Pyrimidinone fused ring compound and application thereof in central nervous system

Abstract

The invention provides application of a compound shown in a formula (III) 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 antagonistic activity on the NMDA receptor (especially a GluN1 / GluN3A receptor).

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field, specifically relating to a pyrimidinone-based fused-ring compound and its application in the central nervous system. Background Technology

[0002] NMDA (N-methyl-D-aspartate) receptors belong to the ionotropic glutamate receptor family and are widely distributed in the central nervous system. They participate in synaptic transmission and plasticity, regulating physiological functions such as learning and memory, and are an important protein target. NMDA receptors are associated with various diseases, such as stroke, depression, epilepsy, Alzheimer's disease, and pain, making them one of the most popular drug development targets for neurological diseases. Drug development targeting NMDA receptors has significant clinical and market value. The NMDA receptor family contains seven subunits: GluN1, GluN2 (2A, 2B, 2C, 2D), and GluN3 (3A, 3B). The overall structure of these subunits is similar, with multiple domains. Functional NMDA receptors are heterotetramers containing at least one GluN1 subunit, and the diversity of subunits determines the subtype diversity of NMDA receptors. The classic NMDA receptor is typically a heterotetramer composed of two GluN1 and two GluN2 subunits. The crystal structures of the GluN1 / GluN2 isoforms have been extensively resolved, and multiple drug-binding pockets have been identified. This subunit diversity determines the isoform diversity of the NMDA receptor, and these isoforms exhibit strong structural similarity, which can be considered as highly similar but not identical keyholes.

[0003] GluN1 / GluN3 includes GluN1 / GluN3A and GluN1 / GluN3B, both NMDA receptor subtypes. GluN3A and GluN3B share high homology, and currently, highly active molecules cannot distinguish between them. The structure of the GluN1 / GluN3 receptor remains unresolved, and it has not yet been widely developed as a target. The lack of specific small-molecule modulators and crystal structure information significantly limits further research on GluN1 / GluN3. Therefore, finding compounds with high antagonistic activity against GluN3 is of great significance. Summary of the Invention

[0004] To address the aforementioned technical problems, this disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof:

[0005]

[0006] in,

[0007] Ring B is selected from unsubstituted or optionally substituted by one, two or more R. bThe following groups are substituted: 3-10 membered heterocycles, 5-14 membered heteroaromatic rings, C 6-14 Aromatic rings; each R b They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy;

[0008] Ring E is absent or selected from unsubstituted or arbitrarily substituted by one, two or more Rs e The following groups are substituted: C 3-10 Cycloalkanes ring, C 3-10 Cyclic olefin rings, 3-10 membered heterocycles, 5-14 membered heteroaromatic rings, C 6-14 Aromatic rings; each R e They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy;

[0009] L is selected from single bond, CH2;

[0010] G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, C 6-14 Aryl, NH2; each R g They may be the same or different, and are independently selected from H, OH, CN, halogen, oxo (=O), NO2, NH2, COOH, unsubstituted, or optionally substituted by one, two, or more R. g1 The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkynyl group, C 6-14 Cycloalkyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl; each R g1 They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 6-14 Cycloalkyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, C 6-14Aryl.

[0011] According to embodiments of this disclosure, ring B is selected from unsubstituted or optionally replaced by one, two or more Rs. b The following groups are substituted: 5-6 membered heterocycles, 5-6 membered heteroaromatic rings, C 6-10 Aromatic rings;

[0012] According to the embodiments of this disclosure, ring B is selected from thiazole ring, oxazole ring, imidazole ring, pyridine ring, and benzene ring.

[0013] According to the implementation scheme of this disclosure, each R b They may be the same or different, and are independently selected from H, halogens, and C. 1-6 alkyl;

[0014] According to the implementation scheme of this disclosure, each R b They are either the same or different, and are independently selected from H, F, Cl, Br, I, and methyl.

[0015] According to the implementation scheme of this disclosure, ring E does not exist or is selected from C. 3-6 Cycloolefin rings, 5-6 membered heterocycles, 5-6 membered heteroaromatic rings, C 6-10 Aromatic rings;

[0016] According to the embodiments of this disclosure, ring E is absent or selected from benzene ring, cyclopentane ring, dihydropyran ring, and pyridine ring;

[0017] According to the implementation scheme of this disclosure, Selected from

[0018] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups are substituted: 9-10 membered heterocyclic group, 5-6 membered heteroaryl group, 9-10 membered heteroaryl group, NH2;

[0019] According to embodiments of this disclosure, G is selected from unsubstituted or optionally replaced by one, two or more R. g The following groups are substituted: NH2, pyrrole,

[0020] According to the implementation scheme of this disclosure, each R g They may be identical or different, and are independently selected from H, CN, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R atoms. g1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkyne, 5-6 quinone heteroaryl, 9-10 quinone heteroaryl, C 6-10Aryl; each R g1 They can be the same or different, and are independently selected from H, CN, halogens, oxometalates (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkyl group.

[0021] According to the implementation scheme of this disclosure, each R g They may be identical or different, and are independently selected from H, CN, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R atoms. g1 The following groups are substituted: methyl, ethyl, propyl, methoxy, butynyl, phenyl, pyridyl, benzothiazolyl, pyrazolyl; each R g1 They can be the same or different, and are independently selected from H, CN, F, oxo (=O), methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl.

[0022] According to the implementation scheme of this disclosure, each R g They are either the same or different, and are independently selected from H, CN, F, Cl, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy,

[0023] According to the implementation scheme of this disclosure, G is selected from N(R) ga (R) gb ); R ga and R gb Each has R independently g The definition stated above; preferably, R ga Selected from C 1-6 Alkyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl; R gb Selected from halogenated C 6-10 Aryl, Halogenated C 1-6 Alkyl-C 6-10 Aryl, Halogenated C 1-6 Alkoxy-C 6-10 Aryl, cyano-C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl;

[0024] According to the implementation scheme of this disclosure, R ga Selected from ethyl, pentyl (e.g.) C3-6 cycloalkyl C 1-3 Alkyl (e.g.) ), Butynyl (e.g.) ); R gb Selected from halophenyl (e.g.) ), halogenated C 1-3 Alkylphenyl (e.g.) ), halogenated C 1-3 Alkoxyphenyl (e.g.) ), cyanophenyl (e.g.) ), benzothiazolyl (e.g.) ), methylpyrazolyl (e.g.) );

[0025] According to the implementation scheme of this disclosure, G is selected from...

