound of formula (III) is substituted by X2 to generate the compound of formula (II),

[0050] (2) the compound of formula (II) undergoes substitution or coupling reaction to generate the compound of formula (I), or X2 in the compound of formula (II) is cyclized with R3

[0051] or R4, respectively,

[0052] wherein the definitions of X, R1 to R5 are the same as defined and preferred above;

[0053] X1 represents H, hydroxyl, C1-C6 alkoxy, preferably hydroxyl, methoxy, ethoxy;

[0054] X2represents a leaving group such as halogen, C1-C6alkylsulfonyloxy, phenylsulfonyloxy, naphthylsulfonyloxy, the above C1-C6alkylsulfonyloxy, phenylsulfonyloxy, naphthylsulfonyloxy being optionally further substituted by one or more groups selected from halogen, hydroxy, amino, nitro, C1-C6alkyl, C1-C6alkoxy and C1-C6alkanoyl;

[0055] X2is preferably halogen, C1-C4alkylsulfonyloxy, phenylsulfonyloxy, naphthylsulfonyloxy, the above C1-C4alkylsulfonyloxy, phenylsulfonyloxy, naphthylsulfonyloxy being optionally further substituted by one or more groups selected from halogen, hydroxy, amino, nitro, C1-C4alkyl, C1-C4alkoxy and C1-C4alkanoyl;

[0056] X2is most preferably chlorine, bromine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy, naphthylsulfonyloxy, methylphenylsulfonyloxy, nitrophenylsulfonyloxy, aminophenylsulfonyloxy, chlorophenylsulfonyloxy, bromophenylsulfonyloxy and methoxyphenylsulfonyloxy.

[0057] The above reaction of step (2) can be carried out with or without a solvent, or in a solvent with or without a base, or with or without a catalyst.

[0058] The solvent includes water; ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether and the like; aromatic compounds such as benzene, toluene, xylene, nitrobenzene, chlorobenzene and the like; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone and the like; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; others such as dimethyl sulfoxide, acetonitrile and the like; or a mixture of the above solvents.

[0059] The base can be selected from inorganic or organic bases, inorganic bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; alkali metals such as potassium, sodium; others such as sodium amide, potassium amide, sodium hydride, potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethyl aniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO). These bases can be used alone or in combination of two or more.

[0060] The catalyst includes copper, iron, nickel, ruthenium, rhodium, palladium and the like metal catalysts, which can be used alone or in combination of two or more.

[0061] If necessary, a suitable ligand can be added as a reaction promoter for the above reaction. Suitable ligands are 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP), tri-tert-butylphosphine (P(t-Bu)3), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (x-phos), 4,5-bis-diphenylphosphino-9,9-dimethylxanthene (Xantphos), tri-tert-butylphosphine tetrafluoroborate, and tris(2-methylphenyl)phosphine (P(o-tolyl)3).

[0062] The above reaction is usually carried out at room temperature to 200°C, preferably at room temperature to 150°C, and the reaction is usually completed in about 1 to 30 hours, preferably in 1 to 20 hours.

[0063] The compound of formula (III), the compound of formula (II) are commercially available compounds or are prepared according to a method known in the art or according to a method similar to the synthesis of similar compounds.

[0064] The starting compounds used in the above reaction formulas can be suitable salts including alkali metal salts and alkaline earth metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts, and the like; organic base salts such as pyridine salts, triethylamine salts, and the like; inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, and the like; organic acid salts such as formates, acetates, propionates, glycolates, oxalates, malonates, succinates, fumarates, maleates, lactates, malates, citrates, tartrates, picrates, glutamates, methanesulfonates, and benzenesulfonates, and the like;

[0065] In addition, the starting compounds used in the above reaction formulas can include solvate forms such as hydrates, alcoholates, and the like.

[0066] The solvate forms of the morphinan compounds represented by the formula (I) and the stereoisomers and racemates thereof, and the solvate forms of the stereoisomers and racemates thereof, are also included within the scope of the present application.

[0067] The pharmaceutically acceptable salts of the morphinan compounds represented by the formula (I) and the stereoisomers thereof mean that the quinolinone compounds represented by the formula (I) or the stereoisomers thereof are treated with an appropriate acid to convert them into a therapeutically active, non-toxic addition salt form. The salts are, for example, hydrochlorides, hydrobromides, hydroiodides, sulfates or bisulfates, nitrates, phosphates or acid phosphates, perchlorates, formates, acetates, trifluoroacetates, propionates, pyruvates, glycolates, oxalates, malonates, succinates, glutarates, maleates, fumarates, lactates, malates, citrates, tartrates, picrates, glutamates, benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, salicylates, ascorbates, camphorates or camphorsulfonates, and the like. Conversely, the salt form can also be converted into the free base form by treatment with a base.

[0068] The term "pharmaceutically acceptable salt" used above also includes solvates of the salts, and the solvates are included within the scope of the present application. Examples of the solvates are, for example, hydrates, alcoholates, and the like.

[0069] As used herein, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, or bromine; more preferably fluorine or chlorine.

[0070] As used herein, "alkyl" refers to straight-chained or branched saturated hydrocarbon groups, for example, C1-C6alkyl refers to straight-chained or branched saturated hydrocarbon groups containing 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl, or n-hexyl, and the like, preferably methyl, ethyl, n-propyl, isopropyl, butyl, or isobutyl.

[0071] As used herein, "C1-C6alkoxy" refers to straight-chained or branched alkoxy groups containing 1 to 6 carbon atoms, "C1-C4alkoxy", "C1-C3alkoxy", and the like, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, isohexoxy, 3-methylpentoxy, or n-hexoxy, and the like, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or isobutoxy.

[0072] As used herein, "C1-C30alkanoyl" refers to straight-chained or branched alkanoyl groups of 1 to 30 carbon atoms, "C1-C6alkanoyl", "C1-C3alkanoyl", and the like, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, and the like, preferably formyl, acetyl, propionyl.

[0073] As used herein, "3-10 membered non-aromatic heterocyclic acyl" refers to a functional group containing an amide group in a 3-10 membered non-aromatic ring, for example, and the like.

[0074] As used herein, "halo C1-C6alkoxy" refers to straight-chained or branched alkoxy groups containing 1 to 6 carbon atoms, in which the hydrogen atoms are replaced by one or more halogen atoms which are the same or different, "halo C1-C3alkoxy", and the like, for example, -OCF3, -OCH2CH2Cl, -OCHBrCH2Cl, or -OCF2CF3, and the like.

[0075] As used herein, "C2-C10alkenyl" refers to straight-chained or branched unsaturated hydrocarbon groups containing 1 to 3 double bonds and 2 to 10 carbon atoms, both cis and trans configurations, C2-C6alkenyl, and the like, for example, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl.

[0076] As used herein, "C2-C10alkynyl" refers to a straight chain or branched chain unsaturated hydrocarbon group containing one to three triple bonds and two to ten carbon atoms, "C2-C6alkynyl" and the like are used in like fashion, examples of which are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, or 2-hexynyl, and the like.

[0077] As used herein, "C5-C6cycloalkenyl" refers to a C5-C6ring containing one alkene. For example, cyclopentenyl, cyclohexenyl, and the like.

[0078] As used herein, "C3-C10cycloalkyl" refers to a saturated ring hydrocarbon group containing three to ten carbon atoms, "C3-C6cycloalkyl" and the like are used in like fashion, examples of which are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.

[0079] As used herein, "C6-C10aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) aromatic ring containing six to ten carbon atoms and containing no heteroatoms, for example, phenyl, naphthyl, and the like.

[0080] As used herein, "C6-C10arylC1-C3alkyl" refers to an aryl group containing six to ten carbon atoms linked to a straight chain or branched chain alkyl group containing one to three carbon atoms, for example, benzyl, p-methoxybenzyl, and the like.

[0081] As used herein, "C1-C30alkoxycarbonyl" refers to a straight chain or branched chain alkoxy group containing one to thirty carbon atoms and a carbonyl group (-0-C=0-) attached thereto, "C1-C6alkoxycarbonyl", "C1-C3alkoxycarbonyl", and the like are used in like fashion, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, and the like.

[0082] As used herein, "C3-C6cycloalkoxycarbonyl" refers to a C3-C6cycloalkyl group attached to -0-(C=0)-, "C3-C6cycloalkyloxycarbonyl" and the like are used in like fashion, for example, cyclopropyloxymethylcarbonyl, cyclobutyloxymethylcarbonyl, cyclohexyloxymethylcarbonyl, and the like.

[0083] As used herein, "C3-C10cycloalkylacyl" refers to a C3-C10cycloalkyl group attached to acyl-(C=0)-, "C3-C6cycloalkylacyl" and the like are used in like fashion, for example, cyclopropylformyl, cyclobutylformyl, cyclohexylformyl, and the like.

[0084] As used herein, "heterocycloalkyl" refers to a saturated monocyclic or polycyclic group containing at least one heteroatom selected from N, O, and S as a ring member, 3-8 membered heterocycloalkyl includes azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, and the like.

[0085] As used herein, "5-10 membered arylacyl" refers to a C5-C10 aryl ring attached to an acyl group -(C=0)-, "C5-C10 arylacyl" is used analogously, e.g. benzoyl, naphthoyl, and the like.

[0086] As used herein, "5-10 membered heteroarylacyl" refers to a 5-10 membered heteroaryl ring attached to an acyl group -(C=0)-, "5-10 membered heteroarylacyl" is used analogously, e.g. furanoyl, thiophenoyl, thiazoyl, oxazoyl, pyridoyl, pyrimidoyl, and the like.

[0087] As used herein, "C1-C6 alkylthio" refers to C1-C6 alkyl attached to -S-, "C3-C6 alkylthio" is used analogously, e.g. methylthio, ethylthio, propylthio, butylthio, hexylthio, and the like.

[0088] As used herein, "C3-C6 cycloalkylthio" refers to C3-C6 cycloalkyl attached to -S-, "C3-C6 cycloalkylthio" is used analogously, e.g. cyclopropylthio, cyclobutylthio, cyclohexylthio, and the like.

[0089] As used herein, "heterocyclyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic radical containing at least one heteroatom selected from N, O, and S as a ring member, 3-8 membered heterocyclyl includes oxetanyl, azetidinyl, thietanyl, oxetanyl, thietanyl, azetidinyl, oxepanyl, azepanyl, thiepanyl, and the like.

[0090] As used herein, "heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical containing at least one heteroatom selected from nitrogen, oxygen, or sulfur as a ring member; 5-10 membered heteroaryl includes, but is not limited to, the following groups: pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, quinolinyl, and the like.

[0091] As used herein, the term "group of an amino acid after removal of the hydroxyl group in the carboxyl group" refers to a group remaining after removal of the hydroxyl group in the carboxyl group attached to the same carbon atom as the amino group of an amino acid, for example, a group remaining after removal of the hydroxyl group in the carboxyl group of L-valine a group remaining after removal of the hydroxyl group in the carboxyl group of L-alanine a group remaining after removal of the hydroxyl group in the carboxyl group of L-phenylglycine and the like.

[0092] In this document, all formulations of features or conditions that are expressed in a range format are intended to include all possible sub-ranges and individual numerical values, specifically integer values, within that range, to the same extent as if each and every possible sub-range and individual numerical value were expressly stated. For example, a range of "0C to 30C" is intended to include all individual numerical values, such as 0C, 10C, 15C, 20C, 25C, 30C, etc. as well as sub-ranges, such as 0C to 10C, 5C to 15C, 10C to 20C, 20C to 30C, etc. unless otherwise indicated. The foregoing method of interpretation is intended to apply regardless of the specific terminology of description in the claims. For example, a term such as "between" should not be interpreted as requiring the presence of every number contained in the given range. For example, "between 10 and 30" should not be interpreted as requiring the presence of 11, 12, 13,..., 29, and 30.

[0093] If amounts or other numerical values or parameters are expressed in a range format, it is intended to include all possible sub-ranges, and individual numerical values, within that range, to the same extent as if each and every possible sub-range and individual numerical value were expressly stated. For example, a range of "0C to 30C" is intended to include all individual numerical values, such as 0C, 10C, 15C, 20C, 25C, 30C, etc. as well as sub-ranges, such as 0C to 10C, 5C to 15C, 10C to 20C, 20C to 30C, etc. unless otherwise indicated. Furthermore, all references to ranges of "values" are to be interpreted as the inclusion of all values within that range, unless otherwise indicated.

[0094] Each target compound obtained from each reaction formula can be isolated and purified from the reaction mixture by, for example, the following methods: the reaction mixture is separated into a crude product by a method such as filtration, extraction, or concentration after cooling, and then purified by a conventional method such as column chromatography, trituration, or recrystallization.

[0095] According to a third aspect of the present application, there is also provided a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the above-mentioned morphinan compounds, isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopically-labeled forms thereof, and optionally a pharmaceutically acceptable carrier.

[0096] According to a fourth aspect of the present application, there is also provided a method of preparing a pharmaceutical composition, comprising mixing one or more selected from the above-mentioned morphinan compounds, isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopically-labeled forms thereof, and optionally a pharmaceutically acceptable carrier.

[0097] In the pharmaceutical composition of the present application, various pharmaceutical preparation forms can be selected according to the purpose of treatment, including but 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.

[0098] According to a fifth aspect of the present application, there is also provided use of the above-mentioned morphinan compounds, isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopically-labeled forms thereof, in the manufacture of a medicament for preventing and / or treating a central nervous system disease.

[0099] According to one embodiment of the present application, the morphinan compound is selected from one or more of the following compounds: A-1, A-2, A-63, A-120, A-121, A-123, A-130, A-131, A-153, A-154, A-156, A-158, A-163, A-168, A-173, A-174, A-176 to A-424.

[0100] According to a sixth aspect of the present application, there is also provided a method for treating and / or preventing a central nervous system disorder, which method comprises administering to a human or animal one or more of the above-mentioned morphinan compounds, isomers, racemates, pharmaceutically acceptable salts, solvates, or isotopically-labeled forms thereof.

