WO2025098212A1 - N,n-dimethyltryptamine derivative, and pharmaceutical composition thereof, preparation method therefor and use thereof - Google Patents

Abstract

Disclosed in the present application are an N,N-dimethyltryptamine derivative, and a pharmaceutical composition thereof, a preparation method therefor and the use thereof. The N,N-dimethyltryptamine derivative is as represented by formula (I), and specific substituents and definitions are as described in the description. The N,N-dimethyltryptamine derivative has a good binding capacity to 5-HT_2A, and the compound or the pharmaceutical composition thereof are used for treating 5-HT_2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions.

Description

N,N-dimethyltryptamine derivative and pharmaceutical composition, preparation method and use thereof

This application claims priority to the Chinese patent application filed on November 6, 2023, with application number 202311463634.6, and invention name “A N,N-dimethyltryptamine derivative and its pharmaceutical composition, preparation method and use”, and the Chinese patent application filed on August 9, 2024, with application number 202411096546.1, and invention name “A N,N-dimethyltryptamine derivative and its pharmaceutical composition, preparation method and use”, the contents of which should be understood as being incorporated into this application by reference.

Technical Field

The present application belongs to the field of pharmaceutical chemistry, and specifically relates to an N,N-dimethyltryptamine derivative and a pharmaceutical composition, a preparation method and use thereof.

Background Art

N,N-dimethyltryptamine (DMT) is an indolealkylamine alkaloid that is endogenously present in a variety of plant and animal species. DMT is a psychoactive hallucinogenic compound that can cause strong changes in human perception, mood, and cognition (Cameron, ACS Chem Neurosci. 17; 9(10): 2344-2357, 2018). DMT interacts with a variety of ionotropic and metabotropic receptors, the most well-known of which are serotonin receptors, especially 5-HT _2A (Rickli, Eur Neuropsychopharmacol. 26(8): 1327-37. 2016).

Serotonin receptors are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems, mediating excitatory and inhibitory neurotransmission. Serotonin receptors are activated by the neurotransmitter serotonin (5-hydroxytryptamine). In autopsies of patients with depression, an increase in density in the cortex can be detected. Long-term use of a variety of antidepressants can downregulate the density of 5-HT _2A receptors and exert antidepressant effects by affecting the forebrain subcortical circuit. In addition, 5-HT _2A receptors are important factors in sleep regulation and cognitive function (Eison, Behav Brain Res. 73 (1-2): 177-81. 1996; Umbricht, Neuropsychopharmacology. 28 (1): 170-81. 2003). 5-HT _2A receptors have become a hot topic of extensive research as a target for the treatment of mental disorders such as depression. Major depressive disorder (MDD) is a chronic recurrent mental disorder with clinical manifestations of persistent low mood, loss of interest, loss of appetite, sleep disorders, etc. The pathogenesis of depression is complex and has not yet been clarified (Chen, Sleep, Vol. 46, Issue Supplement_1, A284-A285, 2023).

Clinically, antidepressant SSRI drugs that act on 5-HT _2A receptors include ritanserin, YM-992 (lubazodone), volinanserin, LY-367265 and nefazodone. They all have high affinity for 5-HT _2A receptors and show effective efficacy in treating depression. However, as clinical trials progress, their shortcomings have gradually become apparent, including more adverse reactions, such as dry mouth, nausea and vomiting, constipation, diarrhea and liver failure; a long onset time, and the drug often takes more than 3 weeks to fully exert its antidepressant effect; low clinical response values, no therapeutic effect on some patients; and even symptoms of poisoning (Seo, J Med Chem, Sep 22; 54(18): 6305-1, 2011; Pullar, Eur J Pharmacol, Oct 27; 407(1-2): 39-46, 2000).

New fast-acting antidepressant psychotherapeutic hallucinogenic compounds, such as psilocybin, lysergic acid diethylamide (LSD), and ketamine, have a rapid onset of action and are effective in relieving anxiety and depressive symptoms ( Curr Top Behav Neurosci, 36:45-73, 2018). However, psilocybin has a strong agonist effect on 5-HT _2B receptors and is cardiotoxic; both LSD and psilocybin show rapid tolerance to serotonin receptors, and neither is well suited to repeated dosing regimens.

From the above reports, we can see that there are limitations in our understanding of the pathogenesis of depression, and existing antidepressant drugs have certain defects and still fail to meet clinical needs. Therefore, it is of great significance to explore more effective and safer antidepressant drugs.

Summary of the invention

The following is a summary of the subject matter described in detail in this application. This summary is not intended to limit the scope of the claims.

In a first aspect, the present application provides a compound as shown in formula (1), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof:

in,

_R1 and _R2 are each independently selected from the group consisting of hydroxy, unsubstituted _C1 - _C6 alkyl, substituted C1- _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted _C1 - _C6 alkoxy, unsubstituted _C3 - _C6 cycloalkyl, substituted _C3 - _{C6 cycloalkyl} , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; or

_R1 and _R2 form an unsubstituted nitrogen-containing heterocyclic ring or a substituted nitrogen-containing heterocyclic ring with the nitrogen atom to which they are directly attached;

R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium and substituted C ₁ -C ₆ alkyl; or, R ₃ and R ₄ or R ₅ and R ₆ and their connecting carbon atoms form a -C(O)- group or a -C(S)- group;

_R7 is one, two, three or four and is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted C1- _C6 alkoxy, substituted _C1 -C6 alkoxy, _C1 - _C6 alkanoyloxy, aryloxy, heteroaryloxy, _{C1 - C6} alkoxy-substituted _C1 - _C6 alkanoyloxy, _C1 - _C6 alkanesulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, phosphoryloxy and hydroxyl _;

R ₈ is hydrogen, deuterium, substituted C ₁ -C ₆ alkyl, unsubstituted C ₃ -C ₆ cycloalkyl or substituted C ₃ -C ₆ cycloalkyl;

Y is N or CR ₁₁ ; when Y is N, R ₉ and R ₁₀ are each independently hydrogen, hydroxyl, thiol; or R ₉ and the carbon atom to which it is connected form a -C(O)- group or a -C(S)- group; when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, and R ₉ is hydrogen, hydroxyl, amino, di(C ₁ -C ₄ alkyl)amino or thiol.

In a second aspect, the present application provides a pharmaceutical composition comprising the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, and a pharmaceutically acceptable carrier.

In a third aspect, the present application provides a method for preparing the above-mentioned DMT derivative or its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs.

In a fourth aspect, the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or pharmaceutical composition thereof, for pharmaceutical use.

In a fifth aspect, the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or pharmaceutical composition thereof, for stimulating 5-HT _2A receptor.

In a sixth aspect, the present application provides the above-mentioned DMT derivatives or their stereoisomers, pharmaceutically acceptable salts, solvates, deuterated substances, metabolites or prodrugs, or pharmaceutical compositions thereof, for use in treating 5-HT _2A receptor-related diseases/disorders.

In a seventh aspect, the present application provides the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvent Use of a deuterated compound, deuterated compound, metabolite or prodrug, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a 5-HT _2A receptor-related central nervous system disease, disorder or condition and/or a neurological disease, disorder or condition.

In an eighth aspect, the present application provides a method for treating a 5-HT _2A receptor-related disease/disorder in a patient, the method comprising administering the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, or a pharmaceutical composition thereof to a patient in need.

Details

The present application provides a DMT derivative and a preparation method and use thereof, which overcomes the shortcomings of the prior art such as limited types of antidepressant drugs, adverse reactions, hallucinogenic side effects, etc. At the same time, the DMT derivative of the present application has good binding ability with 5-HT _2A .

In an embodiment of the first aspect, the present application provides a compound as shown in formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof,

in,

_R1 and _R2 are each independently selected from the following groups: hydroxyl, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted C1- _C6 alkoxy, substituted _C1 -C6 alkoxy, unsubstituted _C3 - _C6 cycloalkyl, substituted _C3 - _{C6 cycloalkyl} , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; herein, the substituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkoxy, substituted C3- _C6 cycloalkyl, substituted aryl or substituted heteroaryl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 _{-C3 alkyl , C1} - _C3 alkoxy, hydroxyl, halogen, halogenated _C1 - _C3 alkyl, halogenated C1- _C3 alkoxy, _C3 - _C6 cycloalkyl, aryl and heteroaryl _{; or}

_R1 and _R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; the substituted nitrogen-containing heterocycle refers to being substituted by 1-3 groups independently selected from the following groups: unsubstituted _C1 - _C6 alkyl, and substituted _C1 - _C6 alkyl; the substituted _C1 - _C6 alkyl refers to being substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen, halogenated _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl;

R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium and substituted C ₁ -C ₆ alkyl; or, R ₃ and R ₄ or R ₅ and R ₆ form a -C(O)- group or a -C(S)- group with the carbon atom to which they are connected; herein, the substituted C ₁ -C ₆ alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, halogenated C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl;

_R7 is one, two, three or four and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _{C6 alkyl, unsubstituted C1-C6} alkoxy, substituted _C1 - _C6 alkoxy, _C1 - _C6 alkanoyloxy, aryloxy, heteroaryloxy, _C1 -C6 alkoxy substituted C1- _C6 alkanoyloxy, _C1 - _{C6 alkanesulfonyloxy} , arylsulfonyloxy, substituted _{arylsulfonyloxy} , phosphoryloxy and hydroxy; herein, the substituted _C1 - _C6 alkyl, substituted _{C1 -} C6 alkoxy or substituted arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: _deuterium , C1- _C3 alkyl, _C1 - _C3 alkoxy, phenyl and substituted phenyl; herein, the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: halogen, C1-C3 alkyl, _C1 - _C3 alkoxy, phenyl and substituted phenyl; ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy;

_R8 is hydrogen, deuterium, substituted _C1 - _C6 alkyl, unsubstituted _C3 - _C6 cycloalkyl or substituted _C3 - _C6 cycloalkyl, wherein the substituted C3- _C6 cycloalkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen, halogenated _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl; the substituted _C1 - _C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkoxy, halogen, halogenated _{C1 - C3} alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl;

Y is N or CR ₁₁ ; when Y is N, R ₉ and R ₁₀ are each independently hydrogen, hydroxyl or thiol, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, and R ₉ is hydrogen, hydroxyl, amino, di(C ₁ -C ₄ alkyl)amino or thiol.

The present application provides a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein, when Y is _CR11 , _R10 and _R11 form a bond, _R8 is hydrogen, _R9 is hydrogen, one or two of _R3 and _R4 are deuterium, and _R5 and _R6 are both hydrogen, _R1 and _R2 are not selected from the following groups: methyl, deuterated methyl, ethyl, propyl, deuterated ethyl and deuterated propyl; and/or

When Y is CR ₁₁ , R ₁₀ forms a bond with R ₁₁ , R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all deuterium, R ₁ and R ₂ are all deuterated methyl, R ₇ is not hydrogen, fluorine, methoxy, deuterated methoxy, benzylphosphoryloxy, phosphoryloxy or hydroxy; and/or

When Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ and R ₂ cannot be deuterated methyl at the same time, and when R ₁ is deuterated methyl, deuterated ethyl or deuterated propyl, R ₂ is not methyl, ethyl, propyl or deuterated ethyl; and/or

When Y is CR ₁₁ , R ₁₀ forms a bond with R ₁₁ , R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is methyl, ethyl, propyl, isopropyl, allyl or cyclopropyl, R ₂ is methyl, ethyl, propyl, isopropyl, allyl, isobutyl, cyclopropylmethyl, cyclopropyl, benzyl or phenyl, R ₇ is not hydrogen, hydroxy, fluoro, methyl or methoxy; and/or;

when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is propylethyl, R ₂ is propyl, R ₇ is not hydroxy, methoxy, acetoxy, phosphoryloxy, p-nitrobenzenesulfonyloxy, p-trifluoromethylbenzoyloxy, p-fluorobenzoyloxy, pivaloyloxy, methanesulfonyloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl; and/or

when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is methyl, R ₂ is methyl or ethyl, R ₇ is not hydroxy, methoxy, acetoxy, phosphoryloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl; and/or

When Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, at least two of R ₃ , R ₄ , R ₅ and R ₆ are deuterium and the rest are hydrogen or all are deuterium, R ₁ is methyl, R ₂ is methyl, R ₇ is not methoxy; and/or

When Y is _CR11 , _R10 and _R11 form a bond, _R8 is hydrogen, _R9 is hydrogen, _R3 , _R4 , _R5 and _R6 are all hydrogen, _R1 and _R2 form a nitrogen-containing heterocyclic ring with the nitrogen atom to which they are directly attached, _R7 is not hydrogen, hydroxy, methoxy, fluorine, chlorine, bromine or iodine.

The present application provides a compound as shown in formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein the compound does not include the following compounds: 5-hydroxy-N,N-dimethyltryptamine, 5-bromo-N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, Psilocybin, Psilocin, 5-methoxy-N,N-diallyltryptamine, 5-methoxy-N-allyl-N-methyltryptamine, 4-hydroxy-N,N-diethyltryptamine, 4-acetoxy-N,N-dimethyltryptamine, 4-hydroxy-N.N-dipropyltryptamine, 5-methoxy-N,N-dipropyltryptamine, 5-methoxy-N-isopropyl-N-methyltryptamine or 4-hydroxy-N-isopropyl-N-methyltryptamine.