[0026] According to embodiments of this disclosure, the compound shown in formula (III) is not selected from:

[0027]

[0028] According to embodiments of this disclosure, the compound represented by formula (III) is selected from the following structures:

[0029]

[0030] Among them, G and R a They each possess the definitions described above independently.

[0031] According to embodiments of this disclosure, the compound represented by formula (III) is selected from the following structures:

[0032]

[0033] Where Z is selected from CH2 or O, R a and R g Each has the definition described above independently. According to an embodiment of this disclosure, the compound represented by formula (III) is selected from the following structures:

[0034]

[0035] Among them, R a and R g1 They each possess the definitions described above independently.

[0036] According to embodiments of this disclosure, the compound represented by formula (III) is selected from the following structures:

[0037] Table 1

[0038]

[0039]

[0040]

[0041] This disclosure also provides a method for preparing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, comprising the following steps: reacting compound a with compound b to obtain the compound represented by formula (III) or a pharmaceutically acceptable salt thereof;

[0042]

[0043] Among them, B, E, L, and G are independently defined as described above; X is selected from leaving groups, such as halogens or OH.

[0044] According to embodiments of this disclosure, the preparation can be carried out in the presence of an alkali selected from inorganic alkalis, such as at least one selected from sodium carbonate, potassium carbonate, and cesium carbonate.

[0045] According to embodiments of this 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, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexylmethyl ether, dimethyl ether, diethyl ether, dimethyl ethylene glycol, biphenyl ether, dipropyl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichlorodiethyl ether, and others. Polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and those that may be substituted with fluorine and chlorine atoms, such as methylene chloride, dichloromethane, trichloromethane, 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.

[0046] This disclosure also provides a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0047] This disclosure also provides a pharmaceutical composition comprising the compounds shown in Table 2 below or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0048] Table 2

[0049]

[0050]

[0051] This disclosure also provides an antibody / peptide-drug conjugate comprising an antibody or peptide, and a compound of formula (III) or a pharmaceutically acceptable salt thereof as a payload, wherein the compound of formula (III) or a pharmaceutically acceptable salt thereof is directly bonded or bonded via a linker to the antibody or peptide.

[0052] This disclosure also provides an antibody / peptide-drug conjugate comprising an antibody or peptide, and a compound shown in Table 2 or a pharmaceutically acceptable salt thereof as a payload, wherein the compound shown in Table 2 or a pharmaceutically acceptable salt thereof is directly bonded or bonded to the antibody or peptide via a linker.

[0053] According to embodiments of this disclosure, the antibody / peptide-drug conjugate is a protein-drug conjugate.

[0054] According to embodiments of this disclosure, the peptide has at least 80% identity with the amino acid sequence of glucagon-like peptide-1 (GLP-1); for example, it has at least about 85%, at least about 90%, at least about 95%, or greater than about 97% amino acid sequence identity.

[0055] According to the embodiments of this disclosure, the peptide is selected from the peptide described in Chinese invention patent application CN115697414A; preferably, the peptide is glucagon-like peptide 1.

[0056] According to embodiments of this disclosure, the connector may be known in the art, such as an acid-cleavable connector, an enzyme-cleavable connector, a peptide-cleavable connector, and a connector containing a disulfide group.

[0057] According to embodiments of this disclosure, the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, or the compound represented by Table 2 or a pharmaceutically acceptable salt thereof, is present in the pharmaceutical composition or the antibody / peptide-drug conjugate in a therapeutically effective amount.

[0058] This disclosure also provides the use of pharmaceutical compositions containing the compound of formula (III) or a pharmaceutically acceptable salt thereof, or the compounds shown in Table 2 or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment and / or prevention of diseases associated with NMDA receptors.

[0059] According to embodiments of this disclosure, the drug is an NMDA receptor antagonist.

[0060] According to the embodiments of this disclosure, the NMDA receptor is a tetramer, and the subunits in the tetramer are selected from combinations of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are selected from any two combinations of GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, such as NMDA receptors composed 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, and GluN1 / GluN2B / GluN3A.

[0061] According to embodiments of this disclosure, the diseases associated with NMDA receptors are selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety disorder, brain injury, Parkinson's disease, Huntington's disease, etc.

[0062] This 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 at least one of a compound of formula (III) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound of formula (III) or a pharmaceutically acceptable salt thereof.

[0063] This 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 at least one of the compounds described in Table 2 or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing the compounds described in Table 2 or pharmaceutically acceptable salts thereof.

[0064] According to the embodiments of this disclosure, the NMDA receptor is a tetramer, and the subunits in the tetramer are selected from combinations of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are selected from any two combinations of GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, such as NMDA receptors composed 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, and GluN1 / GluN2B / GluN3A. According to embodiments of this disclosure, the diseases associated with NMDA receptors are selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety disorder, brain injury, Parkinson's disease, Huntington's disease, etc.

[0065] In preparing the medicaments or pharmaceutical compositions described herein, the compounds or pharmaceutically acceptable salts of this disclosure may be combined or formulated with suitable pharmaceutically acceptable excipients (such as carriers, diluents, or excipients), and may be formulated into solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Routes of administration include oral, intraperitoneal, transdermal, subcutaneous, intravenous, or intramuscular injection, inhalation, local, intralesional, infusion; liposome-mediated delivery; local, intrathecal, gingival pocket, rectal, bronchial, nasal, transmucosal, intestinal, ocular, or ear delivery, or any other method known in the art, all capable of achieving therapeutic effects on tumors.

[0066] The therapeutically effective dose or dosage described in this disclosure will vary depending on several factors, including the chosen route of administration, the formulation of the composition, patient response, severity of the condition, the subject's weight, and the prescribing physician's judgment, for example, 1-200 mg / kg, 40-150 mg / kg, such as 50 mg / kg. The dose may be increased or decreased over time, as required by individual patients. In some cases, patients are initially given a low dose, which is then increased to an effective dose that the patient can tolerate. Furthermore, patients may be given multiple doses over defined time periods, particularly in time increments (e.g., daily, weekly, bi-weekly, monthly, quarterly, bi-annual, or similar).