[0101] The above-mentioned central nervous system disorder is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; affective disorder; psychiatric disorder; mood disorder; bipolar I disorder; bipolar II disorder; depression; endogenous depression; major depression; refractory depression; depression with risk of suicide; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; social phobia; obsessive-compulsive disorder; impulse control disorder; post-traumatic stress disorder; anxiety disorder; depression-related anxiety; acute stress disorder; hysteria; anorexia nervosa; sleep disorder; adjustment disorder; cognitive disorder; obsessive-compulsive disorder; autism; neuralgia; fibromyalgia; trigeminal neuralgia; mania; Parkinson's disease; Huntington's disease; Alzheimer's disease; Alzheimer's disease-related depression or agitation; various dementias; agitation or anxiety associated with various dementias; memory disorder; hyperactivity; attention deficit / hyperactivity disorder and Tourette's syndrome; stroke; pseudobulbar palsy; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; brain injury; disorders of consciousness; tardive dyskinesia; diabetic neuropathy; diseases or disorders caused by homocysteine-induced apoptosis; diseases or disorders caused by high levels of homocysteine; chronic pain; intractable pain; sympathetically-mediated pain; oral pain; back pain; central pain syndrome; complex regional pain syndrome; epileptic seizure; epileptic hemiplegia; acquired epileptic aphasia (Landau-Kleffner syndrome); severe myoclonic epilepsy in infancy (SMEI); early infantile epileptic encephalopathy; post-stroke epilepsy; febrile seizures; post-traumatic epilepsy; tinnitus; cough; intractable cough; addiction; Rett syndrome (RTT); speech disorders caused by uncontrolled laryngeal muscle spasms; methotrexate neurotoxicity; myasthenia; alcohol-related disorders.

[0102] Preferably, the central nervous system disease is selected from schizophrenia; refractory, treatment-resistant or chronic schizophrenia; depression; endogenous depression; major depression; refractory depression; depression with risk of suicide; anxiety; depression-related anxiety; dysthymic disorder; Parkinson's disease; Alzheimer's disease; Alzheimer's disease-related depression or agitation; various dementias; pseudobulbar palsy; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; chronic pain; intractable pain; sympathetically-mediated pain; oral pain; back pain; central pain syndrome; complex regional pain syndrome; cough; intractable cough. Beneficial effects

[0103] 1) The compound of the present application not only has good antagonistic effect on NMDA receptor, but also has good inhibitory effect on 5-HT transporter, and can be used for treating various central nervous system diseases.

[0104] 2) The compound of the present application has good agonistic effect on sigma 1 receptor, and can be used for treating various central nervous system diseases.

[0105] 3) The compound of the present application not only has strong activity, but also has good metabolic stability, and is orally effective (high bioavailability), has low pharmacodynamic dose, small toxic side effects, etc., and has curative effect on diseases in the field of central nervous system, especially good curative effect on diseases such as depression, major depressive disorder (MDD), anxiety, negative symptoms of schizophrenia, cognitive dysfunction, Parkinson's disease, hyperactivity, pain, pseudobulbar affect, cough, etc.

[0106] 3) The present application has high oral bioavailability, and some compounds can be metabolized in mice to have good antagonistic effect on NMDA receptor, and good inhibitory effect on 5-HT transporter.

[0107] In summary, compared with the compounds disclosed in the prior art, the compound of the present application has the advantages of multi-target effect, lower pharmacodynamic dose, fewer toxic side effects, better safety and tolerability, etc., and has good comprehensive drug properties, and has good clinical application prospect. DETAILED DESCRIPTION

[0108] The following preparation examples, examples and pharmacological activity test examples further illustrate the present application, but do not limit the scope of the present application.

[0109] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples and experimental examples are conventional raw materials, reagents, methods in the art.

[0110] The abbreviations used in the present application include:

[0111] 2,2'-diphenylphosphino-1,1 '-binaphthyl (BINAP); tri-tert-butylphosphine (P(t-Bu)3); 1,1 '-bis-(diphenylphosphino)ferrocene (dppf); 2-dicyclohexylphospho-2,4,6- triisopropylbiphenyl (x-phos); 4,5-bis-diphenylphosphino-9,9-dimethylxanthene (Xantphos); tri-tert-butylphosphine tetrafluoroborate and tris(2-methylphenyl)phosphine (P(o-tolyl)3);

[0112] dichloromethane (DCM); tert-butyloxycarbonyl (Boc); triflate (Tf); dimethylformamide (DMF); tris(dibenzylideneacetone)dipalladium (Pd2(dba)3); N,N-diisopropylethylamine (DIPEA); N,N'-carbonyldiimidazole (CDI);

[0113] Preparation Example

[0114] Example 1 : Preparation of compound A-1

[0115] (1) Synthesis of compound A-1-1

[0116] To A-1-0 (1 g, 1.0 eq.) was dissolved in toluene (10 mL), chloroformic acid-2,2,2- trichloroethyl ester (859 mg, 1.1 eq.) was added, and stirring was performed at 100°C for 2 hours. TLC monitoring showed that a small amount of starting material remained, the reaction solution was cooled to room temperature, and ice bath cooling was performed. Quenching was performed with saturated aqueous sodium bicarbonate solution to adjust to basicity, and extraction was performed once with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain 1.6 g of a light yellow oil.

[0117] (2) Synthesis of compound A-1-2

[0118] To A-1-1 (1.6 g, 1 eq.) was dissolved in DCM (10 mL), and nitrogen protection was performed. Ice bath cooling was performed, and boron tribromide (1 M, 18 mL, 5 eq.) was added dropwise. After dropwise addition was completed, stirring was performed at room temperature for 3 hours. TLC monitoring showed that the starting material had been completely reacted, and quenching was performed by pouring into ice water. Saturated aqueous sodium bicarbonate solution was used to adjust to basicity, and extraction was performed three times with 50 mL of dichloromethane. The combined organic phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain 1.4 g of a white solid crude product.

[0119] (3) Synthesis of compound A-1-3

[0120] A-1-2 (500 mg, 1.0 eq.) was dissolved in CH3COOH / H2O = 10:1 (2 mL), zinc powder (235 mg, 3.0 eq.) was added, and stirring was carried out at 90°C for 3 h. LC-MS monitoring showed that the raw material had been completely reacted. The reaction solution was cooled to room temperature, filtered, the filtrate was adjusted to a solution pH of about 8 with 1M aqueous sodium hydroxide solution, extracted with DCM / CH3OH = 3:1 (containing 1% NH3.H2O) for multiple times, the organic phases were combined, dried and concentrated under reduced pressure to obtain 300 mg of the crude product.

[0121] (4) Synthesis of compound A-1-4

[0122] A-1-3 (300 mg, 1.0 eq.) was dissolved in DCM (5 mL), cooled in an ice bath, triethylamine (374 mg, 3.0 eq.) was added, and Boc2O (323 mg, 1.2 eq.) was added dropwise. After the dropwise addition was completed, stirring was carried out at room temperature for 2 h. TLC monitoring showed that the raw material had been completely reacted. The reaction solution was quenched with ice water, extracted with 30 mL of dichloromethane for 3 times, the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure to obtain 330 mg of a yellowish oil.

[0123] (5) Synthesis of compound A-1-5

[0124] A-1-4 (330 mg, 1.0 eq.) was dissolved in DCM (5 mL), cooled in an ice bath, triethylamine (194 mg, 2.0 eq.) was added, and a solution of Tf2O (325 mg, 1.2 eq.) in DCM (0.6 mL) was added dropwise. After the dropwise addition was completed, stirring was carried out at room temperature for 2 h. TLC monitoring showed that the raw material had been completely reacted. The reaction solution was quenched with ice water, extracted with 30 mL of dichloromethane for 3 times, the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure, and column chromatography purification was carried out to obtain 140 mg of a yellowish oil.

[0125] (6) Synthesis of compound A-1-6

[0126] A-1-5 (140 mg, 1.0 eq.) and Zn(CN)2 (69 mg, 2.0 eq.) were dissolved in anhydrous DMF (3 mL), replaced with nitrogen for 3 times, and stirred at room temperature for 10 min. Pd2(dba)3 (27 mg, 0.1 eq.) and dppf (33 mg, 0.2 eq.) were added under nitrogen protection, and stirring was carried out at 80°C for 4 h. TLC monitoring showed that the raw material had been completely reacted. The reaction solution was cooled to room temperature, water was added, extracted with 30 mL of ethyl acetate for 3 times, the organic phases were combined, washed with saturated brine, dried and concentrated under reduced pressure, and column chromatography purification was carried out to obtain 45 mg of a yellowish oil.

[0127] (7) Synthesis of compound A-1

[0128] To a solution of A-1-6 (45 mg, 1.0 eq.) in DCM (1.5 mL) was added a solution of HC1-EtOH (30%, 0.5 mL.) and stirred at room temperature for 1 h. TLC monitoring showed that the starting material was consumed completely. The reaction mixture was adjusted to basic with saturated aqueous NaHC03solution and extracted with DCM (3 x 30 mL). The combined organic phase was dried and concentrated under reduced pressure. The product was obtained as a white solid (25 mg) after purification by preparative TLC.

[0129] 1 H NMR (400 MHz, CDC13) δ 7.60 (d, J = 1.6 Hz, 1H), 7.50 (dd, J = 7.9, 1.6 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 3.72 (t, J = 4.2 Hz, 1H), 3.37 - 3.14 (m, 2H), 3.16 (dd, J = 13.4, 4.4 Hz, 1H), 2.66 - 2.58 (m, 1H), 2.39 (d, J = 14.0 Hz, 1H), 2.23 - 2.18 (m, 1H), 2.09 - 2.01 (m, 1H), 1.71 - 1.39 (m, 6H), 1.33 - 1.13 (m, 1H), 1.01 - 0.91 (m, 1H). LCMS-ESI (m / z): 253.23 [M+H] + .

[0130] Example 2: Preparation of compound A-2

[0131] (1) Synthesis of compound A-2-1:

[0132] A-1-0 (3.0 g, 8.52 mmol, 1.0 eq.) was placed in a 100 mL flask, 20 ml 48% aqueous hydrobromic acid solution was added, and the reaction was stirred at reflux for 24 h. TLC monitoring showed that the starting material was completely consumed. The pH was adjusted to 10 by adding potassium carbonate at 0 °C, and the reaction mixture was extracted with DCM (3 x 30 mL). The combined organic phase was concentrated under reduced pressure to give the crude product (2.4 g), which was used directly in the next step without further purification.

[0133] (2) Synthesis of compound A-2-2:

[0134] A-2-1 (2.4 g, 1.0 eq.) was dissolved in DCM, triethylamine (2 ml, 1.54 eq.) was added, and PhNTf2 (4 g, 1.2 eq.) was added. The reaction was stirred at room temperature for 12 h. TLC monitoring showed that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and column chromatography was used to separate the product to give a yellow oil (1.38 g).

[0135] (3) Synthesis of compound A-2-3:

[0136] A-2-2 (0.8 g, 1.0 eq.), palladium acetate (58 mg, 0.25 eq.), xantphos (296 mg, 0.5 eq.), 0.4 M ammonia-1,4 dioxane solution (5.2 ml, 2 eq.) were dissolved in 1,4-dioxane, and the reaction was stirred in a pressure kettle under a CO atmosphere of 10 atm at 100 °C for 12 h. After cooling to room temperature, the pressure was slowly reduced to standard atmospheric pressure, and the reaction mixture was filtered with diatomite. The filtrate was concentrated under reduced pressure and separated by column chromatography to obtain compound A-2-3 (69 mg, white solid).

[0137] (4) Synthesis of compound A-2:

[0138] A-2-3 (59 mg, 1.0 eq.) was dissolved in 4 ml of phosphorus oxychloride, and the reaction was stirred at 100 °C for 4 h. TLC monitoring showed that the starting material was completely reacted. The reaction mixture was concentrated under reduced pressure, diluted with water, and adjusted to pH = 7 with 10% aqueous KOH solution at 0 °C. The organic phase was extracted with EA three times, combined, and concentrated under reduced pressure. Purification by column chromatography gave A-2 (16 mg, colorless oil).

[0139] 1 H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 3.24 (d, J = 19.9 Hz, 2H), 2.94 (d, J = 20.1 Hz, 1H), 2.74 (s, 1H), 2.57-2.53 (m, 3H), 2.18-2.05 (m, 2H), 1.90-1.84 (m, 1H), 1.61-1.23 (m, 7H), 1.07-0.99 (m, 1H), 0.90-0.83 (m, 1H). LCMS-ESI (m / z): 267.23 [M+H] +

[0140] Example 3: Compound A-8

[0141] (1) Synthesis of compound A-8-1:

[0142] Compound A-8-0 (776.8 mg, 1.0 eq.), chloroform 10 ml, potassium carbonate (800 mg, 2.0 eq.), DIPEA (1.48 g, 4.0 eq.), ethyl chloroformate (1.23 g, 4.0 eq.) were replaced with nitrogen for 3 times, and the reaction was carried out at 65 °C for 7 h. TLC detection showed that there was a small amount of starting material remaining. The temperature was reduced to about 0 °C in an ice bath, 1 M hydrochloric acid was added for quenching, and then sodium bicarbonate solution was washed once. The combined organic phase was dried, concentrated, and purified by column chromatography to obtain 505 mg of colorless liquid.

[0143] (2) Synthesis of compound A-8-2:

[0144] Compound A-8-1 (505 mg, 1.0 eq) was dissolved in 5 ml of dichloromethane, replaced with nitrogen for 3 times, and tri bromide boron dichloride solution (3 ml, 2.5 M) was added dropwise at 0 °C. After reaction at 0 °C for 0.5 h, TLC detection showed that the raw material was completely reacted. The ice bath was cooled to about 0 °C, water was added for quenching, ammonia was added for adjusting pH to 8, dichloromethane was added for extraction, the combined organic phase was dried, and concentrated to obtain 450 mg of white solid.

[0145] (3) Synthesis of compound A-8-3:

[0146] Compound A-8-2 (450 mg, 1.0 eq) was dissolved in 5 ml of dichloromethane, pyridine (226 mg, 2.0 eq) was added, replaced with nitrogen for 3 times, and trifluoromethanesulfonic anhydride (483 mg, 1.2 eq) and dichloromethane were mixed to form a solution, which was added dropwise at 0 °C. After the reaction at room temperature for 3.5 h, TLC detection showed that there was a small amount of raw material left. The ice bath was cooled to about 0 °C, water and 1 M hydrochloric acid were added for quenching, saturated brine was washed, dichloromethane was added for extraction, the combined organic phase was dried, and column chromatography was used for purification to obtain 430 mg of colorless liquid.

[0147] (4) Synthesis of compound A-8:

[0148] Compound A-8-3 (220 mg, 1.0 eq) was dissolved in 5 ml of anhydrous N,N- dimethylformamide, zinc cyanide (115 mg, 2.0 eq) was added, replaced with nitrogen for 3 times, and pd2(dba)3 (45 mg, 10 %), dppf (80 mg, 10 %) were added after reaction at room temperature for 0.5 h. After reaction at 85 °C for 3.5 h, TLC detection showed that the raw material was completely reacted. The ice bath was cooled to about 0 °C, water was added for quenching, ethyl acetate was added for extraction, the combined organic phase was dried, and column chromatography was used for purification to obtain 73 mg of colorless viscous substance.

