Substituted phenyl-containing amine compound, and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a substituted phenyl-containing amine compound, and a preparation method therefor and the use thereof. The substituted phenyl-containing amine compound is as represented by formula (I), has the function of adjusting the activity of an NMDA receptor and / or a monoamine transporter, and can be used in the preparation of a drug for treating and / or preventing diseases associated with the NMDA receptor and / or monoamine transporter, particularly central nervous system diseases.

Description

A class of amine compounds containing substituted phenyl groups, their preparation methods and uses

[0001] This application claims priority to Chinese Patent Application Nos. 2024105708871, 2024105717300 and 2025102930272, the disclosures of which are incorporated herein by reference in their entirety. Technical Field

[0002] This invention belongs to the field of medicinal chemistry. Specifically, this invention relates to a amine compound containing a substituted phenyl group as shown in formula (I), its preparation method and pharmaceutical compositions comprising the same, and its use in the preparation of medicaments for the prevention or treatment of diseases associated with NMDA receptors and / or monoamine transporters, particularly central nervous system diseases. Background Technology

[0003] Depression is a serious mental illness, primarily characterized by depressed mood, low self-esteem, and even suicidal tendencies. Currently, the main medications for treating depression are SSRIs / SSNIs (Selective Serotonin / Norepinephrine Reuptake Inhibitors). However, these drugs are ineffective in nearly one-third of patients and generally have drawbacks such as slow onset of action and even increasing suicidal tendencies. There is a significant unmet clinical need in this area.

[0004] The NMDA (N-methyl-D-aspartic acid) glutamate receptor (NMDA receptor or NMDAR) is a ligand-gated ion channel. In vivo, this receptor can be activated by glutamate, one of the most important excitatory neurotransmitters in the central nervous system, thereby mediating the transmission of excitatory signals at synapses. Once the NMDAR ion channel opens, it inhibits the transmission of Ca2+ ions. 2+ K + Na + Increased permeability of cations generates excitatory postsynaptic potentials, triggering a series of physiological and biochemical reactions. NMDAR molecules have complex structures, with various subtypes exhibiting specificity in spatiotemporal distribution and pharmacological properties. Their quantity, composition, and distribution dynamically change at different developmental stages and in different brain regions, participating in numerous physiological activities and providing the molecular basis for complex neural activity, thus ensuring the normal functioning of neural networks. The integration, localization, reactivation, and intrasynaptic and extrasynaptic distribution of NMDAR depend on the regulation of neural activity; disruption of its functional homeostasis is highly correlated with numerous brain diseases, such as depression, epilepsy, and schizophrenia.

[0005] Monoamine transporters are a class of proteins found on the cell membranes of neurons in the central and peripheral nervous systems, responsible for transporting commonly used neurotransmitters in synaptic transmission. Monoamine transporter inhibitors are commonly used as antidepressants to treat depression and anxiety disorders, such as bupropion, which inhibits norepinephrine and dopamine transporters, and fluoxetine and citalopram, which inhibit 5-HT transporters.

[0006] The NMDA receptor antagonist ketamine has been used in medicine for over 50 years as a good anesthetic. Studies have found that intravenous administration of subanesthetic doses of the NMDAR antagonist ketamine can rapidly relieve symptoms of depression within hours, and the effect can last for at least a week. Eketamine, developed by Johnson & Johnson, was approved by the FDA in 2019 for the treatment of treatment-resistant depression. Given that the main molecular target of ketamine is NMDAR, many have proposed that inhibiting this target is also the reason for ketamine's antidepressant effect. This mechanism suggests that the antidepressant effect and dissociative side effects of ketamine may be inseparable at the mechanistic level. However, much evidence challenges this hypothesis (J Psychiatry Neurosci. 2017, 42(4), 222.). First, the R enantiomer of ketamine (R-ket) has been found to be more effective and longer-lasting as an antidepressant in rodent models than the S enantiomer (S-ket), despite R-ket having a significantly weaker affinity for NMDAR than S-ket (Pharmacol Biochem Behav. 2014, 116, 137.). Similarly, the ketamine metabolite (2R, 6R)-hydroxynorketamine (HNK) has been shown to induce antidepressant effects in rodent models, but does not bind to NMDAR in vivo at doses that induce antidepressant effects (Nature. 2016, 533(7604), 481. and Proc Natl Acad Sci USA. 2019, 116(11), 5160. and Org Lett. 2017, 19(17), 4572.). Therefore, both R-ket and HNK can induce antidepressant effects while limiting the dissociation of ketamine. However, other strategies proposed to mitigate the dissociation side effects of ketamine have yielded poor results, such as targeting the NR2B subunit of NMDAR or utilizing compounds with low capture properties (Nature. 2016, 533(7604), 481. and Sci Rep. 2017, 7(1), 15725. and Int J Neuropsychopharmacol. 2019, 22(2), 119. and J Psychiatr Res. 2017, 86, 55. and Psychiatry Res. 2016, 239, 281.). Therefore, the precise molecular mechanisms supporting the antidepressant effects of ketamine remain poorly understood and may involve other unidentified targets. Furthermore, the antidepressant effects of NMDAR modulators and the magnitude of their associated dissociation are often highly unpredictable. These findings raise the exciting possibility that the antidepressant effects of ketamine may indeed be separate from its dissociation side effects.

[0007] The dissociative side effects and poor oral bioavailability of ketamine and ethacrylamide greatly limit their clinical application. Although other orally available NMDAR antagonists have been developed, none have yet demonstrated rapid antidepressant efficacy similar to ketamine. Therefore, there remains a pressing need for novel antidepressants with potent clinical efficacy, low or no dissociative side effects, and good oral bioavailability. A drug that retains rapid antidepressant activity similar to ketamine while possessing reduced dissociative side effects and good oral bioavailability would offer a new treatment option that is more manageable and potentially feasible for home use due to its reduced dissociative effects and the associated reduced likelihood of abuse.

[0008] The applicant filed a prior patent application on November 9, 2023, with PCT application number PCT / CN2023 / 130755, entitled "A Class of Aromatic Amine Compounds, Their Preparation Methods and Uses," disclosing the following compounds: 3-(2-amino-6-(methylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol (compound A223); 3-(2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol (compound A305), etc. These compounds exhibit good multi-target inhibitory activity against NMDA receptors and / or monoamine transporters, and show significant efficacy in depression-related models; however, the efficacy / side effects of each individual isomer are not described. Summary of the Invention

[0009] Purpose of the invention

[0010] The purpose of this invention is to provide a novel substituted phenyl amine compound with NMDA receptor and / or monoamine transporter regulatory function, its preparation method and uses.

[0011] One object of the present invention is to provide an amine compound of formula (I) containing a substituted phenyl group, or a stereoisomer, geometric isomer, conformational isomer, tautomer, pharmaceutically acceptable salt, polymorph, solvate, hydrate or isotopically labeled compound thereof.

[0012] Another object of the present invention is to provide a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I).

[0013] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound selected from the formula (I), including its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0014] Another object of the present invention is to provide one or more of the following: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds, or the use of the above pharmaceutical compositions in the preparation of medicaments for regulating the activity of NMDA receptors and / or monoamine transporters.

[0015] Another object of the present invention is to provide one or more of the following: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, or the pharmaceutical compositions thereof, in the preparation of medicaments for the prevention and / or treatment of diseases associated with NMDA receptors and / or monoamine transporters, particularly diseases of the central nervous system.

[0016] Technical solution

[0017] According to one aspect of the present invention, a compound of formula (I) or a stereoisomer, geometric isomer, conformational isomer, tautomer thereof, pharmaceutically acceptable salt, polymorph, solvate, hydrate or isotopically labeled compound is provided:

[0018] According to one aspect of the present invention, a compound of formula (I) is provided:

[0019] Wherein, R1 is selected from CN, -C(O)NH2, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C6-C12 aryl C1-C6 alkoxy; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C6-C12 aryl C1-C6 alkoxy;

[0020] R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2 and R3 together with the attached nitrogen atom form a 3-9 member (e.g., 4, 5, 6 member) heterocyclic alkyl ring, wherein the 3-9 member heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, wherein the 3-9 member heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups;

[0021] R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, CN, and halogen; in particular, R4 is selected from hydrogen or halogen.

[0022] G ring is selected from Specifically, ring G is selected from Each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, carbamoyl (-C(O)NH2), formylamino, C1-C3 alkylamino, halo-C1-C3 alkylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl, C1-C3 alkylaminocarbonyl, C3-C5 cycloalkyl, morpholinyl, phenyl, pyridine, pyrrolidinyl, or piperidinyl; each R6 is independently selected from hydrogen and C1-C3 alkyl; in particular, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkylamino, C1-C3 cycloalkyl, morpholinyl, phenyl, pyridine, pyrrolidinyl, or piperidinyl; each R6 is independently selected from hydrogen and C1-C3 alkyl; in particular, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl ... Amino, hydroxy, carboxyl (-COOH), C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, carbamoyl (-C(O)NH2), formylamino, methylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl (e.g., ethoxycarbonyl), C1-C3 alkylaminocarbonyl (e.g., methylaminocarbonyl (-CONHCH3)), C3-C5 cycloalkyl, morpholino, phenyl, pyridine, pyrrolidinyl or piperidinyl; each R6 is independently selected from hydrogen, C1-C3 alkyl (e.g., methyl);

[0023] Furthermore, the compound shown in formula (I) is not one of the following compounds:

[0024] (1) 6-(2-fluoro-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine;

[0025] (2) 6-(2-fluoro-3-methoxyphenyl)-N6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine;

[0026] In a specific embodiment, in formula (I), R1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyl C1-C4 alkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkyl C1-C4 alkoxy, C6-C10 aryl C1-C4 alkoxy, CN, -C(O)NH2, C1-C4 alkylthiol; particularly, R1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated ... 4. Alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyl C1-C4 alkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkyl C1-C4 alkoxy, C6-C10 aryl C1-C4 alkoxy; preferably, R1 is independently selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy, benzyloxy.

[0027] In a specific embodiment, in formula (I), R1 is independently selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy, benzyloxy, methylthio, CN, -C(O)NH2.

[0028] In a specific implementation, in formula (I), R4 is independently selected from hydrogen or halogen; preferably selected from hydrogen, F, or Cl.

[0029] In a specific implementation, in formula (I), R4 is independently selected from hydrogen, F, Cl, methoxy, CF3, methyl, and CN.

[0030] In a specific embodiment, in formula (I), R2 and R3 are independently selected from hydrogen, C1-C4 alkyl or C3-C5 cycloalkyl, C1-C4 alkyl; or R2, R3 and the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl group; preferably, R2 and R3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropylmethyl; or R2, R3 and the nitrogen atom attached thereto form aziridine, 4-pyrrolidinyl, piperidinyl.

[0031] In a specific embodiment, the compound represented by formula (I) is selected from the structures shown in formulas (I-1) to (I-16):

[0032] Specifically selected from the structures shown in equations (I-1) to (I-4):

[0033] Preferably, the compound represented by formula (I) is selected from the structures shown in formulas (I-1-1) to (I-16-2):

[0034] Specifically selected are the structures shown in the following formulas (I-1-1) to (I-4-2):

[0035] The definitions of R1, R2, R3, R4, R5, and R6 are as described above.

[0036] In one specific embodiment, the compound represented by formula (I) is the compound represented by formula (I-1-a).

[0037] Wherein, R1 is selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C1-C6 alkylthio, CN, -C(O)NH2; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy;

[0038] R2 and R3 are each independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2, R3, together with the nitrogen atom attached thereto, form a 3-9 membered heterocyclic alkyl ring, wherein the 3-9 membered heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, wherein the 3-9 membered heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups.

[0039] Preferably, in formula (I-1-a), R1 is independently selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkylC1-C4 alkoxy; and / or

[0040] R2 and R3 are each independently selected from hydrogen, C1-C4 alkyl, or C3-C5 cycloalkyl; or, R2, R3 and the nitrogen atom attached thereto form a 3-9 membered heterocyclic alkyl group, wherein the 3-9 membered heterocyclic alkyl group is optionally substituted by one or more C1-C4 alkyl groups, and preferably R2, R3 and the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl group.

[0041] More preferably, R1 is independently selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy; and / or

[0042] R2 and R3 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropylmethyl; or R2 and R3 together with the nitrogen atom attached thereto form azircyclic butyl, pyrrolidinyl, piperidinyl, azircyclic heptyl, morpholinyl.

[0043] In one specific embodiment, the compound represented by formula (I) is the compound represented by formula (I-1-b).

[0044] in:

[0045] R1 is selected from halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and C3-C6 cycloalkyl-C1-C6 alkoxy.

[0046] R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups.

[0047] Preferably, in formula (I-1-b), R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, and C3-C5 cycloalkyl-C1-C4 alkoxy; more preferably, R1 is selected from Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, ethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy.

[0048] Preferably, in formula (I-1-b), R2 and R3 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R2 and R3 are each independently selected from hydrogen and methyl.

[0049] In one specific embodiment, the compound represented by formula (I) is a compound represented by formula (I-1-b1) or formula (I-1-b2).

[0050] in:

[0051] R1 is selected from halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and C3-C6 cycloalkyl-C1-C6 alkoxy.

[0052] R2 and R3 are each independently selected from hydrogen and C1-C6 alkyl groups.

[0053] Preferably, in formula (I-1-b1), R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, and C3-C5 cycloalkyl-C1-C4 alkoxy; more preferably, R1 is selected from Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, ethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy.

[0054] Preferably, in formula (I-1-b1), R2 and R3 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R2 and R3 are each independently selected from hydrogen and methyl.

