Amino-substituted fused ring compounds and uses thereof

Abstract

The application discloses an amino-substituted fused ring compound shown in formula I and application thereof, and belongs to the technical field of medicinal chemistry. The amino-substituted fused ring compound provided by the application can be used as a P2X7 receptor antagonist, and can be used for preventing and treating P2X7R related diseases, has the advantages of high activity, and has excellent pharmacokinetic properties, excellent safety and potential of brain penetration.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a class of amino-substituted cyclic compounds and their uses. Background Technology

[0002] The P2X7 receptor (P2X7R) belongs to the P2X subtype of the purinergic receptor family and is a ligand-gated ion channel activated by extracellular ATP. Its structural features include three homologous or heterologous subunits, each containing two transmembrane domains (TM1 and TM2), an extracellular ATP-binding site, and a relatively long intracellular C-terminal domain. Unlike other P2X receptors, P2X7R can form non-selective macropores with a diameter of approximately 3.5 nm under high ATP stimulation, significantly increasing cell membrane permeability and promoting the release of small molecules (such as the fluorescent dye YO-PRO-1) and inflammatory mediators. This receptor participates in innate immunity, inflammatory responses, and apoptosis through multiple signal transduction pathways and is widely expressed in dendritic cells, T cells, B cells, neutrophils, monocytes, and macrophages, with the highest expression in microglia of the central nervous system. Because P2X7R plays a key role in the activation of the NLRP3 inflammasome, thereby regulating the maturation and release of IL-1β, this receptor is believed to play an important role in a variety of inflammatory and central nervous system diseases, including rheumatoid arthritis, endotoxin shock, Crohn's disease, colitis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, depression, and neuropathic pain. Summary of the Invention

[0003] The purpose of this invention is to provide a class of amino-substituted cyclic compounds that can be used as P2X7 receptor antagonists to achieve highly selective and efficient prevention or treatment of diseases related to P2X7R function.

[0004] In a first aspect, the present invention provides a compound of Formula I or a pharmaceutically acceptable form thereof, wherein the structure of Formula I is as follows:

[0005]

[0006] Mode

[0007] in:

[0008] Ring A is selected from 6-10 aryl or 5-10 heteroaryl;

[0009] In ring A, the 5-10 membered heteroaryl group contains 1-3 heteroatoms selected from N, S, and O;

[0010] R1 is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, and C. 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 hydroxyl-substituted alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered halocycloalkyl groups, -NR 1a R 1b or -C(O)NHR 1c ;

[0011] R 1a Selected from hydrogen, deuterium, or C 1-4 Alkyl; R 1b Selected from hydrogen, deuterium, or C 1-4 Alkyl; R 1c Selected from hydrogen, deuterium, or C 1-4 alkyl;

[0012] n1 is selected from 0, 1, 2, 3 or 4;

[0013] Ring B is selected from substituted or unsubstituted 5-10 aryl or 5-10 membered heteroaryl rings;

[0014] In ring B, the 5-10 membered heteroaromatic ring contains 1-4 heteroatoms selected from N, S, and O, and contains at least one N;

[0015] In ring B, the substituents of the substituted 5-10 membered heteroaromatic ring are selected from deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl;

[0016] Structural unit Selected from the following groups:

[0017] , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , or ;

[0018] n4 is selected from 0, 1, 2, 3, or 4; n5 is selected from 0, 1, 2, 3, or 4;

[0019] R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl;

[0020] R 4a R 4c Independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl;

[0021] R 3b Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl;

[0022] R 4b Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl;

[0023] R 3b R 4b In this context, the 3-6 membered heterocyclic alkyl group and the 5-10 membered heteroaryl group contain 1-3 heteroatoms selected from N, S, and O;

[0024] R 3b R 4b In, the replaced C 1-6 Alkyl, substituted C 2-6 alkenyl, substituted C 2-6 alkynyl, substituted C 2-6 The substituents of the alkyl carbonyl group are independently selected from deuterium, cyano, hydroxyl, amino, halogen, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuteroxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl;

[0025] R 3b R 4b In this context, the substituents of the substituted 3-6 membered cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted 6-10 membered aryl, and substituted 5-10 membered heteroaryl are independently selected from deuterium, cyano, hydroxyl, amino, halogen, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuterated methoxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl.

[0026] The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs.

[0027] In some embodiments of the present invention, in the compound of Formula I above, ring A is selected from 6-10 aryl or 6-10 heteroaryl; in ring A, the 5-10 heteroaryl contains 1-2 heteroatoms selected from N, S, and O.

[0028] In some preferred embodiments of the present invention, in the compound of Formula I above, ring A is selected from phenyl, naphthyl, pyridyl, quinolinyl or isoquinolinyl.