In some embodiments, the compound provided herein as shown in formula (I), or its stereoisomers, pharmaceutically An acceptable salt, solvate, deuterated compound, metabolite or prodrug, wherein when Y is N, formula (I) is formula (IA):

In formula (IA), R ₁ -R ₈ are as defined in formula (I), R ₉ and R ₁₀ are each independently hydrogen, hydroxyl or thiol, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; or

When Y is CR ₁₁ , formula (I) is formula (IB):

In formula (IB), R ₁ to _{R 8} are as defined in formula (I), and R ₉ is hydrogen, hydroxy, amino, di(C ₁ -C ₄ alkyl)amino or mercapto.

In some embodiments, _R1 and _R2 in Formula (I), (IA) or (IB) are selected from the following groups: hydroxyl, unsubstituted _C1 - _C6 alkyl, substituted C1-C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted _C1 - _C6 alkoxy, unsubstituted _C3 - _C6 cycloalkyl, substituted _C3 - _C6 cycloalkyl, unsubstituted aryl and unsubstituted heteroaryl; herein, the substituted _{C1 - C6} alkyl, substituted _C1 - _C6 alkoxy or substituted _C3 - _C6 cycloalkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, hydroxyl, halogen, halogenated _C1 - _C3 alkyl, halogenated _C1 - _C3 alkoxy, _C3 - _{C6 6} cycloalkyl, phenyl, substituted phenyl, pyridyl and pyrimidyl; the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₃ alkanoyloxy;

Preferably, the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl;

Preferably, the C ₁ -C ₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy;

Preferably, the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

Preferably, the aryl group is phenyl or naphthyl;

Preferably, the heteroaryl group is pyridyl or pyrimidinyl;

Preferably, the substituents of the substituted C ₁ -C ₆ alkyl are independently selected from the following 1-3 groups: deuterium, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl;

Preferably, the substituents of the substituted C ₁ -C ₆ alkoxy group are independently selected from the following 1 to 3 groups: deuterium, fluorine, chlorine, bromine and iodine.

Preferably, the substituents of the substituted C ₃ -C ₆ cycloalkyl are independently selected from the following 1-3 groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl.

In some embodiments, _R1 and _R2 in Formula (I), (IA) or (IB) are selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, isopropyl, substituted isopropyl, n-butyl, tert-butyl, cyclopropyl, substituted cyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; here, the substituted isopropyl refers to substituted by hydroxyl; the substituted cycloalkyl refers to substituted by a group selected from the following groups: deuterium, fluorine, chlorine, bromine and iodine; the substituted phenyl refers to substituted by a substituent selected from the following groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl and phenyl.

In some embodiments, _R1 and _R2 in Formula (I), Formula (IA) or Formula (IB) are each independently selected from the following groups: hydroxyl, methyl, deuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, deuterated cyclopropyl, fluorocyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; here, the substituted phenyl refers to substituted by a group selected from the following groups: methoxy and trifluoromethyl.

In some embodiments, R ₁ and R ₂ in Formula (I), Formula (IA) or Formula (IB) are each independently selected from the following groups: hydroxy, methyl, trideuteromethyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterocyclopropyl, 2,2-dideuterocyclopropyl, 2,2,3,3-tetradeuterocyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl.

In some embodiments, _R1 and _R2 in Formula (I), Formula (IA) or Formula (IB) form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; here, the unsubstituted nitrogen-containing heterocycle is piperidine or piperazine, and the substituted nitrogen-containing heterocycle is a substituted piperazine or piperidine; here, the substituted nitrogen-containing heterocycle is substituted by 1-3 substituents independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl.

In some embodiments, _R1 and _R2 in Formula (I), Formula (IA) or Formula (IB) form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; the unsubstituted nitrogen-containing heterocycle is piperidine, or the substituted nitrogen-containing heterocycle is 4-(cyclopropylmethyl)piperazine.

In some embodiments, R ₃ , R ₄ , R ₅ , and R ₆ in Formula (I), (IA), or (IB) are independently selected from hydrogen and deuterium; or, R ₃ , R ₄ or R ₅ , R ₆ and the carbon atom to which they are attached form a -C(O)- group or a -C(S)- group.

In some embodiments, _R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each R7 is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted C1- _C6 alkoxy, _{C1 - C6} alkanoyloxy, benzoyloxy, _C1 - _C6 alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _C6 alkanesulfonyloxy, benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkoxy or substituted benzenesulfonyloxy refers to being substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 -C6 ₃ alkoxy, phenyl and substituted phenyl, wherein the substituted phenyl refers to substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy.

In some embodiments, _R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy means that its benzene ring is substituted by 1-3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxy, phenyl, formyloxy, acetoxy and propionyloxy;

In some embodiments, _R7 in Formula (I), Formula (IA) or Formula (IB) is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, hydroxyl, fluorine, chlorine, bromine, 1,1-dideuteroethyl, methoxy, (4-acetoxy)benzyloxy, acetoxy, methoxycarbonyloxy, phosphoryloxy, and methanesulfonyloxy.

In some embodiments, _R in Formula (I), (IA) or (IB) is at the 4th position (uppermost position), 5th position, 6th position or 7th position (lowermost position) of the phenyl ring to which it is attached, in counterclockwise order:

In some embodiments, R ₈ in Formula (I), Formula (IA) or Formula (IB) is selected from the group consisting of hydrogen, C ₃ -C ₆ cycloalkyl, substituted C ₁ -C ₆ alkyl.

In some embodiments, R ₈ in formula (I) is selected from the following substituents: hydrogen, cyclopropylmethyl, deuterated methyl.

In some embodiments, the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R1 and _R2 in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, isopropyl, hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, substituted cyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; herein, the substituted cycloalkyl refers to substituted by a group selected from the following groups: deuterium, fluorine, chlorine, bromine and iodine; the substituted phenyl refers to substituted by a substituent selected from the following groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl and phenyl;

Alternatively, in formula (I), formula (IA) or formula (IB), _R1 and _R2 and the nitrogen atom to which they are directly attached form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle; the nitrogen-containing heterocycle is piperidine or piperazine; the substituted nitrogen-containing heterocycle refers to being substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl;

R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen and deuterium; or, R ₃ , R ₄ or R ₅ , R ₆ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group;

_R7 is one, two, three or four, and each is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 -C6 alkoxy, substituted C1- _C6 alkoxy, _C1 - _C6 alkanoyloxy, benzoyloxy, _{C1 - C6} alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _{C6 alkanesulfonyloxy} , benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkoxy or substituted benzenesulfonyloxy refers to being substituted by 1 to 3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 -C6 ₃ alkoxy, phenyl and substituted phenyl, wherein the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

R ₉ is hydrogen, amino or di(C ₁ -C ₄ alkyl)amino, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group.

In some embodiments, the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, ethyl, n-propyl, 2-hydroxyisopropyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, deuterated cyclopropyl, fluorocyclopropyl, deuterated substituted methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; Here, the substituted phenyl refers to substituted by a group selected from the following: methoxy and trifluoromethyl;

Alternatively, _R1 and _R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; the nitrogen-containing heterocycle is piperidine or piperazine; the substituted nitrogen-containing heterocycle refers to being substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; or, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

_R7 is one, two, three or four, and each is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 -C6 alkoxy, substituted C1- _C6 alkoxy, _C1 - _C6 alkanoyloxy, benzoyloxy, _{C1 - C6} alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _{C6 alkanesulfonyloxy} , benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkoxy or substituted benzenesulfonyloxy refers to being substituted by 1 to 3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 -C6 ₃ alkoxy, phenyl and substituted phenyl, wherein the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

R ₉ is hydrogen, amino or di(C ₁ -C ₄ alkyl)amino, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group.

In some embodiments, the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, deuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl;

Alternatively, R ₁ and R ₂ together with the nitrogen atom to which they are directly attached form piperidine or 4-(cyclopropylmethyl)piperazine;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; or, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

In formula (I), Y is N or CR ₁₁ , wherein R ₁₀ and R ₁₁ form a bond;

_R9 is hydrogen, amino or dimethylamino, or _R9 and _R10 and the carbon atom to which they are connected form a -C(O)- group.

In some embodiments, the present application provides a compound represented by formula (I), formula (IA) or formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (I), formula (IA) or formula (IB) are each independently selected from the following groups: hydroxyl, methyl, trideuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, Phenyl and (5-trifluoromethyl-2-methoxy)phenyl;

Alternatively, R ₁ and R ₂ together with the nitrogen atom to which they are directly attached form piperidine or 4-(cyclopropylmethyl)piperazine;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; or, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

In formula (I), Y is N or CR ₁₁ , wherein R ₁₀ and R ₁₁ form a bond;

_R9 is hydrogen, amino or dimethylamino, or _R9 and _R10 and the carbon atom to which they are connected form a -C(O)- group.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (IB) are each independently selected from the following groups: hydroxyl, methyl, trideuterated methyl, ethyl, n-propyl, isopropyl, 2-hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium;

R ₇ is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

In formula (I), Y is N or CR ₁₁ , wherein R ₁₀ and R ₁₁ form a bond;

_R9 is hydrogen, amino or dimethylamino.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein in formula (IB), R ₁ is -CD ₃ , R ₂ is cyclopropyl or cyclopropylmethyl;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium;

R ₇ is one, two, three or four and is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl:

R ₈ is a substituent selected from the following: hydrogen;

_R9 is hydrogen, amino or dimethylamino.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (I), formula (IA) or formula (IB) form piperidine or 4-(cyclopropylmethyl)piperazine with the nitrogen atom to which they are directly attached;

R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; or, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy;

R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl;

_R9 is hydrogen, amino or dimethylamino.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ in formula (I), formula (IA) or formula (IB) form piperidine or 4-(cyclopropylmethyl)piperazine with the nitrogen atom to which they are directly attached;

R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;

R ₈ is a substituent selected from the group consisting of hydrogen and cyclopropylmethyl;

_R9 is hydrogen.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein in formula (I), formula (IA) or formula (IB), R ₁ is methyl, and R ₂ is 2-hydroxyisopropyl;

R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetyloxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;

_R8 is hydrogen;

_R9 is hydrogen.

In some embodiments, the present application provides a compound represented by formula (IB), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein formula (I), formula (IA) or formula (IB) wherein R ₁ is methyl and R ₂ is cyclopropyl;

R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen;

R ₇ is one, two, three or four and is independently selected from the following groups: deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl;

_R8 is hydrogen;

_R9 is hydrogen.

In some embodiments, the compound provided by the present invention is a compound of formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein formula (I) is formula (IC):

Wherein, in formula (IC), n is 0 or 1;

R1 _is unsubstituted _C1 - _C6 alkyl or substituted _C1 - _C6 alkyl, wherein the substituted _C1 - _C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 -C3 alkyl, _C1 - _C3 alkoxy, hydroxy, halogen, halogenated _C1 - _C3 alkyl, halogenated C1- _C3 alkoxy, _{C3 -C6 cycloalkyl} , aryl and heteroaryl _;

_R7 is one, two, three or four and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _{C6 alkyl, unsubstituted C1-C6} alkoxy, substituted _C1 - _C6 alkoxy, _C1 - _C6 alkanoyloxy, aryloxy, heteroaryloxy, _C1 -C6 alkoxy substituted C1- _{C6 alkanoyloxy, C1-C6 alkanesulfonyloxy , arylsulfonyloxy} , substituted _{arylsulfonyloxy} , phosphoryloxy and hydroxy; herein, the substituted _C1 - _C6 alkyl, substituted _{C1 -} C6 alkoxy or substituted arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: _deuterium , C1- _C3 alkyl, _C1 - _C3 alkoxy, phenyl and substituted phenyl; herein, the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: halogen, C1-C3 alkyl, _C1 - _C3 alkoxy, phenyl and substituted phenyl; ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy.

In some embodiments, the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 0.

In some embodiments, the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 1.

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl or deuterated tert-butyl.

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ is a deuterated methyl group.

In some embodiments, the compound provided herein is as shown in formula (IC), or its stereoisomers, pharmaceutically An acceptable salt, solvate, deuterated compound, metabolite or prodrug, wherein R ₁ is -CD ₃ .

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R7 is one, two, three or four, and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted C1- _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted _C1 - _C6 alkoxy, _C1 - _C6 alkanoyloxy, aromatic acyloxy, heteroaroyloxy, _C1 - _C6 alkoxy substituted _C1 - _C6 alkanoyloxy, C1- _C6 alkanesulfonyloxy, aromatic sulfonyloxy, substituted aromatic sulfonyloxy, phosphoryloxy and hydroxyl; herein, the substituted _C1 - _C6 alkyl, substituted _{C1 - C6} alkoxy or substituted aromatic sulfonyloxy refers to being substituted by 1-3 groups independently selected from the following groups: deuterium, C1- _C6 alkoxy or substituted aromatic sulfonyloxy. ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl and substituted phenyl, wherein the substituted phenyl refers to substituted by 1 to 3 groups independently selected from the following groups: halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy.

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R7 is one, two, three or four, and each R7 is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted C1- _C6 alkoxy, _{C1 - C6} alkanoyloxy, benzoyloxy, _C1 - _C6 alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _C6 alkanesulfonyloxy, benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted _C1 - _C6 alkyl, substituted _C1 -C6 _The substituted phenyl group refers to a substituted phenyl group which is independently selected from the following groups: fluorine, chlorine, bromine _{, C 1} -C ₃ alkyl, C _{1 -C 3} alkoxy, hydroxy, phenyl and C _{1 -C 6} alkanoyloxy.