[0055] Unless otherwise stated, the groups in this document are defined as follows:

[0056] As used herein, the term "halogen" generally refers to fluorine, chlorine, bromine, and iodine; preferably fluorine, chlorine, or bromine; more preferably fluorine or chlorine.

[0057] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group. For example, C1-C6 alkyl refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl or isobutyl.

[0058] As used in this article, "halogenated C1-C6 alkyl" refers to a straight-chain or branched saturated hydrocarbon group containing 1-6 carbon atoms in which the hydrogen atom is replaced by one or more identical or different halogen atoms. "Halogenated C1-C4 alkyl" follows the same pattern, such as trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, dichlorofluoromethyl, chloroethyl, bromopropyl, 2-chlorobutyl, or pentafluoroethyl, etc.

[0059] As used herein, “C1-C6 alkoxy” refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms, and “C1-C4 alkoxy”, “C1-C3 alkoxy”, and so on. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, isohexoxy, 3-methylpentoxy, or n-hexoxy, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, or isohexoxy.

[0060] As used in this article, "halogenated C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group containing 1-6 carbon atoms in which the hydrogen atom is replaced by one or more identical or different halogen atoms. "Halogenated C1-C4 alkoxy" follows the same pattern, such as -OCF3, -OCHF2, -OCH2CH2Cl, -OCHBrCH2Cl, or -OCF2CF3, etc.

[0061] As used in this article, “C1-C6 alkoxy-C1-C6 alkyl” refers to the oxygen atom of a C1-C6 alkoxy group being connected to a C1-C6 alkyl group, such as -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2CH2OCH3.

[0062] As used in this article, "C3-C6 cycloalkyl" refers to a saturated cycloalkyl group containing 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0063] As used herein, “C3-C6 cycloalkyloxy” refers to oxygen-bridged C3-C6 cycloalkyl groups as defined herein, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.

[0064] As used in this article, "C3-C6 cycloalkyl C1-C6 alkyl" refers to C3-C6 cycloalkyl linked to C1-C6 alkyl, such as cyclopropylmethyl, cyclobutylmethyl, etc.

[0065] As used herein, “C3-C6 cycloalkyl C1-C6 alkoxy” refers to oxygen-bridged C3-C6 cycloalkyl C1-C6 alkyl groups as defined herein, such as cyclopropylmethyloxy, cyclopropylethyloxy, etc.

[0066] As used herein, “heterocyclic alkyl” refers to a saturated monocyclic or polycyclic group containing at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from N and O as ring members. 3-9 membered heterocyclic alkyl groups include azirrocyclic butyl, pyrrolidinyl, piperidinyl, azirrocyclic heptyl, morpholinyl, etc.

[0067] The substituted phenyl amine compounds and their geometric isomers, conformational isomers, and tautomers represented by general formula (I) of this invention also include solvate forms, such as hydrates and alcohols, and these solvates are also included within the scope of this invention. Pharmaceutically acceptable salts of the heterocyclic compounds and their geometric isomers, conformational isomers, and tautomers represented by general formula (I) of this invention refer to the substituted phenyl amine compounds or their stereoisomers represented by general formula (I) converted into therapeutically active, non-toxic addition salt forms by treatment with appropriate acids. The salts mentioned include, for example, hydrobromide, hydroiodide, sulfate or hydrogen sulfate, nitrate, phosphate or acid phosphate, perchlorate, formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate or camphorsulfonate, etc. Conversely, the salt form can be converted to a free base form by alkali treatment.

[0068] The term "pharmaceutically acceptable salt" as used above also includes their solvates, and these solvates are included within the scope of this invention. Examples of solvates include, for example, hydrates, alcohols, etc.

[0069] Those skilled in the art will recognize that the compounds of the present invention may contain a chiral center, thereby allowing for different isomeric forms. As used herein, "isomer" refers to different compounds having the same molecular formula but differing in the arrangement and configuration of their atoms.

[0070] "Stereoisomers" refer to isomers produced by different spatial arrangements of atoms in a molecule. They can be divided into two types: cis-trans isomers and enantiomers, or two main categories: enantiomers and diastereomers.

[0071] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to refer to racemic mixtures. When indicating the stereochemistry of the compounds of the present invention, a single stereoisomer with known relative and absolute configurations (e.g., (1S,2S)) having two chiral centers is designated using the conventional RS system; a single stereoisomer with a known relative configuration but an unknown absolute configuration is indicated by an asterisk (e.g., (1R*,2R*)); and a racemic mixture with two letters (e.g., (1RS,2RS) is a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) is a racemic mixture of (1R,2S) and (1S,2R)). "Diarrhetomers" are stereoisomers having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is indicated according to the Cahn-Lngold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry at each chiral carbon can be described by R or S. The resolved compounds with unknown absolute configurations can be designated as (+) or (-) based on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D line wavelength. Alternatively, the resolved compounds can be defined by the respective retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0072] Geometric isomerism can occur when a compound contains a double bond or other features that give the molecule a certain degree of structural rigidity. If the compound contains a double bond, the substituent can be in the E or Z conformation. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration.

[0073] "Conformation isomers" are isomers that differ by rotation of one or more valence bonds.

[0074] A tautomer is an isomer formed when a proton is transferred from one atom of a molecule to another atom of the same molecule. For example, the following structures are a set of tautomers that interconvert with each other. All tautomer forms of the compounds of this invention are also included within the scope of this invention.

[0075] "Polymorphic" refers to a crystalline form having the same chemical structure / composition but different spatial arrangements of the molecules and / or ions forming the crystals. The compounds of this invention can be provided as amorphous solids or crystalline solids. Freeze-drying can be used to provide solid compounds of this invention.

[0076] "Solvate" refers to a physical combination of the compound of the present invention with one or more organic or inorganic solvent molecules. Such physical combination includes hydrogen bonds. In some cases, the solvate will be separable, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" includes solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0077] This invention also includes all suitable isotopic variants of the compounds of the invention or pharmaceutically acceptable salts thereof. An isotopic variant of the compounds of the invention or pharmaceutically acceptable salts thereof is defined as one in which at least one atom is replaced by an atom having the same number of atoms but a different atomic mass than those commonly found in nature. Isotopes that can be incorporated into the compounds of the invention and pharmaceutically acceptable salts thereof include, but are not limited to, isotopes of H, C, N, and O, for example... 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 35 S, 18 F, 36 Cl and 125 I. Isotopic variants of the compounds described in this invention or of their pharmaceutically acceptable salts can be prepared using conventional techniques and appropriate isotopic variants with suitable reagents.

[0078] According to the present invention, the amine compounds containing substituted phenyl groups represented by formula (I) have structures selected from the following:

[0079] According to the present invention, the amine compound containing substituted phenyl groups represented by formula (I) has a structure selected from the following: A2, A4, A6, A8, A10, A12, A14, A16, A18, A20, A22, A24, A26, A28, A30, A32, A34, A36, A38, A40, A42, A44, A46, A48, A50, A52, A54, A56, A58, A60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A79, A80, A81, A82, A83, A85, A86, A87, A89, A90, A91, A93, A94, A96, A9 7. A99, A100, A102, A103, A105, A106, A108, A109, A111, A112, A114, A115, A 117, A118, A120, A121, A123, A124, A125, A127, A129, A130, A132, A133, A135 , A136, A138, A139, A141, A142, A144, A145, A147, A148, A150, A151, A153, A 154, A156, A157, A158, A159, A160, A161, A162, A163, A165, A166, A168, A169 ,A171,A172,A174,A175,A176,A177,A178,A179,A180,A182,A183,A185,A 186, A187, A189, A190, A192, A193, A194, A195, A196, A197, A199, A200, A201 ,A203,A204,A206,A207,A208,A210,A211,A212,A213,A214,A216,A217,A 219, A220, A222, A223, A225, A226, A228, A229, A230, A232, A233, A234, A236 , A237, A239, A241, A242, A245, A247, A249, A251, A253, A255, A257, A259, A 261, A263, A265, A267, A269, A271, A273, A275, A277, A279, A281, A283, A285 , A287, A289, A290, A292, A294, A296, A297, A299, A301, A303, A305, A307, A3 09. A310, A312, A315, A317, A319, A320, A323, A325, A327, A329, A330, A332,A333, A335, A336, A338, A339, A341, A342, A344, A346, B2, B3, B5, B6, B8, B9, B11, B12, B14, B15, B17, B18, B20, B21, B23, B24, B26, B27, B29, B30, B32, B33, B35, B36, B38, B40, B41, B43, B44, B46, B47, B49, B50, B52, B53, B55, B56, B58, B59, B61, B62, B64, B65, B67, B68, B69. ,

[0080] According to the present invention, the amine compound containing substituted phenyl groups shown in formula (I) has a structure selected from the following: A2, A4, A6, A8, A10, A12, A14, A22, A24, A30, A32, A34, A36, A50, A52, A54, A56, A58, A60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A85, A89, A108, A111, A1 14. A117, A120, A123, A138, A141, A147, A150, A156, A165, A168, A171, A174, A182, A185, A187, A190, A 199, A203, A206, A210, A216, A219, A222, A225, A226, A230, A234, A237, A239, A242, A245, A247, A249, A251, A253, A255, A257, A259, A261, A263, A265, A271, A273, A275, A277, A279, A281, A283, A285, A28 7. A289, A292, A294, A296, A309, A310, A312, A319, A320, A323, A325, A327, A329, A332, A335, A336, B2 , B3, B5, B6, B8, B9, B11, B12, B14, B15, B17, B18, B20, B21, B23, B24, B26, B27, B29, B30, B32, B33, B35, B40, B41, B43, B44, B46, B47, B49, B50, B52, B53, B55, B56, B58, B59, B61, B62, B64, B65, B67, B68, B69.

[0081] According to a second aspect of the present invention, a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I-1-a) is provided, said method being carried out by a process comprising the steps shown in the following reaction formula:

[0082] a) The compound shown in formula (II) undergoes a condensation reaction with the compound shown in formula (III) to produce the compound shown in formula (IV);

[0083] b) The compound shown in formula (IV) and the compound shown in formula (V) undergo a nucleophilic addition reaction to produce the compound shown in formula (VI);

[0084] c) When both R2 and R3 are hydrogen, the compound shown in formula (VI) is deprotected to produce the compound shown in formula (VII);

[0085] When R2 is H and R3 is C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI) undergoes alkylation and deprotection reactions, or undergoes reductive amination and deprotection reactions to generate the compound shown in formula (VII);

[0086] When R2 and R3 are the same and are both C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI) undergoes deprotection and alkylation reactions, or undergoes deprotection and reductive amination reactions to generate the compound shown in formula (VII).

[0087] When R2 and R3 are C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, and the two are different, the compound shown in formula (VI) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII).

[0088] d) The compound shown in formula (VII) undergoes halogenation at the carbonyl α-position, followed by a ring-closing reaction in the presence of thiourea to produce the compound shown in formula (VIII);

[0089] e) The compound shown in formula (VIII) is salted by chiral acid to obtain the chiral acid salt of the compound shown in formula (I);

[0090] Where R1 and R2 are the same as defined and preferred above;

[0091] G represents a leaving group, such as C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, or benzyl, wherein the aforementioned C1-C6 alkylsulfinyl, benzenesulfinyl, or naphthyl may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, or phenyl; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl... sulfonyl, benzyl, the above-mentioned C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl; G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl;

[0092] M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li.

[0093] According to a second aspect of the present invention, a method for preparing amine compounds containing substituted phenyl groups as shown in formula (I-1-b) is provided, said method being carried out by a process comprising the steps shown in the following reaction formula:

[0094] a) The compound shown in formula (II) undergoes a condensation reaction with the compound shown in formula (III) to produce the compound shown in formula (IV);

[0095] b) The compound shown in formula (IV) and the compound shown in formula (V-2) undergo a nucleophilic addition reaction to produce the compound shown in formula (VI-2);

[0096] c) When R2 and R3 are hydrogen, the compound shown in formula (VI-2) is deprotected to produce the compound shown in formula (VII-2);

[0097] When one of R2 and R3 is H and the other is C1-C6 alkyl or C3-C6 cycloalkyl, the compound shown in formula (VI-2) undergoes alkylation and deprotection reactions, or reductive amination and deprotection reactions to produce the compound shown in formula (VII-2);

[0098] When R2 and R3 are both C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-2) undergoes deprotection and alkylation reactions, or deprotection and reductive amination reactions to generate the compound shown in formula (VII-2);

[0099] When R2 and R3 are different and each is independently a C1-C6 alkyl or a C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-2) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII-2).

[0100] d) The compound shown in formula (VII-2) undergoes halogenation at the carbonyl α-position, followed by a ring-closing reaction in the presence of thiourea to produce the compound shown in formula (I-1-b);

[0101] R1, R2 and R3 are as defined in claim 5;

[0102] G represents a leaving group selected from C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups, wherein the C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, and phenyl groups; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl groups. Sulphinyl, benzyl, C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl; G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl;

[0103] M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li.

[0104] Step a) can be carried out in the presence or absence of acid in a solvent, which may be selected from ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types such as dimethyl sulfoxide, acetonitrile, etc., or mixtures of the above solvents;

[0105] The acid can be selected from organic acids, inorganic acids, or Lewis acids. Inorganic acids may include: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; organic acids may include: formic acid, acetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, glycolic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid, lactic acid, malic acid, citric acid, tartaric acid, picric acid, glutamic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, camphoric acid, or camphorsulfonic acid; Lewis acids include: aluminum chloride, ferric chloride, boron trifluoride, ethyl titanate, etc. These acids can be used alone or in combination of two or more.

