Phenyl fused ring compound and application thereof in central nervous system

Abstract

The invention provides application of a compound shown in a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicine for treating and / or preventing diseases related to an NMDA receptor. The compound has good inhibitory activity on the NMDA receptor (especially a GluN1 / GluN3A receptor).

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a phenyl fused ring compound and its application in the central nervous system. Background Art

[0002] NMDA (N-methyl-D-aspartate) receptors belong to ionotropic glutamate receptors, which are widely distributed in the central nervous system, participate in synaptic transmission and plasticity, and regulate physiological functions such as learning and memory. They are an important class of protein targets. NMDA receptors are associated with a variety of diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, etc. They are one of the most popular drug development targets for neurological diseases. The development of drugs targeting NMDA receptors has important clinical significance and market value. The NMDA receptor family contains 7 subunits: GluN1, GluN2 (2A, 2B, 2C, 2D), and GluN3 (3A, 3B). The overall structure of the subunits is similar and has multiple domains. Functional NMDA receptors are heterotetramers containing at least one GluN1. The diversity of subunits determines the subtype diversity of NMDA receptors. Classical NMDA receptors are usually heterotetramers composed of two GluN1 and two GluN2 subunits. The crystal structure of the GluN1 / GluN2 subtype has been widely resolved, and multiple drug binding pockets have been found. Subunit diversity determines the subtype diversity of NMDA receptors. These subtypes have strong structural similarities and can be regarded as highly similar but not completely identical keyholes.

[0003] GluN1 / GluN3 includes GluN1 / GluN3A and GluN1 / GluN3B, both of which are NMDA receptor subtypes. GluN3A and GluN3B have high homology, and the highly active molecules discovered so far cannot distinguish between GluN1 / GluN3A and GluN1 / GluN3B. The structure of GluN1 / GluN3 receptors has not yet been resolved, nor has it been widely developed as a target. The lack of specific small molecule modulators and crystal structure information has greatly limited further research on GluN1 / GluN3. Therefore, it is of great significance to find compounds with high inhibitory activity against GluN3. Summary of the invention

[0004] In order to improve the above technical problems, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0005]

[0006] wherein A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted C 6-14Aryl, 5-14 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; and when A is C 6-14 When aromatic, is H; each R a the same or different, independently selected from OH, CN, halogen, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy;

[0007] L1, L2, L3 are the same or different and are independently selected from a single bond, -C(=O)O-, unsubstituted or optionally substituted with one, two, three or four R L The following groups substituted: -CH2O-, -CH2C(=O)O-, -CH2CH2C(=O)O-, -C(=O)NH-; each R L The same or different, independently selected from H, C 1-10 alkyl;

[0008] Cy1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R1: 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; each R1 is the same or different and is independently selected from H, halogen, OH, CN, NH2, oxo (=O), aldehyde, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, C 1-10 Alkyl-C(O)-;

[0009] Cy2 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R2: 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 Aryl; each R2 is the same or different, independently selected from H, OH, CN, halogen, NO2, NH2, COOH, unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkenyl, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy; each R 21 are the same or different and are independently selected from H, OH, CN, halogen, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy;

[0010] Cy3 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R3: 3-14 membered heterocyclyl, 5-14 membered heteroaryl or C 6-14 Aryl; each R3 is the same or different and is independently selected from H, OH, halogen, oxo (=O), CN, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyloxy, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 Aryl.

[0011] According to an embodiment of the present disclosure, A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-10 Aryl, 5-6 membered heteroaryl;

[0012] According to an embodiment of the present disclosure, A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: phenyl, pyridyl, for example CH, Each R a are the same or different and are independently selected from halogen, C 1-6 Alkyl, such as H, F or methyl.

[0013] According to an embodiment of the present disclosure, L1 is selected from -CH2O-, -C(=O)O-, -CH2C(=O)O-, -CH2CH2C(=O)O-, -C(=O)NH-.

[0014] According to an embodiment of the present disclosure, L2 is selected from a single bond, -C(=O)NH-, -C(=O)O-.

[0015] According to an embodiment of the present disclosure, L3 is a single bond.

[0016] According to an embodiment of the present disclosure, Cy1 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R1: 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0017] According to an embodiment of the present disclosure, Cy1 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R1: pyridyl, pyrimidinyl, pyridazinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, piperidinyl, cyclohexyl, morpholinyl, indolyl,

[0018] According to an embodiment of the present disclosure, Cy1 is selected from

[0019] According to an embodiment of the present disclosure, Cy1 is selected from

[0021] According to the embodiments of the present disclosure, each R1 is the same or different and is independently selected from H, halogen, OH, CN, NH2, oxo (=O), aldehyde, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-;

[0022] According to the embodiments of the present disclosure, each R1 is the same or different and is independently selected from H, F, Cl, OH, CN, NH2, oxo (=O), aldehyde, methyl, methoxy, CH3C(O)-,

[0023] According to an embodiment of the present disclosure, Cy2 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R2: 6-10 Aryl, 5-6 membered heterocyclyl, 9-10 membered heterocyclyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl;

[0024] According to an embodiment of the present disclosure, Cy2 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R2: phenyl, benzofuranyl, 2,3-dihydro-1H-indenyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, furan[3,2-b]pyridinyl, 2,3-dihydrobenzofuranyl, isothiazolyl, isoxazolyl, benzo[d][1,3]dioxazolyl, 1,2,4-oxadiazolyl, benzo[d]thiazolyl,

[0025] According to an embodiment of the present disclosure, Cy2 is selected from

[0026] According to an embodiment of the present disclosure, Cy2 is selected from

[0028] According to an embodiment of the present disclosure, each R2 is the same or different and is independently selected from H, OH, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, cyano C 3-6 Cycloalkenyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyloxy.

[0029] According to the embodiments of the present disclosure, each R2 is the same or different and is independently selected from H, OH, F, Cl, CN, Cyclopropyloxy.

[0030] According to an embodiment of the present disclosure, Cy3 is selected from the following groups which are unsubstituted or optionally substituted with one, two or more R3: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 9-10 membered heterocyclyl, 9-10 membered heteroaryl;

[0031] According to an embodiment of the present disclosure, Cy3 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R3: phenyl, pyridyl, quinazolinyl, benzothiophenyl,

[0032] According to an embodiment of the present disclosure, Cy3 is selected from

[0033] According to an embodiment of the present disclosure, Cy3 is selected from

[0034] According to the embodiments of the present disclosure, each R3 is the same or different and is independently selected from H, halogen, oxo (=O), CN, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 6-10 Aryl;

[0035] According to an embodiment of the present disclosure, each R3 is the same or different and is independently selected from H, F, oxo (=O), CN, methoxy, cyclobutyloxy, cyclopentyloxy, and phenyl.

[0036] According to an embodiment of the present disclosure, the compound represented by formula (I) is selected from the following structures:

[0037]

[0038] Among them, L1, L2, L3, Cy1, Cy2, Cy3, R a Independently of each other, they have the above definitions; m is selected from 0, 1, 2, 3, 4.

[0039] According to an embodiment of the present disclosure, the compound represented by formula (I) is selected from the following structures:

[0040]

[0041] Among them, L1, L2, Cy1, Cy2, Cy3, R a Independently of each other, they have the above definitions; n is selected from 0, 1, 2; q is selected from 0, 1; Indicates absence or oxo (=O).