In some embodiments, the present application provides a compound as shown in formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₇ is one, two, three or four and is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy;

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, hydroxyl, fluorine, chlorine, bromine, 1,1-dideuteroethyl, methoxy, (4-acetoxy)benzyloxy, acetoxy, methoxycarbonyloxy, phosphoryloxy, and methanesulfonyloxy.

In some embodiments, the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R7 is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl.

In some embodiments, the present application provides a compound as shown in formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R7 is at the 4-position, 5-position, 6-position or 7-position of the benzene ring to which it is attached (i.e., the position determined by the indole structure).

In some embodiments, the compound of formula (IC) provided herein, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug thereof, wherein n is 0; R ₁ is -CD ₃ ; R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl. base.

In some embodiments, the present application provides a compound of formula (IC), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 1: R ₁ is -CD ₃ : R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl.

Furthermore, the compound of formula (I) is selected from the following compounds, and stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs thereof:

In an embodiment of the second aspect, the present application provides a pharmaceutical composition comprising the above-mentioned DMT derivative or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, and a pharmaceutically acceptable carrier.

In some embodiments, the present application also discloses a pharmaceutical composition, comprising: an effective dose of a DMT derivative or a stereoisomer thereof represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents.

This or these pharmaceutically acceptable excipients can be, for example, selected from carriers (e.g., solid, liquid or semisolid carriers), adjuvants, diluents (e.g., solid diluents such as fillers or extenders; and liquid diluents such as solvents and co-solvents), granulating agents, binders, glidants, coating agents, release controlling agents (e.g., polymers or waxes that retard or delay release), binders, disintegrants, buffers, lubricants, preservatives, antifungal and antibacterial agents, antioxidants, buffers, tonicity regulators, thickeners, flavor enhancers, sweeteners, pigments, plasticizers, taste masking agents, stabilizers or any other excipients conventionally used in pharmaceutical compositions.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects (e.g., human subjects) without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio. Each excipient must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intravaginal or transdermal administration.

Suitable pharmaceutical dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets or patches such as buccal patches.

In an embodiment of the third aspect, the present application provides a method for preparing a DMT derivative represented by the above formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug thereof, the preparation method comprising the following steps:

(1) Substitution reaction of the compound (I-1) with oxalyl chloride to obtain a compound (I-2);

(2) Acylation reaction of formula (I-2) with formula (I-3) to obtain a compound of formula (I-3);

(3) The compound of formula (I-4) is subjected to reduction reaction to obtain a compound of formula (I-5);

Optionally, the compound of formula (I-4) is subjected to a thiocarbonylation reaction to obtain a compound of formula (I-5);

Alternatively, the method comprises the following steps: a compound of formula (I-6) is subjected to a substitution reaction with a compound of formula (I-7) to obtain a compound of formula (I-8);

Formula (I-8) and formula (I-9) undergo substitution reaction to obtain a compound of formula (I-5);

(4) Substitution reaction of formula (I-5) with formula (I-10) to obtain a compound of formula (I);

In the above preparation method, X represents a leaving group such as bromine, etc., and other groups are defined as formula (I).

In the fourth aspect of the present invention, the present invention provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer thereof, a pharmaceutically acceptable salt, a solvate, a deuterated A compound, metabolite or prodrug, or a pharmaceutical composition thereof, for pharmaceutical use.

In an embodiment of the fifth aspect, the present application provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, for stimulating 5-HT _2A receptors.

In an embodiment of the sixth aspect, the present application provides a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application and its stereoisomers, pharmaceutically acceptable salts, solvates, deuterated compounds, metabolites or prodrugs, or pharmaceutical compositions thereof, for the treatment of 5-HT _2A receptor-related diseases/disorders.

In an embodiment of the seventh aspect, the present application provides the use of a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating 5- _HT2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions.

In some embodiments, the present application provides the above-mentioned use, and the 5-HT _2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions can be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related diseases, decreased drive, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.

In an embodiment of the eighth aspect, the present application provides a method for treating a 5-HT _2A receptor-related disease/disorder in a patient, the method comprising administering to a patient in need thereof a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described in the present application, or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or a pharmaceutical composition thereof.

In some embodiments, the present application provides a method for treating or preventing a patient's central nervous system disease, disorder or condition and/or neurological disease, disorder or condition, the method comprising administering to a patient in need thereof a DMT derivative or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug of formula (I), formula (IA), formula (IB) or formula (IC) described herein, or the pharmaceutical composition. The central nervous system disease, disorder or condition and/or neurological disease, disorder or condition may be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related illness, drive loss, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.

In some embodiments, the present application provides a method for treating a 5-HT _2A receptor-related disease/disorder in a patient, the method comprising administering a DMT derivative represented by formula (I), formula (IA), formula (IB) or formula (IC) described herein, or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or the pharmaceutical composition.

In some embodiments, the present application provides a method for agonizing 5-HT _2A receptors to treat or prevent a patient's central nervous system disease, disorder or condition and/or neurological disease, disorder or condition, the method comprising administering to a patient in need thereof a DMT derivative of formula (I), formula (IA), formula (IB) or formula (IC) or a stereoisomer thereof, a pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, or the pharmaceutical composition described herein. The central nervous system disease, disorder or condition and/or neurological disease, disorder or condition may be selected from: major depressive disorder, anxiety, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related disorders, drive loss, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances.

Beneficial Effects

The compound of the present application can bind to the 5-HT _2A receptor, has good 5-HT _2A receptor binding activity, and has a short half-life, rapid metabolism, is suitable for medicinal use, and has clinical application value.

Definitions and explanations of terms

Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, illustrative, preferred, recorded in tables, and specific compounds in examples, etc., can be combined and coupled with each other at will. The subsequent definitions of groups and compound structures should fall within the scope of the description.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present application include their isotopes, and the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds are optionally further replaced by one or more of their corresponding isotopes, wherein hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, nitrogen isotopes include ¹⁴ N and ¹⁵ N, oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, fluorine isotopes include ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

In the present application, "alkyl" refers to a linear and branched monovalent saturated hydrocarbon group with a main chain comprising 1 to 10 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. The alkyl group may be further substituted by any substituent.

In the present application, "cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, a single ring, usually having 3 to 10 carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The cycloalkyl group may be optionally further substituted by any substituent.

In the present application, "heterocycloalkane" refers to a saturated cyclic hydrocarbon group containing at least one heteroatom, a monocyclic ring, and the heteroatom is N, O, S, P and its oxidized form, and non-limiting examples include aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thiidine, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, etc. The heterocycloalkane may be optionally further substituted by any substituent.

In the present application, "aryl" refers to a 6-14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6-10 members, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably independently and optionally selected from one or more substituents in hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

In the present application, "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from nitrogen, oxygen, and sulfur. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclic or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring.

In the present application, "pharmaceutically acceptable salt" refers to a salt which retains the biological effectiveness and properties of the free acid or free base and is obtained by reacting the free acid with a non-toxic inorganic base or organic base, or by reacting the free acid with a non-toxic inorganic acid or organic acid.

As used herein, "carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

In the present application, "excipient" refers to an inert substance added to a pharmaceutical composition to further rely on the administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, disintegrants, etc.

In the present application, "prodrug" refers to a compound that can be converted into a biologically active compound of the present application under physiological conditions or by solvolysis. The prodrug of the present application is prepared by modifying the phenolic group in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present application is administered to a mammalian individual, the prodrug is cleaved to form free hydroxyl groups respectively. Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and sodium phosphate derivatives of the compounds of the present application.

As used herein, "effective dose" refers to the amount of a compound that elicits a physiological or medical translation in a tissue, system or subject that is being sought, including an amount of the compound that, when administered to a subject, is sufficient to prevent the occurrence of one or more symptoms of the disorder or condition being treated or to alleviate them to some extent.

In the present application, "solvate" refers to the compounds of the present application or their salts, which also include a stoichiometric or non-stoichiometric solvent bound by non-covalent forces between molecules. When the solvent is water, it is a hydrate.

In the present application, "optionally" or "optionally" means that the event or environment described later may but need not occur, and the description includes the occasions where the event or environment occurs or does not occur. For example, "alkyl optionally substituted with Cl" means that alkyl may but need not be substituted with Cl, and the description includes the situation where alkyl is substituted with Cl and the situation where alkyl is not substituted with Cl.

DETAILED DESCRIPTION

The following will further describe the general formula compounds of the present application and their preparation methods and uses in conjunction with specific examples. The following examples are only for illustration and explanation of the present application and should not be construed as limiting the scope of protection of the present application. All technologies implemented based on the above content of the present application are included in the scope of protection intended by the present application.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

This application uses the following abbreviations:

ACN: acetonitrile;

DCM: dichloromethane

DMF: N,N-dimethylformamide

EA: Ethyl acetate

K ₂ CO ₃ : Potassium carbonate

LiAlD ₄ : lithium aluminum hydride deuterated;

LiAlH ₄ : Lithium aluminum hydride

MTBE: Methyl tert-butyl ether

NaBH ₃ CN: sodium cyanoborohydride;

NaH: Sodium hydride

Na ₂ SO ₄ : Sodium sulfate

PE: petroleum ether;

THF: tetrahydrofuran;

TEA: triethylamine

2-MTHF: 2-Methyltetrahydrofuran

The compounds were named according to the conventional naming conventions in the art; commercial reagents were named according to the supplier's catalog names.

¹ H NMR data were collected and recorded using a Bruker Avance Neo 400MHz/600MHz liquid superconducting nuclear magnetic resonance spectrometer at 400MHz/600MHz, using DMSO-d ₆ as solvent and TMS (δ＝0) as internal standard to report chemical shift δ values (ppm). Mass spectra were collected and recorded using Waters ACQUITY UPLC, and detected using an ACQUITY UPLC BEH C8, 50mm*2.1mm, 1.7μm (20180306-C8-08) column; mobile phase A: 0.01% TFA/H ₂ O; mobile phase B: CH ₃ CN; flow rate: 0.2mL/min; column temperature: 30℃; detection wavelength: UV-210nm. High performance liquid chromatography (HPLC) was determined by Thermo UltiMate 3000 liquid chromatograph, using Venusil ASB C18 (4.6*250mm, 5μm) chromatographic column for detection. Mobile phase A: pH=1.5 phosphoric acid aqueous solution; Mobile phase B: CH ₃ CN; Flow rate: 1.0mL/min; Column temperature: 35°C; Detection wavelength: UV-215nm; Injection volume: 2μL; Gradient elution conditions: Elution at a flow rate of 1.0mL/min throughout the process, first eluting with 95% A and 5% B for 10min, then eluting with 20% A and 80% B for 5min, and finally eluting with 95% A and 5% B for 5min. The percentage is the volume percentage of the mobile phase in the elution solution.

Example 1: Synthesis of 5-(1,1-dideuteroethyl)-3-[1,1,2,2-tetradeuteroyl-2-(dimethylamino)ethyl]-1H-indole, the route is as follows:

Weigh 5-(acetyl)indole (200 mg, 1.26 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (240 mg, 1.89 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5-(acetyl)indole remaining, and 210 mg of intermediate 1a was obtained by vacuum filtration.

Take intermediate 1a (210 mg, 0.84 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh dimethylamine hydrochloride (103 mg, 1.26 mmol, 1.5 eq) and TEA (255 mg, 2.52 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 1a, and LC-MS detected the molecular weight of 1b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 110 mg of intermediate 1b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 1b (110 mg, 0.43 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (90 mg, 2.15 mmol, 5.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 1b, and LC-MS detected the molecular weight of compound 1. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 20 mg of compound 1 as a yellow oil. HPLC purity: 95.01%; MS m/z (ESI): 223.34[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.32 (t, J=8.3Hz, 3H), 2.45 (s, 6H), 6.96-6.94 (m, 1H), 7.02 (d, J=8.3Hz ,1H), 7.10(d,J＝7.5Hz,1H), 7.28(d,J＝1.6Hz,1H), 10.72(d,J＝8.3Hz,1H).

Example 2: Synthesis of 3-[1,1,2,2-tetradeuteride-2-(dimethylamino)ethyl]-1H-indole-7-ol, the route is as follows:

7-(Acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq) was weighed and dissolved in 10 mL of MTBE. Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no 7-(acetoxy)indole remained. 200 mg of intermediate 2a was obtained by filtration under reduced pressure.

Take intermediate 2a (200 mg, 0.75 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh dimethylamine hydrochloride (92 mg, 1.13 mmol, 1.5 eq) and TEA (228 mg, 2.25 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 2a, and LC-MS detected the molecular weight of 2b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 2b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 2b (100 mg, 0.36 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (30 mg, 0.72 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 2b, and LC-MS detected the molecular weight of compound 2. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 22 mg of compound 2 as a yellow oil. HPLC purity: 95.42%; MS m/z (ESI): 209.14[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ2.65 (s, 6H), 6.78-6.73 (m, 1H), 6.89 (d, J = 8.6Hz, 1H), 7.12 (t, J = 7.4Hz, 1H), 7.37-7.34 (m, 1H), 8.51 (s, 1H), 10.72 (d, J = 8.6Hz, 1H).