[0149] 1 H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 1.6 Hz, 1H), 7.43 (dd, J = 7.9, 1.6 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 4.46-4.31 (m, 1H), 4.18-4.10 (m, 2H), 3.97-3.83 (m, 1H), 3.19 (dd, J = 19.5, 5.7 Hz, 1H), 2.77 (dd, J = 19.1, 5.3 Hz, 1H), 2.57-2.48 (m, 1H), 2.38 (d, J = 14.1 Hz, 1H), 1.78-1.52 (m, 5H), 1.44-1.15 (m, 7H), 1.01-0.89 (m, 1H). LCMS-ESI (m / z): 325.1 [M+H] + .

[0150] Example 4: Preparation of compounds A-53 and A-51

[0151] (1) Synthesis of A-53

[0152] Dissolve 100 mg (1.0 eq.) of A-8 in 2 mL of DMF, add 40 mg (2.0 eq.) of sodium azide and 33 mg (2.0 eq.) of ammonium chloride, and stir at 110 °C for 16 hours. TLC monitoring showed that a small amount of raw material residue remained. Cool the reaction solution to room temperature, cool in an ice bath, adjust the pH to about 10 with 1 M sodium hydroxide aqueous solution, and extract with 30 mL of ethyl acetate*3. Adjust the pH of the aqueous phase to about 2 with 1 M hydrochloric acid aqueous solution, and extract with 30 mL of ethyl acetate*3. Combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 82 mg of pale yellow solid.

[0153] 1 H NMR (400MHz, CDCl3) δ8.11(d,J=6.6Hz,1H),7.90(d,J=7.9Hz,1H),7.26–7.20( m,1H),4.40(d,J=38.6Hz,1H),4.29–4.13(m,2H),3.95–3.82(m,1H),3.26-3.1 5(m,1H),2.78(d,J=18.8Hz,1H),2.68–2.46(m,2H),1.82–1.70(m,1H),1.69–1 .58(m,2H),1.57–1.16(m,9H),1.08–0.96(m,1H).LCMS-ESI(m / z):368.3[M+H] + .

[0154] (2) Synthesis of A-51

[0155] Dissolve A-53 (55 mg, 1 eq.) in a hydrobromic acid-acetic acid solution (33% acetic acid, 2 mL) and stir at 80 °C for 5 hours. TLC monitoring showed that the starting material had basically reacted, and a solid was formed in the reaction solution. After cooling to room temperature, filter the solution, wash the solid with ethyl acetate, collect the solid, concentrate it to dryness, and obtain light A-51 hydrobromide (8.7 mg, yellow solid).

[0156] 1H NMR (400 MHz, DMSO-d6) δ 8.95 - 8.70 (m, 2H), 8.03 (d, J = 1.7 Hz, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 4.8 Hz, 1H), 3.33 - 3.27 (m, 1H), 3.11 - 3.05 (m, 2H), 2.57 - 2.41 (m, 2H), 1.99 - 1.94 (m, 1H), 1.85 - 1.77 (m, 1H), 1.65 - 1.31 (m, 6H), 1.19 - 1.09 (m, 1H), 0.96 - 0.85 (m, 1H). LCMS-ESI (m / z): 296.2 [M+H] + .

[0157] Example 5: Preparation of compound A-55

[0158] (1) Synthesis of A-55-1

[0159] Compound A-1-5 (320 mg, 1.0 eq) was dissolved in 3 ml of dioxane, potassium phosphate (300 mg, 2.0 eq) was added, replaced with nitrogen for 3 times, then Pd2(dba)3 (80 mg, 0.2 eq) and t-Buphos (68 mg, 0.2 eq) were added, replaced with nitrogen for 3 times, and the reaction was carried out at 80 °C after warming. TLC was used to detect the disappearance of the raw material, and then the temperature was lowered to room temperature. 10 ml of water was added, and 10 ml of ethyl acetate was extracted for 3 times. The organic phase was combined, dried, concentrated, and purified by column chromatography to obtain 80 mg of oil;

[0160] (2) Synthesis of A-55

[0161] Compound A-55-1 (80 mg, 1.0 eq) was dissolved in 2 ml of dichloromethane, 2 ml of hydrochloric acid ethanol solution was added, and the reaction was carried out at room temperature. TLC was used to detect the disappearance of the raw material, 15 ml of saturated sodium bicarbonate aqueous solution was added to adjust the pH value to about 8, 5 ml of dichloromethane was continuously added, and the organic phase was stirred and separated. The organic phase was dried, concentrated, and purified by column chromatography to obtain 5 mg of oil. 1 ml of hydrogen chloride ethanol solution was added, and A-55 hydrochloride (5 mg, white solid) was obtained after concentration.

[0162] 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.73 (s, 2H), 8.22 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.71 (dd, J = 8.3, 2.2 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 3.73 (s, 1H), 3.29 - 3.23 (m, 1H), 3.10 (d, J = 13.3 Hz, 1H), 3.01 (d, J = 19.5 Hz, 1H), 2.58 - 2.43 (m, 2H), 1.92 (d, J = 12.7 Hz, 1H), 1.79 - 1.74 (m, 1H), 1.64 - 1.47 (m, 4H), 1.39 - 1.33 (m, 2H), 1.15-1.12 (m, 1H), 0.97 - 0.87 (m, 1H). LCMS-ESI (m / z): 295.18 [M+H] + .

[0163] Example 6: Preparation of compound A-58

[0164] Take A-8-3 (90 mg, 1.0 eq), 1,2,4-triazole (16 mg, 1.2 eq), Pd2(dba)3 (11.5 mg, 0.1 eq), t-Buphos (10 mg. 0.1 eq), potassium phosphate (63 mg, 1.5 eq) 1,4-dioxane as solvent, nitrogen protection, 90 °C reaction for 5 h. Post-processing: the reaction solution is poured into water to quench, ethyl acetate is added to extract, the organic phase is dried, concentrated, and purified by thin layer plate to obtain 10 mg of compound A-58.

[0165] 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.21 (s, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.64 (dd, J = 8.3, 2.2 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.29 - 4.20 (m, 1H), 4.05 (s, 2H), 3.77 (s, 1H), 3.15 (dd, J = 18.5, 5.9 Hz, 1H), 2.70 (d, J = 18.7 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.50 - 2.42 (m, 1H), 1.71 - 1.48 (m 5H), 1.40 - 1.30 (m, 3H), 1.26 - 1.13 (m, 4H), 0.99 - 0.92 (m, 1H). LCMS-ESI (m / z): 367.26 [M+H] + .

[0166] Example 7: Preparation of compound A-60

[0167] Compound A-66-2 (150 mg, 0.50 mmol, 1.0 eq.) was dissolved in ethanol (5 mL), and added with trimethyl orthoformate (261 mg, 1.76 mmol, 3.5 eq.) and one drop of formic acid as catalyst. The reaction was refluxed overnight, and TLC was used to monitor the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and then the residue was dissolved in ethyl acetate and washed with 10% sodium hydroxide aqueous solution. The organic phase was dried and concentrated, and then purified by column chromatography to obtain the product A-60 (120 mg, white solid).

[0168] 1 H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 3.22 (d, J = 18.1 Hz, 1H), 2.98-2, 83 (m, 2H), 2.53-2.41 (m, 5H), 2.15-2.05 (m, 1H), 1.97 (d, J = 12.6 Hz, 1H), 1.91-1.84 (m, 1H), 1.69-1.62 (m, 1H), 1.57 (d, J = 12.9 Hz, 1H), 1.50-1.26 (m, 5H), 1.17-1.07 (m, 1H). LCMS-ESI (m / z): 283.1 [M+H] + .

[0169] Example 8: Preparation of compound A-62

[0170] Compound A-64-2 (60 mg, 1.0 eq.) was dissolved in ethanol (5 mL), and added with trimethyl orthoformate (104 mg, 3.5 eq.) and one drop of formic acid as catalyst. The reaction was refluxed overnight, and TLC was used to monitor the reaction. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, and then the residue was dissolved in ethyl acetate and washed with 10% sodium hydroxide aqueous solution. The organic phase was dried and concentrated, and then purified by column chromatography to obtain the product 44 mg, light yellow solid.

[0171] 1H NMR (400 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.84 (dq, J = 13.4, 2.8 Hz, 1H), 3.16 - 3.06 (m, 2H), 2.98 - 2.91 (m, 1H), 2.65 (d, J = 12.1 Hz, 1H), 2.54 (s, 3H), 2.19 - 2.13 (m, 1H), 2.05 - 1.90 (m, 2H), 1.75 - 1.71 (m, 1H), 1.65 - 1.58 (m, 2H), 1.52 - 1.33 (m, 3H), 1.24 - 1.13 (m, 1H), 1.09 - 0.97 (m, 1H). LCMS-ESI (m / z): 283.1 [M+H] + .

[0172] Example 9: Preparation of compound A-63

[0173] Compound A-66-2 (200 mg, 0.67 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and CDI (130 mg, 0.80 mmol, 1.2 eq.) was added. The reaction was refluxed overnight, and TLC monitoring showed that the starting material was substantially reacted. The reaction was extracted with water / ethyl acetate, and the organic phase was washed with saturated ammonium chloride aqueous solution, saturated sodium chloride aqueous solution, and dried and concentrated to obtain a gray-white powder solid. The obtained solid had poor solubility in dichloromethane, and after being slurried in dichloromethane, 70 mg of a gray-white powder solid was obtained.

[0174] 1 H NMR (400 MHz, Chloroform-d) δ 7.10 (s, 1H), 6.80 (s, 1H), 3.05 (d, J = 18.3 Hz, 1H), 2.90 (s, 1H), 2.75 (s, 1H),, 2.53 (s, 1H), 2.45 (s, 3H), 2.32 (d, J = 14.0 Hz, 1H), 2.16 - 2.05 (m, 1H), 1.93 (s, 1H), 1.84 (s, 1H), 1.66 (d, J = 12.5 Hz, 1H), 1.54 (s, 1H), 1.43 (d, J = 14.6 Hz, 2H), 1.39 - 1.30 (m, 2H), 1.28 - 1.19 (m, 1H), 1.17 - 1.03 (m, 1H). LCMS-ESI (m / z): 299.4 [M+H] + .

[0175] Example 10: Preparation of compound A-64

[0176] (1) Preparation of compound A-64-1

[0177] Compound A-2-1 (500 mg, 1.68 mmol, 1.0 eq.) was dissolved in acetic acid (5 mL), 65% nitric acid (166 mg, 1.85 mmol, 1.1 eq.) was dissolved in acetic acid (1 mL) at 25 °C, and the solution was added dropwise to the reaction solution slowly. After 3 h of reaction at room temperature, TLC showed that the starting material was almost completely reacted. Work-up: the reaction solution was poured into saturated ammonium chloride solution under ice bath conditions, and extracted with ethyl acetate three times. The organic phase was combined, dried and concentrated, and then purified by column chromatography to obtain A-64-1 (210 mg, light yellow viscous solid).

[0178] (2) Preparation of compound A-64-2

[0179] Compound A-64-1 (300 mg, 1.0 eq.) was dissolved in methanol (20 mL), and Pd / C (30 mg) was added. After five times of H2replacement, the reaction was carried out at room temperature overnight. TLC showed that the reaction was complete. Work-up: the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and the product was obtained by column chromatography purification, 130 mg, yellow solid

[0180] (3) Synthesis of compound A-64

[0181] Compound VV14963-3A (70 mg, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and CDI (45.5 mg, 1.2 eq.) was added. The reaction was carried out at reflux overnight. TLC showed that the starting material was almost completely reacted. Work-up: the reaction solution was extracted with water / ethyl acetate, and the organic phase was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, respectively. After drying and concentration, column chromatography purification obtained 33 mg of light yellow oil.

[0182] 1 H NMR (400 MHz, Chloroform-d) δ 7.04 (d, J = 8.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 3.07 (d, J = 19.0 Hz, 1H), 3.01 (s, 1H), 2.86 (s, 1H), 2.66 (s, 1H), 2.51 (s, 3H), 2.21 (d, J = 14.6 Hz, 1H), 1.94 (s, 2H), 1.70 (d, J = 12.8 Hz, 2H), 1.61 (d, J = 15.2 Hz, 1H), 1.57 - 1.48 (m, 2H), 1.48 - 1.39 (m, 1H), 1.28 - 1.21 (m, 1H), 1.20 - 1.12 (m, 2H). LCMS-ESI (m / z): 299.4 [M+H] + .

[0183] Example 11: Preparation of compound A-65

[0184] Compound A-66-1 (64 mg, 1.5 mmol, 1.0 eq.) was dissolved in methanol (2 mL), Pd / C (16 mg) was added, and the reaction was replaced with H2for five times. After the reaction was completed by TLC monitoring at room temperature overnight, the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and column chromatography was used for purification to obtain the product A-66-2 (48 mg, light brown foamy solid).

[0185] 1 H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.09 (s, 1H), 5.18 (s, 2H), 3.10 (d, J = 18.1 Hz, 1H), 2.90-2.82 (m, 1H), 2.74 (dd, J = 17.9, 6.0 Hz, 1H), 2.49-2.43 (m, 4H), 2.35 (d, J = 13.8 Hz, 1H), 2.12-2.06 (m, 1H), 1.88 (d, J = 12.8 Hz, 1H), 1.82-1.75 (m, 1H), 1.64 (d, J = 12.6 Hz, 1H), 1.53 (d, J = 10.5 Hz, 1H), 1.41-1.28 (m, 5H), 1.19-1.10 (m, 1H). LCMS-ESI (m / z): 298.2 [M+H] + .

[0186] Example 12: Preparation of compound A-66

[0187] (1) Preparation of compound A-66-1

[0188] Compound A-2-1 (100 mg, 0.388 mmol, 1.0 eq.) was dissolved in dichloromethane (10 mL), 65% nitric acid (1 mL) was dissolved in acetic acid (1 mL) at 0°C, and the reaction solution was slowly dropped. After the reaction was completed by TLC monitoring at room temperature for 4 h, the post-processing was performed by adjusting the pH to neutral with 15% sodium hydroxide solution and extracting with dichloromethane three times. The combined organic phase was dried and concentrated, and column chromatography was used for purification to obtain the product A-66-1 (120 mg, yellow solid).

[0189] (2) Preparation of compound A-66-2

[0190] Compound A-66-1 (64 mg, 1.5 mmol, 1.0 eq.) was dissolved in methanol (2 mL), Pd / C (16 mg) was added, and the reaction was replaced with H2for five times. After the reaction was completed by TLC monitoring at room temperature overnight, the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and column chromatography was used for purification to obtain the product A-66-2 (48 mg, light brown foamy solid).