[0067] Beneficial effects

[0068] This disclosure provides the use of a compound of formula (III) and similar compounds (such as those in Table 2) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of diseases associated with NMDA receptors, said compounds having good antagonistic activity against NMDA receptors (particularly GluN1 / GluN3A receptors).

[0069] Terminology Definitions and Explanations

[0070] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0071] Unless otherwise stated, the numerical ranges described in this specification and claims are equivalent to describing at least 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.

[0072] It should be understood that in this article, when describing one, two or more, "more" should refer to integers greater than 2, such as 3 or greater than or equal to 3, such as 3, 4, 5, 6, 7, 8, 9 or 10.

[0073] The context of this disclosure is used Represents a chemical bond.

[0074] Term "C" 1-10 "alkyl" refers to a straight-chain or branched saturated hydrocarbon group, preferably a straight-chain 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 groups, etc. "C" 1-10 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. 1-8 "Alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. 1-6"Alkyl" means a straight-chain or branched alkyl group 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 their isomers.

[0075] Term "C" 3-10 "Cycloalkyl" refers to a saturated monovalent monocyclic, bicyclic (e.g., fused, bridged, spirocyclic) 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 groups, etc. The C... 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl; or bicyclic hydrocarbon groups, such as borneolyl, 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]nonyl, 2,6-diazaspiro[3,4]octyl; or tricyclic hydrocarbon groups, such as adamantyl.

[0076] Term "C" 3-10 "Cycloalkenyl" represents an unsaturated monovalent monocyclic, bicyclic (e.g., fused ring, bridged ring, spiro ring) hydrocarbon ring, or tricyclic alkene 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. The C... 3-10 Cycloalkenyl groups can be monocyclic hydrocarbon groups, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or cyclodecenyl.

[0077] The term "3-20 membered heterocyclic group" refers to a monocyclic, bicyclic, or tricyclic saturated or unsaturated non-aromatic ring or ring system (preferably 3-14 membered heterocyclic group) containing 1-5 heteroatoms independently selected from N, O, and S, with monovalent or polyvalent rings of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. For example, a 3-14 membered heterocyclic group can be a 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 heterocyclic group contains 1-5 heteroatoms independently selected from N, O, and S. The bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings. The 3-14 membered heterocyclic groups include 3-10 membered heterocyclic groups, 5-8 membered heterocyclic groups, and 3-8 membered heterocyclic groups. The 3-14 membered heterocyclic group can be connected to the rest of the molecule via any one of the carbon atoms or a nitrogen atom (if present). The 3-14 membered heterocyclic group can include fused or bridged rings and spirocyclic rings. Specifically, the heterocyclic group can include, but is not limited to: 3-membered rings, such as azirropropyl or oxacyclopropyl; 4-membered rings, such as azirrobutyl or oxacyclobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group can be benzofused. The heterocyclic group can be bicyclic, such as, but not limited to, a 5,5-membered ring, like a hexahydrocyclopentano[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, like a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclic group can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl. When the 3-14-membered heterocyclic group is linked to other groups to form the compounds of this disclosure, the carbon atom on the 3-14-membered heterocyclic group can be linked to other groups, or a heterocyclic atom (such as a nitrogen atom) on the 3-14-membered heterocyclic group ring can be linked to other groups. For example, when the 3-14 membered heterocyclic group is selected from piperazine or tetrahydropyrrole, the nitrogen atom or carbon atom on the piperazine group can be attached to 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 can be attached to other groups.

[0078] The term "5-20-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms, wherein the ring atoms comprise 1-5 heteroatoms independently selected from N, O, and S, and the bicyclic and tricyclic aromatic ring systems can be fused rings, spirocyclic rings, or bridged rings (preferably 5-14-membered heteroaryl). The 5-14-membered heteroaryl contains 1-5 heteroatoms, preferably 1-3. Additionally, in each case, the 5-14-membered heteroaryl can be benzofused. 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, thiophene, thiazolyl, triazole, imidazolyl, etc.; 6-membered rings, such as pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. The heterocyclic group may be bicyclic, including but not limited to: 5,5-membered rings, such as tetrahydrocyclopentanopyrazole; 5,6-membered rings, such as tetrahydroindole, tetrahydropyrazolopyridine, tetrahydroimidazopyridine, tetrahydrobenzisoxazole, tetrahydrobenzoxazole, tetrahydrobenzothiazole, tetrahydrobenzisoxazole, dihydrofuranopyrazole, tetrahydrobenzofuran, dihydrobenzofuran, tetrahydrobenzothiophene; 6,6-membered rings, such as tetrahydroquinoline; 5,7-membered rings, such as tetrahydrocycloheptazothiazole, tetrahydrocycloheptazofuran. The heterocyclic group can be tricyclic, including but not limited to: 6,7-dihydrospiro[cyclopropane-1,5-pyrrolo[1,2-c]imidazole]. When the 5-14 membered heteroaryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, the hydrogen atom bonded to a carbon atom on the heteroaryl ring can be substituted, or the hydrogen atom bonded to a heteroatom on the heteroaryl ring can be substituted.

[0079] The term "spirocycle" refers to a ring system in which two rings share a single ring atom.

[0080] The term "fused ring" refers to a ring system in which two rings share two cyclic atoms.

[0081] The term "bridged ring" refers to a ring system in which two rings share three or more ring atoms.

[0082] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0083] "Halogenation" refers to the substitution of a substance by one or more halogens.

[0084] Unless otherwise stated, the definitions of terms in this document also apply to groups that contain the term; for example, the definition of alkyl also applies to the definition of alkyl-containing groups such as alkoxy (i.e., alkyloxy).

[0085] Unless otherwise stated, the term “compound” in the context of this disclosure shall be understood to include the compound itself and its tautomers, stereoisomers, solvates or isotopic labels.

[0086] Crystallization often produces solvates of the compounds disclosed herein. As used herein, a solvate is a combination of one or more molecules of the compounds disclosed and one or more solvent molecules.

[0087] The solvent can be water, in which case the solvate is a hydrate; alternatively, it can be an organic solvate.

[0088] As used herein, the term “acceptable” in relation to formulations, compositions or ingredients means that it does not have a lasting harmful effect on the overall health of the subject of treatment.