[0042] According to the embodiments of the present disclosure, the compound represented by formula (I) is selected from the following structures:

[0043]

[0044] Among them, Cy1, Cy2, Cy3, n, Independently of each other have the definitions given above.

[0045] According to the embodiments of the present disclosure, the compound represented by formula (I) is selected from the following structures:

[0046]

[0047] Among them, Cy1, Cy2, Cy3, n, Independently of each other have the definitions given above.

[0048] According to the embodiments of the present disclosure, the compound represented by formula (I) is selected from the following structures:

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] The present disclosure also provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising the following steps: reacting compound a with compound b to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0057]

[0058] wherein A, L1, L2, L3, Cy1, Cy2, and Cy3 are independently defined as above; and X1 is selected from a leaving group, such as halogen or OH.

[0059] According to an embodiment of the present disclosure, the preparation may be carried out in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, pyridine, and DMAP.

[0060] According to an embodiment of the present disclosure, the preparation method can be carried out in the presence of a solvent such as an organic solvent. For example, the organic solvent can be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, and n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and Polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those possibly substituted by fluorine and chlorine atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0061] The present disclosure also provides a pharmaceutical composition, comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0062] The present disclosure also provides an antibody / peptide-drug conjugate, comprising an antibody or a peptide, and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as a payload, wherein the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as the payload is directly bonded to the antibody or peptide or bonded to the antibody or peptide via a linker.

[0063] According to an embodiment of the present disclosure, the antibody / peptide-drug conjugate is a protein-drug conjugate.

[0064] According to an embodiment of the present disclosure, the peptide has at least 80% identity with the amino acid sequence of glucagon-like peptide 1 (GLP-1); for example, at least about 85%, at least about 90%, at least about 95% or greater than about 97% amino acid sequence identity.

[0065] According to an embodiment of the present disclosure, the peptide is selected from the peptides described in Chinese invention patent application CN115697414A; preferably, the peptide is glucagon-like peptide 1.

[0066] According to an embodiment of the present disclosure, the linker may be one known in the art, such as an acid-cleavable linker, an enzyme-cleavable linker, a peptide-cleavable linker, and a linker containing a disulfide group.

[0067] According to an embodiment of the present disclosure, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is present in the pharmaceutical composition or the antibody / peptide-drug conjugate in a therapeutically effective amount.

[0068] The present disclosure also provides use of a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the antibody / peptide-drug conjugate in the preparation of a drug for treating and / or preventing diseases associated with NMDA receptors.

[0069] According to an embodiment of the present disclosure, the drug is an NMDA receptor inhibitor.

[0070] According to the embodiments of the present disclosure, the NMDA receptor is a tetramer, and the subunit composition in the tetramer is selected from a combination of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are any two combinations selected from GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B, for example, an NMDA receptor composed of a combination of subunits such as GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C, GluN1 / GluN2D, GluN1 / GluN2A / GluN2B, GluN1 / GluN2A / GluN2C, GluN1 / GluN2B / GluN2D, GluN1 / GluN3A, GluN1 / GluN3B, GluN1 / GluN2B / GluN3A, etc.

[0071] According to an embodiment of the present disclosure, the disease associated with NMDA receptors is selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety, brain injury, Parkinson's disease, Huntington's disease, etc.

[0072] The present disclosure also provides a method for treating and / or preventing diseases associated with NMDA receptors, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, or a pharmaceutical composition containing the compound of formula (I) or a pharmaceutically acceptable salt, or at least one of the antibody / peptide-drug conjugates.

[0073] According to the embodiments of the present disclosure, the NMDA receptor is a tetramer, and the subunit composition in the tetramer is selected from a combination of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are any two combinations selected from GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B, for example, an NMDA receptor composed of a combination of subunits such as GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C, GluN1 / GluN2D, GluN1 / GluN2A / GluN2B, GluN1 / GluN2A / GluN2C, GluN1 / GluN2B / GluN2D, GluN1 / GluN3A, GluN1 / GluN3B, GluN1 / GluN2B / GluN3A, etc.

[0074] According to an embodiment of the present disclosure, the disease associated with NMDA receptors is selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety, brain injury, Parkinson's disease, Huntington's disease, etc.

[0075] When preparing the medicine or pharmaceutical composition described in the present disclosure, the compound or pharmaceutically acceptable salt of the present disclosure can be combined or formulated with appropriate pharmaceutically acceptable excipients (such as carriers, diluents or excipients) and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. The administration methods include oral, intraperitoneal, transdermal, subcutaneous, intravenous or intramuscular injection, inhalation, topical, intralesional, infusion; liposome-mediated delivery; topical, intrathecal, gingival pocket, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or aural delivery, or any other method known in the art, all of which can achieve the treatment of tumors.

[0076] The therapeutically effective amount or dosage of the present disclosure will vary according to several factors, including the selected route of administration, the formulation of the composition, the patient's response, the severity of the condition, the subject's weight, and the judgment of the prescribing physician, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dosage can be increased or decreased over time, as required by individual patients. In some cases, the patient is initially given a low dose, which is then increased to an effective dose that the patient can tolerate. In addition, the patient can be given multiple doses within a determined time period, particularly time increments (such as daily, weekly, biweekly, monthly, quarterly, every two years or the like).

[0077] Beneficial Effects

[0078] The present disclosure provides a use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating and / or preventing diseases associated with NMDA receptors, wherein the compound has good inhibitory activity on NMDA receptors (particularly GluN1 / GluN3A receptors).

[0079] Definition and explanation of terms

[0080] Unless otherwise specified, the definitions of groups and terms recorded in the specification and claims of this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. The definitions of groups and compound structures after such combinations and combinations should be understood to be within the scope of the specification and / or claims of this application.

[0081] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to at least describing each specific integer value therein. For example, the numerical range "1-14" is equivalent to describing each integer value in the numerical range "1-14", namely 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14.

[0082] It should be understood that herein, when describing one, two or more, "more" should refer to an integer greater than 2, for example, greater than or equal to 3, for example 3, 4, 5, 6, 7, 8, 9 or 10.

[0083] As used in the context of this disclosure Represents a chemical bond.

[0084] The term "C 1-10 "Alkyl" means a straight or branched saturated hydrocarbon group, preferably a straight or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group includes C 1-3 Alkyl, C 1-6 Alkyl, C 3-6 Alkyl, C 1-10 Alkyl, etc. "C 1-10 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 1-8 "Alkyl" means straight chain and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0085] The term "C 3-10 "Cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (such as fused ring, bridged ring, spiro ring) hydrocarbon ring or tricyclic alkane, preferably having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The cycloalkyl group includes C 3-8 Cycloalkyl, C 3-5 Cycloalkyl, C 6-8 Cycloalkyl, C 3-4 Cycloalkyl, C 5-6 Cycloalkyl, C6 cycloalkyl, C 3-10 Cycloalkyl, etc. 3-10 The cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as borneol, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonanyl, 2,6-diazaspiro[3,4]octanyl, or a tricyclic hydrocarbon group such as adamantyl.

[0086] The term "C 3-10 "Cycloalkenyl" means an unsaturated monovalent monocyclic, bicyclic (such as fused, bridged, spiro) hydrocarbon ring or tricyclic olefin containing at least one double bond, preferably having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C 3-10 Cycloalkenyl groups include C 3-8 Cycloalkenyl, C 3-5 Cycloalkenyl, C 6-8 Cycloalkenyl, C 3-4 Cycloalkenyl, C 5-6 Cycloalkenyl, C6 cycloalkenyl, etc. 3-10 The cycloalkenyl group may be a monocyclic hydrocarbon group such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl.