[0029] In some preferred embodiments of the present invention, in the compound of Formula I above, ring A is selected from... , , , , or (The bonds in these structures are connected to ring B).

[0030] In some embodiments of the present invention, in the compound of Formula I above, R1 is selected from hydrogen, deuterium, cyano, hydroxyl, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered fluorocycloalkyl groups, -NR 1a R 1b or -C(O)NHR 1c ;R 1a Selected from hydrogen, deuterium, methyl, or ethyl; R 1b Selected from hydrogen, deuterium, methyl, or ethyl; R 1c Selected from hydrogen, deuterium, methyl or ethyl.

[0031] In some preferred embodiments of the present invention, in the above-mentioned compound of formula I, R1 is selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, N-methylamino, N,N-dimethylamino or -C(O)NHCH3.

[0032] In some preferred embodiments of the present invention, in the above-described compound of formula I, R1 is selected from hydrogen, fluorine, chlorine, methyl or fluoromethyl.

[0033] In some preferred embodiments of the present invention, in the compound of Formula I above, the structural unit Selected from the following groups:

[0034] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0035] In some embodiments of the present invention, in the compound of Formula I above, ring B is selected from the following groups:

[0036] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the upper bond is connected to ring A, and the lower bond is connected to the general formula NH).

[0037] n2 is selected from 0, 1, 2, 3, or 4; n3 is selected from 0, 1, 2, 3, or 4;

[0038] R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl;

[0039] R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl;

[0040] R 2c Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, 3-6 membered cycloalkyl or 3-6 membered halocycloalkyl.

[0041] In some embodiments of the present invention, in the compound of formula I above, R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 2c Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, 3-6 membered cycloalkyl or 3-6 membered fluorocycloalkyl.

[0042] In some preferred embodiments of the present invention, in the compound of formula I above, R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl; R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl; R 2c It is selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, cyclopropyl, cyclobutyl, fluorocyclopropyl or fluorocyclobutyl.

[0043] In some preferred embodiments of the present invention, in the compound of Formula I above, the structural unit Selected from the following groups:

[0044] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or (In these structures, the upper bond is connected to ring A, and the lower bond is connected to the general formula NH).

[0045] In some embodiments of the present invention, in the compound of formula I above, R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl;

[0046] R 4a R 4c Independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl;

[0047] R 3b Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, substituted or unsubstituted C 2-4 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl;

[0048] R 4b Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, substituted or unsubstituted C 2-4 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl;

[0049] R 3b R 4b In this context, the 3- to 6-membered heterocyclic alkyl groups are selected from... , , , , or ;

[0050] R 3b R 4b In this context, the 5-6 heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrroleyl, furanyl, thiophenyl, pyrazolyl, or oxazolyl;

[0051] R 3b R 4b In, the replaced C 1-4 Alkyl, substituted C 2-4 alkenyl, substituted C 2-4 alkynyl, substituted C 2-4The substituents of the alkyl carbonyl group are independently selected from deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuteroxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl;

[0052] R 3b R 4b In this context, the substituents of the substituted 3-6 membered cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted 6 membered aryl, and substituted 5-6 membered heteroaryl are independently selected from deuterium, cyano, hydroxy, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuterated methoxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl.

[0053] In some preferred embodiments of the present invention, in the compound of formula I above, R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, or fluorocyclobutyl;

[0054] R 4a R 4c It is independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl or fluorocyclobutyl;

[0055] R 3b Selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, acetyl, propionyl, fluoroacetyl, fluoropropionyl, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or ;

[0056] R 4b Selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, acetyl, propionyl, fluoroacetyl, fluoropropionyl, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0057] In some preferred embodiments of the present invention, in the compound of Formula I above, the structural unit Selected from the following groups:

[0058] , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , or .

[0059] This invention also provides some specific compounds selected from:

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076] .

[0077] In a second aspect, the present invention provides a pharmaceutical composition having the aforementioned compound of Formula I or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, nitrogen oxide, isotope label, metabolite or prodrug as the active ingredient, supplemented by a pharmaceutically acceptable carrier.

[0078] A further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, the method comprising combining any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, with one or more pharmaceutically acceptable carriers.

[0079] The pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable carriers, and examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (2005).

[0080] Pharmaceutical compositions can be administered in any form, as long as they achieve the purpose of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms depending on the route of administration.

[0081] In other embodiments, the administration of the compounds or pharmaceutical compositions of the present invention may be combined with other treatment methods. These other treatment methods may be selected from, but are not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0082] The present invention also relates to a pharmaceutical formulation comprising any compound of formula I or a pharmaceutically acceptable form thereof, or a mixture thereof, as an active ingredient, or the pharmaceutical composition of the present invention.