[0089] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds disclosed herein and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological response or interacting adversely with any component contained in the composition.

[0090] Those skilled in the art will understand that the compounds of this disclosure can exist in the form of various pharmaceutically acceptable salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form inner salts.

[0091] The term "tautomer" refers to a functional group isomer resulting from the rapid movement of an atom between two positions within a molecule. The compounds disclosed herein can exhibit tautomerism. Tautomers can exist in two or more interconvertible forms. Proton-transfer tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in equilibrium form, and attempts to isolate a single tautomer typically yield a mixture whose physicochemical properties are consistent with those of the mixture of compounds. The equilibrium position depends on the intramolecular chemical characteristics. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; while in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.

[0092] Based on their molecular structure, the compounds disclosed herein can be chiral, and therefore may exist in various enantiomeric forms. Consequently, these compounds can exist in racemic or optically active forms. The compounds disclosed herein cover isomers of each chiral carbon with an R or S configuration, or mixtures thereof, or racemates. The compounds disclosed herein, or intermediates thereof, can be isolated as enantiomers 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 obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as tartaric acid in R and S forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline), or various optically active camphorsulfonic acids. Chromatographic enantiomeric separation can also be advantageously performed using optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silica gel, cellulose triacetate or other carbohydrate derivatives, or chiral derivatized isobutylene ester polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as hexane / isopropanol / acetonitrile.

[0093] In this application, "pharmaceutical composition" refers to a formulation of the disclosed compound and a medium conventionally accepted in the art for delivering a bioactive compound to a mammal (e.g., a human). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0094] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0095] In this application, the term "prodrug" refers to a compound of this disclosure that can be converted into a biologically active form under physiological conditions or by solvation. The prodrugs of this disclosure are prepared by modifying functional groups in the compound; such modification can be performed conventionally or removed in vivo to obtain the parent compound. Prodrugs comprise compounds formed by attaching a hydroxyl or amino group to any group in the compound of this disclosure. When a prodrug of the compound of this disclosure is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group and a free amino group.

[0096] "Isotope" refers to all isotopes of atoms appearing in the compounds disclosed herein. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for inclusion in the compounds disclosed herein are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example, but not limited to, [examples of isotopes]. 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 of this disclosure can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using appropriate isotopically labeled reagents instead of non-isotopically labeled preparations. Such compounds have a variety of potential uses, for example, as standards and reagents in the determination of biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0097] The term "treatment" and other similar synonyms used in this article include the following meanings:

[0098] (i) To prevent the occurrence of disease or condition in mammals, especially when such mammals are susceptible to the disease or condition but have not yet been diagnosed with it;

[0099] (ii) To suppress a disease or symptom, that is, to curb its development;

[0100] (iii) To alleviate a disease or symptom, that is, to cause the condition of the disease or symptom to subside; or

[0101] (iv) To alleviate the symptoms caused by the disease or condition.

[0102] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with humans being the most preferred.

[0103] The term “therapeutic effective amount” refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians are searching for in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) suppression of disease: e.g., suppression of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). Detailed Implementation

[0104] The technical solutions of this disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0105] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0106] Example 1: Preparation of compound C3-1

[0107]

[0108] In a single-necked flask, N,N-dimethylformamide (5 mL) was added as a solvent, followed by the sequential addition of 7-(chloromethyl)-2-methyl-[1,3]thiazolyl[3,2-a]pyrimidin-5-one (100 mg, 0.5 mmol, 1.0 equivalent), 6,7-difluoro-1,2,3,4-tetrahydroquinoline (87 mg, 0.5 mmol, 1.2 equivalent), potassium carbonate (129 mg, 0.9 mmol, 2.0 equivalent), and potassium iodide (154 mg, 0.9 mmol, 2.0 equivalent). The mixture was reacted at 100 °C for 3 hours. The resulting mixture was then extracted with 50 mL of water using ethyl acetate (3 x 20 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the crude product was purified by reversed-phase column chromatography under the following conditions (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 53% B to 65% B over 7 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 5.53), yielding 7-((6,7-difluoro-3,4-dihydroquinolin-1(2H)-yl)methyl)-2-methyl-5-hydrothiazolyl[3,2-a]pyrimidin-5-one (14.7 mg, 99.6% purity), a white solid.

[0109] LCMS(ESI,m / z):[M+H] + =348.10

[0110] 1 H NMR(400MHz,DMSO-d6)δ7.85(s,1H),6.99(t,J=10.2Hz,1H),6.43–6.35(m,1H),5.98(s,1H) ,4.35(s,2H),3.39(t,J=5.6Hz,2H),2.71(t,J=6.2Hz,2H),2.43(s,3H),1.92–1.88(m,2H).

[0111] Example 2 Preparation of compound C3-2

[0112]

[0113] In a single-necked flask, N,N-dimethylformamide (5 mL) was added as a solvent, followed by the sequential addition of 7-(chloromethyl)-2-methyl-[1,3]thiazolyl[3,2-a]pyrimidin-5-one (100 mg, 0.4 mmol, 1.0 equivalent), 5,6-difluoro-2,3-dihydro-1-hydro-indole (79 mg, 0.5 mmol, 1.1 equivalent), potassium carbonate (129 mg, 0.9 mmol, 2.0 equivalent), and potassium iodide (154 mg, 0.9 mmol, 2.0 equivalent). The mixture was reacted at 100 °C for 3 hours. The resulting mixture was extracted with 50 mL of water and 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 reversed-phase column chromatography under the following conditions (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 53% B to 65% B over 7 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 5.53), yielding (7-((5,6-difluoroindol-1-yl)methyl)-2-methyl-5-hydrothiazolyl[3,2-a]pyrimidin-5-one (21.8 mg, purity 99.4%), a white solid.

[0114] LCMS(ESI,m / z):[M+H] + =334.05

[0115] 1 H NMR(400MHz,DMSO-d6)δ7.86(d,J=1.6Hz,1H),7.10(m,1H),6.59(m,1H),6.19(s,1H ), 4.19 (s, 2H), 3.49 (t, J = 8.5Hz, 2H), 2.94 (t, J = 8.5Hz, 2H), 2.43 (d, J = 1.5Hz, 3H).