[0087] The term "3-14 membered heterocyclyl" means a monovalent or polyvalent monocyclic, bicyclic or tricyclic saturated or unsaturated non-aromatic ring or ring system whose ring atoms contain 1-5 heteroatoms independently selected from N, O and S. For example, a 3-14 membered heterocyclyl can be a monovalent or polyvalent monocyclic, bicyclic or tricyclic saturated or unsaturated non-aromatic ring or ring system containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, wherein the 3-14 membered heterocyclyl contains 1-5 heteroatoms independently selected from N, O and S. The bicyclic and tricyclic aromatic ring systems can be fused, spiro or bridged rings. The 3-14 membered heterocyclyl includes 3-10 membered heterocyclyl, 5-8 membered heterocyclyl, 3-8 membered heterocyclyl. The 3-14 membered heterocyclyl can be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The 3-14 membered heterocyclic group may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclic group may include, but is not limited to, a 3-membered ring, such as an aziridine group, an oxirane group; a 4-membered ring, such as an azetidinyl group, an oxetane group; a 5-membered ring, such as a tetrahydrofuranyl group, a dioxolyl group, a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a pyrrolinyl group; or a 6-membered ring, such as a tetrahydropyranyl group, a piperidinyl group, a morpholinyl group, a dithianyl group, a thiomorpholinyl group, a piperazinyl group or a trithianyl group; or a 7-membered ring, such as a diazepanyl group. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The heterocyclic group may be partially unsaturated, i.e., it may contain one or more double bonds, such as but not limited to dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl. When the 3-14 membered heterocyclic group is connected with other groups to form the compounds of the present disclosure, it may be a carbon atom on the 3-14 membered heterocyclic group connected with other groups, or it may be a heterocyclic atom (such as N atom) on the 3-14 membered heterocyclic group ring connected with other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazinyl and tetrahydropyrrolyl, it may be a nitrogen atom or a carbon atom on the piperazinyl connected with other groups. Or when the 3-14 membered heterocyclic group is selected from piperidinyl, the nitrogen atom on the piperidinyl ring or the carbon atom at the ortho, meta or para position thereof may be connected to other groups.

[0088] The term "5-14 membered heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and its ring atoms contain 1-5 heteroatoms independently selected from N, O and S, and the bicyclic and tricyclic aromatic ring systems can be fused rings, spiro rings or bridged rings. The heteroatoms in the 5-14 membered heteroaryl are 1-5, preferably 1-3. In addition, the 5-14 membered heteroaryl may be benzo-fused in each case. The 5-14 membered heteroaryl includes 5-8 membered heteroaryl, 5-9 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, 6 membered heteroaryl, etc. Examples of heteroaryl groups include, but are not limited to, 5-membered rings, such as oxazolyl, pyrazolyl, thienyl, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group may be bicyclic, including, but not limited to, 5,5-membered rings, such as tetrahydrocyclopentapyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisothiazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptathiazole and tetrahydrocycloheptafuran. The heterocyclic group may be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-14 membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. In addition, there is no limitation on the substitution site, for example, the hydrogen bonded to the carbon atom on the heteroaryl ring may be substituted, or the hydrogen bonded to the heteroatom on the heteroaryl ring may be substituted.

[0089] The term "spirocyclic" refers to a ring system in which two rings share one ring-forming atom.

[0090] The term "fused ring" refers to a ring system in which two rings share two ring atoms.

[0091] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0092] The term "halogen" denotes fluorine, chlorine, bromine or iodine.

[0093] "Halo" means substituted with one or more halogens.

[0094] Unless otherwise stated, the definition of a term herein also applies to groups containing the term, for example, the definition of alkyl also applies to the definition of alkoxy (ie, alkyloxy) and the like containing alkyl.

[0095] Unless otherwise stated, a "compound" in the context of the present disclosure should be understood to include the compound itself and its tautomers, stereoisomers, solvates or isotopically labeled forms.

[0096] Crystallization often produces a solvate of the disclosed compound. The term "solvate" as used herein refers to an association of one or more disclosed compound molecules with one or more solvent molecules.

[0097] The solvent may be water, in which case the solvate is a hydrate, or may be an organic solvate.

[0098] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0099] The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the disclosed compounds and is relatively non-toxic, i.e., the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0100] It will be appreciated by those skilled in the art that the compounds of the present disclosure may exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they may form acid addition salts; if these compounds have an acidic center, they may form a base addition salt; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they may also form an inner salt.

[0101] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physicochemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates. The present disclosure encompasses all tautomeric forms of the compounds.

[0102] According to its molecular structure, the compounds of the present invention may be chiral, and therefore various enantiomeric forms may exist. Thus, these compounds may exist in racemic form or optically active form. The compounds of the present invention encompass isomers or mixtures, racemates in which each chiral carbon is in R or S configuration. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods known to those skilled in the art, or used in this form for synthesis. In the case of racemic amines, diastereomers are prepared from the mixture by reaction with an optically active resolution agent. Examples of suitable resolution agents are optically active acids, such as R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline) or various optically active camphorsulfonic acids. Chromatographic enantiomer resolution can also be advantageously carried out with the aid of optically active resolving agents such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chiral derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, for example, hexane / isopropanol / acetonitrile.

[0103] In this application, "pharmaceutical composition" refers to a preparation of the disclosed compound and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0104] In this application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.

[0105] In the present application, the term "prodrug" refers to a compound of the present disclosure that can be converted into a biologically active compound under physiological conditions or by solvolysis. The prodrug of the present disclosure is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. The prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present disclosure to any group. When the prodrug of the compound of the present disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group, respectively.

[0106] "Isotopes" are all isotopes of atoms that occur in the compounds of the present disclosure. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 31 P. 32 P. 35 S. 18 F and 36 C1. The isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying Examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have a variety of potential uses, such as as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to favorably alter biological, pharmacological or pharmacokinetic properties.

[0107] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0108] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0109] (ii) inhibiting a disease or condition, i.e. arresting its development;

[0110] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0111] (iv) alleviating the symptoms caused by the disease or condition.

[0112] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0113] The term "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) Preventing disease: e.g., preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but does not yet experience or develop the pathology or symptoms of the disease. (2) Inhibiting disease: e.g., inhibiting a disease, disorder or condition (i.e., preventing further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. (3) Alleviating disease: e.g., alleviating a disease, disorder or condition (i.e., reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition. DETAILED DESCRIPTION

[0114] The technical solution of the present disclosure will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary illustrations and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included in the scope of protection intended by the present disclosure.

[0115] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0116] Example 1 Preparation of Compound C1

[0117]

[0118] 2-Bromo-1-benzothiophene (10.0 g, 46.929 mmol, 1.0 equivalent) was dissolved in dichloromethane (100 mL). Formic acid (40 mL) and hydrogen peroxide (30%) (60 mL, 8.8 mmol, 18.8 equivalent) were added dropwise to the above solution at room temperature. Stir overnight at room temperature. The desired product was detected by LCMS. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 column, mobile phase, acetonitrile and water (0.1% FA), 10% to 50% gradient for 10 minutes, UV254 nanometer detector, and 2-bromo-benzothiophene-1,1-dioxide (7.9 g, yield 68.69%, purity 94.4%) was obtained as a brown solid.