[0083] In some embodiments, the formulation is in the form of a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0084] Thirdly, the present invention provides the use of the aforementioned Formula I compound, and related specific compounds or pharmaceutically acceptable forms thereof, or the use of the pharmaceutical compositions of the present invention in the preparation of P2X7 receptor antagonists.

[0085] The present invention provides the use of the aforementioned Formula I compounds, and related specific compounds or pharmaceutically acceptable forms thereof, or the pharmaceutical compositions of the present invention in the preparation of medicaments for the prevention and / or treatment of P2X7R-related diseases.

[0086] The present invention provides a method for preventing or treating P2X7R-related diseases, the method comprising administering a compound of formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the present invention, to an individual in need of such treatment.

[0087] The present invention provides a method for preventing or treating P2X7R-related diseases by combining a compound of Formula I or a pharmaceutically acceptable form thereof, or a pharmaceutical composition thereof, with other treatment methods including, but not limited to, radiotherapy, chemotherapy, immunotherapy, or combinations thereof.

[0088] In some embodiments, the P2X7 receptor antagonist is a drug for the prevention and / or treatment of P2X7R-related diseases, which include inflammation and inflammation-related diseases, kidney disease, respiratory diseases, cancer, pain disorders, central nervous system diseases, radiation-induced brain injury, radiation-induced cerebral ischemia, myocardial injury, diabetes, obesity, gout, depression, lupus erythematosus, atherosclerosis, or allergic asthma.

[0089] In some preferred embodiments, the inflammation and inflammation-related diseases are rheumatoid arthritis, endotoxic shock, Crohn's disease, or colitis.

[0090] In some preferred embodiments, the pain condition is headache, migraine, trigeminal neuralgia, atypical facial pain, joint pain, bone pain, neuropathic pain syndrome, or pain caused by cancer invasion.

[0091] In some preferred embodiments, the central nervous system disease is Alzheimer's disease, Parkinson's syndrome, epilepsy, cerebral arteriosclerosis, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, or other demyelinating syndromes.

[0092] The beneficial effects of this invention are:

[0093] This invention provides a novel class of highly active P2X7 receptor antagonist compounds and their uses, which can achieve at least one of the following technical effects: (1) highly efficient and selective P2X7 receptor inhibitory activity; (2) excellent pharmacokinetic properties (e.g., good bioavailability, suitable half-life and duration of action); (3) the P2X7 receptor antagonists of this invention are surprisingly able to cross the blood-brain barrier (BBB) ​​and can be used to treat diseases and conditions occurring in central nervous system tissues (e.g., the brain and spinal cord); (4) the compounds of this invention exhibit significant preventive and therapeutic effects in various animal models of P2X7 receptor-related diseases.

[0094] Terminology definition:

[0095] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0096] In this invention, the terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient can be interpreted as indicating that the composition comprises "one or more" pharmaceutically acceptable excipients.

[0097] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein (in the form of “about a to b”, or equivalently, “approximately a to b”, or equivalently, “about ab”) should be understood to represent each numerical value and range encompassed within a wider range.

[0098] For example, the expression "C" 1-4 "This should be understood as encompassing any subrange and each point value, such as C." 2-4 C 3-4 C 1-2 C 1-3 C 1-4 And so on, as well as C1, C2, C3, C4, etc. For example, the expression "6-10 yuan" should be understood as covering any subrange and each point value within it, such as 6-7 yuan, 6-8 yuan, 6-7 yuan, etc., and 6, 7, 8, 9, 10 yuan, etc.

[0099] In this invention, unless otherwise stated, halogen refers to fluorine, chlorine, bromine or iodine.

[0100] In this invention, unless otherwise stated, "alkyl" includes straight-chain or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, C1-4 in "C1-4 alkyl" refers to a group containing 1, 2, 3, or 4 carbon atoms arranged in a straight-chain or branched form.

[0101] In this invention, unless otherwise stated, “cycloalkyl,” “carbocyclic,” or “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group. Common cycloalkyl groups include (but are not limited to) monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene, etc.; or bicyclic cycloalkyl groups, including fused rings, bridged rings, or spirocyclic groups, such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, bicyclic [5.2.0]nonyl, decahydronaphthyl, etc. For example, “C 3-12 cycloalkyl” refers to a cycloalkyl group having 3-12 cyclic carbon atoms (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12). The cycloalkyl or cycloalkylene groups in this invention may optionally be substituted by one or more substituents described in this invention.