[0116] Example 3 Preparation of compound C3-3

[0117]

[0118] Under nitrogen protection at 0 °C, trifluoroacetic anhydride (3.7 g, 17.9 mmol, 1.0 equiv.) and triethylamine (3.6 g, 35.9 mmol, 2.0 equiv.) were added dropwise to a tetrahydrofuran (20 mL) solution of 4-fluoroaniline (2.0 g, 17.9 mmol, 1.0 equiv.) and stirred at 0 °C for 2 h. The desired product was detected by LCMS. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), the organic phase was washed with water (2 x 20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 2,2,2-trifluoro-N-(4-fluorophenyl)acetamide (2.2 g) as a yellow solid.

[0119] LCMS(ESI,m / z):[M+H] - =206.00.

[0120] Under nitrogen protection at 0°C, a solution of borane tetrahydrofuran (1.0 M in tetrahydrofuran) (0.8 g, 9.6 mmol, 2.0 equivalent) was added dropwise to a solution of 2,2,2-trifluoro-N-(4-fluorophenyl)acetamide (1.0 g, 4.8 mmol, 1.0 equivalent) in 10 mL of tetrahydrofuran. The mixture was stirred overnight at 60°C. The reaction solution was quenched with ice water at room temperature. The resulting mixture was extracted with ethyl acetate (2 x 20 mL), and the organic phase was washed with water (2 x 20 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 4-fluoro-N-(2,2,2-trifluoroethyl)aniline (700 mg) as a yellow solid.

[0121] LCMS(ESI,m / z):[M+H] + =193.05.

[0122] At room temperature, potassium carbonate (286 mg, 2.0 mmol, 2.0 equivalent) and potassium iodide (344 mg, 2.0 mmol, 2.0 equivalent) were added in portions to a solution of 4-fluoro-N-(2,2,2-trifluoroethyl)aniline (200 mg, 1.0 mmol, 1.0 equivalent) and 7-(chloromethyl)-2-methyl-5H-[1,3]thiazo[3,2-a]pyrimidin-5-one (222 mg, 1.0 mmol, 1.0 equivalent) in N,N-dimethylformamide (2 mL). The mixture was stirred at 100 °C for 1 hour. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography under the following conditions: C18 column, mobile phase, acetonitrile and water (0.1%). FA), 10%–50% gradient for 10 minutes, UV 254 nanometer detector, yielded 7-{[(4-fluorophenyl)(2,2,2-trifluoroethyl)amino]methyl}-2-methyl-[1,3]thiazo[3,2-a]pyrimidin-5-one (13.1 mg, purity 99.6%) as a white solid.

[0123] LCMS(ESI,m / z):[M+H] + =372.05.

[0124] 1 ¹H NMR (400 MHz, methanol-d⁴) δ 7.75 (s, 1H), 6.95 (t, J = 8.6 Hz, 2H), 6.85–6.80 (m, 2H), 6.12 (s, 1H), 4.59 (s, 2H), 4.26 (q, J = 9.1 Hz, 2H), 2.48 (s, 3H).

[0125] Example 4 Preparation of compound C3-19

[0126]

[0127] 7-(chloromethyl)-2-methyl-5H-thiazolyl[3,2-A]pyrimidin-5-one (100 mg, 0.4 mmol, 1.0 equivalent), 5,6-difluoro-2-methyl-1H-benzis[d]imidazole (117 mg, 0.7 mmol, 1.5 equivalent), and K₂CO₃ (22 mg, 0.9 mmol, 2.0 equivalent) were dissolved in N,N-dimethylformamide (5 mL) and stirred overnight at 100 °C under nitrogen atmosphere. The desired product was detected by LC-MS. The resulting mixture was extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with water (2 × 20 mL) and dried over anhydrous Na₂SO₄. The filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase chromatography under the following conditions: C18 silica gel column; mobile phase: MeCN in water (10 mmol / L NH4HCO3), gradient: 0%–50%, for 20 min; yield: 7-((5,6-difluoro-2-methyl-1h-benzo[d]imidazol-1-yl)methyl)-2-methyl-5h-thiazolyl[3,2-A]pyrimidine-5-1 (14.7 mg, yield: 9.11%, purity: 97.0%) as a white solid.

[0128] LCMS (ESI, m / z): [M+H]+=347.05.

[0129] 1 H NMR (400MHz, DMSO-d6) δ7.88–7.84(m,1H),7.75–7.70(m,1H),7.63–7.58(m,1H),5.94(s,1H),5.37(s,2H),2.55(s,3H),2.41(d,J=1.5Hz,3H).

[0130] Example 5 Preparation of compound C3-20

[0131]

[0132] K₂CO₃ (270 mg, 1.9 mmol, 3.0 equivalent) was added to a solution of 7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.6 mmol, 1.0 equivalent) and 7-(chloromethyl)-2-methyl-5H-[1,3]thiazo[3,2-A]pyrimidin-5-one (210 mg, 0.9 mmol, 1.5 equivalent) in N,N-dimethylformamide (5 mL). The mixture was stirred at 80 °C under nitrogen for 2 hours. The resulting mixture was extracted with ethyl acetate (2 × 20 mL). The organic layer was washed with water (2 × 20 mL), dried over anhydrous Na₂SO₄, and the filtrate was concentrated under reduced pressure. Purification was performed by reversed-phase chromatography under the following conditions: C18 silica gel column; mobile phase: MeCN in water (10 mmol / L NH4HCO3), gradient: 0%–100%, for 10 min; yielded 7-((7-fluoro-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methyl)-2-methyl-5H-thiazo[3,2-A]pyrimidin-5-one (15.0 mg, purity 99.4%) as a yellow solid.

[0133] LCMS(ESI,m / z):[M+H] + =332.10

[0134] 1 H NMR(400MHz,DMSO-d6)δ7.88–7.84(m,1H),6.64–6.60(m,1H),6.58–6.48(m,2H),6.12 (s,1H),4.34(s,2H),4.31–4.23(m,2H),3.48(t,J=4.4Hz,2H),2.43(d,J=1.6Hz,3H).