[0191] (3) Preparation of compound A-66

[0192] A-66-2 (0.13 g, 0.477 mmol, 1.0 eq.) was dissolved in dichloromethane, triethylamine (0.145 g, 1.43 mmol, 3.0 eq.) was added dropwise, chloroacetyl chloride (56 mg, 0.496 mmol, 1.04 eq.) was slowly added dropwise at room temperature, and the reaction was monitored by TLC after 6 h of reaction at room temperature. The starting material was completely reacted, the solvent was removed by concentration under reduced pressure, 5 mL of acetonitrile was added thereto, potassium carbonate solid (0.19 g, 1.38 mmol, 3.0 eq.) was added, the reaction was stirred at reflux overnight, the next day the reaction was monitored by TLC, the starting material was completely reacted, the solvent was removed by concentration under reduced pressure, and A-66 (6 mg, light yellow solid) was obtained by purification using a preparative column.

[0193] 1 H NMR (400 MHz, Chloroform-d) δ 9.29 (s, 1H), 6.88 (s, 1H), 6.78 (s, 1H), 4.59 (d, J = 3.0 Hz, 2H), 3.44 (d, J = 3.5 Hz, 1H), 3.09-3.06 (m, 3H), 2.79 (s, 3H), 2.57 (s, 1H), 2.37-2.29 (m, 2H), 2.22-2.16 (m, 1H), 1.67 (d, J = 12.6 Hz, 1H), 1.58 (d, J = 12.2 Hz, 1H), 1.51-1.39 (m, 4H), 1.28-1.21 (m, 1H), 1.13-1.05 (m, 1H). LCMS-ESI (m / z): 313.5 [M+H] + .

[0194] Example 13: Preparation of compound A-117

[0195] A-2-1 (300 mg, 1.0 eq.) was dissolved in DMF (4 mL), cooled in an ice bath, and NaH (60%, 70 mg, 1.5 eq.) was added. After being reacted for 15 minutes in an ice bath, dimethylaminothiocarbonyl chloride (173 mg, 1.2 eq.) was added, and the reaction was stirred at 80°C for 5 hours. The starting material was completely reacted, the reaction solution was cooled to room temperature, quenched with ice water, extracted with 40 mL of ethyl acetate *3, the combined organic phase was washed with saturated brine, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 150 mg of a light yellow solid.

[0196] 1H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.3, 2.3 Hz, 1H), 3.50 - 3.48 (m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 3.25 - 3.04 (m, 3H), 2.81 (s, 3H), 2.68 - 2.47 (m, 2H), 2.35 (d, J = 13.5 Hz, 2H), 1.68 (d, J = 12.8 Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.55 - 1.45 (m, 3H), 1.45 - 1.29 (m, 2H), 1.14 (td, J = 12.6, 6.4 Hz, 1H).

[0197] Example 14: Preparation of compound A-120

[0198] A-2-2 (600 mg, 1.5 mmol, 1 eq.), 2-boronic acid pinacol ester furan (600 mg, 3 mmol, 2 eq.), Pd(dppf)Cl2(45 mg, 0.06 mmol, 0.04 eq.), K2CO3(425 mg, 3 mmol, 2 eq.) and 1,4-dioxane / H2O (10 ml / 2 mL) were added into a 50 mL single necked flask, then replaced by nitrogen and heated to 90 °C overnight. Treatment: after dilution with water, extracted by DCM, the organic phase was dried, filtered and concentrated to get the crude product, which was purified by column chromatography (DCM:MeOH = 100:2) to get 200 mg yellow oil

[0199] 1 H NMR (400 MHz, Chloroform-d) δ 7.20 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.3, 2.3 Hz, 1H), 3.50 - 3.48 (m, 1H), 3.46 (s, 3H), 3.35 (s, 3H), 3.25 - 3.04 (m, 3H), 2.81 (s, 3H), 2.68 - 2.47 (m, 2H), 2.35 (d, J = 13.5 Hz, 2H), 1.68 (d, J = 12.8 Hz, 1H), 1.59 (d, J = 12.9 Hz, 1H), 1.55 - 1.45 (m, 3H), 1.45 - 1.29 (m, 2H), 1.14 (td, J = 12.6, 6.4 Hz, 1H).

[0200] Example 15: Preparation of compounds A-176, A-177

[0201] To A-176-0 (1.0 g, 1 eq), 1,4-dioxane (5 mL), water (5 mL), sodium hydroxide (0.16 g, 1 eq), stirred at room temperature, dropwise added benzyl chloroformate (0.77 g, 1.1 eq), stirred at room temperature for 20 min, TLC detected reaction end; reaction liquid was added with water to quench, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, purified by column chromatography to obtain compound A-176-1 (0.95 g, colorless oil).

[0202] A-176-1 (0.95 g, 1 eq) was dissolved in 1,2-dichloroethane (10 mL), 1-fluoropyridine triflate (0.69 g, 1.1 eq) was added, stirred at reflux for 18 h, LC-MS detected; the reaction liquid was concentrated under reduced pressure, purified by column chromatography; to obtain a mixture of compounds A-176-2 and A-177-2 (0.47 g, white solid).

[0203] The mixture of compounds A-176-2 and A-177-2 (0.45 g, 1 eq) was dissolved in acetone (10 mL), added with powdered potassium carbonate (0.31 g, 2 eq), then added with iodomethane (0.24 g, 1.5 eq), stirred at room temperature overnight, TLC detected reaction end; filtered, concentrated under reduced pressure, purified by column chromatography to obtain a mixture of compounds A-176-3 and A-177-3 (0.40 g, colorless oil).

[0204] The mixture of compounds A-176-3 and A-177-3 (0.15 g, 1 eq) was dissolved in methanol (9 mL), added with 10% palladium-carbon (30 mg), stirred at room temperature for 2 h after hydrogen replacement; TLC detected reaction end; filtered, concentrated under reduced pressure to obtain a mixture of compounds A-176-4 and A-177-4, which was directly used in the next step reaction without purification.

[0205] The mixture of compounds A-176-4 and A-177-4 (0.18 g, 1 eq), 37% aqueous formaldehyde solution (1 mL, about 20 eq), THF (2 mL), were stirred at room temperature for 5 min in a reaction bottle, added with sodium triacetoxyborohydride (3 eq), stirred for 15 min, TLC detected reaction end; the reaction was quenched with dilute hydrochloric acid, the pH was adjusted to 8-9 with sodium carbonate solution, extracted with EA, concentrated under reduced pressure to obtain an oil, purified by HPLC to obtain A-176 (50 mg) and A-177 (20 mg) respectively.

[0206] Compound A-176:

[0207] 1H NMR (400 MHz, DMSO-d6) δ 6.95 - 6.90 (m, 2H), 3.78 (s, 3H), 2.88 (d, J = 18.4 Hz, 1H), 2.69 (t, J = 4.4 Hz, 1H), 2.45 - 2.39 (m, 1H), 2.33 - 2.29 (m, 1H), 2.25 (s, 3H), 1.94 - 1.87 (m, 1H), 1.70 (dt, J = 13.0, 3.2 Hz, 1H), 1.63 - 1.56 (m, 2H), 1.49 (d, J = 12.3 Hz, 1H), 1.37 - 1.09 (m, 6H), 1.04 - 0.94 (m, 1H). LCMS-ESI (m / z): 290.20 [M+H] + .

[0208] Compound A-177 trifluoroacetate salt

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.11 - 7.06 (m, 1H), 7.01 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.61 (s, 0.8H), 3.54 (s, 0.2H), 3.21 - 3.16 (m, 1.7H), 3.06 (d, J = 6.3 Hz, 0.6H), 3.02 - 2.97 (m, 1.3H), 2.82 - 2.67 (m, 3.7H), 2.47 - 2.41 (m, 0.7H), 2.16 (d, J = 12.1 Hz, 0.3H), 2.09 - 1.97 (m, 0.3H), 1.88 (dd, J = 9.5, 6.4 Hz, 0.7H), 1.81 - 1.18 (m, 7.7H), 1.13 - 0.96 (m, 2H). LCMS-ESI (m / z): 290.20 [M+H] + .

[0210] Example 16: Preparation of compound A-179

[0211] A-176-2 (0.45 g, 1 eq) was added to DMF (5 mL), 60% sodium hydride (0.1 g, 2 eq), and bromoethane (0.21 g, 1.5 eq) was added with stirring. After the addition was complete, the reaction was stirred at room temperature for about 2 h, and TLC detection showed that the reaction was complete. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. Purification by column chromatography gave compound A-179-1 (0.40 g, colorless oil).

[0212] Compound A-179-1 (0.3 g, 1 eq) was dissolved in THF (9 mL), and lithium aluminum hydride (0.08 g, 3 eq) was added at 0-5 °C. After the addition was completed, the reaction was stirred at reflux for 2 h. The reaction was cooled to 0-5 °C, quenched with water, and adjusted to basicity with sodium hydroxide solution. The mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the residue was purified by HPLC to give compound A-179 (50 mg, colorless oil).

[0213] 1 H NMR (400 MHz, DMSO-d6) δ 6.95 - 6.89 (m, 2H), 4.08 - 4.01 (m, 2H), 2.88 (d, J = 18.3 Hz, 1H), 2.68 (s, 1H), 2.47 - 2.42 (m, 1H), 2.38 (d, J = 13.0 Hz, 1H), 2.30 (d, J = 15.8 Hz, 1H), 2.24 (s, 3H), 1.90 (t, J = 10.7 Hz, 1H), 1.69 (d, J = 12.7 Hz, 1H), 1.62 - 1.56 (m, 2H), 1.48 (d, J = 13.4 Hz, 1H), 1.36 - 1.29 (m, 5H), 1.25 - 1.21 (m, 2H), 1.18 - 1.11 (m, 1H), 1.03 - 0.94 (m, 1H). LCMS-ESI (m / z): 304.20 [M+H] + .

[0214] Example 17: Preparation of compounds A-181, A-182, and A-183

[0215] A-1-0 (500 mg, 1.0 eq) and acetonitrile (5 mL) were added to a 50 mL three-necked flask, and N-chlorosuccinimide (280 mg, 1.2 eq) was slowly added while cooling in an ice bath. After the addition was completed, the mixture was stirred for 30 min, and p-toluenesulfonic acid (630 mg, 1.8 eq) was slowly added. After the addition was completed, the mixture was warmed to room temperature and reacted for 14 h. LC-MS detection was performed. Saturated sodium carbonate aqueous solution was added to the reaction mixture to adjust the pH to 7-8, and the mixture was extracted with ethyl acetate three times. The organic phase was dried, concentrated under reduced pressure, and purified by HPLC to give compound A-181 (65 mg, white solid), compound A-182 (50 mg, yellowish solid), and compound A-183 (20 mg, white solid).

[0216] Compound A-181:

[0217] 1H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.91 (s, 1H), 3.80 (s, 3H), 2.91 (d, J = 18.3 Hz, 1H), 2.72 - 2.67 (m, 1H), 2.46 - 2.41 (m, 2H), 2.34 - 2.31 (m, 1H), 2.26 (s, 3H), 1.94 - 1.87 (m, 1H), 1.74 - 1.69 (m, 1H), 1.65 - 1.58 (m, 2H), 1.52 - 1.48 (m, 1H), 1.38 - 1.23 (m, 4H), 1.19 - 1.12 (m, 1H), 1.03 - 0.93 (m, 1H). LCMS-ESI (m / z): 306.20 [M+H] + .

[0218] Compound A-182 hydrochloride:

[0219] 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 1H), 3.83 (s, 3H), 3.66 (d, J = 14.0 Hz, 1H), 3.58 - 3.49 (m, 1H), 3.14 (d, J = 3.6 Hz, 1H), 3.09 (d, J = 13.2 Hz, 1H), 2.94 (d, J = 5.1 Hz, 1H), 2.72 (d, J = 4.9 Hz, 3H), 2.46 - 2.36 (m, 1H), 2.18 (dt, J = 12.7, 3.3 Hz, 1H), 1.98 - 1.83 (m, 2H), 1.62 - 1.44 (m, 3H), 1.38 - 1.34 (m, 1H), 1.28 - 1.24 (m, 1H), 1.15 - 1.09 (m, 1H), 1.02 - 0.93 (m, 1H). LCMS-ESI (m / z): 306.20 [M+H] + .

[0220] Compound A-183 hydrochloride:

[0221] 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 7.39 (s, 1H), 3.78 (s, 3H), 3.60 (s, 1H), 3.19 (d, J = 6.0 Hz, 1H), 3.13 (s, 1H), 2.98 (d, J = 5.1 Hz, 1H), 2.77 (d, J = 4.9 Hz, 3H), 2.67 (s, 0.5H), 2.33 (s, 0.5H), 2.05 - 1.96 (m, 2H), 1.81 - 1.77 (m, 1H), 1.64 - 1.55 (m, 2H), 1.49 - 1.46 (m, 1H), 1.39 - 1.35 (m, 2H) 1.19 - 1.11 (m, 2H), 1.04 - 0.95 (m, 1H). LCMS-ESI (m / z): 340.10 [M+H] + .

[0222] Example 18: Preparation of compound A-184

[0223] A-1-0 (2 g, 1.0 eq) was dissolved in 20 ml of chloroform, potassium carbonate (1.5 mg, 2.0 eq), diisopropyl ethylamine (2.8 g, 4.0 eq) were added, after stirring at room temperature for 0.5 h, 1-chloroethyl chloroformate (3.0 g, 4.0 eq) was slowly added, after the addition was completed, the temperature was increased to 50 °C and stirred overnight, TLC detection showed that the raw material disappeared. The reaction solution was poured into 20 ml of ice water, extracted with 20 ml of dichloromethane twice, the organic phase was combined, dried, and concentrated under reduced pressure to obtain compound A-184-1 (3.0 g, oil), which was used directly in the next step without purification.

[0224] A-184-1 (400 mg, 1.0 eq) was dissolved in 4 ml of acetonitrile, 0.4 ml of trifluoroacetic acid, NCS (161 mg, 1.0 eq) were added, and stirred at room temperature overnight, TLC detection showed that most of the raw material disappeared. The reaction solution was adjusted to pH = 8-9 with saturated sodium bicarbonate, extracted with ethyl acetate (10 ml x 3), the organic phase was dried and concentrated to obtain compound A-184-2 (450 mg, dark oil), which was used directly in the next step without purification.

[0225] A-184-2 (450 mg, 1.0 eq) was dissolved in 10 ml of methanol, and the temperature was increased to reflux for 2 h. Concentrated under reduced pressure, purified by HPLC to obtain compound A-184 (200 mg, white solid).

[0226] 1H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3.02 - 2.96 (m, 1H), 2.99 (dd, J = 18.3, 6.2 Hz, 1H), 2.73 - 2.66 (m, 2H), 2.43 - 2.35 (m, 2H), 1.72 (d, J = 12.9 Hz, 1H), 1.61 - 1.48 (m, 3H), 1.38 - 1.26 (m, 4H), 1.19 - 1.10 (m, 1H), 0.93 - 0.83 (m, 1H). LCMS-ESI (m / z): 292.20 [M+H] +

[0227] Example 19: Preparation of compound A-189

[0228] To A-1-0 (22 g, 1.0 eq.) was dissolved in dichloromethane (500 mL), replaced with nitrogen for 3 times, added anhydrous tin tetrachloride (83 g, 4.0 eq.) under temperature control at 5 °C, then added dropwise a solution of liquid bromine (28 g, 2.2 eq.) in dichloromethane, after dropwise addition was completed, the temperature was raised to room temperature and reacted for 2 h. TLC monitoring showed that the raw material was completely reacted, the reaction solution was cooled in an ice bath, adjusted to PH = 8 with sodium hydroxide aqueous solution, extracted twice with ethyl acetate, combined the organic phase, dried, concentrated, and purified by column chromatography to obtain red solid A-189, 12 g.