Example 3: Synthesis of 3-[1,1,2,2-tetradeuteride-2-(dimethylamino)ethyl]-1H-indole-5,6-diphenol, the route is as follows:

5,6-(diacetoxy)indole (200 mg, 0.86 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (164 mg, 1.29 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5,6-(diacetoxy)indole remaining. 140 mg of intermediate 3a was obtained by vacuum filtration.

Take intermediate 3a (140 mg, 0.43 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh dimethylamine hydrochloride (53 mg, 0.65 mmol, 1.5 eq) and TEA (131 mg, 1.29 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 3a, and LC-MS detected the molecular weight of 3b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 50 mg of intermediate 3b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 3b (50 mg, 0.15 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (13 mg, 0.30 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 3b, and LC-MS detected the molecular weight of compound 3. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 10 mg of compound 3 as a yellow oil. HPLC purity: 95.42%; MS m/z (ESI): 225.14[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ2.71 (s, 6H), 6.71 (s, 1H), 6.97 (s, 1H), 7.10 (d, J = 8.6Hz, 1H), 8.86. (s, 1H), 9.01 (s, 1H), 10.78 (d, J = 8.6Hz, 1H).

Example 4: Synthesis of 6-methoxy-3-[1,1,2,2-tetradeuteride-2-(diethylamino)ethyl]-1H-indole, the route is as follows:

Weigh 6-(Methoxy)indole (200 mg, 1.36 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (259 mg, 2.04 mmol, 1.5 eq) dropwise under ice bath, solid precipitates, and TLC is performed after 3 h. When no 6-(methoxy)indole remained, 160 mg of intermediate 4a was obtained by filtration under reduced pressure.

Take intermediate 4a (160 mg, 0.67 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diethylamine hydrochloride (111 mg, 1.01 mmol, 1.5 eq) and TEA (203 mg, 2.01 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 4a, and LC-MS detected the molecular weight of 4b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 75 mg of intermediate 4b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 4b (75 mg, 0.27 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (23 mg, 0.54 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 4b, and LC-MS detected the molecular weight of compound 4. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 15 mg of compound 4 as a yellow oil. HPLC purity: 95.71%; MS m/z (ESI): 251.38[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.12(t,J=7.1Hz,6H),2.57-2.72(m,4H),3.87(s,3H),6.72-6.74(m,1H),6. 90 (d, J=2.2Hz, 1H), 7.18 (d, J=2.2Hz, 1H), 7.62 (d, J=8.6Hz, 1H), 10.58 (s, 1H).

Example 5: Synthesis of 5-(1,1-dideuteroethyl)-3-[1,1,2,2-tetradeuteroyl-2-(diethylamino)ethyl]-1H-indole, the route is as follows:

Weigh 5-(acetyl)indole (200 mg, 1.26 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (240 mg, 1.89 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5-(acetyl)indole remaining, and 150 mg of intermediate 5a was obtained by vacuum filtration.

Take intermediate 5a (150 mg, 0.60 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diethylamine hydrochloride (99 mg, 0.90 mmol, 1.5 eq) and TEA (182 mg, 1.80 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 5a, and LC-MS detected the molecular weight of 5b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 80 mg of intermediate 5b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 5b (80 mg, 0.28 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (59 mg, 1.40 mmol, 5.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 5b, and LC-MS detected the molecular weight of compound 5. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 10 mg of compound 5 as a yellow oil. HPLC purity: 95.36%; MS m/z (ESI): 251.04[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.07 (t, J=7.2Hz, 6H), 1.22 (s, 3H), 2.55-2.69 (m, 4H), 6.91-6.93 (m, 1H), 7. 18 (d, J=2.4Hz, 1H), 7.21 (d, J=8.3Hz, 1H), 7.31 (d, J=1.6Hz, 1H), 10.79 (s, 1H).

Example 6: Synthesis of 3-[1,1,2,2-tetradeuteride-2-(diethylamino)ethyl]-1H-indole-7-ol, the route is as follows:

Weigh 7-(acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq), add 10 mL MTBE to dissolve, and add ice Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under a bath, accompanied by solid precipitation. After 3 h, TLC detected that no 7-(acetoxy)indole remained. 130 mg of intermediate 6a was obtained by filtration under reduced pressure.

Take intermediate 6a (130 mg, 0.49 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diethylamine hydrochloride (81 mg, 0.74 mmol, 1.5 eq) and TEA (149 mg, 1.47 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 6a, and LC-MS detected the molecular weight of 6b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 60 mg of intermediate 6b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 6b (60 mg, 0.20 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (17 mg, 0.40 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 6b, and LC-MS detected the molecular weight of compound 6. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 12 mg of compound 6 as a yellow oil. HPLC purity: 95.47%; MS m/z (ESI): 237.49[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.08 (t, J=8.0Hz, 6H), 2.64-2.60 (m, 4H), 6.68-6.64 (m, 1H), 6.94 (d, J=7.5Hz ,1H), 7.01-6.97(m, 1H), 7.54-7.53(m, 1H), 8.45(s, 1H), 10.79(d, J=8.9Hz, 1H).

Example 7: Synthesis of 3-[1,1,2,2-tetradeuteride-2-(diethylamino)ethyl]-1H-indole-5,6-diphenol, the route is as follows:

5,6-(diacetoxy)indole (200 mg, 0.86 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (164 mg, 1.29 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5,6-(diacetoxy)indole remaining. 130 mg of intermediate 7a was obtained by vacuum filtration.

Take intermediate 7a (130 mg, 0.40 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diethylamine hydrochloride (66 mg, 0.60 mmol, 1.5 eq) and TEA (121 mg, 1.20 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 7a, and LC-MS detected the molecular weight of 7b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 65 mg of intermediate 7b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 7b (65 mg, 0.18 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (15 mg, 0.36 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 7b, and LC-MS detected the molecular weight of compound 7. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 10 mg of compound 7 as a yellow oil. HPLC purity: 95.38%; MS m/z (ESI): 253.15[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.09 (t, J=8.0Hz, 6H), 2.64-2.60 (m, 4H), 6.65 (s, 1H), 7.01 (s, 1H), 7.18 (d, J=8.6Hz, 1H), 8.90 (s, 1H), 8.98 (s, 1H), 10.62 (d, J=8.6Hz, 1H).

Example 8: Synthesis of 6-methoxy-3-{1,1,2,2-tetradeuteride-2-[di(propyl-2-yl)amino]ethyl}-1H-indole, the route is as follows:

Weigh 6-(methoxy)indole (200 mg, 1.36 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (259 mg, 2.04 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 6-(methoxy)indole remaining, and 160 mg of intermediate 8a was obtained by vacuum filtration.

Take intermediate 8a (160 mg, 0.67 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diisopropylamine (102 mg, 1.01 mmol, 1.5 eq) and TEA (203 mg, 2.01 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 8a, and LC-MS detected the molecular weight of 8b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 90 mg of intermediate 8b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 8b (90 mg, 0.30 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (25 mg, 0.60 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 8b, and LC-MS detected the amount of compound 8. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 18 mg of compound 8 as a light yellow solid. HPLC purity: 95.71%; MS m/z (ESI): 279.51[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.09 (d, J=6.7Hz, 12H), 3.07-3.04 (m, 2H), 3.87 (s, 3H), 6.73-6.69 (m, 1H), 6. 90 (s, 1H), 7.18 (d, J = 8.6Hz, 1H), 7.68 (d, J = 7.5Hz, 1H), 10.59 (d, J = 8.6Hz, 1H).

Example 9: Synthesis of 5-(1,1-dideuteroethyl)-3-{1,1,2,2-tetradeuteroyl-2-[di(propyl-2-yl)amino]ethyl}-1H-indole, the route is as follows:

Weigh 5-(acetyl)indole (200 mg, 1.26 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (240 mg, 1.89 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5-(acetyl)indole remaining, and 120 mg of intermediate 9a was obtained by vacuum filtration.

Take intermediate 9a (120 mg, 0.48 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diisopropylamine (73 mg, 0.72 mmol, 1.5 eq) and TEA (146 mg, 1.44 mmol, 3.0 eq), add, 60 ° C oil bath, TLC detects no residue of 9a after 5 hours, LC-MS detects the molecular weight of 9b. The reaction solution is washed with saturated brine, extracted with EA, the organic phase is dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, and eluted by column chromatography (PE: EA = 10: 1) to obtain 60 mg of intermediate 9b.

Take intermediate 9b (60 mg, 0.19 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (40 mg, 0.95 mmol, 5.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 9b, and LC-MS detected the molecular weight of compound 9. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 12 mg of compound 9 as a yellow oil. HPLC purity: 95.91%; MS m/z (ESI): 279.25[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.19 (t, J=8.6Hz, 3H), 1.41 (d, J=6.7Hz, 12H), 3.51-3.45 (m, 2H), 7.12-7.07 (m, 1H ), 7.15 (d, J = 8.4Hz, 1H), 7.30 (s, 1H), 7.35 (d, J = 1.3Hz, 1H), 10.71 (d, J = 8.6Hz, 1H).

Example 10: Synthesis of 3-{1,1,2,2-tetradeuteride-2-[di(propyl-2-yl)amino]ethyl}-1H-indole-7-ol, the route is as follows:

Weigh 7-(acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 7-(acetoxy)indole remaining, and 100 mg of intermediate 10a was obtained by vacuum filtration.

Take intermediate 10a (100 mg, 0.38 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diisopropylamine (58 mg, 0.57 mmol, 1.5 eq) and TEA (115 mg, 1.14 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 10a, and LC-MS detected the molecular weight of 10b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 55 mg of intermediate 10b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 10b (55 mg, 0.17 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (14 mg, 0.34 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 10b, and LC-MS detected the molecular weight of compound 10. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 10 mg of compound 10 as a yellow oil. HPLC purity: 95.67%; MS m/z (ESI): 265.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.22 (d, J=6.7 Hz, 12H), 3.61-3.56 (m, 2H), 6.75-6.70 (m, 1H), 7.05-6.98 (m, 1H), 7.14 (d, J=7.5 Hz, 1H), 7.41-7.38 (m, 1H), 8.32 (s, 1H), 10.72 (d, J=8.6 Hz, 1H).

Example 11: Synthesis of 3-{1,1,2,2-tetradeuteride-2-[di(propan-2-yl)amino]ethyl}-1H-indole-5,6-diphenol, the route is as follows:

Weigh 5,6-(diacetoxy)indole (200 mg, 0.86 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (164 mg, 1.29 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5,6-(diacetoxy)indole remaining. Filter under reduced pressure to obtain 130 mg of intermediate 11a.

Take intermediate 11a (130 mg, 0.40 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh diisopropylamine (61 mg, 0.60 mmol, 1.5 eq) and TEA (121 mg, 1.20 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 11a, and LC-MS detected the molecular weight of 11b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 70 mg of intermediate 11b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 11b (70 mg, 0.18 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (15 mg, 0.36 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 11b, and LC-MS detected the molecular weight of compound 11. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 10 mg of compound 11 as a yellow oil. HPLC purity: 95.81%; MS m/z (ESI): 281.10[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ1.09 (d, J=6.7Hz, 12H), 6.77 (s, 1H), 7.01 (s, 1H), 7.18 (d, J=8.6Hz, 1H), 8.85 (s, 1H), 8.98 (s, 1H), 10.66 (d, J=8.6Hz, 1H).

Example 12: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, The line looks like this:

Indole (200 mg, 1.71 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (326 mg, 2.57 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no indole remained. 250 mg of intermediate 12a was obtained by vacuum filtration.

Take intermediate 12a (250 mg, 1.20 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (199 mg, 1.80 mmol, 1.5 eq) and TEA (364 mg, 3.60 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 12a, and LC-MS detected the molecular weight of 12b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 150 mg of intermediate 12b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 12b (150 mg, 0.61 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (51 mg, 1.22 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 12b, and LC-MS detected the molecular weight of compound 12. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 40 mg of compound 12 was eluted by column chromatography (PE:EA=1:1) to obtain 40 mg of compound 12 as a yellow oil. HPLC purity: 95.11%; MS m/z (ESI): 222.34 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.29-0.36 (m, 2H), 0.40-0.48 (m, 2H), 1.67-1.77 (m, 1H), 6.94-7.03 (m, 1H), 7.02-7.10 (m, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.30-7.38 (m, 1H), 7.51 (d, J=7.8 Hz, 1H), 10.75 (s, 1H).

Example 13: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole-4-ol, the route is as follows:

4-(Acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 4-(acetoxy)indole remaining. 210 mg of intermediate 13a was obtained by vacuum filtration.

Take intermediate 13a (210 mg, 0.79 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (132 mg, 1.19 mmol, 1.5 eq) and TEA (240 mg, 2.37 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 13a, and LC-MS detected the molecular weight of 13b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 120 mg of intermediate 13b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 13b (120 mg, 0.40 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (34 mg, 0.80 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 13b, and LC-MS detected the molecular weight of compound 13. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 30 mg of compound 13 as an off-white solid. HPLC purity: 95.91%; MS m/z (ESI): 238.14 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.32-0.38 (m, 2H), 0.38-0.43 (m, 2H), 1.64-1.76 (m, 1H), 6.52-6.54 (m, 1H), 6.78-6.80 (m, 1H), 6.89 (d, J=7.7 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 8.23 (s, 1H), 10.79 (s, 1H).