[0135] Example 6 Preparation of compound C3-21

[0136]

[0137] At room temperature, iodoethane (4.1 g, 26.6 mmol, 2.0 equation) was added dropwise to a solution of 6-aminobenzothiazole (2.0 g, 13.3 mmol, 1.0 equation) and potassium carbonate (5.5 g, 39.9 mmol, 3.0 equation) in N,N-dimethylformamide (20 mL), and the mixture was stirred at 60 °C for 4 hours. The desired compound was detected by LC-MS. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography under the following conditions: C18 column, mobile phase: acetonitrile and water (0.1% FA), gradient of 10%–50% for 10 min, UV 254 nm detector, yielding N-ethyl-6-aminobenzothiazole (300 mg) as a colorless oil.

[0138] LCMS(ESI,m / z):[M+H] + =179.05.

[0139] At room temperature, potassium carbonate (310 mg, 2.2 mmol, 2.0 equivalent) and potassium iodide (372 mg, 2.2 mmol, 2.0 equivalent) were added in portions to a solution of N,N-dimethylformamide (2 mL) containing N-ethyl-6-aminobenzothiazole (200 mg, 1.1 mmol, 1.0 equivalent) and 7-(chloromethyl)-2-methyl-[1,3]thiazole[3,2-a]pyrimidin-5-one (241 mg, 1.1 mmol, 1.0 equivalent) and stirred at 100 °C for 1 hour. The crude product was purified by Prep-HPLC under the following conditions (column: Xselect CSH C185 m, 30mm x 150mm; mobile phase A: water (0.1% FA), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 35% B to 45% B over 7 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 6.65), yielding 7-{[1,3-benzothiazolyl-6-yl(ethyl)amino]methyl}-2-methyl-[1,3]thiazolyl[3,2-a]pyrimidin-5-one (17.9 mg, purity 97.6%) as a white solid.

[0140] LCMS(ESI,m / z):[M+H] + =357.05.

[0141] 1 H NMR (400MHz, DMSO-d6) δ8.95(s,1H),7.83(d,J=9.0Hz,2H),7.31(d,J=2.5Hz,1H),6.95–6.90(m ,1H),5.96(s,1H),4.48(s,2H),3.58(q,J=7.0Hz,2H),2.48–2.39(m,3H),1.19(t,J=6.9Hz,3H).

[0142] Example 7 Preparation of compound C3-22

[0143]

[0144] At room temperature, potassium carbonate (297 mg, 2.1 mmol, 2.0 equivalent) and potassium iodide (356 mg, 2.1 mmol, 2.0 equivalent) were added in portions to a solution of 3-(trifluoromethyl)-1H-indole (200 mg, 1.0 mmol, 1.0 equivalent) and 7-(chloromethyl)-2-methyl-[1,3]thiazolyl[3,2-a]pyrimidin-5-one (230 mg, 1.0 mmol, 1.0 equivalent) and N,N-dimethylformamide (20 mL). The mixture was stirred at 100 °C for 4 hours. The crude product was purified by Prep-HPLC under the following conditions: 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 47% B to 55% B within 7 minutes; wavelength: 254 nm / 220 nm. nm; RT1(min): 6.65), yielded 2-methyl-7-{[3-(trifluoromethyl)indol-1-yl]methyl}-[1,3]thiazolyl[3,2-a]pyrimidin-5-one (22.1 mg, purity 99.3%), as a yellow solid.

[0145] LCMS(ESI,m / z):[M+H] + =365.10.

[0146] 1 ¹H NMR (400MHz, methanol-d⁴) δ 7.88–7.82 (m, 1H), 7.76–7.70 (m, 1H), 7.70 (d, J = 0.9 Hz, 1H), 7.56–7.52 (m, 1H), 7.39–7.34 (m, 1H), 5.85 (d, J = 0.8 Hz, 1H), 5.64 (s, 2H), 2.44 (d, J = 1.5 Hz, 3H).

[0147] Example 8 Preparation of compound C3-31

[0148]

[0149] Under nitrogen atmosphere, 2-(chloromethyl)pyridine[1,2-a]pyrimidine-4-1 (150 mg, 0.8 mmol, 1.0 equivalent) and 6,7-difluoro-1,2,3,4-tetrahydroquinoline (130 mg, 0.8 mmol, 1.0 equivalent), potassium carbonate (213 mg, 1.5 mmol, 2.0 equivalent) were added in portions to N,N-dimethylformamide (2 mL) at room temperature. The mixture was stirred at 100°C for 2 hours after addition. The reaction mixture was extracted with ethyl acetate (3 x 5 mL). The organic phase was mixed, backwashed with saturated brine (3 x 10 mL), and dried with sodium sulfate. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue / crude product was purified by reversed-phase column chromatography to give 2-[(6,7-difluoro-3,4-dihydro-2h-quinolin-1-yl)methyl]pyridine[1,2-a]pyrimidine-4-1 (23.8 mg, purity 97.2%) in white solids under the following conditions: (Column: 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: 44% B to 53% B over 7 min; Wavelength: 254 nm / 220 nm; RT1 (min): 6.42)

[0150] LCMS(ESI,m / z): [M+H] + =328.05.

[0151] 1 H NMR-PH-LPMC-007-003-0(400MHz,Chloroform-d)δ9.08(s,1H),7.84(s,1H),7.22(s,1H),6.72–6.83( m,1H),6.41(s,1H),6.08–6.19(m,1H),4.44(s,2H),3.56–3.40(m,2H),2.79(s,2H),2.16–1.98(m,2H).

[0152] Example 9 Preparation of compound C3-32

[0153]

[0154] Under nitrogen atmosphere and at room temperature, potassium carbonate (284 mg, 2.0 mmol, 2.0 equivalent) was added in portions to N,N-dimethylformamide (3 mL) solution, followed by the reaction of 2-(chloromethyl)pyridine[1,2-a]pyrimidine-4-1 (200 mg, 1.0 mmol, 1.0 equivalent) and 4-fluoroazido-(2,2,2-trifluoroethyl)aniline (198 mg, 1.0 mmol, 1.0 equivalent). The mixture was stirred at 100 °C for 2 hours after addition. The filter cake was washed with ethyl acetate (3 x 5 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography under the following conditions: column size, mobile phase, water and acetonitrile, 10%–50% gradient for 10 min, and UV 254 nm detector. The crude product was purified by high performance liquid chromatography (HPLC) to obtain a white solid 2-{(4-fluorophenyl)(2,2,2-trifluoroethyl)amino]methyl}pyridine[1,2-a]pyrimidine-4-1 (13.5 mg, purity 96.5%), under the following conditions: Xselect CSH C185 m, 30 mm x 150 mm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 7 min 43% B to 55% B; wavelength: 254 nm / 220 nm; RT1 (min): 5.73.