[0229] 1 H NMR (400 MHz, DMSO-d6) δ 7.19 (s, 1H), 6.93 (s, 1H), 3.81 (s, 3H), 3.02 - 2.96 (m, 1H), 2.99 (dd, J = 18.3, 6.2 Hz, 1H), 2.73 - 2.66 (m, 2H), 2.43 - 2.35 (m, 2H), 1.72 (d, J = 12.9 Hz, 1H), 1.61 - 1.48 (m, 3H), 1.38 - 1.26 (m, 4H), 1.19 - 1.10 (m, 1H), 0.93 - 0.83 (m, 1H). LCMS-ESI (m / z): 292.20 [M+H] +

[0230] Example 20: Preparation of compound A-192

[0231] Compound A-190-0 (260 mg, 1.0 eq) was dissolved in 6 ml of acetic acid, triethylamine (505 mg, 5.0 eq) was added, and the mixture was cooled to about 10°C in an ice bath. A solution of liquid bromine (320 mg, 2.0 eq) in dichloromethane was added slowly dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 h. TLC detection showed that the starting material had disappeared. The mixture was cooled to 0°C, and ammonia water was added slowly dropwise to quench the reaction. The pH was adjusted to about 10, and a solid gradually precipitated. The mixture was stirred for another 1 h. The solid was filtered, and the filter cake was purified by column chromatography to obtain compound A-192 (40 mg, white solid).

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (s, 1H), 3.88 (d, J = 13.5 Hz, 1H), 3.43 (t, J = 6.9 Hz, 1H), 3.13 (s, 2H), 3.00 (d, J = 13.2 Hz, 1H), 2.70 (s, 3H), 2.49 - 2.41 (m, 1H), 2.11 - 2.00 (m, 2H), 1.82 - 1.74 (m, 1H), 1.60 (d, J = 13.1 Hz, 1H), 1.52 (d, J = 13.2 Hz, 1H), 1.43 (d, J = 14.2 Hz, 1H), 1.39 - 1.31 (m, 1H), 1.09 - 1.03 (m, 2H), 0.99 - 0.92 (m, 1H). LCMS-ESI (m / z): 414.10 [M+H] +

[0233] Example 21: Preparation of compound A-193

[0234] A-2-2 (2 g, 1 eq), benzamide (740 mg, 1.2 eq), t-Bu-phosphine ligand (200 mg, 0.05 eq), Pd2dba3 (160 mg, 0.02 eq), cesium carbonate (2 g, 1.2 eq), t-butanol (40 mL) were added to a flask, which was replaced with nitrogen, and stirred at 100°C overnight. TLC detection showed that the reaction was complete. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure and purified by column chromatography to obtain compound A-193-1 (1 g, white solid).

[0235] Compound A-193-1 (200 mg, 1 eq) was added to ethanol (1 mL) under nitrogen, and concentrated hydrochloric acid (1 mL) was added. The mixture was heated to reflux for 18 h. LCMS detection showed that the reaction was complete. The mixture was extracted once with EA, and the aqueous phase was adjusted to basicity with a sodium carbonate aqueous solution. The mixture was extracted with dichloromethane, and concentrated under reduced pressure to obtain compound A-193 (140 mg, yellow solid).

[0236] 1H NMR (400 MHz, DMSO-d6) δ 6.75 (d, J = 8.0 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 6.34 (dd, J = 8.0, 2.3 Hz, 1H), 4.69 (s, 2H), 2.81 (d, J = 17.9 Hz, 1H), 2.67 (s, 1H), 2.41 (dd, J = 17.9, 5.7 Hz, 1H), 2.32 - 2.23 (m, 5H), 2.04 - 1.97 (m, 1H), 1.68 - 1.53 (m, 3H), 1.45 (s, 1H), 1.36 - 1.15 (m, 5H), 1.09 - 0.99 (m, 1H). LCMS-ESI (m / z): 257.20 [M+H] +

[0237] Example 22: Preparation of compound A-205

[0238] Into a flask was added A-2-2 (1.0 g, 1 eq), phenylboronic acid (626 mg, 2.0 eq), potassium carbonate (709 mg, 2.0 eq), dioxane (10 mL), water (2 mL), replaced with nitrogen, added Pd(dppf)Cl2(94 mg, 5% eq), stirred at 80 °C for 10 h. The reaction system was diluted with water, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and column chromatography was used for purification to obtain compound A-205 (300 mg, yellowish oil).

[0239] 1 H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.60 (m, 2H), 7.48 - 7.42 (m, 3H), 7.39 - 7.31 (m, 2H), 7.21 (d, J = 7.9 Hz, 1H), 3.02 (d, J = 18.6 Hz, 1H), 2.75 (s, 1H), 2.62 - 2.54 (m, 2H), 2.23 - 2.29 (m, 4H), 1.96 (t, J = 12.0 Hz, 1H), 1.76 (d, J = 12.7 Hz, 1H), 1.70 - 1.58 (m, 2H), 1.51 (d, J = 12.9 Hz, 1H), 1.41 - 1.27 (m, 4H), 1.23 - 1.17 (m, 1H), 1.08 - 0.99 (m, 1H). LCMS-ESI (m / z): 318.30 [M+H] +

[0240] Example 23: Preparation of compound A-240

[0241] Compound A-184 (100 mg,) was dissolved in 2 ml tetrahydrofuran, 60% sodium hydroxide (16, 1.2 eq) was added. After stirring for 20 minutes, iodomethane-d3 (59.6 mg, 1.2 eq) was added to the reaction mixture. Stirring at room temperature for 1 hour, TLC control reaction. Quenching with 10 ml water, extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A-240 (40 mg, white solid).

[0242] 1 H NMR (400 MHz, DMSO-d6) δ 7.16 (s, 1H), 6.91 (s, 1H), 3.80 (s, 3H), 2.90 (d, J = 18.3 Hz, 1H), 2.70-2.68 (m, 1H), 2.48-2.41 (m, 2H), 2.33-2.29 (m, 1H), 1.93-1.86 (m, 1H), 1.71 (dt, J = 13.1, 3.2 Hz, 1H), 1.65-1.57 (m, 2H), 1.50 (d, J = 12.9 Hz, 1H), 1.39-1.23 (m, 4H), 1.19-1.13 (m, 1H), 1.03-0.93 (m, 1H). LCMS-ESI (m / z): 309.30 [M+H] +

[0243] Example 24: Preparation of compound A-243

[0244] A-181 (1 g) was added to a 100 ml three-necked flask, 15 ml chloroform, DIEA (1.69 g, 6.0 eq), ethyl chloroformate (1.06 g, 3.0 eq), and the reaction was carried out at 80°C for 8 hours. TLC control reaction. The reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A-243-1 (1 g, colorless oil), with a yield of 84%.

[0245] Compound A-243-1 (788 mg, 1.0 eq) was taken in DCM (10 mL) and cooled to 0-5°C under nitrogen atmosphere. Then 2.5M BBr3 solution in dichloromethane (2.6 mL, 3.0 eq) was added and stirred at 0-5°C for 2 h. TLC control reaction. The reaction was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic phase was dried and concentrated under reduced pressure to obtain compound A-243-2 (900 mg, oil), which was used directly in the next step without purification.

[0246] Compound A-243-2 (830 mg, 1.0 eq) was dissolved in 10 ml of acetonitrile, potassium carbonate (682 mg, 2.0 eq) was added, and deuterated methyl iodide (516 mg, 1.5 eq) was taken. The reaction was stirred at room temperature for 4 h, and TLC detection showed that the reaction was complete. The reaction solution was quenched with water, and ethyl acetate was added for extraction. The organic phase was concentrated under reduced pressure, and the product was purified by column chromatography to obtain compound A-243-3 (400 mg, white solid).

[0247] LiAlH4(61 mg, 3.0 eq) was taken in THF (2 ml) under nitrogen replacement, and the temperature was controlled at 0-5 °C and stirred. Then compound A-243-3 (200 mg, 1.0 eq) was dissolved in THF and added dropwise to the above system. After the dropwise addition was completed, the temperature was raised to 70 °C and reacted for 2 h. TLC detection showed that the reaction was complete. The reaction solution was quenched with water, diluted with ethyl acetate, filtered, and the filtrate was separated into organic phase. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography. The product was concentrated, and hydrogen bromide aqueous solution was added to form a salt. Lyophilization was performed to obtain compound A-243 hydrobromide.

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.29-7.26 (m, 1H), 6.99 (s, 1H), 3.63-3.57 (m, 1H), 3.20-3.06 (m, 2H), 3.01-2.99 (m, 1H), 2.95 (d, J = 6.2 Hz, 0.5H) 2.81 (d, J = 4.8 Hz, 2.5H), 2.56-2.42 (m, 2H), 2.03-1.99 (m, 1H), 1.85-1.77 (m, 1H), 1.64-1.52 (m, 3H), 1.47-1.24 (m, 3H), 1.14 (q, J = 13.3 Hz, 1H), 1.01-0.88 (m, 1H).

[0249] Example 25: Preparation of compound A-245

[0250] THF (2 ml) and deuterated lithium aluminum hydride (75.7 mg, 3.0 eq) were added to a reaction bottle, and the temperature was lowered to 0 °C. Then compound A-243-3 (200 mg, 1.0 mmol) dissolved in THF (3 ml) was gradually added. The reaction mixture was stirred under N2 atmosphere for 30 min, and TLC monitoring was performed. The reaction solution was quenched with water, filtered, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure, and the product was purified by column chromatography to obtain compound A-245 (100 mg, white solid).

[0251] 1H NMR (400 MHz, DMSO-d6) δ 7.18 (s, 1H), 6.90 (s, 1H), 2.94 (d, J = 18.3 Hz, 1H), 2.74 - 2.69 (m, 1H), 2.48 - 2.42 (m, 2H), 2.36 - 2.30 (m, 1H), 1.95 - 1.88 (m, 1H), 1.74 (dt, J = 13.1, 3.2 Hz, 1H), 1.68 - 1.55 (m, 2H), 1.52 (d, J = 12.9 Hz, 1H), 1.40 - 1.23 (m, 4H), 1.20 - 1.14 (m, 1H), 1.03 - 0.95 (m, 1H). LCMS-ESI (m / z): 278.20 [M+H] +

[0252] Example 26: Preparation of compounds A-262, A-286, A-334

[0253] Preparation of A-286

[0254] A-189 (0.17 g, 1 eq) was added to THF (5 mL), 2.5 M butyllithium (0.5 g, 2.5 eq) was added under ice bath, stirred for 0.5 h, then DMF (0.08 g, 2.1 eq) was added, after the addition was completed, stirred for 2 h, TLC monitored that the reaction was completed; post-processing: EA was added to separate layers, the organic phase was concentrated under reduced pressure, and column chromatography was separated; compound A-286 (0.14 g, colorless oil) was obtained.

[0255] Preparation of A-262

[0256] A-262 (0.14 g, 1 eq) was added to THF (2 mL), concentrated ammonia (0.82 g, 30 eq) was added under cold water bath, and the temperature was raised to room temperature and stirred for 15 min, cooled to 0 °C, and iodine (112 mg, 1.1 eq) was added, and the temperature was raised to room temperature and stirred for about 2 h, TLC showed that the raw material disappeared; cooled to add sodium thiosulfate solution to quench, extract with EA, and concentrate under reduced pressure; column chromatography purification, compound A-262 (30 mg, white solid) was obtained;

[0257] Preparation of A-334-1

[0258] A-262 (1.6 g, 1 eq) was dissolved in DCM (30 mL), 2.5 M boron tribromide (8.6 mL, 4 eq) was added under ice water bath, and stirred overnight; the reaction liquid was poured into saturated sodium bicarbonate solution to quench, extracted with DCM, the organic phase was concentrated under reduced pressure, and MTBE (30 mL) was added to the concentrate and stirred, filtered, and dried to obtain A-334-1 (1.3 g, light yellow solid)

[0259] Preparation of A-334-2

[0260] A-334-1 (0.7 g, 1 eq) was added into DCM (14 mL), TEA (0.75 g, 3 eq) was added, N-phenyl bis(trifluoromethanesulfonate) imine (1.77 g, 2 eq) solution in DCM was added under ice water bath, stirred at room temperature for 1.5 h, TLC showed the starting material disappeared. Work-up, diluted with water, separated, reserved the organic phase, concentrated under reduced pressure, purified by column chromatography, compound A-334-2 (0.45 g, yellowish oil) was obtained.

[0261] Preparation of A-334

[0262] A-334-2 (220 mg, 1 eq) was added into 1,4-dioxane (4.5 mL), methyl butynol (67 mg, 1.5 eq), TEA (215 mg, 4 eq), Pd(PPh3)2Cl2(37 mg, 0.1 eq), cuprous iodide (5 mg, 0.05 eq) were added, after replaced by nitrogen, heated to 90 °C, stirred for 18 h; TLC showed the starting material disappeared, diluted with water, extracted by EA, concentrated the organic phase under reduced pressure, separated by column chromatography, compound A-334 (70 mg, yellowish solid) was obtained.

[0263] Example 27: Preparation of compound A-269

[0264] A-189 (250 mg, 1 eq) was added into THF (5 mL), under nitrogen, cooled to below -50 °C, sec-butyl lithium (6 eq) was added dropwise, stirred for 15 min, iodomethane (6 eq) was added dropwise, stirred for 1 h, LC-MS showed the starting material disappeared, work-up: quenched by water, extracted by EA, concentrated under reduced pressure, purified by preparative column; compound A-269 (25 mg, colorless oil) was obtained; dispersed in THF about 0.5 mL, 48% hydrobromic acid solution (16 mg, 1.1 eq) was added, stirred uniformly, concentrated under reduced pressure, lyophilized; A-269 hydrobromide (36 mg, yellowish solid) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 6.96 (s, 1H), 6.79 (s, 1H), 3.76 (s, 3H), 3.54 - 3.52 (m, 2H), 3.26 - 3.02 (m, 2H), 2.95 - 2.84 (m, 1.5H), 2.73 (d, J = 4.8 Hz, 2.5H), 2.49 - 2.33 (m, 1.2H), 2.19 - 2.14 (m, 3.8H), 2.04 - 1.86 (m, 1H), 1.62 (d, J = 12.5 Hz, 1H), 1.55 - 1.41 (m, 3H), 1.36 - 1.24 (m, 2H), 1.21 - 1.11 (m, 1H), 1.03 - 0.92 (m, 1H).