[0106] Step b) can be carried out in a solvent, which may be selected from ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; esters, such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types, such as dimethyl sulfoxide, acetonitrile, etc., or mixtures of the above solvents;

[0107] In step c), the deprotection can be carried out in a solvent under acid or base catalysis. The acid may include: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, acetic acid, etc.; the base may include: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, etc. The reaction solvent can be water; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether; aromatics such as benzene, toluene, nitrobenzene, and chlorobenzene; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate; other solvents such as dimethyl sulfoxide and acetonitrile; or mixtures of the above solvents.

[0108] The deprotection or reductive amination reaction can be carried out in a solvent under reducing agent conditions. The reducing agent system includes: Pd / C catalyst-catalyzed hydrogenation, Pd / BaSO4 catalyst-catalyzed hydrogenation, PtO2 catalyst-catalyzed hydrogenation, Raney Ni catalyst-catalyzed hydrogenation, PPh3-THF-H2O system, LAH, etc. The reaction solvent can be selected from water; ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; esters, such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; other types, such as dimethyl sulfoxide, acetonitrile, acetic acid, formic acid, tertvalerate, etc., or mixtures of the above solvents.

[0109] The alkylation reaction can be carried out in the presence of an alkylating agent, which includes, but is not limited to, iodomethane, iodoethane, 2-bromopropane, bromocyclopropane, tert-butyl bromide, etc. The reaction solvent can be selected from ethers, such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics, such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; ketones, such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, dichloroethane, carbon tetrachloride; other types, such as dimethyl sulfoxide, acetonitrile, etc., or mixtures of the above solvents.

[0110] Step d) can be carried out in a solvent, selected from water, ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc., or mixtures of the above solvents; the halogenation reaction is, for example, chlorination, bromination, or iodination. The halogenating reagents used include: N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, thioyl chloride, liquid bromine, tribromopyridinium, dibromohydantoin, elemental iodine, etc.

[0111] Step e) can be carried out in a solvent, wherein the chiral acid includes: D- or L-type tartaric acid, mandelic acid, camphorsulfonic acid, gluconic acid, methionine, aspartic acid, proline, phenylalanine, lactic acid, malic acid, and citric acid; in particular, L-tartaric acid can be used for salt formation and separation of R-configured compounds, and D-tartaric acid can be used for salt formation and separation of S-configured compounds. The required solvent is selected from water, ethers such as dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, etc.; aromatics such as benzene, toluene, nitrobenzene, chlorobenzene, etc.; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol, etc., or mixtures of the above solvents;

[0112] The starting compounds used in the above reaction formulas can be suitable salts, including alkali metal salts and alkaline earth metal salts, such as sodium salts, potassium salts, calcium salts, magnesium salts, etc.; organic base salts, such as pyridinium salts, triethylamine salts, etc.; inorganic acid salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; and organic acid salts, such as formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, bis(trimethylammonium salt), picrate, glutamate, methanesulfonate, benzenesulfonate, etc.

[0113] Furthermore, the starting compounds used in the above reaction formulas may include solvates, such as hydrates, alcohols, etc.

[0114] The target compounds obtained from each reaction can be separated and purified from the reaction mixture by methods such as filtration, extraction or concentration after cooling of the reaction mixture to obtain crude products, which are then purified by conventional methods such as column chromatography, pulping or recrystallization.

[0115] Those skilled in the art will understand that in the compound structures of the present invention, any atom (including heteroatoms) having an unsatisfied valence bond is considered to have a hydrogen atom sufficient to satisfy the valence bond, unless otherwise indicated.

[0116] According to a third aspect of the invention, a pharmaceutical composition is provided comprising a therapeutically effective amount of one or more selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0117] The compounds of this invention have multi-target effects on NMDA receptors and / or monoamine transporters, and can be used to treat various central nervous system diseases, especially depression, bipolar disorder, schizophrenia, anxiety disorder, phobia, autism, Alzheimer's disease, bipolar disorder, hysteria, obsessive-compulsive disorder, ADHD, epilepsy, and other diseases.

[0118] Therefore, according to a fourth aspect of the invention, one or more of the following are provided: compounds selected from the compounds shown in formula (I), their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds; or the use of the above pharmaceutical compositions in the preparation of medicaments for regulating the activity of NMDA receptors and / or monoamine transporters, specifically, in the preparation of NMDA receptor antagonists, and in the preparation of monoamine transporter inhibitors.

[0119] According to a fifth aspect of the invention, one or more of the following are provided: amine compounds containing substituted phenyl groups as shown in formula (I) above, their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds, or the use of the above pharmaceutical compositions in the preparation of medicaments for the prevention and / or treatment of diseases associated with NMDA receptors and / or monoamine transporters, particularly diseases of the central nervous system.

[0120] The central nervous system diseases mentioned are selected from: cerebral ischemia; stroke; cerebral infarction; traumatic brain injury; anti-NMDA receptor encephalitis; epilepsy; amyotrophic lateral sclerosis (ALS); schizophrenia; uncontrollable, refractory, or chronic schizophrenia; affective disorders; mental disorders; mood disorders; type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic disorder; panic attacks; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; hysteria; anorexia nervosa; sleep disorders; adjustment disorder; cognitive impairment; autism; neuropathic pain; mania; Parkinson's disease; Huntington's disease; Alzheimer's disease; various dementias; memory impairment; ADHD; attention deficit / hyperactivity disorder; tic disorders; and other neurological events or neurodegenerations caused by NMDA receptor activation.

[0121] In some embodiments, the neuropathic pain includes peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain.

[0122] In some preferred embodiments, the central nervous system disorders are selected from: type I bipolar disorder; type II bipolar disorder; depression; endogenous depression; major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic disorder; panic attack; panic disorder; social phobia; obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; Parkinson's disease; peripheral diabetic neuropathy; postherpetic neuralgia; complex regional pain syndrome; attention deficit hyperactivity disorder.

[0123] According to a sixth aspect of the invention, a method for treating and / or preventing diseases associated with NMDA receptors and / or monoamine transporters, particularly central nervous system diseases, is also provided, the method comprising administering to a human or animal an amine compound containing a substituted phenyl group, its stereoisomer, or a pharmaceutically acceptable salt thereof, as shown in formula (I) above.

[0124] According to a seventh aspect of the present invention, a method for preparing the above-described pharmaceutical composition is also provided, comprising mixing a substituted phenyl amine compound, its stereoisomer or a pharmaceutically acceptable salt thereof, as shown in formula (I) above, with a pharmaceutically acceptable carrier.

[0125] In the pharmaceutical compositions of the present invention, various pharmaceutical formulations may be selected according to the therapeutic purpose, including but not limited to: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., lipid-soluble or oil-soluble injections).

[0126] The "therapeutic effective amount" of the compounds of this invention refers to the amount of the compounds of this invention that can induce a biological or medical response in an individual, or improve symptoms, slow or delay disease progression, or prevent disease, etc. The "therapeutic effective amount" can be determined by the participating physician or veterinary practitioner and will vary with factors such as the compound, the disease state being treated, the severity of the disease being treated, the individual's age and related health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner.

[0127] As used herein, "individual" refers to an animal. Preferably, the animal is a mammal. "Individual" also refers to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a preferred embodiment, the individual is a human being.

[0128] As used in this article, “inhibition” refers to the reduction or suppression of a specific patient, symptom, condition, or disease, or a significant reduction in biological activity or baseline activity of a process.

[0129] As used herein, in one embodiment, the term "treatment" refers to improving a disease or condition (i.e., halting or slowing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" refers to improving at least one bodily parameter, which may not be perceptible to the patient. In yet another embodiment, "treatment" refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both.

[0130] As used herein, “prevention” means administering one or more pharmaceutical substances, particularly the compounds of the present invention and / or their pharmaceutically acceptable salts, to an individual with a predisposition to the disease in order to prevent the individual from contracting the disease. Beneficial effects

[0131] This invention provides a novel NMDAR antagonist, belonging to the category of channel pore blockers, which can inhibit channel opening caused by excessive NMDA activation under pathological conditions, thereby preventing Ca2+. 2+ Excessive influx of NMDAR receptors does not affect the normal function of NMDAR. The NMDAR antagonist described in this invention is a reversible NMDAR antagonist that dissociates very rapidly after binding without affecting the normal function of NMDA receptors.

[0132] The compounds of this invention have the following beneficial effects:

[0133] 1) The compounds of the present invention have modulatory NMDA receptor activity, and can therefore be used to treat and / or prevent diseases associated with NMDA receptors.

[0134] 2) In vitro studies showed that the compounds of this invention dissociated from NMDAR at a faster rate than ketamine, suggesting that the compounds of this invention have a lower risk of psychoactive adverse reactions and a larger safety window.

[0135] 3) The compounds of this invention exhibit good inhibitory effects on monoamine transporters (5-HT transporters and / or norepinephrine transporters and / or dopamine transporters), and can improve comorbidities such as anxiety and depression in anxiety disorders, depression, or other central nervous system diseases. Specific configurations of certain compounds of this invention, relative to their racemic or isomer forms, have achieved unexpected effects in inhibiting specific monoamine transporters (dopamine transporters), and have greater potential in treating and / or preventing diseases associated with specific monoamine transporters.

[0136] 4) The compounds of this invention have the characteristics of high oral bioavailability, low effective dose and few toxic side effects, and are effective for diseases of the central nervous system, especially for central nervous system diseases related to NMDA receptors and / or dopamine transporters. Attached Figure Description

[0137] Figure 1 shows the results of the forced swimming experiment in pharmacological example 4; *p<0.05, ***p<0.001 (unpaired T-test).

[0138] Figure 2 shows the X-ray crystal structure of compound A3 crystals grown in a methanol-ethyl acetate mixed solvent.

[0139] Figure 3 shows the ADHD experiment results (total activity distance within 60 min) in pharmacological example 5. The Wistar group consisted of normal rats, and the SHR group consisted of spontaneously hypertensive rats; *p<0.05, ***p<0.001 (one-way ANOVA, Dunnett's multiple comparison test).

[0140] Figure 4 shows the ADHD experimental results (object recognition index) in pharmacological example 5. The Wistar group consisted of normal rats, and the SHR group consisted of spontaneously hypertensive rats; **p<0.01 (one-way ANOVA, Dunnett's multiple comparison test). Detailed Implementation

[0141] The following examples and pharmacological examples further illustrate the present invention, but do not limit the scope of the invention.

[0142] Unless otherwise specified, the raw materials, reagents, and methods used in the examples and pharmacological examples are all conventional raw materials, reagents, and methods in the art.

[0143] Unless otherwise specified, the high-performance liquid chromatography (HPLC) detection conditions in the examples are as follows:

[0144] Example

[0145] Example 1: (R)-3-(2-amino-6-(methylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol and (S)-3-(2-amino-6-(methylamino)-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol

[0146] Step 1:

[0147] Dissolve 40g of A1-a in 200mL of toluene, add benzylamine (28.26g, 1.0eq), reflux under N2 protection to remove water for 4h, concentrate under normal pressure to remove toluene, and obtain compound A1-b (63g, light brown oily substance). No further post-treatment is required to proceed directly to the next reaction.

[0148] Step Two:

[0149] The obtained A1-b (63g) was dissolved in 620mL of tetrahydrofuran (THF), and 72.6g of boron trifluoride ether was added dropwise with stirring at low temperature (-60℃). After the addition was completed, the mixture was stirred at low temperature for 60min to obtain an imine solution.

[0150] m-Bromoanisole (86.4 g, 1.5 eq) was dissolved in tetrahydrofuran (320 mL), and n-butyllithium (2.5 M, 160 mL) was added dropwise with stirring at low temperature (-60 °C). After the addition was complete, the mixture was stirred at low temperature for 60 min to obtain a phenyllithium solution.

[0151] A phenyllithium solution was added dropwise to the imine solution at low temperature. After the addition was complete, the mixture was stirred at low temperature (-60℃) for 1 hour and allowed to naturally rise to room temperature. After the reaction was monitored by TLC, 20.5 mL of 20% NaOH aqueous solution was added to quench the reaction. Water (400 mL) was added, and the mixture was extracted with EA (400 mL × 2). The organic phase was washed once with 400 mL of water and once with 400 mL of saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily substance. The concentrate was dissolved in 100 g of ethanol and heated to 0–5℃. The mixture was then stirred for 2 hours and filtered to obtain compound A1-c (56.5 g white solid).

[0152] Step 3:

[0153] Add A1-c (30g), 200mL acetonitrile, formaldehyde aqueous solution (40g), and sodium cyanoborohydride (12g) to a 500mL three-necked flask. Stir at room temperature for 30min. Then add 100mL water and 60mL acetic acid. Stir at room temperature for 2 hours. After the reaction is complete, concentrate under reduced pressure to remove acetonitrile. Adjust the pH to 7-8 with ammonia. Add 300mL ethyl acetate and extract to separate the layers. Wash the organic phase successively with 150mL water and 2 x 150mL saturated sodium chloride aqueous solution. Concentrate under reduced pressure to dryness to obtain compound A1-d (42g white solid).

[0154] Step Four:

[0155] Add A1-d (42g), 400mL methanol, acetic acid (15g), and 10% palladium on carbon (10g) to a 500mL three-necked flask. Replace with hydrogen, heat to 30°C and stir overnight. Filter, concentrate under reduced pressure to remove methanol, and obtain compound A1-e (40g oily substance).

[0156] Step 5:

[0157] Add 40 g of Al-f, 400 mL of water, and 40 mL of hydrochloric acid to a 25 mL three-necked flask. Heat to 95 °C and stir overnight. After the reaction is complete, cool to room temperature. Adjust the pH of the system to 7-8 with sodium carbonate aqueous solution. Extract with ethyl acetate. Combine the organic phases and wash successively with water and saturated sodium chloride aqueous solution. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Add 200 mL of ethyl acetate and 12 g of 30% hydrogen chloride ethanol solution to the concentrate. Stir at room temperature for 2 hours. Filter and dry to obtain compound Al-f (17 g white solid).