[0155] LCMS(ESI,m / z):[M+H] + =352.15.

[0156] 1 H NMR-PH-LPMC-007-007: (400MHz, Chloroform-d) δ9.05–9.10(m,1H),7.71–7.79(m,1H),7.66–7.62(m,1H) ),7.17–7.32(m,1H),6.98–6.90(m,2H),6.82–6.70(m,2H),6.35(s,1H),4.63(s,2H),4.01–4.08(m,2H).

[0157] Example 10 Preparation of compound C3-33

[0158]

[0159] At room temperature, ethyl 4-chloroacetoacetate (4.4 g, 26.7 mmol, 1.5 equivalent) was added in portions to polyphosphoric acid (10 mL) containing 2.0 g of 5-fluoropyridine-2-amino (17.8 mmol, 1.0 equivalent). The mixture was stirred overnight at 100 °C. The mixture was diluted with water (30 mL) and the pH was adjusted to 8 with saturated sodium bicarbonate. The solid was collected by filtration, and the filter cake was washed with water (3 x 10 mL) to give 3.4 g of 2-(chloromethyl)-7-fluoropyridine[1,2-a]pyrimidin-4-one as a white solid.

[0160] LCMS(ESI,m / z):[M+H] - =212.95.

[0161] At room temperature, N,N-dimethylformamide (2 mL) containing 2-(chloromethyl)-7-fluoropyridine[1,2-a]pyrimidin-4-one (200 mg, 0.9 mmol, 1.0 equivalent) and 6,7-difluoro-1,2,3,4-tetrahydroquinoline (159 mg, 0.9 mmol, 1.0 equivalent) was added in portions to potassium iodide (312 mg, 1.8 mmol, 2.0 equivalent) and potassium carbonate (260 mg, 1.8 mmol, 2.0 equivalent), and the mixture was stirred at 100 °C for 1 hour. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with water (3 x 20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (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 50% B to 60% B within 7 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 5.5) to obtain 2-[(6,7-difluoro-3,4-dihydro-2H-quinolin-1-yl)methyl]-7-fluoropyridin[1,2-a]pyrimidin-4-one (16.7 mg, purity 99.0%), as a white solid.

[0162] LCMS(ESI,m / z):[M+H] + =346.05.

[0163] 1H NMR(400MHz,DMSO-d6)δ8.94–8.88(m,1H),8.13–8.08(m,1H),7.80–7.76(m,1H),7.09–6.95(m,1H),6.40 –6.35(m,1H),6.19(s,1H),4.45(s,2H),3.45(t,J=5.6Hz,2H),2.73(t,J=6.3Hz,2H),1.97–1.94(m,2H).

[0164] Test Example 1: GluN1 / GluN3A Receptor Antagonistic Activity Test

[0165] HEK-293 cells stably expressing the GluN1 / GluN3A receptor were seeded at a density of 10,000 cells / well in 384-well plates and induced with 1 μg / ml doxycycline for 24–28 hours. The culture medium was then removed, and Fluo-4 (Thermo Fisher Scientific) was loaded. The cells were incubated at 37°C in the dark for 1 hour (Gee et al., 2000). Ca-free... 2+ The plates were gently washed twice with buffer and then incubated with the synthesized test compound for 20 minutes. Initial concentrations were 100 μM, diluted 3-fold, and two replicates were set for each of the eight concentration points. 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 cells with 10 μl of glycine (Amresco, working concentration 100 μM). Fluorescence signals were measured using an FDSS / μCell platform (Hamamatsu). Excitation (Ex) and emission (Em) wavelengths were set to 480 and 540 nm, respectively. Fluorescence signals were measured using (F... drug ) and not using (F control The antagonistic effect of the test compound was compared to the fluorescence (F) of the compound. These measurements of F... control The value represents the fluorescence value of basic Fluo-4 fluorescence stimulated with glycine, F. drug This indicates the total Fluo-4 luminescence after drug treatment. drug and F control All values ​​were collected at their peak values. Ca-free reagents were used to dilute Fluo-4 and wash the cell plates. 2+ The buffer solution contains (in mM): 140 NaCl, 5 KCl, 1 MgCl2, 10 Glucose, 10 HPES, and 0.5 EGTA. The pH is adjusted to 7.2 using NaOH. To dilute the compound, 2 mM of free Ca2+ is added in addition to the other components of the buffer solution. 2+ .

[0166] compound <![CDATA[IC 50 (μM)]]> C2-2 8.69 C2-8 9.15 C3-3 2.1 C3-21 99.27 C3-32 62.31

[0167] As can be seen from the table above, the compounds in the embodiments of this disclosure have excellent antagonistic activity against GluN1 / GluN3A.