[0102] In this invention, unless otherwise stated, "heterocyclic alkyl," "heterocyclic alkylene," or "heterocycle" refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic, e.g., fused, bridged, or spirocyclic) non-aromatic group whose ring atoms consist of a carbon atom and at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl groups can be linked to the remainder of the molecule via any one ring atom, provided valence requirements are met. For example, "3-8 membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 3 to 8 ring atoms. Common heterocyclic alkyl groups include (but are not limited to) ethylene oxide, oxocyclobutane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, homopiperazinyl, sulfolane, etc. The heterocyclic alkyl, heterocyclic alkylene, or heterocycle in this invention may optionally be substituted with one or more substituents (e.g., oxo groups) described in this invention.

[0103] In this invention, unless otherwise stated, "halogenated alkyl" refers to the alkyl group described above, wherein one or more hydrogen atoms are replaced by a halogen. For example, the term "C" 1-6 "Halogenated alkyl" refers to a C-aryl group optionally substituted with one or more (e.g., 1-3) halogens. 1-6 Alkyl groups. Those skilled in the art will understand that when there is more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of alkyl halogens include, for example, -CH2F, -CHF2, -CF3, -CCl3, -C2F5, -C2Cl5, -CH2CF3, -CH2Cl, or -CH2CH2CF3. The alkyl halogens in this invention are optionally substituted with one or more substituents described in this invention.

[0104] In this invention, unless otherwise stated, "deuterated alkyl" refers to the "alkyl" group described above, in which hydrogen atoms are replaced by deuterium, and the number of hydrogen atoms replaced is any integer from 1 to the maximum number of hydrogen atoms that the group can be substituted. For example, the term "deuterated methyl" refers to a methyl group optionally substituted with one or more deuterium atoms, and the number of hydrogen atoms replaced can be 1, 2, or 3. Those skilled in the art will understand that when there is more than one deuterium substituent, the deuterium can be located on the same or different C atoms.

[0105] In this invention, unless otherwise stated, "fluoroalkyl" refers to the "alkyl" group described above, in which hydrogen atoms are replaced by fluorine, and the number of hydrogen atoms replaced is any integer from 1 to the maximum number of hydrogen atoms that the group can be substituted. For example, the term "fluoromethyl" refers to a methyl group optionally replaced by one or more fluorine atoms, and the number of hydrogen atoms replaced can be 1, 2, or 3. Those skilled in the art will understand that when there is more than one fluorine substituent, it can be located on the same or different C atoms.

[0106] In this invention, unless otherwise stated, "haloalkoxy" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, the number of hydrogen atoms being replaced being any integer from 1 to the maximum number of hydrogen atoms that can be substituted in the group. The halogen is selected from fluorine, chlorine, bromine, or iodine. Those skilled in the art will understand that when there are more than one halogen substituent, the halogens can be the same or different, and can be located on the same or different C atoms. Examples of haloalkoxy groups are -OCH2F, -OCHF2, -OCHCl2, -OCH2CF3, etc.

[0107] In this invention, unless otherwise stated, "alkenyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C=C double bond. For example, "C..." 2-4 "Alkenyl" refers to an alkenyl group having 2 to 4 carbon atoms. Common alkenyl groups include (but are not limited to) vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, n-octenyl, n-decenyl, etc. The alkenyl groups in this invention may optionally be substituted by one or more substituents described in this invention.

[0108] In this invention, unless otherwise stated, "alkynyl" refers to a straight-chain or branched aliphatic hydrocarbon group having at least one C≡C triple bond. For example, "C 2-4 "Alynyl" refers to an alkynyl group having 2 to 4 carbon atoms. Common alkynyl groups include (but are not limited to) ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. The alkynyl group in this invention may optionally be substituted by one or more substituents described in this invention.

[0109] In this invention, unless otherwise stated, "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (e.g., bicyclic) aromatic group or aromatic ring having a conjugated π-electron system. As used herein, the term "C" refers to... 6-10 "Aryl" refers to an aromatic group containing 6-10 carbon atoms. Examples include, but are not limited to, phenyl and naphthyl groups. The aryl or aromatic ring in this invention may optionally be substituted by one or more substituents described in this invention.

[0110] In this invention, unless otherwise stated, "heteroaryl" or "heteroary ring" refers to an aromatic ring having a conjugated π-electron system, wherein one or more (e.g., 1, 2, or 3) ring atoms are heteroatoms selected from N, O, P, and S, and the remaining ring atoms are C. A heteroaryl or heteroary ring can be characterized by the number of ring atoms. For example, a 5-12 membered heteroaryl may contain 5-12 (e.g., 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, particularly 5, 6, 9, or 10 ring atoms. Examples of heteroaryl groups include, for example, thiophene, furanyl, pyrrole, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; the term also covers cases where the heteroaryl or heteroary ring may optionally be further fused to an aryl or heteroaryl ring to form a fused ring. In this invention, the heteroaryl or heterocyclic group may optionally be substituted by one or more substituents described in this invention.