[0158] Step Six:

[0159] Add 17g of A1-f, 23.8g of iodine, and 340mL of 1,4-dioxane to a 50mL three-necked flask. After the addition is complete, stir at room temperature for half an hour. Add 8.5g of thiourea and heat to 100℃ to react overnight. Concentrate under reduced pressure to remove the solvent. Add 10mL of ethyl acetate to the concentrate, stir for 1 hour, filter, dissolve the filter cake in 10mL of water, wash with 2*200mL of ethyl acetate (EA), adjust the pH of the system to 9-10 with sodium hydroxide, and a large amount of solid precipitates. Stir in an ice-water bath for 1 hour, filter, and dry at 55℃ to obtain compound A1-g (13.75g of white solid), yield 75.56%.

[0160] Step Seven:

[0161] Add 8 g of A1-g and 120 mL of dichloromethane (DCM) to a 500 mL three-necked flask, cool to 0–5 °C, and add 33 mL of commercially available 2.5 M BBr3 dichloromethane solution dropwise. After the addition is complete, heat to room temperature and react for 4 hours. Lower the system temperature to 0–5 °C, slowly add 100 mL of methanol, concentrate under reduced pressure to dryness, dissolve the concentrate in 150 mL of water, adjust the pH of the system to 7–8 with sodium bicarbonate, extract with 2-methyltetrahydrofuran, combine the organic phases, concentrate under reduced pressure, and purify by column chromatography to obtain compound A1-h (6.2 g white solid).

[0162] 1 H NMR(400MHz,DMSO-d6)δ9.24(s,1H),7.08(d,J=7.8Hz,1H),6.90–6.78(m,2H),6.62(d,J=5.8Hz,3H),3.47 –3.41(m,1H),3.04(d,J=16.0Hz,1H),2.66(d,J=15.8Hz,1H),2.41–2.37(m,1H),2.05–1.94(m,6H).ESI-MS m / z 276.30[M+H] + HPLC purity: >96%, retention time: 5.216 min.

[0163] Step 8:

[0164] Compound A1-h (1.3 g) was added to 2.6 mL of water, 5 mL of methanol, and 2.6 mL of isopropanol. The mixture was stirred at 60 °C for 10 min, then L-tartaric acid (723 mg, 1.02 eq) was added, and stirring continued for 1 h. The mixture was cooled to room temperature, filtered, and the filter cake was dried to obtain crude compound A1 tartrate. The filtrate was adjusted to a weakly alkaline pH with sodium bicarbonate, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. D-tartaric acid was used to form a salt to obtain crude compound A2 tartrate.

[0165] Crude tartrates of compounds A1 and A2 were recrystallized from a methanol:water:isopropanol mixture of 1:2:1 to obtain compounds A1 and A2 tartrates, respectively. The resulting compounds were then extracted with ethyl acetate after adjusting the pH to weakly alkaline using sodium bicarbonate and concentrated under reduced pressure to obtain compounds A1 (R configuration) and A2 (S configuration).

[0166] Chiral HPLC purity detection conditions:

[0167] Chromatographic column: UniChiral CMD-5H ss 4.6x250mm; Mobile phase A: n-hexane, Mobile phase B: isopropanol containing 0.1% diethylamine; Isocratic elution A:B = 70:30; Detection wavelength: 270nm; Column temperature: 35℃; Flow rate: 1.0mL / min; Injection volume: 10μL; Sample preparation: The compound was dissolved in ethanol at a concentration of 1.0mg / mL.

[0168] A1 (R configuration): HPLC purity: >99%, retention time: 5.155 min. Chiral HPLC purity: >99%, retention time: 5.672 min. Specific rotation. (c = 0.33 g / 100 mL, MeOH).

[0169] A2 (S configuration): HPLC purity: >99%, retention time: 5.132 min. Chiral HPLC purity: >99%, retention time: 8.019 min. Specific rotation. (c = 0.11 g / 100 mL, MeOH). Single-crystal X-ray diffraction results showed that it had an S-configuration.

[0170] Example 2: (R)-3-(2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol and (S)-3-(2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)phenol

[0171] Step 1:

[0172] Under nitrogen protection, tert-butylsulfinamide (9.7 g, 80.02 mmol, 2.5 eq) and tetraethyl titanate (22 g, 96.03 mmol, 3 eq) were dissolved in THF, and A3-a (5 g, 32.01 mmol, 1 eq) was added. The mixture was refluxed for 4–5 h. The reaction was monitored by TLC until complete. The reaction solution was poured into a saturated sodium chloride aqueous solution, filtered, and the filtrate was extracted three times with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-b (5.36 g of yellow oil, yield: 64.5%).

[0173] Step Two:

[0174] Under nitrogen protection, 3-bromoanisole (9.46 g, 50.58 mmol, 2.45 eq) was dissolved in THF. A 2.5 M n-butyllithium solution (21 mL, 52.50 mmol, 2.54 eq) was slowly added dropwise at -78 °C, and the mixture was stirred at -75 °C for approximately 0.5 h. A THF solution of compound A3-b (5.36 g, 20.67 mmol, 1 eq) was then slowly added dropwise to the above system. After the addition was complete, the mixture was stirred at -70 °C for 3–4 h, and then slowly heated to room temperature. The reaction was monitored by TLC until completion. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, extracted three times with EA, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-c (2.94 g yellow solid, yield 38.7%).

[0175] Step 3:

[0176] Under nitrogen protection, compound A3-c (2.94 g, 8 mmol, 1 eq) was dissolved in methanol, and 4 M dioxane hydrochloride solution (11 mL, 44 mmol, 5.5 eq) was slowly added. The mixture was stirred at 35 °C for 4–5 h. After the reaction was complete, the mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted three times with DCM, and the organic phase was passed through anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-d (1.21 g, yield 57.3%).

[0177] Step Four:

[0178] Under nitrogen protection, A3-d (1.21 g, 4.58 mmol, 1 eq) was dissolved in methanol and stirred at -5 to 0 °C for 5 min. Acetic acid (1.1 g, 18.32 mmol, 4 eq) and sodium cyanoborohydride (662 mg, 10.53 mmol, 2.3 eq) were then added, and the mixture was stirred for 5 min. Finally, a 37% aqueous solution of formaldehyde (1.04 g, 12.82 mmol, 2.8 eq) was added. The mixture was slowly heated to room temperature. After the reaction was complete as monitored by TLC, the reaction was quenched with a saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound A3-e (1.65 g of orange oil). No further purification was required, and the mixture was directly added to the next reaction step.

[0179] Step 5:

[0180] A3-e (4.58 mmol, 1 eq) was dissolved in a mixture of acetone and water (1:1, v / v), and p-toluenesulfonic acid monohydrate (871 mg, 4.58 mmol, 1 eq) and 4.6 mL of 2 M HCl (aq) were added. The mixture was refluxed, and after TLC monitoring of the reaction, the pH was adjusted to 9-10 with 5% sodium hydroxide aqueous solution. After three extractions with EA, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-f (0.682 g of yellow oil, 60% yield).

[0181] Step Six:

[0182] A3-f (682 mg, 2.76 mmol, 1 eq) was dissolved in 1,4-dioxane, and elemental iodine (772 mg, 3.04 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 1–2 h, followed by the addition of thiourea (241 mg, 3.17 mmol, 1.15 eq). The mixture was refluxed overnight and monitored by TLC. After the reaction was complete, the reaction solution was concentrated. Sodium thiosulfate aqueous solution, sodium bicarbonate aqueous solution, and EA were added. The mixture was extracted three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give compound A3-g (322 mg of yellow oil, yield 38.5%).

[0183] Step Seven:

[0184] A3-g (322 mg, 1.06 mmol, 1 eq) was dissolved in 5 mL of DCM and stirred at -20 °C for 20 min. Then, a commercially available 1 M boron tribromide solution in dichloromethane (10 mL, 10 mmol, 10 eq) was added dropwise. After the addition was complete, the mixture was brought to room temperature and stirred for 15 min. The reaction was monitored by TLC. After the reaction was complete, the solution was quenched with saturated sodium bicarbonate solution, extracted 2-3 times with DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound A3-h (154 mg pale yellow solid).

[0185] 1 H NMR(500MHz,Chloroform-d)δ7.10(t,J=7.9Hz,1H),6.93–6.86(m,1H),6.83(t,J=2.1Hz,1H),6.71–6.63(m,1H),5.0 9–4.65(m,2H),2.99–2.91(m,2H),2.51–2.46(m,1H),2.23–2.16(m,7H),2.08–2.04(m,1H),1.93–1.84(m,1H).ESI-MS m / z 290.1[M+H] + HPLC purity: >95%, retention time: 4.484 min.

[0186] Step 8:

[0187] Compounds A3 (R configuration) and A4 (S configuration) were obtained using a method similar to step eight in Example 1:

[0188] The chiral HPLC purity detection conditions are the same as in Example 1:

[0189] Compound A3 (R configuration): HPLC purity: >96%, retention time: 4.542 min. Chiral HPLC purity: >99%, retention time: 6.577 min. Specific rotation. (c = 0.11 g / 100 mL, MeOH).

[0190] Single-crystal X-ray diffraction results showed that it had an R configuration. The X-ray crystal structure of the crystal grown in a methanol-ethyl acetate mixed solvent is shown in Figure 2.

[0191] Compound A4 (S configuration): HPLC purity: >97%, retention time: 4.485 min. Chiral HPLC purity: >99%, retention time: 7.820 min. Specific rotation. (c = 0.11 g / 100 mL, MeOH). Single-crystal X-ray diffraction results showed that it had an S-configuration.

[0192] Example 3 Preparation of 6-(2-fluoro-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, (R)-6-(2-fluoro-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and (S)-6-(2-fluoro-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0193] Step 1:

[0194] Dissolve B1-a (3.05 g, 1 eq.) and benzylamine (2.15 g, 1.03 eq.) in toluene (30 mL), reflux at 150 °C for 3 hours to separate water, and concentrate the reaction solution directly for the next step after cooling.

[0195] Step Two:

[0196] Dissolve 6 g (1.5 eq.) of 1-bromo-2-fluoro-3-methoxybenzene in 60 mL of THF under nitrogen protection, cool to below -60 °C, and slowly add n-butyllithium (2.5 M, 12.1 mL, 1.55 eq.). Stir at this temperature for 1 hour after the addition is complete. In a separate reaction flask, dissolve B1-b in 100 mL of THF under nitrogen protection, cool to approximately -60 °C, and slowly add boron trifluoride diethyl ether (5.54 g, 2 eq.). Stir at this temperature for 40 minutes after the addition is complete. Maintaining the temperature below -60 °C, add the reaction solution of 1-bromo-2-fluoro-3-methoxybenzene dropwise to the reaction solution of B1-b. After the addition is complete, allow the temperature to rise naturally overnight. Quench with water, extract with ethyl acetate, wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain compound B1-c (3.6 g, white solid).

[0197] Step 3:

[0198] Dissolve 3.6 g (1.0 eq.) of B1-c in methanol (60 mL), add 10% Pd / C (360 mg), purge with hydrogen five times, and stir overnight at 30 °C. Filter, and concentrate the filtrate under reduced pressure to give 2.1 g of compound B1-d, a white solid.

[0199] Step Four:

[0200] Dissolve 2.1 g (1.0 eq.) of B1-d in 20 mL of THF, add 20 mL of 4 M hydrochloric acid, and stir at 70 °C for 16 hours. LC-MS monitoring showed the reactants had reacted completely. After cooling to room temperature, extract with water and ethyl acetate, retaining the aqueous phase. Adjust the pH of the aqueous phase to approximately 10 with 4 M NaOH aqueous solution, extract with ethyl acetate, wash the organic phase with saturated brine, dry to anhydrous sodium sulfate, concentrate under reduced pressure, dissolve the concentrate in MTBE, and salt with 1.5 equivalents of 4 M HCl-EA solution under ice bath conditions. After stirring for one hour, filter, and dry the filter cake to obtain 2.8 g of compound B1-e, a white solid. ESI-MS m / z 238.2 [M+H] + .

[0201] Step 5:

[0202] Dissolve 2.8 g (1 eq.) of B1-e and 3.89 g (1.5 eq.) of iodine in 60 mL of dioxane. After the iodine is completely dissolved, add 1.4 g (1.8 eq.) of thiourea. Heat the reaction solution to 100 °C and stir overnight. After cooling, concentrate the reaction solution to remove dioxane. Add ethyl acetate and slurry. Filter the solution. Disperse the filter cake with hot water. Adjust the pH to 1 with 4 M hydrochloric acid. Extract with ethyl acetate and retain the aqueous phase. Adjust the pH of the aqueous phase to approximately 10 with 4 M NaOH aqueous solution. A solid precipitates out. Filter the solution and collect the solid. Dry the solid to obtain compound B1-f (1.4 g, off-white solid).

[0203] 1 H NMR (400MHz, DMSO-d6) δ7.06–7.00(m,3H),6.63(s,2H),3.81(s,3H),3.07(d,J=16.1Hz, 1H),2.59–2.50(m,2H),2.31–2.29(m,1H),2.18–2.11(m,3H),1.80–1.74(m,1H).ESI-MS m / z 294.1[M+H] + HPLC purity: >98%, retention time: 6.986 min.