[0168] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt thereof: in, Ring B is selected from unsubstituted or optionally substituted by one, two or more R. b The following groups are substituted: 3-10 membered heterocycles, 5-14 membered heteroaromatic rings, C 6-14 Aromatic rings; each R b They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy; Ring E is absent or selected from unsubstituted or arbitrarily substituted by one, two or more Rs e The following groups are substituted: C 3-10 Cycloalkanes ring, C 3-10 Cyclic olefin rings, 3-10 membered heterocycles, 5-14 membered heteroaromatic rings, C 6-14 Aromatic rings; each R e They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy; L is selected from single bond, CH2; G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: 3-10 membered heterocyclic groups, 5-14 membered heteroaryl groups, C 6-14 Aryl, NH2; each R g They may be the same or different, and are independently selected from H, OH, CN, halogen, oxo (=O), NO2, NH2, COOH, unsubstituted, or optionally substituted by one, two, or more R. g1 The following groups are substituted: C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 alkynyl group, C 6-14 Cycloalkyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl; each R g1 They may be the same or different, and are independently selected from H, OH, CN, halogens, oxometalates (=O), NO2, NH2, COOH, and C. 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 cycloalkyl, halogenated C 1-10 Alkyl, Halogenated C 1-10 Alkoxy, C 6-14 Cycloalkyl, 3-10 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl; The compound shown in formula (III) is not selected from:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Ring B is selected from unsubstituted or optionally substituted by one, two or more R. b The following groups are substituted: 5-6 membered heterocycles, 5-6 membered heteroaromatic rings, C 6-10 Aromatic rings; Preferably, ring B is selected from thiazole ring, oxazole ring, imidazole ring, pyridine ring, and benzene ring; Preferably, each R b They are either the same or different, and are independently selected from H, halogens, and C. 1-6 alkyl; Preferably, each R b They are either the same or different, and are independently selected from H, F, Cl, Br, I, and methyl.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, Ring E does not exist or is selected from C. 3-6 Cycloolefin rings, 5-6 membered heterocycles, 5-6 membered heteroaromatic rings, C 6-10 Aromatic rings; Preferably, ring E is absent or selected from benzene ring, cyclopentane ring, dihydropyran ring, and pyridine ring; Preferably, Selected from 4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, G is selected from unsubstituted or optionally by one, two or more Rs. g The following groups are substituted: 9-10 membered heterocyclic group, 5-6 membered heteroaryl group, 9-10 membered heteroaryl group, NH2; Preferably, G is selected from unsubstituted or optionally substituted by one, two or more R. g The following groups are substituted: NH2, pyrrole, Preferably, each R g They may be identical or different, and are independently selected from H, CN, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R atoms. g1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkyne, 5-6 quinone heteroaryl, 9-10 quinone heteroaryl, C 6-10 Aryl; each R g1 They can be the same or different, and are independently selected from H, CN, halogens, oxometalates (=O), and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy; Preferably, each R g They may be identical or different, and are independently selected from H, CN, halogen, oxo (=O), unsubstituted, or optionally substituted by one, two, or more R atoms. g1 The following groups are substituted: methyl, ethyl, propyl, methoxy, butynyl, phenyl, pyridyl, benzothiazolyl, pyrazolyl; each R g1 They can be the same or different, and are independently selected from H, CN, F, oxo (=O), methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl. Preferably, each R g They are either the same or different, and are independently selected from H, CN, F, Cl, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy, 5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, G is selected from N(R) ga (R) gb ); R ga and R gb Each has R independently g The definition stated above; preferably, R ga Selected from C 1-6 Alkyl, C 2-6 alkynyl, halogenated C 1-6 Alkyl, C 3-6 cycloalkyl C 1-6 Alkyl, cyano C 1-6 Alkyl; R gb Selected from halogenated C 6-10 Aryl, Halogenated C 1-6 Alkyl-C 6-10 Aryl, Halogenated C 1-6 Alkoxy-C 6-10 Aryl, cyano-C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Alkyl-5-6-membered heteroaryl; Preferably, R ga Selected from ethyl, pentyl (e.g.) C 3-6 cycloalkyl C 1-3 Alkyl (e.g.) ), Butynyl (e.g.) ); R gb Selected from halophenyl (e.g.) ), halogenated C 1-3 Alkylphenyl (e.g.) ), halogenated C 1-3 Alkoxyphenyl (e.g.) ), cyanophenyl (e.g.) ), benzothiazolyl (e.g.) ), methylpyrazolyl (e.g.) ); Preferably, G is selected from 6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that, The compound shown in formula (III) is selected from the following structures: Among them, G and R a Each of them independently possesses the definition described in any one of claims 1-5; Preferably, the compound represented by formula (III) is selected from the following structures: Where Z is selected from CH2 or O, R a and R g Each of them independently possesses the definition described in any one of claims 1-5; Preferably, the compound represented by formula (III) is selected from the following structures: Among them, R a and R g1 Each has independently the definition described in any one of claims 1-5.

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

8. A method for preparing the compound of formula (III) according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, comprising the following steps: Compound a reacts with compound b to give the compound of formula (III) or a pharmaceutically acceptable salt thereof; Wherein, B, E, L, and G independently have the definitions described in any one of claims 1-7; X is selected from leaving groups, such as halogens or OH; Preferably, the preparation method can be carried out in the presence of an alkali, wherein the alkali is selected from inorganic alkalis, such as at least one selected from sodium carbonate, potassium carbonate, and cesium carbonate.

9. A pharmaceutical composition comprising the compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; Alternatively, a pharmaceutical composition comprising the compounds shown in C2-1 to C2-12 below or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients; Alternatively, an antibody / peptide-drug conjugate comprising an antibody or peptide, and a compound of formula (III) of any one of claims 1-7 or a pharmaceutically acceptable salt thereof as a payload, wherein the compound of formula (III) of the payload or a pharmaceutically acceptable salt thereof is directly bonded or bonded via a linker to the antibody or peptide. Alternatively, an antibody / peptide-drug conjugate comprising an antibody or peptide, and a compound shown in C2-1 to C2-12 as a payload, or a pharmaceutically acceptable salt thereof, wherein the compound shown in C2-1 to C2-12 as a payload or a pharmaceutically acceptable salt thereof is directly bonded to the antibody or peptide or via a linker. Preferably, the antibody / peptide-drug conjugate is a protein-drug conjugate; Preferably, the peptide has at least 80% amino acid sequence identity with glucagon-like peptide-1 (GLP-1); preferably, the peptide is glucagon-like peptide-1. Preferably, the connector can be one known in the art, such as an acid-cleavable connector, an enzyme-cleavable connector, a peptide-cleavable connector, and a connector containing a disulfide group.

10. The use of a pharmaceutical composition of any one of the compounds of claims 1-7 or a pharmaceutically acceptable salt thereof, or the compounds shown in C2-1 to C2-12 of claims 9 or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating and / or preventing diseases associated with NMDA receptors; Preferably, the drug is an NMDA receptor antagonist; Preferably, the NMDA receptor is a tetramer, and the subunits in the tetramer are selected from combinations of GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B subunits, wherein two subunits are GluN1, and the other two subunits are selected from any two combinations of GluN2A, GluN2B, GluN2C, GluN2D, GluN3A, and GluN3B, for example, NMDA receptors composed of combinations 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, and GluN1 / GluN2B / GluN3A; Preferably, the diseases associated with NMDA receptors are selected from central nervous system diseases or neurodegenerative diseases, such as stroke, depression, epilepsy, Alzheimer's disease, pain, attention deficit disorder, schizophrenia, anxiety disorder, brain injury, Parkinson's disease, Huntington's disease, etc.

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