[0111] In this invention, unless otherwise stated, "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents. Typical substituents include, but are not limited to, halogens (F, Cl, Br, or I), hydroxyl groups, amino groups, and C. 1-8 Alkyl, C 3-7 Cycloalkyl, -OR', -SR', =O, =S, -C(O)R', -C(S)R', =NR', -C(O)OR', -C(S)OR', -NR' R'', -C(O)NR' R'', cyano, nitro, -S(O)2R', -OS(O)2OR', -OS(O)2R', -OP(O)(OR')(OR''); wherein R' and R'' are independently selected from -H, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups. In some embodiments, the substituents are independently selected from groups comprising -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH3, -SC2H5, formaldehyde, -C(O)CH3, cyano, nitro, -CF3, -OCF3, amino, dimethylamino, methylthio, sulfonyl, and acetyl groups.

[0112] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 13 C and 14 C); isotopes of chlorine (e.g., 37Cl); isotopes of iodine (e.g., 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 34 S).

[0113] In this invention, "polymorph" refers to different solid crystalline phases resulting from the presence of two or more different molecular arrangements in the solid state of certain compounds of this invention. Some compounds of this invention may exist in more than one crystal form, and this invention aims to include various crystal forms and mixtures thereof. Typically, crystallization produces solvates of the compounds of this invention. The term "solvate" as used in this invention refers to an aggregate comprising one or more molecules of the compound of this invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of this invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of this invention can form true solvates, but in some cases, they may also remain only as indeterminate water or a mixture of water and a portion of indeterminate solvent. The compounds of this invention can react in a solvent or precipitate or crystallize from a solvent. The solvates of the compounds of this invention are also included within the scope of this invention. This invention also covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0114] Unless otherwise specified, the compounds in this invention include racemic mixtures, single enantiomers, mixtures of diastereomers, and single diastereomers.

[0115] In this invention, "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. It is to be understood that the scope of this invention covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0116] In this invention, pharmaceutically acceptable salts include their acid addition salts and base addition salts. Suitable acid addition salts are formed by acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed by bases that form pharmaceutically acceptable salts. A review of suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences,” Mack Publishing Company, Easton, Pa., (2005); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of this invention are known to those skilled in the art. “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecanoate, glycolate, gluconate, lactate, sebate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylic acid, and naphthalenedisulfonate. These salts can be prepared by methods known in this patent. "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amines, secondary amines, and tertiary amines; substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in this patent.

[0117] In this invention, unless otherwise stated, "ester" refers to an ester derived from the compounds described herein, including physiologically hydrolyzable esters (compounds of this invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of this invention may themselves be esters.

[0118] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0119] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form nitrogen oxides because nitrogen requires available lone pairs of electrons to be oxidized. Those skilled in the art will identify nitrogen-containing heterocycles capable of forming nitrogen oxides. They will also recognize that tertiary amines can form nitrogen oxides. Synthetic methods for preparing nitrogen oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (mCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane.

[0120] In this invention, "metabolite" refers to a substance formed in the body upon administration of a compound of the present invention. Metabolites of the compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of the present invention, including compounds obtained by methods that expose the compounds of the present invention to mammals for a time sufficient to produce their metabolites.

[0121] In this invention, a "prodrug" refers to certain derivatives of the compounds of the invention that, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the desired therapeutically active compounds. Further information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with portions known to those skilled in the art as "pro-moiety" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0122] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, promote the absorption of the active ingredient, and thereby exert its bioactivity.

[0123] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that is permitted by the relevant government regulatory authority or is acceptable for human or livestock use.

[0124] As used herein, the terms “drug combination,” “drug co-administration,” “combination therapy,” “administration of other treatments,” and “administration of other therapeutic agents” refer to pharmaceutical treatments achieved by mixing or combining more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or dosage form. The term “non-fixed combination” refers to the simultaneous, combined, or sequential administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity at variable intervals. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0125] "Effective dose" or "therapeutic effective dose" refers to the amount of the compound of the present invention that will elicit the desired biological response in a subject. It can vary depending on the compound, the disease and its severity, and the age and weight of the subject to be treated. In some implementations, examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1000 mg, 2-1000 mg, 3-1000 mg, 4-1000 mg, 5-1000 mg, 10-1000 mg, 20-1000 mg, 25-1000 mg, 30-1000 mg, 40-1000 mg, 50-1000 mg, 60-1000 mg, 70-1000 mg, 75-1000 mg, 80-1000 mg, 90-1000 mg, 100-1000 mg, 200-900 mg, 200-800 mg, 200-700 mg, 200-600 mg, 200-500 mg, 300-500 mg, etc.