Example 14: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole-5-ol, the route is as follows:

5-(Acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5-(acetoxy)indole remaining. 150 mg of intermediate 14a was obtained by vacuum filtration.

Take intermediate 14a (150 mg, 0.56 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (93 mg, 0.84 mmol, 1.5 eq) and TEA (170 mg, 1.68 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 14a, and LC-MS detected the molecular weight of 14b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 60 mg of intermediate 14b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 14b (60 mg, 0.20 mmol, 1.0 eq), add 5 mL 2-MTHF to dissolve, weigh LiAlD ₄ (17 mg, 0.40 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 14b, and LC-MS detected the molecular weight of compound 14. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 10 mg of compound 14 as an off-white solid. HPLC purity: 95.21%; MS m/z (ESI): 238.07[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ0.27-0.39(m,2H),0.38-0.46(m,2H),1.62-1.76(m,1H),6.75(m,1H),7.03(d,J＝ 2.3Hz, 1H), 7.12 (d, J = 2.3Hz, 1H), 7.23 (d, J = 8.5Hz, 1H), 8.91 (s, 1H), 10.72 (s, 1H).

Example 15: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole-6-phenol, the route is as follows:

Weigh 6-(acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 6-(acetoxy)indole remaining, and 210 mg of intermediate 15a was obtained by vacuum filtration.

Take intermediate 15a (210 mg, 0.79 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (132 mg, 1.19 mmol, 1.5 eq) and TEA (240 mg, 2.37 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 15a, and LC-MS detected the molecular weight of 15b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 120 mg of intermediate 15b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 15b (120 mg, 0.40 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (34 mg, 0.80 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 15b, and LC-MS detected the molecular weight of compound 15. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 30 mg of compound 15 as an off-white solid. HPLC purity: 95.08%; MS m/z (ESI): 238.22 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.25-0.31 (m, 2H), 0.40-0.51 (m, 2H), 1.65-1.76 (m, 1H), 6.88-7.02 (m, 1H), 7.15 (d, J=2.1 Hz, 1H), 7.30 (d, J=2.1Hz, 1H), 7.43 (d, J=8.4Hz, 1H), 9.23 (s, 1H), 10.79 (s, 1H).

Example 16: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole-7-ol, the route is as follows:

7-(Acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 7-(acetoxy)indole remaining. 210 mg of intermediate 16a was obtained by vacuum filtration.

Take intermediate 16a (210 mg, 0.79 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (132 mg, 1.19 mmol, 1.5 eq) and TEA (240 mg, 2.37 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 16a, and LC-MS detected the molecular weight of 16b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 120 mg of intermediate 16b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 16b (120 mg, 0.40 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (34 mg, 0.80 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 16b, and LC-MS detected the molecular weight of compound 16. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to obtain 20 mg of compound 16 as an off-white solid. HPLC purity: 95.34%; MS m/z (ESI): 238.14[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ0.34-0.40(m,2H),0.46-0.57(m,2H),1.61-1.80(m,1H),6.85(d,J＝7.5Hz,1H),7.10( d, J=7.7Hz, 1H), 7.20 (d, J=7.9Hz, 1H), 7.43 (d, J=2.4Hz, 1H), 8.33 (s, 1H), 10.79 (s, 1H).

Example 17: Synthesis of 3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole-5,6-diphenol, the route is as follows:

5,6-(diacetoxy)indole (200 mg, 0.86 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (164 mg, 1.29 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 5,6-(diacetoxy)indole remaining. 150 mg of intermediate 17a was obtained by vacuum filtration.

Take intermediate 17a (150 mg, 0.46 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (76 mg, 0.69 mmol, 1.5 eq) and TEA (140 mg, 1.38 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 17a, and LC-MS detected the molecular weight of 17b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 80 mg of intermediate 17b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 17b (80 mg, 0.22 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (18 mg, 0.44 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 17b, and LC-MS detected the molecular weight of compound 17. The reaction solution was quenched with 10% NaOH aqueous solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to obtain 10 mg of compound 17 as an off-white solid. HPLC purity: 95.05%; MS m/z (ESI): 254.14 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ 0.31-0.28(m,2H), 0.46-0.34(m,2H), 1.70-1.65(m,1H), 6.95(s,1H), 7.03(s , 1H), 7.12 (d, J=8.4Hz, 1H), 8.83 (s, 1H), 8.99 (s, 1H), 10.79 (d, J=8.6Hz, 1H).

Example 18: Synthesis of 4-bromo-3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, the route is as follows:

4-Bromoindole (200 mg, 1.02 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (194 mg, 1.53 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 4-bromoindole remaining. 200 mg of intermediate 18a was obtained by vacuum filtration.

Take intermediate 18a (200 mg, 0.70 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (116 mg, 1.05 mmol, 1.5 eq) and TEA (212 mg, 2.10 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 18a, and LC-MS detected the molecular weight of 18b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 18b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 18b (100 mg, 0.31 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (26 mg, 0.62 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 18b, and LC-MS detected the molecular weight of compound 18. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 20 mg of compound 18 as a yellow oil. HPLC purity: 95.32%; MS m/z (ESI): 300.04[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ0.35-0.24(m,2H),0.49-0.35(m,2H),1.79-1.75(m,1H),7.16(d,J=8.6hZ,1H),7 .23 (d, J=7.5Hz, 1H), 7.34-7.30 (m, 1H), 7.61-7.58 (m, 1H), 10.68 (d, J=8.6Hz, 1H).

Example 19: Synthesis of 5-bromo-3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, the route is as follows:

5-Bromoindole (200 mg, 1.02 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (194 mg, 1.53 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no 5-bromoindole remained. 200 mg of intermediate 19a was obtained by vacuum filtration.

Take intermediate 19a (200 mg, 0.70 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (116 mg, 1.05 mmol, 1.5 eq) and TEA (212 mg, 2.10 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 19a, and LC-MS detected the molecular weight of 19b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 19b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 19b (100 mg, 0.31 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (26 mg, 0.62 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 19b, and LC-MS detected the molecular weight of compound 19. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 20 mg of compound 19 as a yellow oil. HPLC Purity: 95.91%; MS m/z (ESI): 300.06 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.27-0.36 (m, 2H), 0.47-0.57 (m, 2H), 1.76-1.89 (m, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.20-7.30 (m, 1H), 7.30-7.32 (m, 1H), 7.63 (d, J=2.4 Hz, 1H), 10.71 (s, 1H).

Example 20: Synthesis of 6-bromo-3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, the route is as follows:

Weigh 6-bromoindole (200 mg, 1.02 mmol, 1.0 eq), add 10 mL MTBE to dissolve, slowly add oxalyl chloride (194 mg, 1.53 mmol, 1.5 eq) dropwise in an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 6-bromoindole remaining. Filter under reduced pressure to obtain 200 mg of intermediate 20a.

Take intermediate 20a (200 mg, 0.70 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (116 mg, 1.05 mmol, 1.5 eq) and TEA (212 mg, 2.10 mmol, 3.0 eq), add, 60 ° C oil bath, TLC detected 20a after 5 hours, LC-MS detected the molecular weight of 20b. The reaction solution was washed with saturated brine, extracted with EA, the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, and eluted by column chromatography (PE: EA = 10: 1) to obtain 100 mg of intermediate 20b.

Take intermediate 20b (100 mg, 0.31 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (26 mg, 0.62 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 20b, and LC-MS detected the molecular weight of compound 20. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 25 mg of compound 20 as a yellow oil. HPLC purity: 95.22%; MS m/z (ESI): 300.01[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ0.35-0.24(m,2H), 0.49-0.38(m,2H), 1.69-1.57(m,1H), 7.16(d, J=8.6Hz,1H), 7. 33-7.29 (m, 1H), 7.54 (d, J = 1.5Hz, 1H), 7.61 (d, J = 7.5Hz, 1H), 10.77 (d, J = 8.6Hz, 1H).

Example 21: Synthesis of 7-bromo-3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, the route is as follows:

7-Bromoindole (200 mg, 1.02 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (194 mg, 1.53 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that there was no 7-bromoindole remaining. 200 mg of intermediate 21a was obtained by filtration under reduced pressure.

Take intermediate 21a (200 mg, 0.70 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (116 mg, 1.05 mmol, 1.5 eq) and TEA (212 mg, 2.10 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 21a, and LC-MS detected the molecular weight of 21b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 21b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 21b (100 mg, 0.31 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (26 mg, 0.62 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 21b, and LC-MS detected the molecular weight of compound 21. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and dried over anhydrous Na ₂ SO _4. The organic phase was concentrated under reduced pressure and eluted by column chromatography (PE:EA=1:1) to obtain 12 mg of compound 21 as a yellow oil. HPLC purity: 95.31%; MS m/z (ESI): 300.15 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.31-0.24 (m, 2H), 0.41-0.34 (m, 2H), 1.74-1.64 (m, 1H), 7.11 (d, J=8.0 Hz, 1H), 7.31-7.27 (m, 1H), 7.58-7.48 (m, 1H), 7.66-7.64 (m, 1H), 10.79 (d, J=8.0 Hz, 1H)

Example 22: Synthesis of 5,6-dibromo-3-{2-[cyclopropyl(trideuterylmethyl)amino]-1,1,2,2-tetradeuterylethyl}-1H-indole, the route is as follows:

5,6-Dibromoindole (200 mg, 0.73 mmol, 1.0 eq) was weighed and dissolved in 10 mL MTBE. Oxalyl chloride (140 mg, 1.10 mmol, 1.5 eq) was slowly added dropwise under ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no 5,6-bromoindole remained. 200 mg of intermediate 22a was obtained by vacuum filtration.

Take intermediate 22a (200 mg, 0.55 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (trideuterylmethyl) amine hydrochloride (92 mg, 0.83 mmol, 1.5 eq) and TEA (167 mg, 1.65 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 22a, and LC-MS detected the molecular weight of 22b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 22b was eluted by column chromatography (PE: EA = 10: 1).

Take intermediate 22b (100 mg, 0.25 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlD ₄ (21 mg, 0.50 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 22b, and LC-MS detected the molecular weight of compound 22. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 22 mg of compound 22 as a yellow oil. HPLC purity: 95.83%; MS m/z (ESI): 380.07 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.39-0.25 (m, 2H), 0.54-0.43 (m, 2H), 1.81-1.70 (m, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 7.62 (s, 1H), 10.70 (d, J=8.6 Hz, 1H).

Example 23: Synthesis of 3-{2-[(cyclopropylmethyl)(methyl)amino]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, methylamine (42 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed, and an oil bath was added at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 23a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 80 mg of intermediate 23a was obtained by column chromatography (PE:EA=1:5).

Take intermediate 23a (80 mg, 0.46 mmol, 1.0 eq), add 3 mL ACN to dissolve, weigh bromomethylcyclopropane (93 mg, 0.69 mmol, 1.5 eq) and TEA (140 mg, 1.38 mmol, 3.0 eq) and add them. After 5 hours, TLC detected that there was no residue of 23a, and LC-MS detected the molecular weight of compound 23. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 30 mg of compound 23 was eluted by column chromatography (PE:EA=1:1) to obtain yellow oil. HPLC purity: 95.77%; MS m/z (ESI): 229.34 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.37-0.45 (m, 2H), 1.17-1.39 (m, 2H), 1.68-1.87 (m, H), 2.21 (s, 3H), 2.51-2.52 (m, 2H), 2.73-2.86(m, 2H), 2.93-3.06(m, 2H), 7.08(d,J=7.4Hz, 1H), 7.08-7.15(m, 1 H), 7.18 (d, J=2.3Hz, 1H), 7.28-7.37 (m, 1H), 7.52 (d, J=7.8Hz, 1H), 10.67 (s, 1H).

Example 24: Synthesis of 3-{2-[(cyclopropylmethyl)(trideuterylmethyl)amino]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, deuterated methylamine hydrochloride (95 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed and added, and the mixture was placed in an oil bath at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 24a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 70 mg of intermediate 24a was obtained by column chromatography (PE:EA=1:5).

Take intermediate 24a (70 mg, 0.39 mmol, 1.0 eq), add 3 mL ACN to dissolve, weigh bromomethylcyclopropane (80 mg, 0.59 mmol, 1.5 eq) and TEA (118 mg, 1.17 mmol, 3.0 eq) and add them. After 5 hours, TLC detected that there was no residue of 24a, and LC-MS detected the molecular weight of compound 24. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 20 mg of compound 24 as a yellow oil. HPLC purity: 95.15%; MS m/z (ESI): 232.40 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.42-0.53 (m, 2H), 1.24-1.39 (m, 2H), 1.62-1.75 (m, H), 2.53 (d, J=6.5 Hz, 2H), 2.66-2.77 (m, 2H), 2.84-2.99 (m, 2H), 7.07-7.14 (m, 1H), 7.11-7.17 (m, 1H), 7.21-7.22 (m, 1H), 7.34-7.36 (m, 1H), 7.45-7.50 (m, 1H), 10.71 (s, 1H).

Example 25: Synthesis of 1-(cyclopropylmethyl)-3-[2-(piperidin-1-yl)ethyl]indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL of DMF was added to dissolve, piperidine (114 mg, 1.34 mmol, 1.5 eq) and K ₂ CO ₃ (369 mg, 2.67 mmol, 3.0 eq) were weighed, and an oil bath was added at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 25a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 150 mg of intermediate 25a was obtained by column chromatography (PE:EA=10:1).