[0119] LCMS (ESI, m / z): [M+H] + =245.00

[0120] 2-Bromo-benzothiophene-1,1-dioxide (1.0 g, 4.1 mmol, 1.0 equiv) was dissolved in tetrahydrofuran solution (10 mL). Phenylmagnesium chloride (1.0 M in tetrahydrofuran) (1.4 g, 8.1 mmol, 2.0 equiv) was added dropwise to the above solution under nitrogen at -78 °C, stirred for 30 minutes, and then 1-benzofuran-5-acetaldehyde (0.6 g, 4.0 mmol, 1.0 equiv) was added dropwise at -78 °C. The resulting mixture was stirred for another 2 hours at -78 °C. The desired product was detected by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was extracted with ethyl acetate (2 × 20 mL), and the organic phase was washed with water (2 × 20 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 column, mobile phase, acetonitrile and water (0.1% FA), 10% to 50% gradient over 10 minutes, UV254 nanometer detector to give 2-[1-benzofuran-5-yl(hydroxy)methyl]-benzothiophene-1,1-dioxy compound (420 mg) as a yellow solid.

[0121] LCMS (ESI, m / z): [M+H] + =295.00.

[0122] Under nitrogen protection at 0°C, trifluoroacetic acid (2 mL, 0.01 mmol, 0.01 equivalent) was added dropwise to a solution of 2-[1-benzofuran-5-yl(hydroxy)methyl]-benzothiophene-1,1-dioxy compound (500 mg, 1.601 mmol, 1.0 equivalent) and 5-methoxypyridine-2-methanol (445 mg, 3.2 mmol, 2 equivalents) in 1,4-dioxane (6 mL), and stirred at 100°C for 2 hours. The obtained residue was concentrated under reduced pressure, and the crude product was purified by high performance liquid phase to obtain 2-(benzofuran-5-yl((5-methoxypyridinyl-2-yl)methoxy)methyl)benzothiophene-1,1-dioxy compound (23.1 mg, yield 3.3%, purity 99.7%) as a white solid.

[0123] LCMS (ESI, m / z): [M+H] + =434.10.

[0124] 1H NMR (400MHz, methanol-d4) δ8.13(d,J=2.9Hz,1H),7.79(t,J=1.9Hz,2H),7.69–7.65(m,2H),7.59-7.50(m,3H),7.48–7.35( m,3H),7.04(d,J=1.9Hz,1H),6.87(t,J=2.7Hz,1H),5.71(d,J=1.7Hz,1H),4.70–4.55(m,2H),3.85(d,J=6.1Hz,3H).

[0125] Example 2 Preparation of Compound C3

[0126]

[0127] To a solution of 4-bromo-3-fluorophenol (10.0 g, 52.3 mmol, 1.0 equiv.) and cesium carbonate (34.1 g, 104.7 mmol, 2.0 equiv.) in dimethyl sulfoxide (100 mL) was added cyclobutyl bromide (7.0 g, 52.3 mmol, 1.0 equiv.) in portions at room temperature and stirred at 60 ° C overnight. The desired compound was detected by LCMS, and the crude product was eluted by silica gel column chromatography with PE / EA (20:1) to give 1-bromo-4-cyclobutyloxy-2-fluorobenzene (10.4 g, yield 81.05%, purity 94.7%) as a colorless oil.

[0128] To a solution of 1-bromo-4-cyclobutyloxy-2-fluorobenzene (500 mg, 2.0 mmol, 1.0 equiv) in tetrahydrofuran (0.5 mL) was added n-butyl lithium (2.5 M in n-hexane) (261 mg, 4.0 mmol, 2.0 equiv) dropwise under nitrogen at -78°C, and the mixture was stirred at -78°C for 30 minutes. To the above solution was added benzofuran-5-carboxaldehyde (313 mg, 2.1 mmol, 1.05 equiv) and the mixture was stirred at -78°C for 2 hours. The desired compound was detected by LCMS, and the crude product was eluted with PE / EA (1 / 1) on a silica gel column to give 1-benzofuran-5-yl(4-cyclobutyloxy-2-fluorophenyl)methanol (420 mg, yield 65.91%, purity 96.0%) as a white oil.

[0129] LCMS (ESI, m / z): [M+H] + =295.05.

[0130] To a solution of 1-benzofuran-5-yl(4-cyclobutyloxy-2-fluorophenyl)methanol (200 mg, 0.6 mmol, 1.0 equiv) and 2-(bromomethyl)-5-methoxypyridine (129 mg, 0.6 mmol, 1.0 equiv) in N,N-dimethylformamide (2 mL) was added potassium iodide (212 mg, 1.2 mmol, 2.0 equiv) and potassium carbonate (177 mg, 1.2 mmol, 2.0 equiv) in portions at room temperature. Equivalent), stirred at 100 ° C for 1 hour. The resulting residue was purified by reverse phase column chromatography under the following conditions: C18 chromatography column, mobile phase, acetonitrile and water (0.1% FA), 10% to 50% gradient for 10 minutes, UV254 nanometer detector to obtain 2-{[1-benzofuran-5-yl(4-cyclobutyloxy-2-fluorobenzene)methoxy]methyl}-5-methoxypyridine (24.3 mg, yield 8.75%, purity 96.3%) as a brown oil.

[0131] LCMS (ESI, m / z): [M+H] + =434.20.

[0132] 1H NMR (400MHz, methanol-d4) δ8.13(t,J=2.9Hz,1H),7.78–7.68(m,1H),7.63(s,1H),7.54–7.25(m,5H),6.77(q,J=2.5Hz,1H),6.65-6.60(m, 1H),6.55–6.50(m,1H),5.86(s,1H),4.68–4.52(m,3H),3.91–3.79(m,3H),2.45–2.35(m,2H),2.12–2.01(m,2H),1.90–1.59(m,2H).

[0133] Example 3 Preparation of Compound C5

[0134]

[0135] Under nitrogen protection, n-butyl lithium (2.5M hexane) (547 mg, 8.5 mmol, 2.5 equivalents) was added to a solution of 5-bromo-2-(cyclopentyloxy)pyridine (2.1 g, 8.5 mmol, 2.5 equivalents) in tetrahydrofuran (5 mL). After stirring the reaction at -78 ° C for 30 min, 5-bromo-2-(cyclopentyloxy)pyridine (2.1 g, 8.5 mmol, 2.5 equivalents) was added dropwise at -78 ° C. After addition, stirring was continued at -78 ° C for 2 hours. The reaction mixture was quenched with water at 0 degrees Celsius. The reaction mixture was extracted with ethyl acetate (3X20 ml). The organic phases were mixed, backwashed with saturated brine (3X20 ml), and dried over sodium sulfate. After filtering the resulting mixture, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography under the conditions of mobile phase, water and acetonitrile, 10% to 50% gradient, 10 min, UV254 nm detector. [6-(Cyclopentyloxy)pyridin-3-yl](2,3-dihydro-1h-indol-5-yl)methanol (240 mg) was obtained as a pale yellow solid.