[0204] Compound B1-f (1.3 g) was added to 2.6 mL of water, 5 mL of methanol, and 2.6 mL of isopropanol. The mixture was stirred at 60 °C for 10 min, then L-tartaric acid (678 mg, 1.02 eq) was added, and stirring continued for 1 h. The mixture was cooled to room temperature, filtered, and the filter cake was dried to obtain crude compound B1 tartrate. The filtrate was adjusted to a weakly alkaline pH using sodium bicarbonate, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. Using the above method, crude compound B2 tartrate was obtained by salt formation with D-tartaric acid.

[0205] Crude compounds B1 and B2 tartrates were recrystallized from a methanol:water:isopropanol mixture of 1:2:1 to obtain compounds B1 and B2 tartrates, respectively. The purified compounds were then adjusted to a weakly alkaline pH using sodium bicarbonate solution, extracted with ethyl acetate, and concentrated under reduced pressure to obtain compounds B1 and B2, respectively.

[0206] Chiral HPLC detection conditions:

[0207] Chromatographic column: UniChiral CMD-5H ss 4.6x250mm; Mobile phase A: n-hexane; Mobile phase B: isopropanol, isocratic elution A:B = 60:40; Detection wavelength: 260nm; Column temperature: 30℃; Flow rate: 1.0mL / min; Injection volume: 5μL; Sample preparation: 1.0mg / mL in ethanol.

[0208] The HPLC detection conditions are the same as above.

[0209] B1 (R configuration): HPLC purity: >98%, retention time: 6.802 min. Chiral HPLC purity: >99%, retention time: 8.920 min. Single-crystal X-ray diffraction results show that it is of the R configuration.

[0210] B2 (S configuration): HPLC purity: >99%, retention time: 6.854 min. Chiral HPLC purity: >98%, retention time: 11.124 min.

[0211] Example 4 Preparation of 6-(2-fluoro-3-ethoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, (R)-6-(2-fluoro-3-ethoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and (S)-6-(2-fluoro-3-ethoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0212] Step 1:

[0213] Dissolve B3-a (2.52 g, 1 eq.) and benzylamine (1.78 g, 1.03 eq.) in toluene (30 mL), reflux at 150 °C for 3 hours to separate water, and concentrate the reaction solution directly for the next step after cooling.

[0214] Step Two:

[0215] Dissolve 5.3 g (1.5 eq.) of 1-bromo-2-fluoro-3-ethoxybenzene in 50 mL of THF under nitrogen protection and cool to approximately -60 °C in a dry ice-ethanol bath. Slowly add commercially available n-butyllithium (2.5 M, 10 mL, 1.55 eq.) dropwise, maintaining the temperature and stirring for 1 hour after the addition is complete. In a separate reaction flask, add B3-b and 80 mL of THF under nitrogen protection and cool to approximately -60 °C. Slowly add 4.58 g (2 eq.) of boron trifluoride diethyl ether dropwise, maintaining the temperature and stirring for 40 minutes after the addition is complete. Then, add the reaction solution of 1-bromo-2-fluoro-3-ethoxybenzene dropwise to the reaction solution of B3-b, maintaining the temperature below -50 °C. After the addition is complete, allow the temperature to rise naturally overnight. Extract with water and ethyl acetate, wash the organic phase with saturated sodium chloride aqueous solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain compound B3-c, a brown oily substance, 3.45 g.

[0216] Step 3:

[0217] Compound B3-c (3.45 g, 1.0 eq.) was dissolved in methanol (50 mL), and 10% Pd / C (350 mg) was added. The mixture was purged with hydrogen five times and stirred overnight at 30 °C. The reaction solution was filtered, and the filtrate was concentrated to give 2.4 g of compound B3-d, a white solid.

[0218] Step Four:

[0219] Compound B3-d (2.4 g, 1.0 eq.) was dissolved in THF (20 mL), and 4M hydrochloric acid (30 mL) was added. The mixture was stirred at 70 °C for 16 hours. The reaction was monitored by LC-MS until completion. After cooling to room temperature, the mixture was extracted with water and ethyl acetate. The aqueous phase was retained, and the solution pH was adjusted to approximately 10 with 4M NaOH aqueous solution. The solution was then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in MTBE and salted with 1.5 equivalents of 4M HCl-EA solution under ice bath conditions. After stirring for 1 hour, the mixture was filtered, and the filter cake was dried to obtain 1.67 g of compound B3-e, a pale yellow solid.

[0220] Step 5:

[0221] Compound B3-e (1.67 g, 1 eq.) and iodine (2.21 g, 1.5 eq.) were dissolved in dioxane (60 mL). After the elemental iodine was completely dissolved, thiourea (800 mg, 1.8 eq.) was added. The reaction solution was heated to 100 °C and stirred overnight. After cooling, the reaction solution was concentrated under reduced pressure to remove dioxane. Ethyl acetate was added and the mixture was stirred. The filter cake was dispersed in hot water, and the pH was adjusted to 1 with 4 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the pH of the aqueous phase was adjusted to approximately 10 with 4 M NaOH aqueous solution. A solid precipitated out. The mixture was filtered, and the filter cake was dried to obtain compound B3 (1.23 g white solid).

[0222] 1 H NMR (400MHz, DMSO-d6) δ7.03–6.97(m,3H),6.63(s,2H),4.06(q,J=6.9Hz,2H),3.06(d,J=16.1Hz,1H),2.59–2.50 (m,2H),2.34–2.27(m,1H),2.16–2.09(m,1H),2.02–1.99(m,2H),1.79–1.73(m,1H),1.34(t,J=6.9Hz,3H).ESI-MS m / z 308.1[M+H] + HPLC purity: >99%, retention time: 8.451 min.

[0223] Compound B3 was separated by chiral column chromatography to yield isomers B4 (R configuration) and B5 (S configuration):

[0224] Chiral HPLC detection conditions:

[0225] Chromatographic column: UniChiral CMD-5H ss 4.6x250mm; Mobile phase A: n-hexane; Mobile phase B: ethanol, isocratic elution A:B = 45:55; Detection wavelength: 270nm; Column temperature: 35℃; Flow rate: 1.0mL / min; Run time: 30min; Injection volume: 10μL; Sample preparation: 1.0mg / mL in ethanol.

[0226] The HPLC detection conditions are the same as above.

[0227] B4 (R configuration): HPLC purity: >99%, retention time: 8.403 min. Chiral HPLC purity: >99%, retention time: 6.391 min. Single-crystal X-ray diffraction results show that it is of the R configuration.

[0228] B5 (S configuration): HPLC purity: >99%, retention time: 8.387 min. Chiral HPLC purity: >99%, retention time: 15.147 min.

[0229] Example 5: 6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine, (R)-6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine and (S)-6-(2-fluoro-3-isopropoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine

[0230] Step 1:

[0231] 3-Isopropoxy-2-fluorobromobenzene (5.584 g, 2.0 eq) was dissolved in 50 mL of tetrahydrofuran under nitrogen protection and cooled to -60 °C. 2.5 M n-butyllithium (10.5 mL, 2.2 eq) was slowly added dropwise. After the addition was complete, the reaction was maintained at -55 °C for approximately 1 h. Then, it was slowly added to a tetrahydrofuran solution of B6-a (3.107 g, 1.0 eq). After the addition was complete, the mixture was allowed to naturally warm to room temperature and reacted for 2 h. Post-treatment: The reaction was quenched with an appropriate amount of water, and the mixture was extracted three times with an appropriate amount of ethyl acetate. The combined organic phases were dried and concentrated under reduced pressure to obtain compound B6-b (6 g of brown oily liquid).

[0232] Step Two:

[0233] B6-b (6 g, 1.0 eq) was dissolved in 60 mL of tetrahydrofuran by stirring. Then, 6 mL of water and 6 mL of 6N hydrochloric acid were added, and the mixture was heated and stirred at 60 °C for 6 h. Post-treatment: Tetrahydrofuran was removed by concentration under reduced pressure. A suitable amount of water was added to the concentrate, and the pH was adjusted to weakly alkaline using a saturated sodium bicarbonate aqueous solution. The solution was then extracted three times with ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 1.123 g of a yellow oily liquid. 500 mg of this liquid was dissolved in 5 mL of ethyl acetate by stirring. 5 mL of hydrochloric acid / ethyl acetate was added, and the mixture was stirred for 30 min. The solvent was then concentrated to obtain compound B6-c (607 mg, brown solid). Step 3:

[0234] B6-c (607 mg, 1.0 eq), iodine (581 mg, 1.0 eq), and thiourea (174 mg, 1.0 eq) were added to a reaction flask, dissolved in 10 mL of 1,4-dioxane, and the mixture was heated and stirred at 80 °C for 15 h under nitrogen protection. Post-treatment: The reaction was quenched with saturated sodium bicarbonate solution, the pH was adjusted to approximately 7–8, and the mixture was extracted three times with an appropriate amount of ethyl acetate. The organic phases were combined, dried, concentrated under reduced pressure, and purified by column chromatography to obtain 100 mg of off-white solid B6.

[0235] 1 H NMR (400MHz, DMSO-d6) δ7.03–6.97(m,3H),6.61(s,2H),4.60–4.50(m,1H),3.05(d,J=16.1Hz,1H),2.57(d, J=15.8Hz,2H),2.33–2.28(m,1H),2.21–1.93(m,3H),1.80–1.75(m,1H),1.27(dd,J=6.0,1.1Hz,6H).ESI-MS m / z 323.2[M+H] + HPLC purity: >95%, retention time: 9.967 min.

[0236] Compound B6 was separated by chiral column chromatography to yield isomers B7 (R configuration) and B8 (S configuration):

[0237] Chiral HPLC detection conditions:

[0238] Chromatographic column: UniChiral CMD-5H ss 4.6x250mm; Mobile phase A: n-hexane; Mobile phase B: ethanol, isocratic elution A:B = 45:55; Detection wavelength: 270nm; Column temperature: 35℃; Flow rate: 1.0mL / min; Run time: 30min; Injection volume: 10μL; Sample preparation: 1.0mg / mL in ethanol.

[0239] The HPLC detection conditions are the same as above.

[0240] B7 (R configuration): HPLC purity: >98%, retention time: 9.852 min. Chiral HPLC purity: >99%, retention time: 5.135 min. Single-crystal X-ray diffraction results show that it is of the R configuration.

[0241] B8 (S configuration): HPLC purity: >99%, retention time: 9.870 min. Chiral HPLC purity: >99%, retention time: 9.090 min.

[0242] Example 6 Preparation of 6-(2-fluoro-3-methoxyphenyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine,(R)-6-(2-fluoro-3-methoxyphenyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine; (S)-6-(2-fluoro-3-methoxyphenyl)-N 6 -Methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine

[0243] Step 1:

[0244] Dissolve 40g of B39-a in 200mL of toluene, add benzylamine (28.26g, 1.0eq), reflux under N2 protection to remove water for 4h, concentrate under normal pressure to remove toluene, and obtain compound B39-b (63g, light brown oily substance). No further post-treatment is required to proceed directly to the next reaction.

[0245] Step Two:

[0246] The obtained B39-b (63g) was dissolved in 620mL of tetrahydrofuran, and 72.6g of boron trifluoride ether was added dropwise with stirring at low temperature (-60℃). After the addition was completed, the mixture was stirred at low temperature for 60min to obtain an imine solution.

[0247] 2-Fluoro-3-bromoanisole (94.7 g, 1.5 eq) was dissolved in tetrahydrofuran (320 mL), and n-butyllithium (2.5 M, 176 mL) was added dropwise with stirring at low temperature (-60 °C). After the addition was complete, the mixture was stirred at low temperature for 60 min to obtain a phenyllithium solution.

[0248] A phenyllithium solution was added dropwise to the imine solution at low temperature. After the addition was complete, the mixture was stirred at low temperature (-60℃) for 1 hour, allowed to rise naturally to room temperature, and monitored by TLC. After the reaction was complete, 20% NaOH aqueous solution (20.5 mL) was added to quench the reaction. Water (400 mL) was added, and the mixture was extracted with EA (400 mL × 2). The organic phase was washed once with 400 mL of water and once with 400 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily substance. The concentrate was dissolved in 100 g of ethanol by heating, then cooled to 0–5℃, stirred for 2 hours, and filtered to obtain compound B39-c (50 g white solid).

[0249] Step 3:

[0250] Add B39-c (30g), 200mL acetonitrile, formaldehyde aqueous solution (36g), and sodium cyanoborohydride (11g) to a 500mL three-necked flask. Stir at room temperature for 30min. Then add 100mL water and 60mL acetic acid. Stir at room temperature for 2h. Concentrate under reduced pressure to remove acetonitrile. Adjust the pH to 7-8 with ammonia. Add 300mL ethyl acetate. Extract and separate the layers. Wash the organic phase successively with 150mL water and 2 x 150mL saturated sodium chloride aqueous solution. Concentrate under reduced pressure to dryness to obtain compound B39-d (30g white solid).

[0251] Step Four:

[0252] Add B39-d (30g), 400mL methanol, acetic acid (10g), and 10% palladium on carbon (10g) to a 500mL three-necked flask. Replace with hydrogen, heat to 30°C and stir overnight. Filter, concentrate under reduced pressure to remove methanol, and obtain compound B39-e (25g oily substance).

[0253] Step 5:

[0254] Add 25 g of B39-e, 400 mL of water, and 40 mL of hydrochloric acid to a 25 mL three-necked flask. Heat to 95 °C and stir overnight. After the reaction is complete, cool to room temperature and adjust the pH of the system to 7-8 with saturated sodium carbonate aqueous solution. Extract with ethyl acetate, combine the organic phases, and wash successively with water and saturated sodium chloride aqueous solution. Dry the organic phase with anhydrous sodium sulfate and concentrate under reduced pressure. Add 200 mL of ethyl acetate and 12 g of 30% hydrogen chloride ethanol solution to the concentrate, stir at room temperature for 2 hours, filter, and dry to obtain compound B39-f (10 g, white solid).