Take intermediate 25a (150 mg, 0.66 mmol, 1.0 eq), add 5 mL DMF to dissolve, weigh NaH (53 mg, 1.32 mmol, 2.0 eq) and add, stir for 30 min, weigh bromomethylcyclopropane (134 mg, 0.99 mmol, 1.5 eq) and add, after 5 h, TLC detected that there was no residue of 25a, and LC-MS detected the molecular weight of compound 25. The reaction solution was washed with saturated brine, extracted with EA, the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, and eluted by column chromatography (PE: EA = 1: 1) to obtain 120 mg of compound 25 as a yellow oil. HPLC purity: 95.72%; MS m/z (ESI): 283.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ0.29-0.35(m,2H), 0.38-0.50(m,2H), 1.03-1.21(m,H), 1.29-1.43 (m,2H), 1.41-1.59(m,4H), 2.38-2.40(m,4H), 2.48-2.55(m,2H), 2.77 -2.79 (m, 2H), 3.87 (d, J = 6.9Hz, 2H), 6.97 (t, J = 7.4Hz, 1H), 7.05 (t, J = 7.6Hz, 1H), 7.14 (s, 1H), 7.33 (d, J = 8.2Hz, 1H), 7.50 (d, J = 7.8Hz, 1H).

Example 26: Synthesis of N-(cyclopropylmethyl)-N-[2-(1H-indol-3-yl)ethyl]hydroxylamine, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL of DMF was added to dissolve, hydroxylamine hydrochloride (93 mg, 1.34 mmol, 1.5 eq) and K ₂ CO ₃ (369 mg, 2.67 mmol, 3.0 eq) were added, and the mixture was placed in an oil bath at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 26a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 50 mg of intermediate 26a was obtained by column chromatography (PE:EA=1:5).

Take intermediate 26a (50 mg, 0.28 mmol, 1.0 eq), add 3 mL DMF to dissolve, weigh bromomethylcyclopropane (57 mg, 0.42 mmol, 1.5 eq) and K ₂ CO ₃ (116 mg, 0.84 mmol, 3.0 eq) and add. After 5 h, TLC detected that there was no residue of 26a, and LC-MS detected the molecular weight of compound 26. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 10 mg of compound 26 as a yellow oil. HPLC purity: 95.01%; MS m/z (ESI): 231.35 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ0.45-0.36(m,2H),0.67-0.54(m,2H),1.22-1.15(m,H),2.51(d,J=7.0Hz,2H),3.05(t,J=7.0Hz,2H),3.25(t,J=7.1Hz,2H),7.08- 7.05 (m, 1H), 7.16-7.11 (m, 1H), 7.28-7.22 (m, 1H), 7.35 (d, J = 7.3Hz, 1H), 7.42 (d, J = 7.1Hz, 1H), 7.68 (s, 1H), 10.72 (d, J = 8.3Hz, 1H).

Example 27: Synthesis of 3-{2-[(cyclopropylmethyl)(2-methylpropan-2-yl)amino]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, 2-methylpropan-2-amine hydrochloride (147 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed, and an oil bath was added at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 27a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 60 mg of intermediate 27a was obtained by column chromatography (PE:EA=1:5).

Take intermediate 27a (60 mg, 0.28 mmol, 1.0 eq), add 3 mL ACN to dissolve, weigh bromomethylcyclopropane (57 mg, 0.42 mmol, 1.5 eq) and TEA (85 mg, 0.84 mmol, 3.0 eq) and add. After 5 h, TLC detected that there was no residue of 27a, and LC-MS detected the molecular weight of compound 27. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 1: 1) was used to elute to obtain 15 mg of compound 27 as a yellow oil. HPLC purity: 95.36%; MS m/z (ESI): 271.46 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ1.35-1.25(m,2H),1.39-1.35(m,2H),1.44(,9H),1.73-1.58(m,H),2.18-2.07(m,2H),2.49-2.36(m,2H),2.89-278(m,2H),2.95-2.9 0 (m, 2H), 6.85-6.72 (m, 1H), 6.94 (d, J=8.5Hz, 1H), 7.08-7.00 (m, 1H), 7.25-7.12 (m, 1H), 7.45 (d, J=7.0Hz, 1H), 10.61 (d, J=8.6Hz, 1H).

Example 28: Synthesis of 3-(2-{[2-methoxy-5-(trifluoromethyl)phenyl](methyl)amino}ethyl)-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, 2-methoxy-5-trifluoromethylaniline (256 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed, and an oil bath was added at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 28a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 40 mg of intermediate 28a was obtained by column chromatography (PE:EA=10:1).

Take intermediate 28a (40 mg, 0.12 mmol, 1.0 eq), add 3 mL THF to dissolve, weigh formaldehyde (5 mg, 0.18 mmol, 1.5 eq) and acetic acid (7 mg, 0.12 mmol, 1.0 eq) and add them. After 8 h, weigh NaBH ₃ CN (15 mg, 0.24 mmol, 2.0 eq) and add them. After 12 h, LC-MS detects the molecular weight of compound 28. The reaction solution is washed with saturated brine, extracted with EA, and the organic phase is dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 5: 1) is used to elute to obtain 10 mg of compound 28 as a yellow oil. HPLC purity: 95.21%; MS m/z (ESI): 349.21 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ2.43 (t, J=7.1Hz, 2H), 2.81 (t, J=7.0Hz, 2H), 3.04 (s, 3H), 3.85 (s, 3H), 6.84 (d, J=7.5Hz, 1H), 7.03-6.94 (m, 1H), 7.08-7. 04 (m, 1H), 7.12 (d, J = 8.3Hz, 1H), 7.21 (m, 1H), 7.32 (m, 1H), 7.45-7.36 (m, 1H), 7.58 (d, J = 7.3Hz, 1H), 10.69 (d, J = 8.6Hz, 1H).

Example 29: Synthesis of 3-{2-[methyl(pyridin-2-ylmethyl)amino]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, 2-pyridinemethylamine (145 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed and added, and the mixture was placed in an oil bath at 60°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of 29a. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 90 mg of intermediate 29a was obtained by column chromatography (PE:EA=1:5).

Take intermediate 29a (90 mg, 0.36 mmol, 1.0 eq), add 3 mL THF to dissolve, weigh formaldehyde (16 mg, 0.54 mmol, 1.5 eq) and acetic acid (22 mg, 0.36 mmol, 1.0 eq) and add them. After 8 h, weigh NaBH ₃ CN (45 mg, 0.72 mmol, 2.0 eq) and add them. After 12 h, LC-MS detects the molecular weight of compound 29. The reaction solution is washed with saturated brine, extracted with EA, and the organic phase is dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE: EA = 5: 1) is used to elute to obtain 30 mg of compound 29 as a yellow oil. HPLC purity: 95.12%; MS m/z (ESI): 266.32 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ2.47(s,3H),2.81-2.70(m,2H),2.97-2.83(m,2H),3.72(s,2H),7.11(d,J＝8.1Hz,1H),7.14(s,1H),7.18(d,J＝8.3Hz,1H),7.33-7.23( m, 1H), 7.35 (d, J=7.1Hz, 1H), 7.54-7.45 (m, 1H), 7.59 (d, J=7.0Hz, 1H), 7.71-7.64 (m, 1H), 8.58 (d, J=7.6Hz, 1H), 10.70 (d, J=8.6Hz, 1H).

Example 30: Synthesis of 3-{2-[4-(cyclopropylmethyl)piperazin-1-yl]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, 1-cyclopropylmethylpiperazine (188 mg, 1.34 mmol, 1.5 eq) and TEA (270 mg, 2.67 mmol, 3.0 eq) were weighed and added, and the mixture was placed in an oil bath at 60°C. After 8 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of compound 30. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=5:1) was used to elute to obtain 180 mg of compound 30 as a yellow solid. HPLC purity: 95.95%; MSm/z(ESI): 284.35[M+H] ⁺ ; ¹ H NMR(400 MHz, DMSO-d ₆ )δ0.29-0.52(m,2H),0.66-0.84(m,2H),1.23-1.41(m,1H),2.25(d,J=6 .6Hz,2H), 2.54-2.56(m,4H), 2.56-2.58(m,4H), 2.90-2.92(m,2H), 2.8 6-3.04 (m, 2H), 6.91 (d, J = 7.4Hz, 1H), 7.08 (d, J = 7.5Hz, 1H), 7.27 (d, J = 2.2Hz, 1H), 7.44 (d, J = 8.0Hz, 1H), 7.64 (d, J = 7.8Hz, 1H), 10.70 (s, 1H).

Example 31: Synthesis of 2-{[2-(1H-indol-3-yl)ethyl](methyl)amino}propan-2-ol, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL ACN was added to dissolve, 2-(methylamino)propan-2-ol (119 mg, 1.34 mmol, 1.5 eq) and TEA (450 mg, 4.45 mmol, 5.0 eq) were weighed and added, and an oil bath was added at 60°C. After 12 h, the molecular weight of compound 31 was detected by LC-MS. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 10 mg of compound 31 was eluted by column chromatography (PE:EA=5:1) to obtain 10 mg of compound 31 as a yellow oil. HPLC purity: 95.21%; MS m/z (ESI): 233.37[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ )δ1.12(s, 6H), 2.50(s, 3H), 3.00-2.91(m, 4H), 4.75(s, 1H), 7.03-6.95(m, 1H), 7.11-7.05 (m, 1H), 7.23 (d, J = 2.4Hz, 1H), 7.35 (d, J = 8.1Hz, 1H), 7.53 (d, J = 7.9Hz, 1H), 10.90 (s, 1H).

Example 32: Synthesis of 3-{2-[cyclopropyl(methyl)amino]ethyl}-1H-indol-5-amine, the route is as follows:

5-Nitroindole (200 mg, 1.23 mmol, 1.0 eq) was weighed and dissolved in 10 mL of MTBE. Oxalyl chloride (235 mg, 1.85 mmol, 1.5 eq) was slowly added dropwise under an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no 5-nitroindole remained. 200 mg of intermediate 32a was obtained by filtration under reduced pressure.

Take intermediate 32a (200 mg, 0.79 mmol, 1.0 eq), add 10 mL ACN, weigh cyclopropyl (methyl) amine hydrochloride (128 mg, 1.19 mmol, 1.5 eq) and TEA (240 mg, 2.37 mmol, 3.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of 32a, and LC-MS detected the molecular weight of 32b. The reaction solution was washed with saturated brine, extracted with EA, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 100 mg of intermediate 32b was obtained by column chromatography (PE: EA = 10: 1).

Take intermediate 32b (100 mg, 0.35 mmol, 1.0 eq), add 5 mL 2-MTHF, weigh LiAlH ₄ (27 mg, 0.70 mmol, 2.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of 32b, and LC-MS detected the molecular weight of compound 32. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 15 mg of compound 32 as a yellow oil. HPLC purity: 95.36%; MS m/z (ESI): 230.15[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ )δ0.34-0.30(m, 2H), 0.49-0.44(m, 2H), 1.71-1.66(m, 1H), 2.34(s, 3H), 2.73-2.70(m, 4H), 4.45(s, 2H) ), 6.47-6.42 (m, 1H), 6.64 (d, J = 2.1Hz, 1H), 6.92 (d, J = 2.3Hz, 1H), 7.01 (d, J = 8.4Hz, 1H), 10.25 (s, 1H).

Example 33: Synthesis of 3-{2-[cyclopropyl(methyl)amino]ethyl}-1H-indole, the route is as follows:

3-(2-bromoethyl)indole (200 mg, 0.89 mmol, 1.0 eq) was weighed, 10 mL of acetonitrile was added to dissolve, N-methylcyclopropylamine hydrochloride (191 mg, 1.78 mmol, 2.0 eq) and TEA (450 mg, 4.45 mmol, 5.0 eq) were weighed and added, and the mixture was placed in an oil bath at 80°C. After 5 h, TLC detected that no 3-(2-bromoethyl)indole remained, and LC-MS detected the molecular weight of compound 33. The reaction solution was washed with saturated brine, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. 80 mg of compound 33 was eluted by column chromatography (PE:EA=1:1) to obtain 80 mg of compound 33 as a yellow oil. HPLC purity: 95.66%; MS m/z (ESI): 215.37[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ )δ10.77 (s, 1H), 7.49 (d, J = 7.9Hz, 1H), 7.32 (d, J = 8.1Hz, 1H), 7.12 (d, J = 2.3Hz, 1H), 7.07-7.02 (m, 1H), 6.99-6.94 ( m, 1H), 2.88-2.81 (m, 2H), 2.80-2.73 (m, 2H), 2.35 (s, 3H), 1.75-1.67 (m, 1H), 0.49-0.38 (m, 2H), 0.35-0.27 (m, 2H).

Example 34: Synthesis of 3-{2-[cyclopropyl(methyl)amino]ethyl}-1H-indole-4-ol, the route is as follows:

4-(Acetoxy)indole (200 mg, 1.14 mmol, 1.0 eq) was weighed and dissolved in 10 mL of MTBE. Oxalyl chloride (217 mg, 1.71 mmol, 1.5 eq) was slowly added dropwise under an ice bath, accompanied by solid precipitation. After 3 h, TLC detected that no 4-(acetoxy)indole remained. 210 mg of intermediate 34a was obtained by filtration under reduced pressure.