[0265] Example 28: Preparation of compound A-273

[0266] A-269 (0.15 g, 1 eq) was added into chloroform (3 mL), DIPEA (0.2 g, 3 eq) was added, 1-chloroethyl chloroformate (0.23 g, 3 eq), heated to reflux under nitrogen for about 1 h, TLC showed the starting material was almost consumed. Work-up: cooled to room temperature, quenched with potassium carbonate aqueous solution, partitioned, the organic phase was concentrated, 5 mL of methanol was added, heated to reflux for 4 h, concentrated under reduced pressure, added MTEB to slurry, A-273 hydrochloride (45 mg, off-white solid) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 2H), 6.95 (s, 1H), 6.79 (s, 1H), 3.76 (s, 3H), 3.59 (dd, J = 6.0, 3.2 Hz, 1H), 3.09 - 2.91 (m, 3H), 2.49 - 2.39 (m, 2H), 2.11 (s, 3H), 1.93 - 1.90 (m, 1H), 1.78 - 1.70 (m, 1H), 1.60 (d, J = 12.6 Hz, 1H), 1.53 - 1.41 (m, 3H), 1.33 - 1.25 (m, 2H), 1.20 - 1.11 (m, 1H), 0.98 - 0.87 (m, 1H).

[0267] Example 29: Preparation of compounds A-348, A-354, A-355

[0268] Preparation of A-348-1

[0269] Take A-192 (3.3g, 1.0eq), add methanol (600mL), hydrogen replacement, room temperature stirring overnight, TLC detection reaction end. Post-processing, filtration, reduced pressure concentration, get A-348-1 hydrobromic acid salt (3.36g, white solid)

[0270] Preparation of A-348-2

[0271] A-348-1 hydrobromic acid salt (1.5g, 1eq) is added to DCM (30mL), TEA (1.1g, 3eq) is added, N-phenyl bis (trifluoromethanesulfonic acid) imine (2.32g, 1.8eq) is added, and the natural temperature is raised to room temperature after the addition is completed. Stir overnight; TLC raw material basically disappears; treatment: add dilute hydrochloric acid and wash once with water, dilute sodium carbonate solution and wash once, dry, reduce pressure concentration, column chromatography purification, get A-348-2 (1.4g, colorless oil).

[0272] Preparation of A-348-3

[0273] A-348-2 (1.0g, 1eq) is added to toluene (10mL), DIPEA (892mg, 3eq) is added, ethyl chloroformate (700mg, 3eq) is added, and the temperature is raised to 100℃ after the addition is completed. Stir for 18h, TLC detection; treatment: add sodium bicarbonate solution / EA extraction separation, organic phase is reduced pressure concentration, column chromatography separation, get A-348-3 (1.4g);

[0274] Preparation of A-348-4

[0275] A-348-3 (1.4g, 1eq) is added to THF (14mL), furan (1.82g, 10eq) is added, and the temperature is lowered to-60℃ under nitrogen. Slowly add 2.5M n-butyllithium (1.6mL, 1.5eq), and after the addition is completed, keep warm for 40min, TLC raw material basically disappears, treatment: add methanol 0.5mL to quench, natural temperature rise to room temperature, add EA water treatment, extraction separation, dry, reduced pressure concentration, get A-348-4 (1.2g, yellow oil);

[0276] Preparation of A-348-5

[0277] A-348-4 (1.2g, 1eq) is added to toluene (24mL) and dispersed, triphenyl phosphite (1.5g, 1.5eq) is added, and the temperature is raised to 100℃ after the addition of rhenium oxide (72mg, 5%eq) is added. Keep overnight, TLC monitoring to reaction end, wash once with water, organic phase is reduced pressure concentration, column chromatography separation and purification, get A-348-5 (colorless gum 1.6g) crude product.

[0278] Preparation of A-348-6

[0279] A-348-5 (1.6 g of crude product, 1 eq) was added to 33% hydrobromic acid acetic acid solution (10 mL), and the temperature was raised to 90°C and stirred for about 5 h. TLC showed that the starting material was almost gone. Treatment: dropwise addition of potassium carbonate aqueous solution to quench, and EA was added for extraction. The organic phase was concentrated and column chromatography was used for separation and purification to obtain A-348-6 (0.65 g of yellow gum);

[0280] Preparation of A-348

[0281] A-348-6 (0.65 g, 1 eq) was added to THF (6.5 mL), and 37% formaldehyde aqueous solution (6.5 mL, 10V) was added. After stirring for 5 min, sodium triacetoxyborohydride (2.5 g, 5 eq) was added in batches under ice water bath. After the addition was completed, the temperature was raised to 90°C and stirred for about 5 h. TLC showed that the starting material was almost gone. Treatment: dropwise addition of potassium carbonate aqueous solution to quench, and EA was added for extraction. The organic phase was concentrated and column chromatography was used for separation and purification to obtain A-348 (0.73 g). 48% Hydrobromic acid solution (1.1 eq) was added and stirred uniformly. After being concentrated under reduced pressure, A-348 hydrobromide was obtained by freeze-drying; 1 H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.32-8.27 (m, 1H), 7.91-7.89 (m, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.46-7.44 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 3.70 (s, 0.8H), 3.63 (s, 0.2H), 3.39-3.21 (m, 4H), 3.07 (d, J = 0.4 Hz, 1H), 2.83 (d, J = 4.8 Hz, 2.6H), 2.61-2.50 (m, 0.8H), 2.41 (d, J = 11.8 Hz, 0.8H), 2.32-2.28 (m, 0.2H), 2.23 (s, 0.4H), 2.18-2.14 (m, 0.2H), 2.06 (d, J = 12.0 Hz, 0.8H), 1.99-1.91 (m, 0.8H), 1.66-1.18 (m, 6H), 1.15-1.11 (m, 1H).

[0282] Preparation of A-354 and A-355

[0283] A-348 (0.5 g, 1 eq) was dissolved in acetic acid (5 mL), and nitric acid (5 mL) was added under stirring. After stirring for 2 h, nitric acid (5 mL) was added and stirring was continued for 18 h. LCMS showed that the reaction was completed. Treatment: dropwise addition of potassium carbonate aqueous solution to quench, and EA was added for extraction. The organic phase was concentrated under reduced pressure, and HPLC preparation was used for separation to obtain A-354 (120 mg, yellow solid) and A-355 (110 mg, yellow solid).

[0284] A-354 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 - 7.58 (m, 2H), 3.27 (d, J = 14.2 Hz, 1H), 3.08 - 2.87 (m, 3H), 2.50 - 2.45 (m, 1H), 2.33 - 2.27 (m, 4H), 1.99 - 1.93 (m, 1H), 1.85 (d, J = 11.5 Hz, 2H), 1.48 - 1.39 (m, 3H), 1.35 - 1.25 (m, 3H), 1.14 - 1.05 (m, 1H).

[0285] A-355 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.68 - 7.58 (m, 2H), 3.27 (d, J = 14.2 Hz, 1H), 3.08 - 2.87 (m, 3H), 2.50 - 2.45 (m, 1H), 2.33 - 2.27 (m, 4H), 1.99 - 1.93 (m, 1H), 1.85 (d, J = 11.5 Hz, 2H), 1.48 - 1.39 (m, 3H), 1.35 - 1.25 (m, 3H), 1.14 - 1.05 (m, 1H).

[0286] Example 30: Preparation of compound A-353

[0287] Preparation of A-353-1

[0288] A mixture of A-348-5 (0.5 g, 1 eq), acetic acid (10 mL), ZnCl2(196 mg, 1 eq), bromine (342 mg, 1.5 eq) was stirred at room temperature for 1.5 h; LCMS detected that the reaction was completed; treatment: quenching by dropwise addition of potassium carbonate aqueous solution, EA was added to extract, the organic phase was concentrated under reduced pressure to give A-353-1 (0.72 g, yellow oil) which was used directly in the next step without purification;

[0289] Preparation of A-353-2

[0290] A-353-1 crude (0.72 g, 1 eq) was added to 33% hydrobromic acid acetic acid solution (7 mL), and the mixture was warmed to 80 °C and stirred for 18 h. TLC detection showed that the reaction was complete. The reaction was quenched by dropwise addition of an aqueous potassium carbonate solution, and EA was added to extract the mixture. The organic phase was concentrated under reduced pressure, and column chromatography was used to separate A-353-2 crude (0.3 g, yellowish gum)

[0291] Preparation of A-353

[0292] A-353-2 crude (0.3 g, 1 eq) was added to THF (3 mL), and 37% formaldehyde aqueous solution (2.0 g, 30 eq) was added. After stirring for 5 min, sodium triacetoxyborohydride (895 mg, 5 eq) was added portionwise under ice water bath. After stirring for 1 h, LCMS detection showed that the starting material was consumed. The reaction was quenched by dropwise addition of an aqueous potassium carbonate solution, and EA was added to extract the mixture. The organic phase was concentrated under reduced pressure, and HPLC preparation was used to obtain A-353 (105 mg, white solid). Hydrobromic acid was added to form a salt, and freeze-drying was used to obtain A-353 hydrobromide (131 mg, light red solid). 1 H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.36 (d, J = 8.7 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 6.7 Hz, 1H), 7.65 - 7.55 (m, 2H), 3.72 (s, 0.8H), 3.64 (s, 0.2H), 3.41 - 3.09 (m, 4H), 3.07 (d, J = 5.0 Hz, 0.4H), 2.82 (d, J = 4.8 Hz, 2.6H), 2.67 - 2.54 (m, 1H), 2.44 (d, J = 14.1 Hz, 1H), 2.08 (d, J = 12.3 Hz, 1H), 1.99 - 1.93 (m, 1H), 1.48 - 1.26 (m, 6H), 1.18 - 1.04 (m, 1H).

[0293] Example 31: Preparation of compound A-420

[0294] A-2-2 (150 mg, 1.0 eq.), 2-methylbut-3-yn-2-ol (98 mg, 3 eq.), DBU (176 mg, 3 eq.), dppb (33 mg, 0.2 eq.) and dichlorobis(triphenylphosphine)palladium (27 mg, 0.1 eq.) were dissolved in DMSO (3 mL), and the mixture was stirred at 90 °C overnight under nitrogen replacement. LC-MS detection showed that the reaction was complete. The reaction was cooled to room temperature, water and ethyl acetate were added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 67 mg of white solid product; 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 5.42 (s, 1H), 3.58 - 3.52 (m, 1H), 3.28 - 3.19 (m, 1H), 3.04 (d, J = 21.2 Hz, 2H), 2.86 - 2.65 (m, 3H), 2.45 (d, J = 13.9 Hz, 1H), 2.20 (d, J = 12.4 Hz, 1H), 2.00 - 1.89 (m, 1H), 1.66 - 1.59 (m, 1H), 1.58 - 1.38 (m, 10H), 1.37 - 1.26 (m, 2H), 1.13 - 1.02 (m, 1H), 0.99 - 0.84 (m, 1H).

[0295] The specific data of compounds A-3 to A-7, A-9 to A-50, A-52, A-54, A-56, A-57, A-59, A-61, A-67 to A-116, A-118 to A-119, A-121 to A-124, A-178, A180, A185-A-188, A-190-A-191, A-194 to A-204, A-206 to A-239, A-241 to A-242, A-244, A-246 to A-424 are shown in the following table, and these compounds can be prepared by using the same method as in the above examples, except that the starting materials and intermediates corresponding to the final products are used.

[0296] Pharmacological Example 1 Test of NMDA receptor antagonistic activity

[0297] The effect of the compound on NMDA receptor (N-methyl-D-aspartate receptor, NR1 / 2A) channel current was tested by using the whole-cell manual patch clamp method of electrophysiology.

[0298] Experimental instruments:

[0299] Multiclamp 700B, Axopatch 200B, Axon, USA

[0300] Digidata 1440A, Digidata 1550B, Axon, USA

[0301] IX71, IX51, Olympus, Japan

[0302] RSC-200, Bio-Logic, France

[0303] MX7600R, Syskiyou, USA

[0304] P-97, Sutter, USA

[0305] BF150-86-10, Sutter, USA

[0306] 63-534, TMC, USA

[0307] Data acquisition and analysis software (pClamp, Axon, USA)

[0308] Carbon dioxide incubator (HERAcell 150i, Thermo, USA)

[0309] Biosafety cabinet (MODEL 1384, Thermo, USA)

[0310] Millipore water system (Milli Q, Millipore, USA)

[0311] Reagents:

[0312] Sodium chloride (NaCl) (Sigma, Cat: S7653)

[0313] Potassium chloride (KCl) (Sigma, Cat: P9333)

[0314] Cesium chloride (CsCl) (Sigma, Cat: V900481)

[0315] Cesium fluoride (CsF) (Sigma, Cat: 289345)

[0316] Calcium chloride (CaCl2) (Sigma, Cat: 21115)

[0317] Glucose (Sigma, Cat: G7528)

[0318] 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-hydroxyethyl)piperazine-N’-(2-ethanesulfonic acid) (abbreviated as HEPES) (Sigma, Cat: H3375)

[0319] Ethyleneglycol bis(2-aminoethylether)tetraacetic acid (abbreviated as EGTA) (Sigma, Cat: E3889)

[0320] Lipofectamine 3000 transfection kit (Gibco, Cat: L3000015) (contains two reagents, Lipofectamine 3000 and P3000)

[0321] DMEM (Gibco, Cat: C11995500BT)

[0322] Fetal bovine serum (FBS) (Gibco, Cat: 10099141)

[0323] Opti-MEM (Gibco, Cat: 31985070)

[0324] Sodium hydroxide (NaOH) (National Pharmaceutical, Cat: 10019718)

[0325] Cesium hydroxide (CsOH) (Sigma, Cat: 232068)

[0326] Dimethyl sulfoxide (DMSO) (Sigma, Cat: 276855)

[0327] Glutamic acid (Sigma, Cat: G1626-100G)

[0328] Glycine (Amresco, Cat: 0167-1KG)

[0329] Extracellular solution formulation (mM): 140 NaCl, 2.8 KCl, 1 CaCl2, 10 HEPES and 20 Sucrose, pH adjusted to 7.4 with NaOH.

[0330] Intracellular solution formulation (mM): 10 CsCl, 115 CsF, 10 EGTA and 10 HEPES, pH adjusted to 7.2 with CsOH.

[0331] Specific procedures:

[0332] a. Cell culture and handling

[0333] HEK293 cell line was cultured in DMEM medium containing 10% fetal bovine serum at 37°C with 5% carbon dioxide concentration.