[0255] Step Six:

[0256] Add 10 g of B39-f, 13.9 g of iodine, and 340 mL of 1,4-dioxane to a 50 mL three-necked flask. After addition, stir at room temperature for half an hour. Add 4.2 g of thiourea and heat to 100 °C to react overnight. Concentrate under reduced pressure to remove the solvent. Add 10 mL of ethyl acetate to the concentrate, stir for 1 hour, filter, dissolve the filter cake in 10 mL of water, wash with 2 x 200 mL of ethyl acetate, adjust the pH of the system to 9-10 with sodium hydroxide, and a large amount of solid precipitates. Stir in an ice-water bath for 1 hour, filter, and dry at 55 °C to obtain compound B39-g (6.7 g white solid), yield 60%.

[0257] 1 H NMR (400MHz, DMSO-d6) δ7.13–7.04(m,2H),6.80–6.76(m,1H),6.66(s,2H),3.82(s,3H),3.29(d,J=19.9Hz,1H ),2.80(d,J=16.1Hz,1H),2.51–2.45(m,1H),2.35–2.32(m,1H),2.16–2.10(m,4H),1.98–1.93(m,1H).ESI-MS m / z 308.1[M+H] + HPLC purity: >99%, retention time: 6.705 min.

[0258] Step Seven:

[0259] Compound B39-g (1.1 g) was added to 2.6 mL of water, 5 mL of methanol, and 2.6 mL of isopropanol. The mixture was stirred at 60 °C for 10 min, then L-tartaric acid (548 mg, 1.02 eq) was added, and stirring continued for 1 h. The mixture was cooled to room temperature, filtered, and the filter cake was dried to obtain crude compound B39 tartrate. The filtrate was adjusted to a weakly alkaline pH using saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. D-tartaric acid was used to form a salt to obtain crude compound B40 tartrate.

[0260] Crude tartrates of compounds B39 and B40 were recrystallized from a methanol:water:isopropanol mixture of 1:2:1 to obtain compounds B39 and B40 tartrates, respectively. The resulting compounds were then extracted with ethyl acetate after adjusting the pH to a weakly alkaline state using saturated sodium bicarbonate solution, and concentrated under reduced pressure to obtain compounds B39 and B40.

[0261] Chiral HPLC detection conditions:

[0262] Chromatographic column: UniChiral CMD-5H ss 4.6x250mm; Mobile phase A: n-hexane; Mobile phase B: ethanol, isocratic elution A:B = 50:50; Detection wavelength: 260nm; Column temperature: 35℃; Flow rate: 1.0mL / min; Injection volume: 5μL; Sample preparation: 1.0mg / mL in ethanol.

[0263] The HPLC detection conditions are the same as above.

[0264] B39 (R configuration): HPLC purity: >99%, retention time: 6.700 min. Chiral HPLC purity: >99%, retention time: 5.194 min. Single-crystal X-ray diffraction results show that it is of the R configuration.

[0265] B40 (S configuration): HPLC purity: >99%, retention time: 6.705 min. Chiral HPLC purity: >99%, retention time: 8.508 min.

[0266] Compounds A5-A347, B9-B38, and B41-B70 shown in the table below were prepared using the same / similar methods as in the examples above, except that the starting materials and intermediates corresponding to the final products were used. For salt-forming compounds, their salts were prepared according to methods generally accepted in the art after the compounds were prepared as described above. Referring to the foregoing examples, the chiral isomers in the table below were separated using a UniChiral CMD-5H ss 4.6x250mm, 5μm column (or a column of equivalent performance); the detection wavelength was selected according to the specific compound; and the mobile phase ratio and flow rate were adjusted appropriately.

[0267] Pharmacological Example 1: NMDA receptor antagonistic activity assay. The effect of the compound on the channel current of NMDA receptor (N-methyl-D-aspartate receptor, NR1 / 2A subtype) was tested using the electrophysiological whole-cell manual patch-clamp method.

[0268] Experimental apparatus:

[0269] Patch clamp amplifier (Multiclamp 700B, Axopatch 200B, Axon, USA)

[0270] Digital-to-analog converters (Digidata 1440A, Digidata 1550B, Axon, USA)

[0271] Inverted microscopes (IX71, IX51, Olympus, Japan)

[0272] Rapid drug delivery system (RSC-200, Bio-Logic, France)

[0273] Micromanipulator (MX7600R, Syskiyou, USA)

[0274] Electrode drawing apparatus (P-97, Sutter, USA)

[0275] Glass electrode (BF150-86-10, Sutter, USA)

[0276] Vibration damping platform and shielding mesh (63-534, TMC, USA)

[0277] Data acquisition and analysis software (pClamp, Axon, USA)

[0278] CO2 incubator (HERAcell 150i, Thermo, USA)

[0279] Biosafety cabinet (MODEL 1384, Thermo, USA)

[0280] Pure water system (Milli Q, Millipore, USA)

[0281] Reagents:

[0282] Sodium chloride (NaCl) (Sigma, Cat: S7653)

[0283] Potassium chloride (KCl) (Sigma, Cat: P9333)

[0284] Cesium chloride (CsCl) (Sigma, Cat: V900481)

[0285] Cesium fluoride (CsF) (Sigma, Cat: 289345)

[0286] Calcium chloride (CaCl2) (Sigma, Cat: 21115)

[0287] Glucose (Sigma, Cat: G7528)

[0288] 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (abbreviated as HEPES) (Sigma, Cat: H3375)

[0289] Ethylene glycol bis(2-aminoethyl ether)tetraacetic acid (EGTA) (Sigma, Cat: E3889)

[0290] Lipofectamine 3000 Transfection Kit (Gibco, Cat: L3000015) (includes both Lipofectamine 3000 and P3000 reagents)

[0291] DMEM (Gibco, Cat: C11995500BT)

[0292] Fetal bovine serum (FBS) (Gibco, Cat: 10099141)

[0293] Opti-MEM (Gibco, Cat:31985070)

[0294] Sodium hydroxide (NaOH) (National Pharmaceutical Group Co., Ltd., Cat: 10019718)

[0295] Cesium hydroxide (CsOH) (Sigma, Cat: 232068)

[0296] Dimethyl sulfoxide (DMSO) (Sigma, Cat: 276855)

[0297] Glutamic acid (Sigma, Cat: G1626-100G)

[0298] Glycine (Amresco, Cat: 0167-1KG)

[0299] Extracellular fluid formulation (mM): 140 NaCl, 2.8 KCl, 1 CaCl2, 10 HEPES and 20 Sucrose, pH adjusted to 7.4 with NaOH.

[0300] Intracellular fluid formulation (mM): 10 CsCl, 115 CsF, 10 EGTA and 10 HEPES, pH adjusted to 7.2 with CsOH.

[0301] Specific operations:

[0302] a. Cell culture and processing

[0303] HEK293 cell lines were cultured in DMEM medium containing 10% fetal bovine serum at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0304] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at room temperature for 1 minute. When the cells detach from the bottom of the dish, add 3 mL of pre-warmed 37°C complete culture medium (90% DMEM + 10% FBS). Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 800 rpm for 3 minutes to collect the cells. Seed the cells at a 1:5 ratio in T25 cell culture flasks (final volume: 6 mL) for expansion or maintenance culture.

[0305] Transient transfection: 24 hours before transient transfection, HEK-293 cells with a cell density of approximately 80% were reseeded to a depth of 35 mm. 2 In each cell culture dish, the inoculum size is 3 × 10⁶ cells / mL. 5 Each cell.

[0306] Prepare the instantaneous reagent for each well according to the following volume:

[0307] 1) Add 7.5 μL of Lipofectamine 3000 to 250 μL of Opti-MEM medium, gently mix by pipetting, and use as component A. Incubate at room temperature for 5 min.

[0308] 2) Take 3.6 μg of pCDNA5-FRT-TO-hNR1-T2A-2A plasmid, 0.4 μg of GFP plasmid, and 7.5 μL of P3000 and add them to 250 μL of Opti-MEM medium. Gently pipette to mix well. This is component B. Incubate at room temperature for 5 min.

[0309] 3) Add component B to component A, gently pipette until fully mixed, and incubate at room temperature for 15 minutes to form a DNA liposome mixture;

[0310] 4) Add the DNA-liposome mixture to 35 mm 2 500 μL of the solution was placed in each well of a cell culture dish and incubated in an incubator.

[0311] 5) Change the solution after 6 hours, using 35mm. 2 All the culture medium in the cell culture dish was aspirated, and 2 mL of complete culture medium (90% DMEM + 10% FBS) was added to each well. After culturing for 18 hours, patch-clamp detection was performed.

[0312] b. Compound preparation: On the day of testing, the stock solution of the compound of this invention is diluted with DMSO to the working concentration, and then diluted with extracellular fluid (containing 100 μM Glutamic acid + 100 μM Glycine) to obtain the final concentration to be tested. The DMSO content in the final test concentration shall not exceed 0.2%.

[0313] c. Electrophysiological recording process

[0314] HEK293 cells transiently expressing NMDA receptor channels were used to record the current induced by 100 μM glutamic acid (containing 100 μM glycine) at room temperature using whole-cell patch-clamp technique. The glass microelectrode was fabricated from a glass electrode blank (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrode was connected to the patch-clamp amplifier by inserting it into the amplifier probe. Clamping voltage and data recording were controlled and recorded via computer using pClamp software, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, cells were clamped at -70 mV. A rapid drug delivery system was used to administer 100 μM glutamic acid (containing 100 μM glycine) via gravity to induce channel currents. Once the current stabilized, 100 μM glutamic acid (containing 100 μM glycine) containing the compound was administered to observe changes in current amplitude. The compound was administered continuously from low to high concentrations, with a final administration of 100 μM glutamic acid (containing 100 μM glycine). Each test concentration of the compound was administered for at least 20 seconds, and at least two cells (n≥2) were tested for each concentration.

[0315] d. Data processing

[0316] Data analysis and processing were performed using pClamp, GraphPad Prism 8, and Excel software. The degree of inhibition of channel current (current amplitude induced by 100 μM Glutamic acid (containing 100 μM Glycine) at -70 mV) by different compound concentrations was calculated using the following formula:

[0317] Inhibition%=[1–(I / Io)]×100%

[0318] Wherein, Inhibition% represents the percentage of NMDA channel current inhibited by the compound, and I and Io represent the current amplitude induced by 100 μM Glutamic acid (containing 100 μM Glycine) before and after drug administration.

[0319] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 8 software:

[0320] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0321] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively. Test results for some compounds are shown in Table 1.

[0322] Table 1:

[0323] The data above show that the compounds in the embodiments of the present invention have certain antagonistic activity against NMDA receptors, and are expected to have a therapeutic effect on NMDA receptor-related central nervous system diseases.

[0324] Pharmacological Example 2: Monoamine Transporter Inhibitory Activity Test

[0325] (1) 5-HT transporter inhibitory activity test:

[0326] Main reagents and instruments:

[0327] HEPES(Invitrogen,Cat:15630-106)

[0328] HBSS (Invitrogen, Cat: 14025)

[0329] Bovine Serum Albumin(Sigma,Cat:B2064-100G)

[0330] Neurotransmitter transporter uptake assay kit(Molecular devices,Cat:R8174)

[0331] Incubator (Thermo, 240)

[0332] Envision(Perkin Elmer,envision2014)

[0333] 384 well plate(Greiner,Cat:784075)

[0334] In HEK-293 cells overexpressing human SERT, the inhibitory effect of the test compound on human SERT transporters was detected using a Neurotransmitter transporter uptake assay kit (Molecular devices). The assay was performed according to the kit instructions, with citalopram used as a positive control. The specific procedures are as follows:

[0335] a) Seed HEK-293-hSERT cells at 20,000 cells / well into 384-well plates, and then transfer the 384-well plates to an incubator and incubate overnight at 37°C;

[0336] b) The following day, test solutions for citalopram and the compounds of the present invention were prepared in 384-well plates using experimental buffer (HBSS solution containing 0.1% BSA and 20 mM HEPES). The initial test concentration of citalopram was 1 μM, diluted 3X, and the initial test concentration of the test compound was 10 μM or 100 μM, diluted 3X. Each concentration was repeated twice.

[0337] c) Remove the 384-well plate containing HEK-293-hSERT cells from the incubator, remove the culture medium from the wells, and add 25 μL of the test compound solution to each well; incubate at 37°C for 30 min.

[0338] d) Add 25 μL of dye to each well and incubate at 37°C for 30 min;

[0339] e) Fluorescence values ​​were read on Envision and the data were analyzed using Graphpad Prism software. The results are shown in Table 2.

[0340] (2) DAT and NET transporter inhibitory activity test:

[0341] Main reagents and instruments:

[0342] The inhibitory effect of the compounds on transporters in HEK-293 cells expressing human DAT and NET was detected using a Neurotransmitter transporter uptake assay kit (Molecular devices). The assay was performed according to the kit instructions, with Centanafadine used as a positive control. The specific procedures are as follows:

[0343] NET Transient Cell Preparation:

[0344] Day 1 Cell Plating: HEK 293T cells were trypsinized, centrifuged, resuspended in culture medium, counted, and seeded into 6cm culture dishes at a density of 3×10⁻⁶ cells / cm². 6 cells / pores;

[0345] On the second day, cell transfection was performed: HEK 293T cells were changed in medium, and then the NET-pcDNA5 / FRT plasmid to be transfected was prepared into two tubes, A and B. 200 μL of Opti-MEM was added to tube A, followed by 10 μL of Lipofectamine. TM Mix thoroughly. Add 200 μL of Opti-MEM to tube B, then add 5 μg of NET-pcDNA5 / FRT plasmid, mix well, and then add 10 μL of P3000 to tube B. TM Mix thoroughly (plasmid to transfection reagent ratio: 1 μg: 2 μL). Add the diluted solution from tube A to the diluted solution from tube B, mix well, and incubate at room temperature for 15 minutes. Finally, gently add the mixture to the cells that have had their medium changed, gently shake to mix, and then incubate overnight at 37°C with 5% CO2. Cells are used for compound functional activity assays 18-20 hours after transfection.