Take intermediate 34a (210 mg, 0.79 mmol, 1.0 eq), add 10 mL ACN to dissolve, weigh cyclopropyl (methyl) amine hydrochloride (128 mg, 1.19 mmol, 1.5 eq) and TEA (400 mg, 3.95 mmol, 5.0 eq), add, 60 ° C oil bath, after 5 hours, TLC detected that there was no residue of intermediate 34a, LC-MS detected the molecular weight of intermediate 34b. The reaction solution was washed with saturated brine, extracted with DCM, the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, and eluted by column chromatography (PE: EA = 10: 1) to obtain 100 mg of intermediate 34b.

Take intermediate 34b (100 mg, 0.33 mmol, 1.0 eq), add 5 mL of 2-methyltetrahydrofuran to dissolve, weigh LiAlH ₄ (63 mg, 1.65 mmol, 5.0 eq), and place in an oil bath at 60°C. After 8 h, TLC detected that there was no residue of intermediate 34b, and LC-MS detected the molecular weight of compound 34. The reaction solution was quenched with 10% aqueous NaOH solution, extracted with DCM, and the organic phase was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Column chromatography (PE:EA=1:1) was used to elute to obtain 30 mg of compound 34 as an off-white solid. HPLC purity: 95.97%; LC-MS (ESI) m/z: 231.29 (M+H) ⁺ ; ¹ H NMR (600MHz, DMSO-d6) δ10.57 (s, 1H), 9.87 (s, 1H), 6.90 (d, J = 2.2Hz, 1H), 6.78 (d, J = 7.6Hz, 1H), 6.74 (dd, J = 8.1, 1.0Hz, 1H), 6.26 (dd, J =7.4, 1.0Hz, 1H), 2.91 (t, J = 7.2Hz, 2H), 2.80 (d, J = 7.2Hz, 2H), 2.36 (s, 3H), 1.76 (s, 1H), 0.42 (dd, J = 6.6, 2.3Hz, 2H), 0.38-0.23 (m, 2H).

Biological activity test

1. 5-HT _2A Binding Affinity Determination Experiment

1. Experimental equipment and reagents

5-HT _2A -HEK293 cells were purchased from WuXi AppTec; polyethyleneimine was purchased from Sigma, P3143; 96-well plates were purchased from Agilent, #5042-1385; [ ³ H]-Ketanserin was purchased from Sigma, S006; Filtermate collector was purchased from Perkin Elmer, C961961; TopSeal-A sealing membrane was purchased from Perkin Elmer, #6050185; Unifilter-96GF/C filter plate was purchased from Perkin Elmer; Microscint 20cocktail scintillation fluid was purchased from PerkinElmer, #6013329.

2. Experimental Preparation

The test compound was dissolved in DMSO to 0.02 mM and diluted 4-fold to 8 concentrations; the detection buffer solution was 50 mM Tris-HCl, pH 7.4, and the washing buffer solution was 50 mM Tris-HCl, pH 7.4.

3. Experimental Procedure

1 μL of different concentrations of the test compound (LC) and 1 μL of DMSO (HC) were added to a 96-well plate containing 100 μL of buffer solution and incubated with 5-HT _2a -HEK293 cells, and then 100 μL of radioligand [ ³ H]-Ketanserin (1 μM) was added. Incubate at room temperature at 3000 rpm. Then, soak the Unifilter-96GF/C filter plate with 50 μL of 0.3% polyethyleneimine per well for 0.5 hour at room temperature. Filter the reaction mixture using a Filtermate collector and wash the plate 4 times with cold washing buffer. Dry the filter plate at 50°C for 1 hour, add 50 μL of Microscint 20 cocktail scintillation fluid, seal the plate with TopSeal-A sealing film, let it stand, and detect the [ ³ H] content in a Perkin Elmer MicroBeta2 counter.

4. Analysis methods and results

The inhibition rate was calculated using the formula: % inhibition rate = (1-(assay well-mean_LC)/(mean_HC-mean_LC))*100%.

Data were analyzed using Prism 5. The data were fitted using a “log(inhibitor) vs. response—variable slope” model and are shown in Table 1.

Table 1 5-HT _2A receptor binding affinity data


*Data from Anna Rickli et al., European Neuropsychopharmacology, 2016

As can be seen from Table 1, compared with DMT and Psilocin, compounds 13, 14 and 19 have higher binding affinity to 5-HT _2A .

2. FLIPR Calcium Assays in Whole Cells

1. Experimental equipment and reagents

384-well plates were purchased from Greiner, #781090; Fluo-4 Direct ^TM crystals were purchased from Invitrogen, F10471.

2. Experimental Preparation

The test compound was serially diluted 4-fold to 10 concentrations for later use; probenecid was dissolved in FLIPR assay buffer to prepare a 2.5 mM test solvent for later use; 25 mg of poly-L-lysine hydrobromide was added to 500 mL of ddH ₂ O to prepare a coating solution; a vial of Fluo-4 Direct ^TM crystals was thawed and 10 mL of FLIPR assay buffer was added to the vial to prepare Fluo-4 Direct ^TM loading buffer;

3. Experimental Procedure

5HT _2A -HEK293 cells were trypsinized, centrifuged and the medium was removed. The cells were resuspended in growth medium, counted and seeded at a density of 10×10 ⁵ /mL in a 384-well plate treated with coating solution, and incubated overnight at 37°C, 5% CO _2. The prepared test compound solution was added to the 384-well compound plate. The cell plate was removed, 20 μL of assay buffer and 20 μL of 2×Fluo-4 Direct ^TM loading buffer were added to the 384-well plate, incubated at 37°C, 5% CO ₂ for 50 minutes, and incubated at room temperature for 10 minutes. The cell plate and compound plate were then placed in the FLIPR system, 10 μL of compound and test solvent were transferred from the compound plate to the cell plate, and the fluorescence signal was read.

4. Analysis methods and results

The "max-min" from readings 1 to 90 was calculated to generate the final signal for % effect calculation; data were analyzed using the Prism curve fit equation "log(agonist) vs. response - variable slope." Table 2 shows the results of these assays.

Table 2 Effects of compounds on FLIPR calcium concentration in cells

*Data from Anna Rickli et al., European Neuropsychopharmacology, 2016

As can be seen from the table, by measuring the changes in calcium ion levels, it was found that compounds 13 and 19 can significantly activate intracellular 5-HT _2A receptors, and the ability of compounds 24 and 25 to activate intracellular 5-HT2A receptors is not as good as DMT, but stronger than compound 23 and Psilocin.

3. Experiment on the stability of liver microsomes

1. Experimental equipment and reagents

Male SD rat liver microsomes were purchased from Shanghai Ruide Liver Disease Research Co., Ltd., LM-DS-02M; testosterone was purchased from Shanghai Aladdin Biochemical, L2209423; 7-hydroxycoumarin was purchased from Shanghai Aladdin Biochemical, A2224109; NADPH was purchased from Biyuntian Biotechnology; D-glucarboxylic acid-1,4-lactone-water was purchased from Shanghai Bid Pharmaceutical, GCP490; HPLC-acetonitrile was purchased from Wuhan Futon, FT36F121301; formic acid was purchased from Chengdu Cologne, 2023020601; HPLC instrument was purchased from Thermo, U3000.

2. Experimental Preparation

The samples obtained at each time point in the liver microsome incubation system were precipitated with 3 volumes of acetonitrile, centrifuged, and the supernatant was transferred to a liquid sample bottle with a pipette; NADPH regeneration system (15mM NADPH and 3.2mM magnesium chloride); UGT incubation system (10.8mM UDPGA, 10.8mM D-glucaric acid-1,4-lactone and 83.8μg/mL alamethicone)

3. Experimental Procedure

Referring to the incubation system recommended by Shanghai Ruizhi Chemical Research Co., Ltd. and Suzhou Huizhi Heyuan Biotechnology Co., Ltd., taking the total volume of each incubation system as 60 μL, the system includes 0.1M buffer, 6mg/mL rat liver microsomal protein, NADPH regeneration system, UGT incubation system and the test compound at an appropriate concentration, incubated at 37°C, 600rpm, each sample was paralleled 3 times, testosterone was used as the positive control of phase I metabolic reaction, 7-hydroxycoumarin was used as the positive control of phase II metabolic reaction, and the system without NADPH regeneration system and UGT system was used as the negative control. At the preset reaction time points, such as 0, 5, 15, 30, 60, 90 and 120min, 3 volumes of acetonitrile (containing 0.5% formic acid) were added to terminate the reaction.

4. Analysis methods and results

According to the HPLC detection of each compound in the liver microsome incubation system at each time point, the liquid chromatography peak area value was statistically analyzed, and the obtained data was imported into Excel software for processing and analysis to obtain the residual percentage content-time scatter plot of each compound after metabolism in the liver microsome incubation system and its half-life (T _1/2 ) value. The specific data processing method is as follows:

1) Compound remaining percentage-time diagram:

The formula for calculating the remaining percentage of the compound (Percent Remaining %) is:

Percent Remaining%＝A0/At*100%

A0: HPLC peak area response value of the compound in the liver microsome incubation system at 0h.

At: th, the liquid chromatography peak area response value of the compound in the liver microsome incubation system.

This figure can show the metabolic trend of the compound in the liver microsome incubation system.

2)T _1/2 ：

T _1/2 = ln2/k

k: The slope of the trend line fitted on the ln(Percent Remaining%)-time graph.

This test uses Microsoft Office Excel to process the data. Based on the obtained data, a scatter plot of the remaining percentage of the compound-time is drawn, and the half-life of each compound is calculated. The data are shown in Table 3.

Table 3 Liver microsome stability

The above test results show that compared with compounds 23, 33 and 34, the half-lives of compounds 24, 12 and 13 with deuteration at specific sites are significantly shortened, the metabolic clearance rate is increased, and the safety of the drug is improved.

Claims (21)