[0136] LCMS (ESI, m / z): [M+H] + =310.15

[0137] Under nitrogen protection, a solution of [6-(cyclopentyloxy)pyridin-3-yl](2,3-dihydro-1h-indol-5-yl)methanol (100 mg, 0.3 mmol, 1 equivalent) in N,N-dimethylformamide (2 mL) was stirred at 0 ° C, sodium hydride (23 mg, 1.0 mmol, 3.0 equivalents) was added in batches, and stirring was continued for 30 minutes. At room temperature, 2-(bromoethyl)-5-methoxypyridine (78 mg, 0.4 mmol, 1.2 equivalents) was added and stirred for 30 minutes. The reaction mixture was quenched with water at 0 degrees Celsius. The reaction mixture was extracted with ethyl acetate (3X20 ml). The organic phases were mixed, backwashed with saturated brine (3X20 ml), and dried over sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography to obtain 2-[(6-cyclopentyloxy)pyridin-3-yl](2,3-dihydro-indanone-5-methoxymethyl-5-methoxypyridine) (16.7 mg, yield 11.9%, purity 97.4%) as a brown oil. The conditions were: Xselect CSH C185 m, 30 mm X 150 mm; mobile phase A: water (0.1% FA), mobile phase B: CAN; flow rate: 60 mL / min; gradient: 65% B to 90% B, 10 min; wavelength: 254 nm / 220 nm nm; RT1 (min):

[0138] 5.33 / 8.60).

[0139] LCMS (ESI, m / z): [M+H] + =431.15

[0140] 1 H NMR-PH-LPMC-005-0(400MHz,CD3OD)δ8.12–8.20(m,2H),7.56–7.63(m,1H),7 .45–7.56(s,1H),7.36–7.45(m,1H),7.28–7.18(m,2H),6.73–6.76(m,1H),6.7 1(s,1H),5.51(s,1H),5.29(m,1H),4.66–4.47(m,2H),3.89(s,3H),2.90(s,4H ),2.08-2.16(m,2H),2.03–1.88(m,2H),1.87–1.74(m,4H),1.70–1.56(m,2H).

[0141] Example 4 Preparation of Compound C9

[0142]

[0143] Under -78°C nitrogen environment, n-butyl lithium (1.6M n-hexane) (0.29mL, 0.7mmol, 0.7equiv) was added to a solution of triethyl phosphoacetate (2.7g, 12.3mmol, 1.2equiv) in ether (10mL). After stirring for 2 hours, oxazole-4-acetaldehyde (1g, 10.3mmol, 1.0equiv) was added dropwise at -78°C. The resulting mixture was stirred for 4 hours under -78°C nitrogen environment. The desired product was detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product was used directly in the next step without further purification.

[0144] LCMS (ESI, m / z): [M+H] + =168.25.

[0145] Pd / C (1.2 g, 11.9 mmol, 2.0 equivalents) was added to a solution of (E)-3-(oxazol-4-yl) ethyl acrylate (1.0 g, 5.9 mmol, 1.0 equivalents) in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 2 hours after replacing the hydrogen. The desired product was detected by LCMS. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (2×20 mL), and the filtrate was concentrated under reduced pressure. Reverse phase chromatography was used for purification under the following conditions: the chromatographic column was C18 silica gel; the mobile phase was MeCN in Water (10 mmol / L NH4HCO3), the gradient was 0% to 100%, 15 min; the UV detector was 254 nm, and ethyl 3-(oxazol-4-yl) propionate (900 mg, yield 88.93%, purity 80%) was obtained as a white solid.

[0146] LCMS (ESI, m / z): [M+H] + =170.10.

[0147] Ethyl 3-(oxazol-4-yl)propanoate (900 mg, 5.3 mmol, 1.0 equiv), LiOH·H2O (446 mg, 10.6 mmol, 2.0 equiv) were dissolved in THF (5 mL) and H2O (5 mL) and stirred overnight at room temperature. The desired product was detected by LCMS. The mixture was acidified to pH = 5 with 2M hydrochloric acid. The precipitate was collected by filtration and washed with MeCN (2×20 mL) to give 3-(1,3-oxazol-4-yl)propanoic acid (300 mg, yield 39.96%, purity 80%) as a white solid.

[0148] LCMS(ESI):[MH] - =140.10.

[0149] EDCI (203 mg, 1.0 mmol, 1.5 equiv) and 1H-1,2,3-benzotriazole-1-ol (143 mg, 1.0 mmol, 1.5 equiv) were added to a solution of 2-(benzofuran-5-acyl(hydroxy)methyl)benzo[b]thiophene (265 mg, 0.8 mmol, 1.2 equiv) and 3-(1,3-oxazol-4-acyl)propionic acid (100 mg, 0.7 mmol, 1.0 equiv) in N,N-dimethylformamide (5 mL) and stirred. The resulting mixture was stirred at room temperature under nitrogen for 1.5 hours. The resulting mixture was concentrated under vacuum at 0°C. The crude product was purified by preparative HPLC under the following conditions to give 1-benzofuran-5-yl(1,1-dioxy-1λ-6-benzothiophen-2-yl)methyl 3-(1,3-oxazol-4-yl)propanoate (15.5 mg, yield 5.02%, purity 96.4%) as a white solid.

[0150] LCMS(ESI):[M+H] + =436.10.

[0151] 1 H NMR (400 MHz, methanol-d4) δ 8.09 (s, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.71 (d, J = 7.4 Hz, 1H), 7.67–7.54 (m, 4H), 7.48–7.42 (m, 2H), 7.07–7.00 (m, 2H), 6.89 (d, J = 2.2 Hz, 1H), 2.95–2.90 (m, 2H), 2.85–2.80 (m, 2H).

[0152] Example 5 Preparation of Compound C10

[0153]

[0154] To a solution of 2,6-difluoro-4-formylbenzonitrile (1.0 g, 5.9 mmol, 1.0 equiv) in dimethyl sulfoxide (50 mL) was added a solution of sodium chlorite (1.4 g, 15.5 mmol, 2.6 equiv) in H2O (20 mL) and a solution of K2HPO4 (2.2 g, 12.5 mmol, 2.1 equiv) in H2O (20 mL) at room temperature. The resulting mixture was stirred in air at room temperature for 1 hour. The resulting mixture was washed with 2×100 mL of ethyl acetate. The resulting mixture was concentrated under vacuum to give 4-cyano-3,5-difluorobenzoic acid (800 mg, yield 73.01%, purity 80%) as a yellow solid

[0155] LCMS (ESI, m / z): [M+H] + =183.10.

[0156] To a solution of 2-(2,3-dihydrobenzofuran-5-yl)(hydroxy)methyl)benzo[b]thiophene 1,2-dioxide (200 mg, 0.8 mmol, 1.0 equiv) in tetrahydrofuran (20 mL) was added n-butyl lithium (1.6 M in n-hexane) (0.4 mL, 1.1 mmol, 1.3 equiv) dropwise under nitrogen at -78°C, stirred for 1.5 hours under nitrogen at -78°C, and then 2,3-dihydrobenzofuran-5-acetaldehyde (120.9 mg, 0.821 mmol, 1.0 equiv) was added dropwise at -78°C. The resulting mixture was stirred overnight under nitrogen at -78°C. The desired product was detected by LCMS. The reaction was quenched by adding 10 mL of NH4Cl (aq.) at room temperature. The resulting mixture was extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with water (2×20 mL) and dried over anhydrous Na2SO4. The filtered filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with PE / EA (5 / 1) to give 2-((2,3-dihydrobenzofuran-5-yl)(hydroxy)methyl)benzo[b]thiophene 1,1-dioxide (160 mg, yield 63.00%) as a white solid.