[0334] Cell passage: Remove old medium and wash once with PBS, then add 1 mL of 0.25% Trypsine-EDTA solution, incubate at room temperature for 1 minute. When the cells are detached from the dish bottom, add 3 mL of 37°C preheated complete medium (90% DMEM + 10% FBS). Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 800 rpm for 3 minutes to collect the cells. Seed the cells in T25 cell culture flask at a ratio of 1:5 (final volume: 6 mL) for expansion or maintenance of culture.

[0335] Transient transfection: Replate HEK-293 cells at 80% confluency 24 h before transfection into 35 mm 2 dishes at a seeding density of 3 x 10 5 cells per dish.

[0336] Prepare the transfection reagent in each well as follows:

[0337] 1) Take 7.5 μL Lipofectamine TM 3000 into 250 μL Opti-MEM medium, mix gently by blowing, as component A, incubate at room temperature for 5 min;

[0338] 2) Take 3.6 μg pCDNA5-FRT-TO-hNRl-T2A-2A plasmid, 0.4 μg GFP plasmid, 7.5 μL P3000 into 250 μL Opti-MEM medium, mix gently by blowing, as component B, incubate at room temperature for 5 min;

[0339] 3) Add component B into component A, mix gently by blowing until well mixed, incubate at room temperature for 15 min to form DNA-liposome mixture;

[0340] 4) Add the DNA-liposome mixture into 35 mm 2 cell culture dish, 500 μL per well. Put into incubator for further culture;

[0341] 5) Change medium after 6 h, remove all medium in 35 mm 2 cell culture dish, add 2 mL / well of complete medium (90% DMEM + 10% FBS), continue culture for 18 h before patch clamp detection;

[0342] b. Compound preparation: On the day of test, dilute the mother liquor of the compound of the present application with DMSO to intermediate concentration, then dilute with extracellular solution (containing 100 μM glutamate + 100 μM glycine) to the final concentration required for test. The DMSO content in the final test concentration is not more than 0.2%.

[0343] c. Electrophysiological recording process

[0344] HEK293 cells transiently expressing NMDA receptor channels were used to record currents induced by 100 μΜ glutamate (containing 100 μΜ glycine) at room temperature using the whole-cell patch-clamp technique. Glass microelectrodes were pulled from glass electrode capillaries (BF150-86-10, Sutter) using a micropipette puller and had a tip resistance of 2-5 MΩ after being filled with internal solution. The glass microelectrode was inserted into the amplifier probe to connect to the patch-clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -70 mV, and 100 μΜ glutamate (containing 100 μΜ glycine) was given by gravity using a fast drug delivery system to induce channel current. After the current was stable, 100 μΜ glutamate (containing 100 μΜ glycine) containing the compound was given to observe the change in current amplitude. The compound was given continuously from low concentration to high concentration, and finally 100 μΜ glutamate (containing 100 μΜ glycine) was given again. Each test concentration of the compound was given for at least 20 s, and at least 2 cells were tested for each concentration (n≥2).

[0345] d. Data processing

[0346] Data analysis and processing were performed using pClamp, GraphPad Prism 8 and Excel software. The degree of inhibition of channel current (100 μΜ glutamate (containing 100 μΜ glycine) induced current amplitude at -70 mV) by different concentrations of compounds was calculated using the following formula:

[0347] Inhibition% = [1 - (I / Io)] x 100%

[0348] where Inhibition% represents the percentage inhibition of NMDA channel current by the compound, I and Io represent the current amplitude induced by 100 μΜ glutamate (containing 100 μΜ glycine) after and before drug administration, respectively.

[0349] Compound IC 50 The IC50value was calculated using GraphPad Prism 8 software by fitting the following equation:

[0350] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0351] where X is the Log value of the test concentration of the test product, Y is the percentage inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively. The activity of dextromethorphan was tested in the same way. The test results of some compounds are shown in Table 1.

[0352] Table 1

[0353] The above data show that the compound of the present application has certain antagonistic activity on NMDA receptor, and is expected to have therapeutic effect on NMDA receptor related central nervous system diseases

[0354] Test Example 2. 5-HT transporter inhibitory activity test

[0355] The transporter inhibitory effect of HEK-293 cells expressing human SERT was tested using Neurotransmitter transporter uptake assay kit (Molecular devices product). The test was performed according to the method in the kit instructions, and citalopram was used as a positive control. The specific operation is as follows:

[0356] a) HEK-hSERT cells were seeded at 20000 cells / well in a 384-well plate, then transferred to an incubator at 37°C for overnight incubation.

[0357] b) The next day, citalopram was transferred to the 384-well plate with 0.1% BSA solution, and the test final concentration of citalopram was 2 μM, 0.5 μM, 0.125 μM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, 0.03 nM. The test starting concentration of the test compound was 10 μM, 3X dilution, and each concentration was repeated twice.

[0358] c) The 384-well plate was taken out of the incubator, the culture medium was aspirated from the well, and 25 μL / well of the test compound and dextromethorphan solution was added. Incubate at 37°C for 30 min. Add 25 μL of dye solution per well, and incubate at 37°C for 30 min.

[0359] d) Read the fluorescence value on Flexstation 3, analyze the data using Graphpad Prism, and the results are shown in Table 2.

[0360] Table 2:

[0361] The above data show that the compound of the present application has strong 5-HT transporter inhibitory effect

[0362] Test Example 3. Sigma-1 receptor affinity test:

[0363] 1) Using a multichannel pipette, 1 pL of serially diluted reference and test compounds were transferred to the assay plate. 1 pL of non-specific binding compound was transferred to the assay plate according to the non-specific binding plate map (low control: LC). 1 pL of DMSO was transferred to the assay plate according to the plate map for total binding (high control: HC);

[0364] (2) Follow the plate map. Add 100 pL of membrane stock solution to the plate;

[0365] (3) Add 100 pL of radioligand;

[0366] (4) Seal the steel plate. Shake the plate at 300 rpm under the specified conditions;

[0367] (5) Soak the unfilter-96 GF / C filter plates with 50 pL of 0.3% PEI per well for at least 0.5 hours at room temperature;

[0368] (6) After the binding experiment is complete, filter the reaction mixture through the GF / C plates using the Perkin Elmer Filtermate Harvester, then wash each plate 4 times with cold buffer;

[0369] (7) Dry the filter plates at 50 °C for 1 hour;

[0370] (8) After drying, seal the bottom of the filter plate wells with Perkin Elmer unfilter-96 Backer Seal Tape. Add 40 pL of Perkin Elmer Microscint 20 cocktail. Seal the top of the filter plate with Perkin Elmer TopSeal-A sealing film;

[0371] (9) Count the captured radioactivity on the filters using the Perkin Elmer MicroBeta2 Reader 3 H.

[0372] (10) Calculate the inhibition using the following formula: % Inhibition = (1 - (assay well - mean LC) / (mean HC - mean LC))*100%;

[0373] (11) Data analysis was performed using Prism 5. The data was fitted using the “log(inhibitor) vs. response - Variable slope” model. % Inhibition = (1 - (assay well - mean LC) / (mean HC - mean LC))*100%. Data was analyzed using Prism 5. The data was fitted using the “log(inhibitor) vs. response - Variable slope” model.

[0374] The experimental results are shown in Table 3 below

[0375] Table 3 Note: a Substitution of radioligand ([[ 3 H]DTG) at 1000 nM

[0376] Test Example 4: Pharmacokinetic experiment in mice

[0377] Animals: Male ICR mice. Animals were randomly assigned to treatment groups and fasted for 12 h prior to dosing.

[0378] Drugs: The compounds of the present application were dissolved in a vehicle (5% DMSO + 5% solutol HS151 + 90% Saline). The oral (po) dose was 10 mg / kg and the volume of administration was 10 mL / kg body weight.

[0379] Sample collection and bioanalysis: After dosing, blood was taken from the orbital sinus of the mice at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24 h (n = 3 at each time point) into EP tubes containing sodium heparin.

[0380] Plasma samples were obtained by centrifugation of whole blood and 10 μL of plasma was mixed with 190 μL of internal standard solution (20 ng / mL in acetonitrile containing 0.1% formic acid). After mixing, the samples were centrifuged at 13000 rpm for 10 min and 120 μL of supernatant was taken from each sample. 0.5-10 μL (depending on the sensitivity of the compound) was taken for drug analysis using a suitable liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Standard samples of each analyte were used for calibration and identification.

[0381] Data analysis: Drug concentrations below the lower limit of quantification (LLOQ) were recorded as zero. Pharmacokinetic data analysis was performed in PK Solver using a non-compartmental, rapid intravenous bolus or extravascular input analysis model. Data points below the LLOQ were not included in the analysis to improve the validity of the calculations. The data for dextromethorphan were measured in the same way. The experimental results are shown in Table 4 below: 1 / 2

[0382] Table 4

[0383] As can be seen from the above table, the compounds of Example 1, Example 14, and compounds A-181, A-240, A-262, A-273 of the present application have higher maximum plasma concentrations and bioavailability in mice than the control compound DEXT (dextromethorphan) after oral administration at 10 mg / kg.

[0384] ​Test Example 5: Human and mouse liver microsomal experiments

[0385] Control articles and reagents: NADPH, magnesium chloride, testosterone, phosphate buffer, etc. were provided by Dalian Milen Biotechnology Co., Ltd., etc.

[0386] Liver microsomes: Mouse, human liver microsomes were provided by Corning.

[0387] Experimental procedure: The composition of the human and ICR / CD-1 mouse liver microsomal incubation system was designed and implemented according to the CDE guidance document, as follows:

[0388] The total volume of each incubation system was 100 μL, the medium was 100 mM Tris-HCl buffer (pH 7.4), including liver microsomal protein with a final concentration of 0.300 mg / mL, 1.00 μM of the test compound or 1.00 μM of the positive compound 7-ethoxycoumarin and 1.00 mM of NADPH and UDPGA, incubated in a 37°C incubator, and an equal volume of acetonitrile was added to terminate the reaction at 0, 5, 15, 30 and 60 min, respectively. The negative control used liver microsomes of the corresponding species without NADPH and UDPGA, and the incubation time point was 60 min, with the same operation as the experimental group; the solvent group used compound and buffer solution incubation, and the incubation time points were 0 and 60 min; 7-ethoxycoumarin did not set up a negative control group, and the incubation time was 0 and 30 min. The residual amount of the test compound or positive compound in the incubation sample was detected by LC-MS / MS method, and all the incubation samples were 2 samples.

[0389] Sample analysis: After the incubation sample was treated by organic solvent extraction and protein precipitation, the concentration of the test drug or positive control drug in the sample was semi-quantitatively determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. The ratio of the peak area of the analyte to the peak area of the internal standard was used to represent the concentration in the sample.

[0390] Data processing and analysis: Using Excel software, the ln residual rate of the drug in the incubation system was plotted against the incubation time, and the slope k was obtained by linear regression, and the half-life T was calculated according to the following formula: 1 / 2 (min), intrinsic clearance CLint (mL / min / kg):

[0391] T 1 / 2 = -0.693 / k

[0392] The data of dextromethorphan were measured in the same way. The experimental results are shown in Tables 5 and 6 below:

[0393] Table 5 Human liver microsomal metabolic stability Note: NA means almost no metabolism, DEXT data from literature

[0394] Table 6 Metabolic stability in mouse liver microsomes Note: NA means almost no metabolism

[0395] The above data show that the compounds of the present application have good metabolic stability in mouse and human liver microsomes compared with the control compound DEXT (dextromethorphan).

[0396] Pharmacological Example 6: Forced Swim Test:

[0397] Drug: The compound of the present application is mixed with 5% DMSO, then mixed with 5% HS15, and then added with 90% physiological saline to prepare a solution of a suitable concentration, which is prepared and used immediately. Dextromethorphan (10 mpk) + quinidine (30 mpk) combination is used as a positive control.

[0398] Animals: Male C57 mice, about 22g. The animals are randomly divided into groups, including a blank control group (Vehicle group) and each test drug group, 8 animals in each group, and each group of mice is given intraperitoneal injection of the vehicle prescription or each test drug.

[0399] Experimental procedure: 0.5h after administration, the mice are subjected to forced swim test. The water level in the forced swim equipment is 45cm, and the water temperature is 25℃. The mice are placed in the experimental room for 1h before the experiment starts. The mice are placed in the equipment at the start of the experiment, for a duration of 6min, and the whole process is recorded by a camera. When analyzing the data, only the immobility time of the mice in the last 4min is counted.

[0400] The experimental results are shown in Tables 7, 8 and 9 below:

[0401] Table 7

[0402] The above data show that the drug groups at doses of 3mpk, 10mpk and 20mg / kg all showed significant antidepressant-like effects.

[0403] Table 8

[0404] The above data show that the drug groups at doses of 3mpk, 10mpk and 20mg / kg all showed significant antidepressant-like effects.

[0405] Table 9

[0406] The above data show that the drug groups at doses of 10mpk and 20mg / kg all showed significant antidepressant-like effects.​

[0407] Test Example 7: ICR mouse pk experiment:

[0408] ICR mice were orally administered with compounds A-134 to A-162, A-165, A-171, A-172, A-175, A-195 to A-204, A-389 to A-414, A-422, A-449, respectively. The compounds can be metabolized into active forms in mice.