[0346] DAT stable culture: The DAT-HEK cell line was cultured in DMEM medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at a temperature of 37°C and a carbon dioxide concentration of 5%.

[0347] DAT stable cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL TrypLE TM Incubate with Express solution at 37°C for approximately 2 minutes. Once the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate any aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes. To maintain cell physiological viability, the cell confluence should be maintained at approximately 80%.

[0348] a) After overnight transfection with NET cells, the cells were trypsinized, resuspended in DMEM + 10% Dialyzed FBS medium, and seeded at 20,000 cells / well in 384-well plates for overnight culture. Stable transfected DAT cells were trypsinized, resuspended in DMEM + 10% Dialyzed FBS medium, and seeded at 2,500 cells / well in 384-well plates for overnight culture.

[0349] b) Prepare 1×Assay Buffer according to the kit instructions; perform serial dilutions of the positive compound and the test compound with DMSO, and then dilute with 1×Assay Buffer to 2×.

[0350] c) Centrifuge to remove the culture medium from the 384-well plate;

[0351] d) Take 16 μL of the compound prepared in step b) and add it to the corresponding experimental wells. Add the first concentration of 2× positive control compound to the positive control wells and add 0.2% DMSO buffer to the negative control wells. After centrifugation, incubate at 37°C for 30 min.

[0352] e) Prepare the test reagent with 1×HBSS, add 16μL of the test reagent to each well, centrifuge, and incubate at 37℃ for 60min;

[0353] f) After incubation, the values ​​at 510 nm were measured using a microplate reader under excitation at 425 nm. Curve fitting and IC50 were performed using the nonlinear regression method in GraphPad Prism software. 50 Calculations were performed. The results are shown in Table 2 below.

[0354] Table 2

[0355] The above data show that the compounds in the embodiments of the present invention have certain antagonistic activity against monoamine transporters, and are expected to have therapeutic effects on central nervous system diseases associated with monoamine transporters. Specifically, compound B1 exhibits significantly better 5-HTT inhibitory activity than B2, compound B4 exhibits significantly better 5-HTT inhibitory activity than B5, and compound B39 exhibits significantly better 5-HTT inhibitory activity than B40. 50 Values ​​≤200 nM are expected to have therapeutic effects on central nervous system diseases associated with 5-HT transporters.

[0356] For some of the compounds in the examples, the DAT-inhibiting activity of the S-configuration compounds was significantly better than that of the R-configuration compounds. For example, the DAT-inhibiting activity of compound A2 was significantly better than that of A1, and the DAT-inhibiting activity of compound A4 was significantly better than that of A3. Furthermore, the IC50 values ​​of some S-configuration compounds were significantly higher than those of the R-configuration compounds. 50 Values ​​≤500 nM are expected to have therapeutic effects on dopamine transporter-related central nervous system disorders, such as attention deficit hyperactivity disorder (ADHD).

[0357] Pharmacological Example 3: Forced Swim Test and Spontaneous Activity Test:

[0358] Drug: The compound of this invention is mixed with 5% DMSO and then added with 5% Mix HS15 thoroughly, then add 90% physiological saline to prepare a solution of appropriate concentration. Prepare and use immediately.

[0359] Animals: Male C57 mice, approximately 22g. Animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Mice in each group were administered either the solvent prescription or the test drug via intraperitoneal injection (ip).

[0360] Experimental Procedure: Mice were subjected to forced swimming tests 0.5 h or 24 h after drug administration. The water level in the forced swimming device was 45 cm, and the water temperature was 25 °C. Before the experiment, the mice were placed in the experimental room for 1 h to acclimatize. At the start of the experiment, the mice were placed in the device for 6 minutes. The entire process was recorded by a camera, and only the immobile time of the mice in the last 4 minutes was counted when analyzing the data. The experimental results are shown in Table 3 (0.5 h time point) and Table 4 (24 h time point):

[0361] Table 3

[0362] The data above show that, at the above doses, the swimming immobility time of mice in the drug group was significantly reduced compared to the blank control group (solvent group), demonstrating a significant antidepressant-like effect.

[0363] Table 4

[0364] –: No effect

[0365] The data above show that, at a dose of 30 mg / kg, the swimming immobility time of mice in the drug group was significantly reduced compared to the blank control group at 24 hours after administration, demonstrating a significant antidepressant-like effect. In contrast, the traditional SSRI fluoxetine showed no antidepressant-like effect 24 hours after administration.

[0366] Pharmacological Example 4: Forced Swim Test and Spontaneous Activity Test:

[0367] Drug: The compound of this invention is mixed with 5% DMSO and then added with 5% Mix HS15 thoroughly, then add 90% physiological saline to prepare a solution of appropriate concentration. Prepare and use immediately.

[0368] Animals: Male C57 mice, approximately 22g. Animals were randomly divided into a blank control group and each test drug group, with 8 animals in each group. Mice in each group were administered either the solvent prescription or the test drug via intraperitoneal injection (ip).

[0369] Forced swimming experiment:

[0370] Forced swimming test procedure: Mice were subjected to forced swimming tests 1 hour or 24 hours after drug administration. The water level in the forced swimming device was 45 cm, and the water temperature was 25°C. Before the experiment, the mice were placed in the experimental room for 1 hour to acclimatize to the environment. At the start of the experiment, the mice were placed in the device for 6 minutes. The entire process was recorded by a camera, and only the immobile time of the mice in the last 4 minutes was counted when analyzing the data.

[0371] Spontaneous activity experiment:

[0372] The Locomotor Activity (LMA) test is used to detect psychostimulant activity. LMA is a behavioral test developed to predict the potency of psychostimulants. It is an attractive test for psychostimulants due to its sensitivity and specificity. Marketed psychostimulants, including methylphenidate, amphetamines, and modafinil, all exhibit enhanced ambulatory activities in LMA tests.

[0373] Procedure: The experimental environment was maintained at (22℃±1℃). Mice were first placed in a spontaneous incubator to adapt for 15 minutes, and their spontaneous activities were recorded within 15 minutes. Then, the mice were removed from the spontaneous incubator, and after intraperitoneal administration of the drug, they were immediately placed in a spontaneous incubator (25cm long, 25cm wide, and 45cm high). The activity trajectory of the mice within 60 minutes after drug administration was recorded using the Nordas video analysis system, and the data was analyzed and statistically analyzed.

[0374] Results of the forced swimming experiment:

[0375] One hour after administration, the positive control drug esketamine exhibited a significant antidepressant-like effect. At the same dose (20 mg / kg), compound A4 showed a lower immobility time (in seconds) compared to compound A3, and both were significantly lower than the blank control group (solvent group), indicating a more significant antidepressant-like effect (see Figure 1). At the same dose (20 mg / kg), compound A24 showed a more significant antidepressant-like effect compared to compound A23. At the same dose (10 mg / kg), compound A28 showed a more significant antidepressant-like effect compared to compound A27. At the same dose (10 mg / kg), compound A36 showed a more significant antidepressant-like effect compared to compound A35. At 24 hours after administration, compound A4 (20 mg / kg) showed a significant antidepressant-like effect, while the traditional SSRI fluoxetine showed no antidepressant-like efficacy.

[0376] Results of spontaneous activity experiments:

[0377] Compared to the blank control group, compounds A2 and A4 significantly increased spontaneous activity (total distance of movement within 60 min) in mice in a dose-dependent manner within the dose range of 10-40 mg / kg (10, 20, 40 mg / kg), demonstrating psychostimulant effects. They can be used to treat diseases related to dopamine reuptake, such as ADHD.

[0378] Pharmacological Example 5: Experimental drug for ADHD in rats: The compound of the present invention was mixed with 5% DMSO and then 90% physiological saline to prepare a solution of appropriate concentration, which was prepared and used immediately.

[0379] Animals: Male spontaneously hypertensive rats (SHR), weighing between 100g and 300g, and male Wistar rats weighing between 200g and 400g were used as control rats. All rats were 1-3 months old. SHR rats were randomly divided into a model group and each test drug group, with 6-8 animals in each group. Mice in each group received an intraperitoneal injection of either the solvent formulation or the test drug, while Wistar rats received the same solvent formulation via intraperitoneal injection.

[0380] Experimental Procedure: Before the experiment, rats were placed in the experimental room to acclimatize for 1 hour. Immediately after intraperitoneal injection of the drug, rats were placed in an open field for spontaneous activity testing, which lasted for 1 hour. Object recognition was then performed 3 hours after drug administration. Specific experimental procedures are as follows:

[0381] 1. Spontaneous activities in open spaces

[0382] Rats were intraperitoneally injected with the test drug or solvent at a volume of 5 ml / kg. Immediately after injection, the rats were placed in an open enclosure (80cm*80cm*40cm, L*W*H) and allowed to explore freely for 1 hour. Anymaze software was used to record the movement distance and trajectory of each rat. The activity level of the animals was analyzed every 15 minutes and the total activity level over 60 minutes.

[0383] 2. Object Recognition (Spatial Object Recognition)

[0384] Three hours after intraperitoneal injection of the test drugs or solvents, rats were placed in an open-field box containing two identical objects (cylinders with a base diameter of 6 cm and a height of 15 cm) and allowed to explore freely for 10 minutes; this was the training period. One hour after the training period, one of the objects was moved to a new location, and the rat was placed back in the same box and allowed to explore freely for another 10 minutes. The exploration time for each object was manually timed by the experimenter, and the behavior of each rat was recorded using video software. The 1-hour object recognition index of the rats was calculated using the following formula:

[0385] Statistical analysis was performed using one-way ANOVA, followed by Dunnett's multiple comparison test. * p<0.05 vs SHR group, ** p<0.01 vs SHR group, *** p<0.001 vs SHR group.

[0386] Experimental results:

[0387] Compared with the model group, compounds A2, A4, A60, A83 maleate, A197, A204, A217 and A223 reduced total spontaneous activity in rats (Figure 3) and improved spatial memory (Figure 4) in the dose range of 10-40 mg / kg, and have anti-ADHD effects. They can be used to treat diseases related to dopamine or norepinephrine reuptake, such as ADHD.

[0388] Pharmacological Example 6: Sigma2 Receptor Affinity Experiment

[0389] The experiment was conducted according to the procedures described in Pharmacological Example 4 of patent application PCT / CN2023 / 130755. The experimental results are shown in Table 5 below:

[0390] Table 5

[0391] The data in Table 5 above show that the compounds in the embodiments of the present invention have a good affinity for the sigma2 receptor and are expected to have a therapeutic effect on central nervous system diseases related to the sigma2 receptor.

Claims

1. A compound of formula (I), or its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or isotopically labeled compounds, in, R1 is selected from CN, -C(O)NH2, halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 alkylthio, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C6-C12 aryl C1-C6 alkoxy; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyl C1-C6 alkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C6-C12 aryl C1-C6 alkoxy; R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl / C1-C6 alkyl; Alternatively, R2, R3 and the nitrogen atom attached thereto form a 3-9 membered heterocyclic alkyl group, wherein the 3-9 membered heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, and the 3-9 membered heterocyclic alkyl group is optionally substituted by one or more C1-C6 alkyl groups; R4 is selected from hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, CN, and halogen; in particular, R4 is selected from hydrogen or halogen. G ring is selected from Specifically, ring G is selected from Wherein, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, carbamoyl (-C(O)NH2), formylamino, C1-C3 alkylamino, halogenated C1-C3 alkylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl, C1-C3 alkylaminocarbonyl, C3-C5 cycloalkyl, morpholinyl, phenyl, pyridine, pyrrolidinyl, or piperidinyl; each R6 is independently selected from hydrogen, C1-C3 alkyl; specifically, each R5 is independently selected from hydrogen, amino, hydroxyl, carboxyl, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylacyl, carbamoyl (-C(O)NH2), formylamino, methylamino, N,N-dimethylamino, C1-C3 alkoxycarbonyl, C1-C3 alkylaminocarbonyl, C3-C5 cycloalkyl, morpholinyl, phenyl, pyridine, pyrrolidinyl or piperidinyl; each R6 is independently selected from hydrogen and C1-C3 alkyl; Furthermore, the compound shown in formula (I) is not one of the following compounds: (1) 6-(2-fluoro-3-methoxyphenyl)-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine; (2) 6-(2-fluoro-3-methoxyphenyl)-N6-methyl-4,5,6,7-tetrahydrobenzo[d]thiazol-2,6-diamine; 2. The compound of formula (I) according to claim 1, or its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or isotopically labeled compounds, characterized in that, R1 is independently selected from halogens, hydroxyl groups, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, C1-C4 alkoxy groups, halogenated C1-C4 alkoxy groups, C3-C5 cycloalkyl groups, C3-C5 cycloalkyl C1-C4 alkyl groups, C3-C5 cycloalkyl C1-C4 alkoxy groups, C6-C10 aryl C1-C4 alkoxy groups, CN, -C(O)NH2, and C1-C4 alkylthio groups; in particular, R1 is selected from halogens, hydroxyl groups, C1-C4 alkyl groups, halogenated C1-C4 alkyl groups, and C1-C4 alkoxy groups. The following are alkyl, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkylC1-C4 alkyl, C3-C5 cycloalkylC1-C4 alkoxy, C6-C10 arylC1-C4 alkoxy; preferably, R1 is independently selected from F, C1, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy, benzyloxy; and / or R2 and R3 are independently selected from hydrogen, C1-C4 alkyl, or C3-C5 cycloalkyl; or R2 and R3 together with the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl group; preferably, R2 and R3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, or cyclopropylmethyl; or R2 and R3 together with the nitrogen atom attached thereto form an aza-heterocyclic butyl, 4-pyrrolidinyl, or piperidinyl; and / or R4 is selected from hydrogen or halogen; preferably from hydrogen, F, or Cl.