[0157] LCMS (ESI, m / z): [M+H] + =314.10.

[0158] To a solution of 2-((2,3-dihydrobenzofuran-5-yl)(hydroxy)methyl)benzo[b]thiophene 1,1-dioxide (206 mg, 0.6 mmol, 1.2 eq) and 4-cyano-3,5-difluorobenzoic acid (100 mg, 0.5 mmol, 1.0 eq) in dichloromethane (20 mL) was added benzotriazole-1-acyloxytripyrrolidine diphosphophosphate (426 mg, 0.8 mmol, 1.5 eq) and Et3N (166 mg, 1.6 mmol, 3.0 eq) and the resulting mixture was stirred at room temperature under nitrogen for 2 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give (2,3-dihydrobenzofuran-5-yl)(1,1-dioxidobenzo[b]thiophen-2-yl)methyl 4-cyano-3,5-difluorobenzoate (20.9 mg, yield 7.98%, purity 95.1%) as a yellow solid.

[0159] LCMS(ESI):[MH] - =478.20.

[0160] 1H NMR (400MHz, DMSO-d6) δ8.02(d,J=8.6Hz,2H),7.88(d,J=7.4Hz,1H),7.71(t,J=7.4Hz,1H),7.67–7.59(m,2H),7.54(d,J=1.9Hz,1H) ,7.49(d,J=1.7Hz,1H),7.43–7.38(m,1H),7.05(d,J=1.7Hz,1H),6.83(d,J=8.2Hz,1H),4.56(t,J=8.7Hz,2H),3.21(t,J=8.7Hz,2H).

[0161] Example 6 Preparation of Compound C11

[0162]

[0163] 3-Cyano-4-methoxybenzoic acid (68 mg, 0.384 mmol, 1.2 equiv) was mixed with thionyl chloride (5 mL) and stirred at 40 °C under nitrogen for 2 hours. The resulting mixture was concentrated under reduced pressure. The mixture was dissolved in DCM (5 mL) and a solution of 2-(benzofuran-5-hydroxymethyl)benzo[b]thiophene 1,1-dioxide (100 mg, 0.3 mmol, 1.0 equiv) and Et3N (97 mg, 0.9 mmol, 3.0 equiv) in DCM (5 mL) was added to the above mixed solution at 0 °C. The resulting mixture was stirred at 0 °C for another 30 minutes. The desired compound was detected by LCMS. The crude product was purified by preparative HPLC, column type: XBridge BEH C18OBD Prep column 130, 5m, 30mm*150mm; mobile phase A: water (10mmol / L NH4HCO3+0.1% NH4OH), mobile phase B: ACN; flow rate: 60mL / min; gradient: 49% B to 67% B in 8min; wavelength: 254 / 220nm; RT1(min):7.22) to obtain benzofuran-5-yl(1,1-dioxidobenzo[b]thiophen-2-yl)methyl 3-cyano-4-methoxybenzoate (12.9mg, yield 8.55%, purity 99.7%) as a white solid.

[0164] LCMS (ESI, m / z): [M+H]+=294.95.

[0165] 1 H NMR (400MHz, DMSO-d6) δ8.45–8.35(m,2H),8.08–8.00(m,3H),7.77–7.35(m,7H),7.18–7.08(m,2H),4.03(s,3H).

[0166] Example 7 Preparation of Compound C15

[0167]

[0168] Add N,N-dimethylformamide (10 mL) as solvent to a single-mouth bottle, add ethyl 2-(1-hydrogen-pyrazol-3-yl)acetate (500 mg, 3.2 mmol, 1.0 equivalent), 1,1-difluoro-2-iodoethane (934 mg, 4.5 mmol, 1.5 equivalent), potassium carbonate (896 mg, 6.5 mmol, 2.0 equivalent), and react at 60°C for 12 hours. Add 50 ml of water to the resulting mixture, extract with ethyl acetate (3 x 20 mL), dry the organic phase with anhydrous sodium sulfate, and concentrate the organic phase under reduced pressure. Purify by reverse phase column chromatography, elute with acetonitrile / water (7 / 3) to obtain ethyl 2-(1-(2,2-difluoroethyl)-1-hydrogen-pyrazol-3-yl)acetate (200 mg, purity 86.0%) as a colorless oil.

[0169] LCMS (ESI, m / z): [M+H] + =219.09

[0170] Tetrahydrofuran and water (6mL / 2mL) were added as solvents in a single-mouth bottle, and ethyl 2-[1-(2,2-difluoroethyl)pyrazol-3-yl]acetic acid (100mg, 0.45mmol, 1.0 equivalent) and lithium hydroxide (21.6mg, 0.9mmol, 2.0 equivalent) were added in sequence, and the mixture was reacted at 25°C for 2 hours. 50mL of water was added to the resulting mixture, and ethyl acetate (3x 20mL) was extracted, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification by reverse phase column chromatography and elution with acetonitrile / water (4 / 1) gave ethyl 2-(1-(2,2-difluoroethyl)-1hydrogen-pyrazol-3-yl)acetic acid (80mg, purity 88.0%) as a colorless oil.

[0171] LCMS (ESI, m / z): [M+H] + =197.06

[0172] In a single-mouth bottle, dichloromethane (10 mL) was added as solvent, and [1-(2,2-difluoroethyl)pyrazol-3-yl]acetic acid (100 mg, 0.5 mmol, 1.0 equivalent), 2-[2,3-dihydro-1-benzofuran-5-yl(hydroxy)methyl]-benzo[d]thiophene-1,1-dioxide (182 mg, 0.6 mmol, 1.1 equivalent), 4-lutidine (96 mg, 0.79 mmol, 1.5 equivalent), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.8 mmol, 1.5 equivalent) were added in sequence, and the mixture was reacted at 25°C for 4 hours. 50 mL of water was added to the resulting mixture, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (chromatographic column: Xselect CSH C185 m, 30 mm X 150 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 46% B to 57% B in 7 minutes; wavelength: 254 nm / 220 nm nm; RT1 (min): 6.2) to obtain 2-(benzofuran-5-yl((2-methylpyrimidin-5-yl)methoxy)methyl)benzo[b]thiophene 1,1-dioxide (23.6 mg, purity 97.8.0%, yield 9.22%) as a white solid.

[0173] LCMS (ESI, m / z): [M+H] + =487.15

[0174] Example 8 Preparation of Compound C19

[0175]

[0176] In a single-mouth bottle, 1,4-dioxane (50 mL) was added as solvent, followed by 2-bromo-1,3-benzothiazole (500 mg, 2.3 mmol, 1.0 equivalent), 2-hydroxyphenylboronic acid (483 mg, 3.5 mmol, 1.5 equivalent), and cesium carbonate (1.5 g, 4.6 mmol, 2.0 equivalent), and the mixture was reacted at 100°C for 12 hours. 50 mL of water was added to the resulting mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purification was performed by silica gel column chromatography, and elution with petroleum ether / ethyl acetate (10 / 1) gave 2-(benzo[d]thiazol-2-yl)phenol (400 mg, purity 86%) as a white solid.