Claims

1. A morphinan compound represented by formula (I), or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopic label thereof: wherein: X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 3-8 membered heterocyclyl containing from 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-10 membered heteroaryl containing from 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C10aryl, or wherein Y and Y1 are each independently selected from O, NH, NR6, or S, Y2 is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6 is independently selected from substituted or unsubstituted C1-C30 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6-C10 aryl, or 5-10 membered heteroaryl, or, two R6 and the attached atoms form a substituted or unsubstituted 3-8 membered ring containing 1-3 heteroatoms selected from N, O, and S; and when substituted, the substituents are R7; R1 is hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted C1-C30 alkanoyl, substituted or unsubstituted C3-C10 cycloalkanoyl, substituted or unsubstituted 3-10 membered non-aromatic heterocyclylcarbonyl, substituted or unsubstituted C1-C30 alkoxycarbonyl, substituted or unsubstituted C3-C6 cycloalkoxycarbonyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted 5-10 membered aryloyl or heteroaryloyl, -COO(substituted or unsubstituted C6-C20 aryl), -COO(substituted or unsubstituted 5-20 membered heteroaryl), -C(R8)2O-(CO)-(substituted or unsubstituted C1-C30 alkyl or substituted or unsubstituted C3-C30 cycloalkyl), -C(R8)2O-(CO)O-(substituted or unsubstituted C1-C30 alkyl or substituted or unsubstituted C3-C30 cycloalkyl), -C(R8)2O-(CO)-(substituted or unsubstituted C6-C20 aryl), -C(R8)2O-(CO)-(substituted or unsubstituted 5-20 membered heteroaryl), a residue of an amino acid after removal of the hydroxyl group from the carboxyl group, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S; wherein R8 is H or C1-C6 alkyl; and when substituted, the substituents are R7; R2, R3, R4 are each independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C6-C10 aryl, or 5-10 membered heteroaryl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted C3-C6 cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted with one or two C1-C6 alkyl groups, amino substituted with one or two C3-C6 cycloalkyl groups, mercapto, substituted or unsubstituted C1-C6 alkylthio, substituted or unsubstituted C3-C6 cycloalkylthio, halogen; and when substituted, the substituents are R7; or X and R3, R2and R3, or X and R4, together with the carbon atoms on the phenyl ring to which they are attached, form a 4-10 membered ring containing 0-3 heteroatoms selected from N, O, and S, said 4-10 membered ring being aromatic or non-aromatic, said 4-10 membered ring is optionally substituted with one or more R5, each R5is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, oxo, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, haloC3-C6cycloalkyl, C1-C6alkoxy, C3-C6cycloalkoxy, C1-C6alkanoyl, C3-C6cycloalkanoyl, carbamoyl, carbamoyl substituted with one or two C1-C6alkyl or C3-C6cycloalkyl, amino substituted with one or two C1-C6alkyl or C3-C6cycloalkyl, amino substituted with one or two C1-C6alkanoyl or C3-C6cycloalkanoyl, C1-C6alkoxycarbonyl, C3-C6cycloalkoxycarbonyl, 3-10 membered heterocycloalkyl, C6-14aryl, or 5-10 membered heteroaryl, R7is one or more substituents each independently selected from deuterium, halogen, cyano, hydroxyl, thiol, amino, oxo, C1-C6alkyl, C3-C6cycloalkyl, 3-8 membered heterocyclyl containing 1-3 heteroatoms unsubstituted or substituted with oxo or C1-C6alkyl, C6-C20aryl unsubstituted or substituted with oxo or C1-C6alkyl, 5-20 membered heteroaryl unsubstituted or substituted with oxo or C1-C6alkyl, 3-8 membered heterocyclyl C1-C6alkyl unsubstituted or substituted with oxo or C1-C6alkyl, 5-20 membered heteroaryl C1-C6alkyl unsubstituted or substituted with oxo or C1-C6alkyl, C1-C6alkoxy, C3-C6cycloalkyloxy, C1-C6alkylthio, C3-C6cycloalkylthio, amino substituted with one or two C1-C6alkyl, and amino substituted with one or two C3-C6cycloalkyl, -NHCO-(C1-C6alkyl or C3-C6cycloalkyl), -N(C1-C6alkyl or C3-C6cycloalkyl)CO-(C1-C6alkyl or C3-C6cycloalkyl), -CHO, -CO(C1-C6alkyl or C3-C6cycloalkyl), -COOH, -COO(C1-C6alkyl or C3-C6cycloalkyl), -OCOO(C1-C6alkyl or C3-C6cycloalkyl), -OCO(C1-C30alkyl or C3-C30cycloalkyl), -OCO(5-20 membered heteroaryl), -CH2OCO(C1-C30alkyl), -CH2OCO(C6-C20aryl), -CH2OCO(5-20 membered heteroaryl), -CONH(C1-C6alkyl or C3-C6cycloalkyl), -CON(C1-C6alkyl or C3-C6cycloalkyl)2.

2. The morphinan compound of claim 1, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, wherein, X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 4-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted C6-C10aryl, or wherein Y and Y1are each independently selected from O, NH, NR6, or S, Y2is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6is independently selected from substituted or unsubstituted C1-C20alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl, or 5-10 membered heteroaryl, or, two R6and the attached atoms form a substituted or unsubstituted 4-6 membered ring containing 1-3 heteroatoms selected from N, O, and S; and when substituted, the substituents are R7; R1is the same as defined in claim 1 ; R2, R3, R4are each independently selected from hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl, or 5-10 membered heteroaryl, substituted or unsubstituted C2-C10alkenyl, substituted or unsubstituted C2-C10alkynyl, substituted or unsubstituted C1-C10alkoxy, substituted or unsubstituted C3-C6cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted with one or two C1-C6alkyl groups, amino substituted with one or two C3-C6cycloalkyl groups, mercapto, substituted or unsubstituted C1-C6alkylthio, substituted or unsubstituted C3-C6cycloalkylthio, halogen; and when substituted, the substituents are R7; or X and R3, R2and R3, or X and R4and the C atoms of the phenyl ring to which they are attached together form a 5-6 membered ring selected from: wherein Z1, Z2, Z3are independently selected from C, N, O, S, NR5, CR5, C(R5)2; provided that at least one of Z1, Z2, and Z3is a heteroatom; each R5is independently selected from hydrogen, halogen, hydroxy, amino, cyano, carboxy, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6alkanoyl, carbamoyl, carbamoyl substituted with C1-C6alkyl, amino substituted with one or two C1-C6alkyl groups, amino substituted with one or two C1-C6alkanoyl groups, C1-C6alkoxycarbonyl, 4-8 membered heterocycloalkyl, C6-10aryl, or 5-10 membered heteroaryl; R7is the same as defined in claim 1.

3. The morphinan compound of claim 1, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, wherein X is substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C5-C6cycloalkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, -OH, -CN, cyano-substituted C1-C6alkyl, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted 5-6 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S, substituted or unsubstituted phenyl, or wherein Y and Y1are each independently selected from O, NH, NR6, or S, Y2is selected from OH, NH2, SH, CH(R6)2, OR6, SR6, NHR6, or N(R6)2, each R6is independently selected from substituted or unsubstituted C1-C18alkyl, or, two R6and the attached atoms form a substituted or unsubstituted 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, S, O, and when substituted, the substituents are R7; R1is hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C6-C10aryl, substituted or unsubstituted C1-C30alkanoyl, substituted or unsubstituted C3-C8cycloalkanoyl, substituted or unsubstituted 3-10 membered non-aromatic heterocycloyl, substituted or unsubstituted C1-C30alkoxycarbonyl, substituted or unsubstituted C3-C6cycloalkoxycarbonyl, substituted or unsubstituted 5-8 membered heteroaryl, substituted or unsubstituted 5-10 membered aroyl or heteroaroyl, -COO(substituted or unsubstituted C6-C8aryl), -COO(substituted or unsubstituted 5-8 membered heteroaryl), -C(R8)2O-(CO)-(substituted or unsubstituted C1-C30alkyl), -C(R8)2O-(CO)O-(substituted or unsubstituted C1-C30alkyl), -C(R8)2O-(CO)-(substituted or unsubstituted C6-C10aryl), -C(R8)2O-(CO)-(substituted or unsubstituted 5-7 membered heteroaryl), a residue of an amino acid after removal of the hydroxyl group from the carboxyl group, substituted or unsubstituted 3-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O and S; wherein R8is H or C1-C3alkyl; and when substituted, the substituents are R7; R2, R3, R4are each independently selected from hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl or 5-10 membered heteroaryl, substituted or unsubstituted C2-C6alkenyl, substituted or unsubstituted C2-C6alkynyl, substituted or unsubstituted C1-C6alkoxy, substituted or unsubstituted C3-C6cycloalkoxy, hydroxy, nitro, cyano, amino, amino substituted by one or two C1-C6alkyl groups, amino substituted by one or two C3-C6cycloalkyl groups, mercapto, substituted or unsubstituted C1-C6alkylthio, substituted or unsubstituted C3-C6cycloalkylthio, halogen; and when substituted, the substituents are R7; or X and R3, R2and R3, or X and R4and the C atoms of the phenyl ring to which they are attached together form a 5-6 membered ring selected from: each R5is independently selected from hydrogen, amino, hydroxy, carboxy, C1-C3alkyl, haloC1-C3alkyl, C1-C3alkoxy, C1-C3alkanoyl, carbamoyl, formylamino, methylamino, N,N-dimethylamino, C1-C3alkoxycarbonyl, C3-C5cycloalkyl, phenyl, pyridyl, pyrrolidinyl, piperidinyl or morpholinyl, R7is the same as defined in claim 1.

4. The moφhinan compound of any one of claims 1-3, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically labeled version thereof, wherein, The morphinan compound is selected from the group consisting of: wherein M1, M2, M3and M4are each independently selected from C, S, O, N, C=0, M5is C or N, and M1to M5are not simultaneously C atoms; represents a single or double bond; preferably, said is thiazole, thiophene, furan, imidazole, triazole or tetrazole; is thiazole, thiophene, furan, imidazole, triazole or tetrazole; n＝0～3； Z is selected from halogen, cyano, cyanomethyl, nitro, amino, Ci-C6alkyl substituted amino, mercapto, Ci-C6alkylthio, deuterium-substituted or unsubstituted Ci-C6alkyl, fluorine-substituted Ci-C6alkyl, deuterium-substituted or unsubstituted C3-C6cycloalkyl, hydroxy, deuterium-substituted or unsubstituted Ci-C6alkoxy, deuterium-substituted or unsubstituted C3-C6cycloalkoxy, substituted or unsubstituted C6-C10aryl, or 5-10 membered heteroaryl; preferably, Z is selected from halogen, cyano, deuterium-substituted or unsubstituted Ci-C3alkyl, fluorine-substituted Ci-C6alkyl, deuterium-substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C6-C10aryl, or 5-6 membered heteroaryl; when substituted, the substituents are R7; R1to R7are defined as in claim 1; X1is deuterium-substituted or unsubstituted Ci-C6alkoxy, preferably, X1is 0-3 deuterium-substituted methoxy, 0-5 deuterium-substituted ethoxy, 0-7 deuterium-substituted n-propoxy, 0-7 deuterium-substituted isopropoxy.

5. The morphinan compound of any one of claims 1-4, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, wherein: R1 is selected from: hydrogen, methyl, methyl with 1-3 deuterated groups, ethyl, ethyl with 1-5 deuterated groups, n-propyl, n-propyl with 1-7 deuterated groups, isopropyl, isopropyl with 1-7 deuterated groups, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, formyl, acetyl, propionyl, butyryl, isopropionyl, isobutyryl, tert-butyryl, benzoyl, p-toluyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyryl, isopropoxycarbonyl. Isobutyrooxycarbonyl, tert-butyrooxycarbonyl, trichloroethoxycarbonyl, dodecanealkyloxycarbonyl, hexadecanealkyloxycarbonyl, phenoxycarbonyl, p-methoxyphenoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzyl, p-methoxybenzyl, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, tert-valeryloxymethyl, lauroyloxymethyl, palmitoyloxymethyl, 1-(pyridin-3-yl)acyloxymethyl, methoxymethyl, 2-aminoacetyl, 2-amino-3-methylbutyryl, 2-aminophenylpropionyl, pyrrole-2-acyl, 2-amino-4-carboxypropionyl, 2-amino-3-(1-H-imidazol-4-yl)propionyl, 2-amino-3-hydroxybutyryl 6. A morphinan compound, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, characterized by, The morphinan compound is any one of the compounds having the following structures, or combinations thereof:

7. A method of preparing the morphinan compound of any one of claims 1-6, the method comprising: Reaction Scheme 1: (1) substituting X1in the compound of formula (III) with X2to form the compound of formula (II), (2) substituting or coupling the compound of formula (II) to form the compound of formula (I), or forming a ring with X2and R3or R4, respectively, in the compound of formula (II); wherein X, R1to R5are defined as in the claims; X1represents H, hydroxy, Ci-C6alkoxy; X2represents a leaving group.

8. A pharmaceutical composition comprising a therapeutically effective amount of the morphinan compound of any one of claims 1-6, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, and optionally a pharmaceutically acceptable carrier.

9. Use of the morphinan compound of any one of claims 1-6, or an isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopically-labeled form thereof, or the pharmaceutical composition of claim 8, in the manufacture of a medicament for preventing and / or treating a central nervous system disease.

10. The use of claim 9, wherein The central nervous system disease is selected from the group consisting of schizophrenia; refractory, intractable or chronic schizophrenia; affective disorder; psychotic disorder; mood disorder; bipolar I disorder; bipolar II disorder; depressive disorder; endogenous depression; major depressive disorder; treatment-resistant depression; depression with risk of suicide; dysthymic disorder; cyclothymic disorder; panic attack; panic disorder; social phobia; Obsessive-compulsive disorder; Impulse control disorders; Post-traumatic stress disorder; Anxiety disorders; Anxiety associated with depression; Acute stress disorder; Hysteria; Anorexia nervosa; Sleep disorders; Adjustment disorders; Cognitive disorders; Obsessive-compulsive disorder; Autism; Migraine; Fibromyalgia; Trigeminal neuralgia; Mania; Parkinson's disease; Huntington's disease; Alzheimer's disease; Depression or agitation associated with Alzheimer's disease; Various dementias; Agitation or anxiety associated with various dementias; Memory disorders; Attention deficit / hyperactivity disorders and Tourette's syndrome; Stroke; Pseudobulbar palsy; Pseudobulbar affect; Autism; Neurological disorders and neurodegenerative diseases; Brain injury; Disorders of consciousness; Tardive dyskinesia; Diabetic neuropathy; Diseases or disorders caused by homocysteine-induced apoptosis; Diseases or disorders caused by high levels of homocysteine; Chronic pain; Intractable pain; Sympathetically-mediated pain; Oral pain; Back pain; Central pain syndromes; Complex regional pain syndrome; Seizures; Hemiplegic seizures; Acquired epileptic aphasia; Severe myoclonic epilepsy in infancy; Early infantile epileptic encephalopathy; Post-stroke seizures; Febrile seizures; Post-traumatic seizures; Tinnitus; Cough; Intractable cough; Addiction; Rett's syndrome; Speech disorders caused by uncontrolled laryngeal muscle spasms; Methotrexate neurotoxicity; Muscle weakness; Alcohol-related disorders.

11. The use of a morphinan compound, or its isomer, racemate, pharmaceutically acceptable salt, solvate, or isotopic label, in the preparation of a medicament for the prevention and / or treatment of central nervous system diseases, characterized in that, The morphinan compound is selected from one or more of the following compounds: A-1, A-2, A-63, A-120, A-121, A-123, A-130, A-131, A-153, A-154, A-156, A-158, A-163, A-168, A-173, A-174, A-176 to A-424.

12. Use according to claim 10 or 11, characterized in that, The central nervous system disease is selected from: schizophrenia; refractory, treatment-resistant or chronic schizophrenia; depression; endogenous depression; major depression; refractory depression; depression with risk of suicide; anxiety; anxiety associated with depression; dysthymic disorder; Parkinson's disease; Alzheimer's disease; depression or agitation associated with Alzheimer's disease; cognitive disorders; various dementias; pseudobulbar palsy; pseudobulbar affect; autism; neurological disorders and neurodegenerative diseases; chronic pain; intractable pain; sympathetically-mediated pain; oral pain; back pain; central pain syndromes; complex regional pain syndrome; cough; intractable cough.

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