A compound as represented by formula (I), or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof;
in, _R1 and _R2 are each independently selected from the following groups: hydroxyl, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted C1- _C6 alkoxy, substituted _C1 -C6 alkoxy, unsubstituted _C3 - _C6 cycloalkyl, substituted _C3 - _{C6 cycloalkyl} , unsubstituted aryl, substituted aryl, unsubstituted heteroaryl and substituted heteroaryl; herein, the substituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkoxy, substituted C3- _C6 cycloalkyl, substituted aryl or substituted heteroaryl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C1 _{-C3 alkyl , C1} - _C3 alkoxy, hydroxyl, halogen, halogenated _C1 - _C3 alkyl, halogenated C1- _C3 alkoxy, _C3 - _C6 cycloalkyl, aryl and heteroaryl _{; or R1} and _R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; the substituted nitrogen-containing heterocycle is substituted by 1 to 3 groups independently selected from the following groups: unsubstituted _C1 - _C6 alkyl and substituted _C1 - _C6 alkyl; the substituted _C1 - _C6 alkyl is substituted by 1 to 3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen, halogenated _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl; R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, deuterium and substituted C ₁ -C ₆ alkyl; or, R ₃ and R ₄ or R ₅ and R ₆ form a -C(O)- group or a -C(S)- group with the carbon atom to which they are connected; herein, the substituted C ₁ -C ₆ alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogen, halogenated C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, aryl and heteroaryl; _R7 is one, two, three or four and each is independently selected from hydrogen, deuterium, halogen, amino, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted C1-C6 alkoxy, substituted _C1 - _C6 alkoxy, _C1 - _C6 alkanoyloxy, aryloxy, heteroaryloxy, _{C1 - C6} alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _C6 alkanesulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, phosphoryloxy _and hydroxy; _{herein, the substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted} arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, phenyl and substituted phenyl; herein, the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: halogen, C1-C3 ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy; _R8 is hydrogen, deuterium, substituted _C1 - _C6 alkyl, unsubstituted _C3 - _C6 cycloalkyl or substituted _C3 - _C6 cycloalkyl, wherein the substituted C3- _C6 cycloalkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkyl, _C1 - _C3 alkoxy, halogen, halogenated _C1 - _C3 alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl; the substituted _C1 - _C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 - _C3 alkoxy, halogen, halogenated _{C1 - C3} alkyl, _C3 - _C6 cycloalkyl, aryl and heteroaryl; Y is N or CR ₁₁ ; when Y is N, R ₉ and R ₁₀ are each independently hydrogen, hydroxyl or thiol, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, and R ₉ is hydrogen, hydroxyl, amino, di(C ₁ -C ₄ alkyl)amino or thiol; It is also provided that when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, one or both of R ₃ and R ₄ are deuterium, and R ₅ and R ₆ are both hydrogen, R ₁ and R ₂ are not selected from the group consisting of methyl, deuterated methyl, ethyl, propyl, deuterated ethyl and deuterated propyl; and/or When Y is CR ₁₁ , R ₁₀ forms a bond with R ₁₁ , R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all deuterium, R ₁ and R ₂ are all deuterated methyl, R ₇ is not hydrogen, fluorine, methoxy, deuterated methoxy, benzylphosphoryloxy, phosphoryloxy or hydroxy; and/or When Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ and R ₂ cannot be deuterated methyl at the same time, and when R ₁ is deuterated methyl, deuterated ethyl or deuterated propyl, R ₂ is not methyl, ethyl, propyl or deuterated ethyl; and/or When Y is CR ₁₁ , R ₁₀ forms a bond with R ₁₁ , R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is methyl, ethyl, propyl, isopropyl, allyl or cyclopropyl, R ₂ is methyl, ethyl, propyl, isopropyl, allyl, isobutyl, cyclopropylmethyl, cyclopropyl, benzyl or phenyl, R ₇ is not hydrogen, hydroxy, fluoro, methyl or methoxy; and/or; When Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is propyl or ethyl, R ₂ is propyl, R ₇ is not hydroxy, methoxy, acetoxy, phosphoryloxy, p-nitrobenzenesulfonyloxy, p-trifluoromethylbenzoyloxy, p-fluorobenzoyloxy, pivaloyloxy, methanesulfonyloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl; and/or; when Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen, R ₁ is methyl, R ₂ is methyl or ethyl, R ₇ is not hydroxy, methoxy, acetoxy, phosphoryloxy, amino, fluorine, chlorine, bromine, iodine, methyl or trifluoromethyl; and/or When Y is CR ₁₁ , R ₁₀ and R ₁₁ form a bond, R ₈ is hydrogen, R ₉ is hydrogen, at least two of R ₃ , R ₄ , R ₅ and R ₆ are deuterium and the rest are hydrogen or all are deuterium, R ₁ is methyl, R ₂ is methyl, R ₇ is not methoxy; and/or When Y is _CR11 , _R10 and _R11 form a bond, _R8 is hydrogen, _R9 is hydrogen, _R3 , _R4 , _R5 and _R6 are all hydrogen, _R1 and _R2 form a nitrogen-containing heterocyclic ring with the nitrogen atom to which they are directly attached, _R7 is not hydrogen, hydroxy, methoxy, fluorine, chlorine, bromine or iodine. The compound according to claim 1, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein when Y is N, formula (I) is formula (IA):
In formula (IA), R ₁ -R ₈ are as defined in formula (I), R ₉ and R ₁₀ are each independently hydrogen, hydroxyl or thiol, or R ₉ and R ₁₀ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; When Y is CR ₁₁ , formula (I) is formula (IB):
In formula (IB), R ₁ to _{R 8} are as defined in formula (I), and R ₉ is hydrogen, hydroxy, amino, di(C ₁ -C ₄ alkyl)amino or mercapto. The compound according to claim 1 or 2, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R1 and _R2 are each independently selected from the following groups: hydroxyl, unsubstituted _C1 - _C6 alkyl, substituted C1- _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted _C1 -C6 alkoxy, unsubstituted _C3 - _C6 cycloalkyl, substituted _C3 - _C6 cycloalkyl, unsubstituted aryl and unsubstituted heteroaryl; wherein the substituted _C1 - _{C6 alkyl, substituted C1-C6 alkoxy or substituted C3-C6 cycloalkyl refers to} substituted by 1 to 3 groups independently selected from the following groups: deuterium, C1- _C3 alkyl, C1- _C3 alkoxy, hydroxyl, halogen, halogenated _C1 - _C3 alkyl, halogenated _{C1 -C3 alkoxy} , _C3 - _C6 cycloalkyl, substituted _C3 - _C6 cycloalkyl, substituted aryl and substituted heteroaryl _. -C ₆ cycloalkyl, phenyl, substituted phenyl, pyridyl and pyrimidyl; the substituted phenyl refers to substituted by 1-3 groups independently selected from the following groups: halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₃ alkanoyloxy; Preferably, the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl; Preferably, the C ₁ -C ₆ alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy; Preferably, the C ₃ -C ₆ cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Preferably, the aryl group is phenyl or naphthyl; Preferably, the heteroaryl group is pyridyl or pyrimidinyl; Preferably, the substituents of the substituted C ₁ -C ₆ alkyl are independently selected from the following 1-3 groups: deuterium, hydroxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl; Preferably, the substituents of the substituted C ₁ -C ₆ alkoxy are independently selected from the following 1-3 groups: deuterium, fluorine, chlorine, bromine and iodine; Preferably, the substituents of the substituted C ₃ -C ₆ cycloalkyl are independently selected from the following 1-3 groups: deuterium, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, trifluoromethoxy, cyclopropyl, phenyl and pyridyl. A compound according to any one of claims 1 to 3, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₁ and R ₂ are each independently selected from the following groups: hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, substituted cyclopropyl, deuterated methyl, cyclopropylmethyl, pyridine-substituted methyl, phenyl and substituted phenyl; herein, the substituted cycloalkyl refers to substituted by a group selected from the following groups: deuterium, fluorine, chlorine, bromine and iodine; the substituted phenyl refers to substituted by a substituent selected from the following groups: deuterium, hydroxy, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl and phenyl; Preferably, _R1 and _R2 are each independently selected from the following groups: hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-hydroxyisopropyl, tert-butyl, cyclopropyl, deuterated cyclopropyl, fluorocyclopropyl, deuterated methyl, cyclopropylmethyl Here, the substituted phenyl group refers to a substituted group selected from the following groups: methoxy and trifluoromethyl; Preferably, R ₁ and R ₂ are each independently selected from the following groups: hydroxy, methyl, trideuteromethyl, ethyl, n-propyl, isopropyl, n-butyl, 2-hydroxyisopropyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterocyclopropyl, 2,2-dideuterocyclopropyl, 2,2,3,3-tetradeuterocyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl. The compound of claim 1 or 2, or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug thereof, wherein _R1 and _R2 form an unsubstituted nitrogen-containing heterocycle or a substituted nitrogen-containing heterocycle with the nitrogen atom to which they are directly attached; wherein the nitrogen-containing heterocycle is piperidine or piperazine; the substituted nitrogen-containing heterocycle refers to being substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyclopropyl, cyclopropylmethyl and phenyl; Preferably, _R1 and _R2 together with the nitrogen atom to which they are directly attached form piperidine or 4-(cyclopropylmethyl)piperazine. The compound according to any one of claims 1 to 2 and 5, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated product, a metabolite or a prodrug thereof, wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen and deuterium; or R ₃ , R ₄ or R ₅ , R ₆ and the carbon atom to which they are connected form a -C(O)- group or a -C(S)- group; Preferably, R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; or, R ₃ , R ₄ , R ₅ and R ₆ are all hydrogen. The compound according to any one of claims 1 to 6, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R7 is one, two, three or four and each is independently selected from the following substituents: hydrogen, deuterium, amino, fluorine, chlorine, bromine, unsubstituted _C1 - _C6 alkyl, substituted _C1 - _C6 alkyl, unsubstituted _C1 - _C6 alkoxy, substituted _C1 - _C6 alkoxy, _C1 - _C6 alkanoyloxy, benzoyloxy, _C1 - _C6 alkoxy substituted _C1 - _C6 alkanoyloxy, _C1 - _C6 alkanesulfonyloxy, benzenesulfonyloxy, substituted benzenesulfonyloxy, phosphoryloxy and hydroxy; _{wherein the substituted C1-C6 alkyl, substituted C1-C6 alkoxy or substituted} benzenesulfonyloxy refers to being substituted by 1 to 3 groups independently selected from the following groups: deuterium, _C1 -C6 C 1 -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl and substituted phenyl, wherein the substituted phenyl refers to substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxy, phenyl and C ₁ -C ₆ alkanoyloxy; Preferably, R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy means that its phenyl ring is substituted by 1-3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy; Preferably, R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, deuterium, hydroxyl, amino, fluorine, chlorine, bromine, 1,1-dideuteroethyl, methoxy, (4-acetyloxy)benzyloxy, acetoxy, methoxycarbonyloxy, phosphoryloxy, methanesulfonyloxy. The compound according to any one of claims 1 to 7, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein R ₈ is selected from the following substituents: hydrogen, cyclopropylmethyl, deuterated methyl. The compound according to any one of claims 1 to 8, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein the formula (I) is the formula (IB), wherein R ₁ and R ₂ in the formula (IB) are each independently selected from the following groups: hydroxyl, methyl, trideuterated methyl, ethyl, n-propyl, isopropyl, 2- hydroxyisopropyl, n-butyl, tert-butyl, cyclopropyl, 2-fluorocyclopropyl, 2-deuterated cyclopropyl, 2,2-dideuterated cyclopropyl, 2,2,3,3-tetradeuterated cyclopropyl, cyclopropylmethyl, (pyridin-2-yl)methyl, phenyl and (5-trifluoromethyl-2-methoxy)phenyl; R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; R ₇ is one, two, three or four and each is independently selected from the following groups: hydrogen, deuterium, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, substituted benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; Here, the substituted benzyloxy group refers to a benzyl ring substituted by 1 to 3 groups independently selected from the following groups: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, hydroxyl, phenyl, formyloxy, acetoxy and propionyloxy; R ₈ is a substituent selected from the group consisting of hydrogen, cyclopropylmethyl, deuterated methyl; In formula (I), Y is N or CR ₁₁ , wherein R ₁₀ and R ₁₁ form a bond; _R9 is hydrogen, amino or dimethylamino. The compound of claim 9, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein in formula (IB), R ₁ is -CD ₃ , and R ₂ is cyclopropyl or cyclopropylmethyl; R ₃ , R ₄ , R ₅ and R ₆ are all deuterium; R ₇ is one, two, three or four and is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, benzyloxy, formyloxy, acetoxy, propionyloxy, benzoyloxy, tert-butoxycarbonyloxy, methoxycarbonyloxy, methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, phosphoryloxy and hydroxyl; R ₈ is a substituent selected from the following: hydrogen; _R9 is hydrogen, amino or dimethylamino. The compound according to claim 1, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein formula (I) is formula (IC):
Wherein, in formula (IC), n is 0 or 1; R1 _is unsubstituted _C1 - _C6 alkyl or substituted _C1 - _C6 alkyl, wherein the substituted _C1 - _C6 alkyl refers to substituted by 1-3 groups independently selected from the following groups: deuterium, _C1 -C3 alkyl, _C1 - _C3 alkoxy, hydroxy, halogen, halogenated _C1 - _C3 alkyl, halogenated C1- _C3 alkoxy, _{C3 -C6 cycloalkyl} , aryl and heteroaryl _{; R7} is one, two, three or four and each is independently selected from hydrogen, deuterium, amino, halogen, unsubstituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkyl, unsubstituted C ₁ -C ₆ alkoxy, substituted C 1 -C 6 alkoxy, C ₁ -C ₆ alkanoyloxy, aryloxy, heteroaryloxy, C _{1 -C 6} alkoxy substituted C ₁ -C ₆ alkanoyloxy, C ₁ -C ₆ alkanesulfonyloxy, arylsulfonyloxy, substituted arylsulfonyloxy, phosphoryloxy and hydroxy; Here, the substituted C ₁ -C ₆ alkyl, substituted C ₁ -C ₆ alkoxy or substituted arylsulfonyloxy refers to substituted by 1-3 groups independently selected from the following groups: deuterium, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, phenyl and substituted phenyl; Here, the substituted phenyl _{refers to substituted by 1-3 groups independently selected from the following groups: halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy , hydroxy ,} phenyl and C ₁ -C _6Alkanoyloxy . The compound according to claim 11, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein _R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, deuterated methyl, deuterated ethyl, deuterated n-propyl, deuterated isopropyl, deuterated n-butyl or deuterated tert-butyl; preferably, _R1 is methyl or deuterated methyl; more preferably, _R1 is _-CD3 . The compound according to claim 11 or 12, or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated compound, a metabolite or a prodrug thereof, wherein n is 0; R ₁ is -CD ₃ ; R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl; or, n is 1; R ₁ is -CD ₃ ; R ₇ is one, two, three or four, and each is independently selected from the following groups: hydrogen, amino, fluorine, chlorine, bromine and hydroxyl. The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug, is selected from any one of the following compounds:

or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug, and a pharmaceutically acceptable carrier. A compound according to any one of claims 1 to 14 or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15, for use in treating a central nervous system disease, disorder or condition and/or a neurological disease, disorder or condition. A compound according to any one of claims 1 to 14 or a stereoisomer, a pharmaceutically acceptable salt, a solvate, a deuterated substance, a metabolite or a prodrug thereof, or a pharmaceutical composition according to claim 15, for use in treating a 5-HT _2A receptor-related disease/disorder. The compound according to any one of claims 1 to 14 or its stereoisomer, pharmaceutically acceptable salt, solvate, deuterated compound, metabolite or prodrug for treating 5- _HT2A receptor-related diseases/disorders according to claim 17, or the pharmaceutical composition according to claim 15, wherein the 5- _HT2A receptor-related central nervous system disease, disorder or condition and/or neurological disease, disorder or condition can be major depressive disorder, anxiety disorder, attention deficit hyperactivity disorder, post-traumatic stress disorder, cancer-related disorders, decreased drive, burnout, cluster headache, migraine, Parkinson's disease, schizophrenia, eating disorders, nausea or vomiting, and abuse of addictive psychoactive substances. A compound according to any one of claims 1 to 14 or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15, for use in treating 5- _HT2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions. Use of a compound according to any one of claims 1 to 14 or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15 in the preparation of a medicament for treating 5- _HT2A receptor-related central nervous system diseases, disorders or conditions and/or neurological diseases, disorders or conditions. A method for treating the following diseases, comprising administering to an individual in need thereof a compound according to any one of claims 1 to 14 or a stereoisomer, pharmaceutically acceptable salt, solvate, deuterated substance, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 15; the disease is a 5- _HT2A receptor-related central nervous system disease, disorder or condition and/or a neurological disease, disorder or condition.