[0177] LCMS (ESI, m / z): [M+H] + =278.04

[0178] Dichloromethane (10 mL) was added as solvent in a single-mouth bottle, followed by 2-(1,3-benzothiazol-2-yl)phenol (200 mg, 0.9 mmol, 1.0 equivalent), 5-nitro-2H-pyrazole-3-carboxylic acid (166 mg, 1.1 mmol, 1.2 equivalent), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)urea hexafluorophosphate (669 mg, 1.7 mmol, 2.0 equivalent), and N,N-diisopropylethylamine (227.47 mg, 1.760 mmol, 2 equivalent), and the mixture was reacted at 25° C. for 2 hours. 50 mL of water was added to the resulting mixture, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purify by silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 2-(benzo[d]thiazol-2-yl)phenyl-3-nitro-1H-pyrazole-5-carboxylate (150 mg, purity 85%) as a white solid.

[0179] LCMS (ESI, m / z): [M+H] + =367.04

[0180] Ethanol and water (10 ml / 1 ml) were added as solvents in a single-mouth bottle, and 2-(Benzo[d]thiazol-2-yl)phenyl-3-nitro-1-hydrogen-pyrazole-5-carboxylate (80 mg, 0.2 mmol, 1.0 equivalent), iron powder (60.9 mg, 1.1 mmol, 5.0 equivalent), and ammonium chloride (58.4 mg, 1.09 mmol, 5.0 equivalent) were added in sequence, and the mixture was reacted at 80°C for 12 hours. 50 ml of water was added to the resulting mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phase was dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (chromatographic column: Xselect CSH C185 m, 30 mm × 150 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 35% B to 47% B in 7 minutes; wavelength: 254 nm / 220 nm nm; RT1 (min): 6.17) to give 2-(benzo[d]thiazol-2-yl)phenyl-3-amino-1H-pyrazole-5-carboxylate (19.2 mg, yield 26.2%, purity 98.9%) as a light yellow solid.

[0181] LCMS (ESI, m / z): [M+H] + =367.05

[0182] 1H NMR (400 MHz, methanol-d4) δ 8.38–8.34 (m, 1H), 7.98–7.92 (m, 2H), 7.67–7.62 (m, 1H), 7.57–7.48 (m, 2H), 7.48–7.37 (m, 2H), 6.33 (s, 1H).

[0183] Example 9 Preparation of Compound C21

[0184]

[0185] In a single-mouth bottle, dichloromethane (10 mL) was added as solvent, followed by 2-(benzofuran-5-yl(hydroxy)methyl)benzo[b]thiophene-1,1-dioxide (150 mg, 0.5 mmol, 1.0 equivalent), 3-cyano-4-fluorobenzoic acid (95 mg, 0.57 mmol, 1.2 equivalent), 1-hydrogen-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (499 mg, 0.960 mmol, 2.0 equivalent), and triethylamine (97 mg, 0.9 mmol, equivalent), and the mixture was reacted at 25°C for 12 hours. 50 mL of water was added to the resulting mixture, and the mixture was extracted with ethyl acetate (3 x 20 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by reverse phase column chromatography under the following conditions (chromatographic column: Xselect CSH C185 m, 30 mm x 150 mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 55% B to 70% B in 7 minutes; wavelength: 254 nm / 220 nm nm; RT1 (min): 6.87) gave benzofuran-5-yl-(1,1-oxybenzo[b]thiophen-2-yl)methyl-3-cyano-4-fluorophenyl ester (13.8 mg, purity 99.5%, yield 6.25%) as a white solid.

[0186] LCMS (ESI, m / z): [M+H] - =458.00

[0187] 1 H NMR (400MHz, DMSO-d6) δ8.68–8.62(m,1H),8.48–8.42(m,1H),8.07(d,J=2.2Hz,1H),8.00(d,J=1.7Hz,1H),7.90 –7.86(m,1H),7.79–7.68(m,3H),7.67–7.59(m,3H),7.52–7.48(m,1H),7.24(d,J=1.6Hz,1H),7.06–7.02(m,1H).

[0188] Example 10 Preparation of Compound C22

[0189]

[0190] In a single-mouth bottle, 1,4-dioxane (5 ml) was added as solvent, followed by (2-methylpyrimidin-5-yl)methanol (100 mg, 0.8 mmol, 1.0 equivalent), 2-[1-benzofuran-5-yl(hydroxy)methyl]benzo[b]thiophene 1,1-dioxide (302 mg, 1.0 mmol, 1.2 equivalent), and trifluoroacetic acid (18.3 mg, 0.16 mmol, 0.2 equivalent), and the mixture was reacted at 60°C for 4 hours. 50 mL of water was added to the resulting mixture, extracted with ethyl acetate (3 x 20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. Purify by silica gel column chromatography with petroleum ether / ethyl acetate (3 / 1) to give 2-(benzofuran-5-yl((2-methylpyrimidin-5-yl)methoxy)methyl)benzo[b]thiophene 1,1-dioxide (19.2 mg, purity 99.6%, yield 5.70%) as a white solid.

[0191] LCMS (ESI, m / z): [M+H] + =419.05

[0192] 1 H NMR(400MHz, DMSO-d6)δ8.73(s,2H),8.05(d,J=2.2Hz,1H),7.87–7.82(m,2H),7.80–7.64(m,2H),7.61–7.57(m,2H),7.49–7.45(m ,1H),7.34(t,J=1.2Hz,1H),7.05–7.01(m,1H),5.82(d,J=1.7Hz,1H),4.66(d,J=12.1Hz,1H),4.56(d,J=12.1Hz,1H),2.62(s,3H).

[0193] The following compounds were obtained by the preparation method of Reference Examples 1-10:

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200] Test Example 1 GluN1 / GluN3A receptor inhibitory activity test

[0201] HEK-293 cells stably expressing GluN1 / GluN3A receptors were seeded in 384-well plates at a density of 10,000 cells / well and induced with 1 μg / ml doxycycline for 24-28 hours. The culture medium was then removed, Fluo-4 (Thermo Fisher Scientific) was loaded, and the cells were incubated in a light-proof incubator at 37°C for 1 hour (Gee et al., 2000). 2+ The plates were gently washed twice with buffer and then incubated with the synthesized test compounds for 20 minutes. The initial concentration was 100 μM, and 3-fold dilutions were performed at 8 concentration points with two replicates for each condition. After adding the test compound, 10 μl of CGP-78608 (Tocris, working concentration 500 nM) was added and incubated for 3 minutes, followed by stimulation of the cells with 10 μl of glycine (Amresco, working concentration 100 μM). The fluorescence signal was measured using the FDSS / μCell platform (Hamamatsu). The excitation (Ex) and emission (Em) wavelengths were set to 480 and 540 nm, respectively. By using (F drug ) and not using (F control The inhibitory effects of the test compounds were compared by comparing the fluorescence (F) of the tested compounds. control The values ​​represent the basal Fluo-4 fluorescence plus the fluorescence stimulated by glycine, F drug represents the total Fluo-4 luminescence after drug treatment. drug and F control The values ​​were collected at the peak. Ca-free 2+ The buffer contained (in mM): 140 NaCl, 5 KCl, 1 MgCl2, 10 glucose, 10 HPES and 0.5 EGTA. The pH was adjusted to 7.2 using NaOH. To dilute the compounds, 2 mM free Ca was added in addition to the other components of the buffer. 2+ .

[0202]

[0203]

[0204] As can be seen from the above table, the compounds of the embodiments of the present disclosure have excellent inhibitory activity against GluN1 / GluN3A.