3. The compound of formula (I) according to claim 1 or 2, or its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from the structures shown in formulas (I-1) to (I-16): Specifically selected are the structures shown in the following formulas (I-1) to (I-4): Preferably, the compound represented by formula (I) is selected from the structures shown in formulas (I-1-1) to (I-16-2): Specifically selected are the structures shown in the following formulas (I-1-1) to (I-4-2): R1, R2, R3, R4, R5, and R6 are defined as described in any one of claims 1-2.

4. The compound of formula (I) according to claim 1, or its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from the structure shown in formula (I-1-a): Wherein, R1 is selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy, C1-C6 alkylthio, CN, -C(O)NH2; particularly selected from halogen, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl C1-C6 alkoxy; R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2 and R3 together with the attached nitrogen atom form a 3-9 membered heterocyclic alkyl ring, wherein the 3-9 membered heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, wherein the 3-9 membered heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups; Preferably, R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, C3-C5 cycloalkylC1-C4 alkoxy; and / or R2 and R3 are independently selected from hydrogen, C1-C4 alkyl or C3-C5 cycloalkylC1-C4 alkyl; or R2, R3 and the nitrogen atom attached thereto form a 4-7 membered heterocyclic alkyl group. More preferably, R1 is selected from F, Cl, hydroxyl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, ethoxy, trifluoroethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, cyclopropylmethoxy; and / or R2 and R3 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropylmethyl; or R2 and R3 together with the attached nitrogen atom form azirrocyclobutyl, 4-pyrrolidinyl, or piperidinyl.

5. The compound of formula (I) according to claim 1, or its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, or isotopically labeled compounds, characterized in that, The compound represented by formula (I) is selected from the structure shown in formula (I-1-b): Specifically, the compound represented by formula (I) is a compound represented by formula (I-1-b1) or formula (I-1-b2). in: R1 is selected from halogen, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, and C3-C6 cycloalkyl-C1-C6 alkoxy. R2 and R3 are independently selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl; or, R2 and R3 together with the attached nitrogen atom form a 3-9 membered heterocyclic alkyl ring, wherein the 3-9 membered heterocyclic alkyl ring optionally contains one or more (e.g., 2, 3, 4) additional heteroatoms selected from nitrogen and oxygen atoms, wherein the 3-9 membered heterocyclic alkyl ring is optionally substituted by one or more C1-C6 alkyl groups; Preferably, R1 is selected from halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy, C3-C5 cycloalkyl, C3-C5 cycloalkyloxy, and C3-C5 cycloalkylC1-C4 alkoxy; more preferably, R1 is selected from Cl, hydroxyl, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, ethoxy, isopropoxy, isobutoxy, cyclopropyl, cyclopropyloxy, and cyclopropylmethoxy; and / or R2 and R3 are each independently selected from hydrogen and C1-C4 alkyl; more preferably, R2 and R3 are each independently selected from hydrogen and methyl.

6. Amine compounds containing substituted phenyl groups, having a structure selected from the following:

7. The substituted phenyl amine compound according to claim 6, wherein the substituted phenyl amine compound has a structure selected from the structure shown in claim 5: A2, A4, A6, A8, A10, A12, A14, A16, A18, A20, A22, A24, A26, A28, A30, A32, A34, A36, A38, A40, A42, A44, A46, A48, A50, A52, A54, A56, A58, A60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A79, A80, A81, A82, A83, A85, A86, A87, A89, A90 , A91, A93, A94, A96, A97, A99, A100, A102, A103, A105, A106, A108, A109, A1 11. A112, A114, A115, A117, A118, A120, A121, A123, A124, A125, A127, A129, A130, A132, A133, A135, A136, A138, A139, A141, A142, A144, A145, A147, A1 48. A150, A151, A153, A154, A156, A157, A158, A159, A160, A161, A162, A163, A165, A166, A168, A169, A171, A172, A174, A175, A176, A177, A178, A179, A1 80, A182, A183, A185, A186, A187, A189, A190, A192, A193, A194, A195, A196, A197, A199, A200, A201, A203, A204, A206, A207, A208, A210, A211, A212, A2 13. A214, A216, A217, A219, A220, A222, A223, A225, A226, A228, A229, A230, A232, A233, A234, A236, A237, A239, A241, A242, A245, A247, A249, A251, A2 53. A255, A257, A259, A261, A263, A265, A267, A269, A271, A273, A275, A277, A279, A281, A283, A285, A287, A289, A290, A292, A294, A296, A297, A299, A3 01. A303, A305, A307, A309, A310, A312, A315, A317, A319, A320, A323, A325,A327, A329, A330, A332, A333, A335, A336, A338, A339, A341, A342, A344, A346, B2, B3, B5, B6, B8, B9, B11, B12, B14, B15, B17, B18, B20, B21, B23, B24, B26, B27, B29, B30, B32, B33, B35, B36, B38, B40, B41, B43, B44, B46, B47, B49, B50, B52, B53, B55, B56, B58, B59, B61, B62, B64, B65, B67, B68, B69; preferably A2, A4, A6, A8, A10, A12, A14, A22, A24, A30, A32, A34, A36, A50, A52, A54, A56, A58, A60, A62, A64, A66, A68, A70, A72, A74, A76, A78, A85, A89, A108, A111, A114, A117, A120, A123, A138, A141, A147, A150, A156, A165, A168, A171, A174, A182, A185, A187, A190, A199, A203, A206, A210, A216, A219, A222, A225, A226, A230, A234, A237, A239, A242, A245, A247, A249, A251, A253, A255, A257, A259, A261, A263, A265, A271, A273, A275, A277, A279, A281, A283, A285, A287, A289, A292, A294, A296, A309, A310, A312, A319, A320, A323, A325, A327, A329, A332, A335, A336, B2, B3, B5, B6, B8, B9, B11, B12, B14, B15, B17, B18, B20, B21, B23, B24, B26, B27, B29, B30, B32, B33, B35, B40, B41, B43, B44, B46, B47, B49, B50, B52, B53, B55, B56, B58, B59, B61, B62, B64, B65, B67, B68, B69.

8. A method for preparing amine compounds containing substituted phenyl groups as shown in formula (I-1-a) of claim 4 or formula (I-1-b) of claim 5; in, (i) The method for preparing the amine compound containing a substituted phenyl group as shown in formula (I-1-a) is carried out by a method comprising the following steps as shown in the following reaction formula: a) The compound shown in formula (II) undergoes a condensation reaction with the compound shown in formula (III) to produce the compound shown in formula (IV); b) The compound shown in formula (IV) and the compound shown in formula (V-1) undergo a nucleophilic addition reaction to produce the compound shown in formula (VI-1); c) When both R2 and R3 are hydrogen, the compound shown in formula (VI-1) is deprotected to produce the compound shown in formula (VII-1); When R2 is H and R3 is C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-1) undergoes alkylation and deprotection reactions, or undergoes reductive amination and deprotection reactions to generate the compound shown in formula (VII-1); When R2 and R3 are the same and are both C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-1) undergoes deprotection and alkylation reactions, or undergoes deprotection and reductive amination reactions to generate the compound shown in formula (VII-1); When R2 and R3 are C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, and the two are different, the compound shown in formula (VI-1) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII-1). d) The carbonyl α-position of the compound shown in formula (VII-1) undergoes halogenation, followed by a ring-closing reaction in the presence of thiourea to produce the compound shown in formula (VIII-1); e) The compound shown in formula (VIII-1) is salted by chiral acid to obtain the chiral acid salt of the compound shown in formula (I-1-a); Wherein R1 and R2 are as defined in claim 4; G represents a leaving group selected from C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups, wherein the C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, and phenyl groups; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl groups. Sulphinyl, benzyl, C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl; G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl; M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li; (ii) The method for preparing the amine compound containing a substituted phenyl group as shown in formula (I-1-b) is carried out by a method comprising the following steps as shown in the following reaction formula: a) The compound shown in formula (II) undergoes a condensation reaction with the compound shown in formula (III) to produce the compound shown in formula (IV); b) The compound shown in formula (IV) and the compound shown in formula (V-2) undergo a nucleophilic addition reaction to produce the compound shown in formula (VI-2); c) When R2 and R3 are hydrogen, the compound shown in formula (VI-2) is deprotected to produce the compound shown in formula (VII-2); When one of R2 and R3 is H and the other is C1-C6 alkyl or C3-C6 cycloalkyl, the compound shown in formula (VI-2) undergoes alkylation and deprotection reactions, or reductive amination and deprotection reactions to produce the compound shown in formula (VII-2); When R2 and R3 are both C1-C6 alkyl or C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-2) undergoes deprotection and alkylation reactions, or deprotection and reductive amination reactions to generate the compound shown in formula (VII-2); When R2 and R3 are different and each is independently a C1-C6 alkyl or a C3-C6 cycloalkyl C1-C6 alkyl, the compound shown in formula (VI-2) undergoes a three-step reaction of alkylation or reductive amination, deprotection, and alkylation or reductive amination to generate the compound shown in formula (VII-2). d) The compound shown in formula (VII-2) undergoes halogenation at the carbonyl α-position, followed by a ring-closing reaction in the presence of thiourea to produce the compound shown in formula (I-1-b); R1, R2 and R3 are as defined in claim 5; G represents a leaving group selected from C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups, wherein the C1-C6 alkylsulfinyl, benzenesulfinyl, naphthylsulfinyl, and benzyl groups may optionally be further substituted by one or more groups selected from halogen, C1-C6 alkyl, nitro, hydroxyl, amino, C1-C6 alkylacyl, C1-C6 alkoxy, and phenyl groups; G is preferably C1-C4 alkylsulfinyl, benzenesulfinyl, or naphthyl groups. Sulphinyl, benzyl, C1-C4 alkyl sulfinyl, benzene sulfinyl, naphthyl sulfinyl, benzyl are optionally further substituted by one or more groups selected from halogen, C1-C4 alkyl, nitro, hydroxyl, amino, C1-C4 alkyl, C1-C4 alkoxy, phenyl; G is more preferably tert-butyl sulfinyl, p-toluene sulfinyl, trifluoromethyl sulfinyl, p-bromosulfinyl, benzyl, p-methoxybenzyl or triphenylmethyl; M represents a leaving group, such as a metal element, halogen, metal compound, borane, silane, diazonium salt, etc., preferably -MgBr, -MgCl, or -Li.

9. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds selected from the compound of formula (I) according to any one of claims 1-5, their stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds, or amine compounds containing substituted phenyl groups according to claim 6 or 7, and optionally one or more pharmaceutically acceptable carriers, diluents, or excipients.

10. The use of the compound of formula (I) according to any one of claims 1-5, its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates, and isotopically labeled compounds thereof, or the amine compound containing a substituted phenyl group according to claim 6 or 7, or the use of the pharmaceutical composition according to claim 9 in the preparation of a medicament for modulating the activity of NMDA receptors and / or monoamine transporters; preferably in the preparation of NMDA receptor antagonists, and / or in the preparation of monoamine transporter inhibitors.

11. The use of the compound of formula (I) according to any one of claims 1-5, its stereoisomers, geometric isomers, conformational isomers, tautomers, pharmaceutically acceptable salts, polymorphs, solvates, hydrates and isotopically labeled compounds thereof, or the amine compound containing a substituted phenyl group according to claim 6 or 7, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for the prevention and / or treatment of diseases associated with NMDA receptors and / or monoamine transporters, particularly diseases of the central nervous system; Preferably, the central nervous system diseases are selected from: cerebral ischemia; stroke; cerebral infarction; traumatic brain injury; anti-NMDA receptor encephalitis; epilepsy; amyotrophic lateral sclerosis; schizophrenia; refractory, difficult-to-manage, or chronic schizophrenia; affective disorders; mental disorders; mood disorders; type I bipolar disorder; type II bipolar disorder; depression; Intrinsic depression; Major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic affective disorder; panic attack; Panic disorder; social phobia; Obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; hysteria; anorexia nervosa; sleep disorder; adjustment disorder; cognitive impairment; autism; neuropathic pain; bipolar disorder; Parkinson's disease; Huntington's disease; Alzheimer's disease; various dementias; memory impairment; ADHD; attention deficit / hyperactivity disorder; tic disorders; and other neurological events or neurodegeneration caused by NMDA receptor activation. Preferably, the neuropathic pain includes peripheral diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, peripheral neuropathy, chemotherapy-induced neuropathic pain, cancer neuropathic pain, neuropathic lower back pain, HIV neuropathic pain, trigeminal neuralgia, and central post-stroke pain. More preferably, the central nervous system disease is selected from: Type I bipolar disorder; Type II bipolar disorder; depression; endogenous depression; major depressive disorder; uncontrollable depression; dysphoric disorder; cyclothymic disorder; panic attack; Panic disorder; social phobia; Obsessive-compulsive disorder; impulsivity disorder; post-traumatic stress disorder; anxiety disorder; acute stress disorder; Parkinson's disease; peripheral diabetic neuropathy; postherpetic neuralgia; complex regional pain syndrome; attention deficit hyperactivity disorder.

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