[0126] In this invention, unless otherwise stated, "treatment" means reversing, alleviating, or inhibiting the progression of a disease or condition or one or more symptoms of such a disease or condition, or preventing such a disease or condition or one or more symptoms of such a disease or condition.

[0127] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention. Detailed Implementation

[0128] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they shall be performed in accordance with the techniques or conditions described in the literature in the art or in accordance with the product manual.

[0129] The general synthetic method is described below: Compounds 1 to 28 are prepared according to this method.

[0130]

[0131] Example 1: Synthesis of N-(1-(2,3-dichlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6,7,8-tetrahydroquinoline-5-amine (1).

[0132]

[0133] Step 1: Synthesis of 1-(2,3-dichlorophenyl)-1H-1,2,4-triazole (Intermediate 1). Formamide (50 mL) was added to substituted phenylhydrazine (5 g, 1.0 eq), and the reaction mixture was heated at 140 °C for 12 hours. After cooling to room temperature, the reaction mixture was slowly poured into 100 mL of water. The reaction mixture was extracted three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, and then dehydrated with anhydrous sodium sulfate. The crude intermediate was concentrated under reduced pressure to obtain the crude product. The crude product was mixed with silica gel and eluted with a gradient of petroleum ether / ethyl acetate (100:1~10:1) to purify intermediate 1, yielding 70%. LC-MS: ESI [M+H] + =214.1, 216.1.

[0134] Step 2: Synthesis of 5-bromo-1-(2,3-dichlorophenyl)-1H-1,2,4-triazole (Intermediate 2). Intermediate 1 (2 g, 1.0 eq) was dissolved in ultradry carbon tetrachloride (30 mL), and NBS (2.0 eq) and a catalytic amount of phthaloyl peroxide (10%) were added at room temperature. The reaction mixture was refluxed for 12 hours, cooled, filtered through diatomaceous earth, and the filter cake was washed with warm carbon tetrachloride (10 mL). The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc = 50:1~5:1) to obtain intermediate 2 in 35% yield. LC-MS: ESI [M+H] + =292.0, 294.0, 296.0.

[0135] Step 3: Synthesis of 7,8-dihydroquinoline-5(6H)-ketooxime (intermediate 3). 7,8-Dihydroquinoline-5(6H)-one (2 g, 1.0 eq) was dissolved in anhydrous ethanol (30 mL). Hydroxylamine aqueous solution (50% aqueous solution, 10 eq) and a catalytic amount of acetic acid (20%) were added at room temperature. The reaction system was heated to 85 °C and refluxed for 6 hours. After the reaction was completed by TLC monitoring, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH / DCM = 10:1) to obtain 7,8-dihydroquinoline-5(6H)-ketooxime (intermediate 3) in 87% yield. LC-MS: ESI [M+H] + =148.1.

[0136] Step 4: Synthesis of 5,6,7,8-tetrahydroquinoline-5-amine (Intermediate 4). 7,8-Dihydroquinoline-5(6H)-ketooxime (1 g, 1 eq) was dissolved in methanol (20 mL), and palladium on carbon (10%) was added at room temperature, followed by three purgings with a hydrogen balloon. The reaction was carried out overnight under hydrogen conditions. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the organic phase was concentrated under reduced pressure to obtain the crude product 5,6,7,8-tetrahydroquinoline-5-amine, which could be used directly in the next step without further purification. LC-MS: ESI [M+H]+ =149.1.

[0137] Step 5: Synthesis of N-(1-(2,3-dichlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6,7,8-tetrahydroquinoline-5-amine (compound 1). Intermediate 2 (500 mg, 1 eq), intermediate 4 (1 eq), Pd2(dba)3 (10%), cesium carbonate, and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene were added sequentially to a 35 mL sealed tube. Finally, 10 mL of toluene solution was added, the mixture was purged with nitrogen three times, and the temperature was raised to 105 °C. The reaction was allowed to proceed overnight. After the reaction was completed by TLC monitoring, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and washed twice with dichloromethane. The organic phase was concentrated under reduced pressure and then purified by silica gel column chromatography (MeOH / DCM = 100:1~10:1) to obtain N-(1-(2,3-dichlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6,7,8-tetrahydroquinoline-5-amine, with a yield of 43%.