[0205] The above is an exemplary description of the implementation of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-mentioned implementation. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in, A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted C 6-14 Aryl, 5-14 membered heteroaryl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group; and when A is C 6-14 When aromatic, is H; each R a the same or different, independently selected from OH, CN, halogen, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy; L1, L2, L3 are the same or different and are independently selected from a single bond, -C(=O)O-, unsubstituted or optionally substituted with one, two, three or four R L The following groups substituted: -CH2O-, -CH2C(=O)O-, -CH2CH2C(=O)O-, -C(=O)NH-; each R L The same or different, independently selected from H, C 1-10 alkyl; Cy1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R1: 3-10 Cycloalkyl, 3-14 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl; each R1 is the same or different and is independently selected from H, halogen, OH, CN, NH2, oxo (=O), aldehyde, C 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, halogenated C 1-10 Alkoxy, C 1-10 Alkyl-C(O)-; Cy2 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R2: 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 Aryl; each R2 is the same or different, independently selected from H, OH, CN, halogen, NO2, NH2, COOH, unsubstituted or optionally substituted by one, two or more R 21 Substituted with the following groups: C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkenyl, C 3-10 Cycloalkenyloxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyloxy; each R 21 are the same or different and are independently selected from H, OH, CN, halogen, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy; Cy3 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R3: 3-14 membered heterocyclyl, 5-14 membered heteroaryl or C 6-14 Aryl; each R3 is the same or different and is independently selected from H, OH, halogen, oxo (=O), CN, NO2, NH2, COOH, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyloxy, 3-14 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 Aryl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: C 6-10 Aryl, 5-6 membered heteroaryl; Preferably, A is selected from CH, unsubstituted or optionally substituted with one, two or more R a Substituted with the following groups: phenyl, pyridyl, for example CH, Each R a are the same or different and are independently selected from halogen, C 1-6 Alkyl, such as H, F or methyl; Preferably, L1 is selected from -CH2O-, -C(=O)O-, -CH2C(=O)O-, -CH2CH2C(=O)O-, -C(=O)NH-; Preferably, L2 is selected from a single bond, -C(=O)NH-, -C(=O)O-; Preferably, L3 is a single bond.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, characterized in that: Cy1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R1: 3-6 Cycloalkyl, 5-10 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl; Preferably, Cy1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R1: pyridyl, pyrimidinyl, pyridazinyl, phenyl, pyrrolyl, pyrazolyl, oxazolyl, piperidinyl, cyclohexyl, morpholinyl, indolyl, Preferably, Cy1 is selected from Preferably, Cy1 is selected from Preferably, each R1 is the same or different and is independently selected from H, halogen, OH, CN, NH2, oxo (=O), aldehyde, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, C 1-6 Alkyl-C(O)-; Preferably, each R1 is the same or different and is independently selected from H, F, Cl, OH, CN, NH2, oxo (=O), aldehyde, methyl, methoxy, CH3C(O)-, 4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, characterized in that: Cy2 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R2: 6-10 Aryl, 5-6 membered heterocyclyl, 9-10 membered heterocyclyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl; Preferably, Cy2 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R2: phenyl, benzofuranyl, 2,3-dihydro-1H-indenyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, furan[3,2-b]pyridinyl, 2,3-dihydrobenzofuranyl, isothiazolyl, isoxazolyl, benzo[d][1,3]dioxazolyl, 1,2,4-oxadiazolyl, benzo[d]thiazolyl, Preferably, Cy2 is selected from Preferably, Cy2 is selected from Preferably, each R2 is the same or different and is independently selected from H, OH, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, cyano C 3-6 Cycloalkenyl, halogenated C 1-6 Alkoxy, C 3-6 Cycloalkyloxy; Preferably, each R2 is the same or different and is independently selected from H, OH, F, Cl, CN, Cyclopropyloxy.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: Cy3 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R3: 6-10 Aryl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, 9-10 membered heterocyclyl, 9-10 membered heteroaryl; Preferably, Cy3 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more R3: phenyl, pyridyl, quinazolinyl, benzothiophenyl, Preferably, Cy3 is selected from Preferably, Cy3 is selected from Preferably, each R3 is the same or different and is independently selected from H, halogen, oxo (=O), CN, C 1-6 Alkoxy, C 3-8 Cycloalkyloxy, C 6-10 Aryl; Preferably, each R3 is the same or different and is independently selected from H, F, oxo (=O), CN, methoxy, cyclobutyloxy, cyclopentyloxy, phenyl.

6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from the following structures: Among them, L1, L2, L3, Cy1, Cy2, Cy3, R a Independently of each other, they have the definitions in any one of claims 1 to 5; m is selected from 0, 1, 2, 3, 4; Preferably, the compound represented by formula (I) is selected from the following structures: Among them, L1, L2, Cy1, Cy2, Cy3, R a Independently of each other, they have the definitions of any one of claims 1 to 5; n is selected from 0, 1, 2; q is selected from 0, 1; Indicates absence or oxo (=O); Preferably, the compound represented by formula (I) is selected from the following structures: Among them, Cy1, Cy2, Cy3, n, Independently of each other, it has the definitions in any one of claims 1 to 5. Preferably, the compound represented by formula (I) is selected from the following structures: Among them, Cy1, Cy2, Cy3, n, Independently of each other, it has the definitions in any one of claims 1 to 5.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) is selected from the following structures:

8. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, comprising the following steps: Compound a reacts with compound b to obtain a compound represented by formula (I) or a pharmaceutically acceptable salt thereof; wherein A, L1, L2, L3, Cy1, Cy2, and Cy3 are independently defined as in any one of claims 1 to 7; X1 is selected from a leaving group, such as a halogen or OH; Preferably, the preparation can be carried out in the presence of a base, and the base is selected from at least one of triethylamine, N,N-diisopropylethylamine, pyridine and DMAP.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; Alternatively, an antibody / peptide-drug conjugate comprising an antibody or peptide, and a compound of formula (I) or a pharmaceutically acceptable salt thereof as a payload according to any one of claims 1 to 7, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof as the payload is directly bonded to the antibody or peptide or bonded to the antibody or peptide via a linker; Preferably, the peptide has at least 80% identity to the amino acid sequence of glucagon-like peptide 1 (GLP-1); preferably, the peptide is glucagon-like peptide 1; Preferably, the linker may be one known in the art, such as an acid-cleavable linker, an enzyme-cleavable linker, a peptide-cleavable linker, and a linker containing a disulfide group.

10. Use of a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 or the antibody / peptide-drug conjugate in the preparation of a medicament for treating and / or preventing diseases associated with NMDA receptors; Preferably, the drug is an NMDA receptor inhibitor; Preferably, the NMDA receptor is a tetramer, and the subunit composition in the tetramer is selected from the combination of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are any two combinations selected from GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B, for example, an NMDA receptor composed of a subunit combination of GluN1 / GluN2A, GluN1 / GluN2B, GluN1 / GluN2C, GluN1 / GluN2D, GluN1 / GluN2A / GluN2B, GluN1 / GluN2A / GluN2C, GluN1 / GluN2B / GluN2D, GluN1 / GluN3A, GluN1 / GluN3B, GluN1 / GluN2B / GluN3A, etc.; Preferably, the disease associated with NMDA receptors is selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety, brain injury, Parkinson's disease, Huntington's disease, etc.

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