[0138] LC-MS:ESI[M+H] + =360.1, 362.1. 1 H NMR (400 MHz, Chloroform-d) δ 8.33 (dd,J = 4.7, 1.7 Hz, 1H), 7.73 – 7.63 (m, 3H), 7.54 (dd, J = 8.0, 1.8 Hz, 1H), 7.38 (dd, J = 8.0, 1.8 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.06 (dd, J = 7.9,4.7 Hz, 1H), 5.24 – 5.10 (m, 1H), 4.37 (d, J = 8.6 Hz, 1H), 2.84 (t, J = 6.1Hz, 2H), 2.22 – 2.10 (m, 1H), 1.89 (t, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 157.38, 154.92, 150.41, 148.59, 136.69, 135.31, 134.76,132.27, 131.99, 131.22, 128.25, 128.19, 121.55, 52.06, 32.14, 29.70, 19.51.

[0139] Example 2

[0140]

[0141] The synthesis method was the same as that used for compound 1, resulting in compound 2. 1 H NMR (400 MHz, Chloroform-d)δ 8.39 (dd, J = 4.8, 1.7 Hz, 1H), 7.77 – 7.67 (m, 2H), 7.42 – 7.36 (m, 1H),7.31 – 7.26 (m, 2H), 7.09 (dd, J = 7.9, 4.7 Hz, 1H), 5.24 – 5.15 (m, 1H), 4.29 (d, J = 8.7 Hz, 1H), 2.89 (t, J = 6.0 Hz, 2H), 2.25 – 2.12 (m, 1H), 1.96– 1.88 (m, 3H).

[0142] Example 3

[0143]

[0144] The synthesis method was the same as that used for compound 1, resulting in compound 3. 1 H NMR (400 MHz, Chloroform-d)δ 8.33 (dd, J = 4.8, 1.7 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.47 – 7.38 (m, 2H),7.20 (td, J = 8.1, 1.5 Hz, 1H), 7.08 (dd, J = 7.8, 4.7 Hz, 1H), 5.23 – 5.15(m, 1H), 4.76 (d, J = 8.6 Hz, 1H), 2.84 (t, J = 6.2 Hz, 2H), 2.23 – 2.13 (m,1H), 1.97 – 1.87 (m, 3H).

[0145] Example 4

[0146]

[0147] The synthesis method was the same as that used for compound 1, resulting in compound 4. 1H NMR (400 MHz, Chloroform-d)δ 8.35 (dd, J = 4.8, 1.8 Hz, 1H), 7.76 – 7.67 (m, 2H), 7.53 – 7.48 (m, 1H),7.48 – 7.43 (m, 1H), 7.43 – 7.36 (m, 2H), 7.07 (dd, J = 7.8, 4.7 Hz, 1H), 5.24 – 5.11 (m, 1H), 4.38 (d, J = 8.8 Hz, 1H), 2.86 (t, J = 6.1 Hz, 2H), 2.25– 2.10 (m, 1H), 1.99 – 1.82 (m, 3H).

[0148] Example 5

[0149]

[0150] The synthesis method was the same as that used for compound 1, resulting in compound 5. 1 H NMR (400 MHz, Chloroform-d)δ 8.38 (dd, J = 4.9, 1.7 Hz, 1H), 7.71 (d, J = 6.9 Hz, 2H), 7.55 – 7.50 (m,1H), 7.48 – 7.45 (m, 1H), 7.44 – 7.37 (m, 2H), 7.08 (dd, J = 7.8, 4.7 Hz,1H), 5.24 – 5.12 (m, 1H), 4.28 (d, J = 8.8 Hz, 1H), 2.89 (t, J = 6.1 Hz, 2H), 2.24 – 2.14 (m, 1H), 1.98 – 1.86 (m, 3H).

[0151] Example 6

[0152]

[0153] The synthesis method was the same as that used for compound 1, resulting in compound 6. 1H NMR (400 MHz, Chloroform-d)δ 8.35 (dd, J = 4.9, 1.7 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.51 (d, J = 2.2 Hz,1H), 7.43 – 7.34 (m, 2H), 7.08 (dd, J = 7.9, 4.8 Hz, 1H), 5.23 – 5.11 (m,1H), 4.39 (d, J = 8.7 Hz, 1H), 2.85 (t, J = 6.2 Hz, 2H), 2.21 – 2.13 (m, 1H), 1.98 – 1.87 (m, 3H).

[0154] Example 7

[0155]

[0156] The synthesis method was the same as that used for compound 1, resulting in compound 7. 1 H NMR (400 MHz, Chloroform-d)δ 8.36 (dd, J = 4.8, 1.7 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.71 (s, 1H), 7.65 (td, J = 8.0, 7.5, 2.1 Hz, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.08 (dd, J =7.8, 4.7 Hz, 1H), 5.24 – 5.11 (m, 1H), 4.14 (d, J = 8.7 Hz, 1H), 2.86 (t, J =6.1 Hz, 2H), 2.21 – 2.10 (m, 1H), 1.95 – 1.81 (m, 3H).

[0157] Example 8

[0158]

[0159] The synthesis method was the same as that used for compound 1, resulting in compound 8. 1H NMR (400 MHz, Chloroform-d)δ 8.40 (dd, J = 4.7, 1.7 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.35 – 7.31 (m, 2H),7.19 (dd, J = 8.1, 1.9 Hz, 1H), 7.09 (dd, 1.97 – 1.86 (m, 3H).

[0160] Example 9

[0161]

[0162] The synthesis method was the same as that used for compound 1, resulting in compound 9. 1 H NMR (400 MHz, Chloroform-d)δ 8.29 (dd, J = 4.9, 1.8 Hz, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.70 (d, J =7.6 Hz, 1H), 7.66 – 7.59 (m, 2H), 7.06 (dd, J = 7.9, 4.7 Hz, 1H), 5.24 – 5.14(m, 1H), 4.63 (d, J = 8.6 Hz, 1H), 2.79 (t, J = 6.2 Hz, 2H), 2.23 – 2.12 (m,1H), 1.98 – 1.85 (m, 3H).

[0163] Example 10

[0164]

[0165] The synthesis method was the same as that used for compound 1, resulting in compound 10. 1H NMR (400 MHz, Chloroform-d)δ 8.32 (dd, J = 4.8, 1.7 Hz, 1H), 7.74 – 7.67 (m, 2H), 7.48 (d, J = 2.4 Hz,1H), 7.42 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 8.7, 2.4 Hz, 1H), 7.08 (dd, J =7.9, 4.7 Hz, 1H), 5.24 – 5.13 (m, 1H), 4.61 (d, J = 8.6 Hz, 1H), 2.82 (t, J =6.2 Hz, 2H), 2.22 – 2.12 (m, 1H), 2.00 – 1.85 (m, 3H).

[0166] Example 11

[0167]

[0168] The synthesis method was the same as that used for compound 1, resulting in compound 11. 1 H NMR (400 MHz, Chloroform-d)δ 8.41 (dd, J = 4.8, 1.7 Hz, 1H), 7.75 – 7.71 (m, 1H), 7.67 (s, 1H), 7.46 –7.38 (m, 4H), 7.12 (dd, J = 7.8, 4.8 Hz, 1H), 5.25 – 5.16 (m, 1H), 4.62 (d, J= 8.6 Hz, 1H), 3.00 – 2.86 (m, 2H), 2.23 – 2.15 (m, 1H), 2.00 – 1.89 (m, 3H).

[0169] Example 12

[0170]

[0171] The synthesis method was the same as that used for compound 1, resulting in compound 12. 1H NMR (400 MHz, Chloroform-d)δ 8.39 (dd, J = 4.9, 1.7 Hz, 1H), 7.70 (s, 1H), 7.68 (dd, J = 7.7, 1.7 Hz,1H), 7.16 – 7.11 (m, 2H), 7.11 – 7.04 (m, 2H), 5.20 – 5.11 (m, 1H), 4.11 (d,J = 9.0 Hz, 1H), 2.89 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H), 2.19 – 2.13 (m, 1H),2.10 (s, 3H), 1.94 – 1.84 (m, 3H).

[0172] Example 13

[0173]

[0174] The synthesis method was the same as that used for compound 1, resulting in compound 13. 1 H NMR (400 MHz, Chloroform-d)δ 8.42 (dd, J = 4.8, 1.7 Hz, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 1H), 7.67 (s,1H), 7.35 (t, J = 8.2 Hz, 1H), 7.12 (dd, J = 7.9, 4.7 Hz, 1H), 7.03 – 6.98 (m, 2H), 6.92 – 6.86 (m, 1H), 5.25 – 5.16 (m, 1H), 4.72 (d, J = 8.7 Hz, 1H), 3.81 (s, 3H), 2.99 – 2.85 (m, 2H), 2.27 – 2.13 (m, 1H), 2.01 – 1.86 (m, 3H).

[0175] Example 14

[0176]

[0177] The synthesis method was the same as that used for compound 1, resulting in compound 14. 1H NMR (400 MHz, Chloroform-d)δ 8.36 (dd, J = 4.8, 1.8 Hz, 1H), 7.83 – 7.79 (m, 1H), 7.75 (dt, J = 7.9, 1.4Hz, 1H), 7.71 – 7.64 (m, 2H), 7.63 – 7.57 (m, 2H), 7.11 (dd, J = 7.9, 4.8 Hz,1H), 5.27 – 5.15 (m, 1H), 4.84 (d, J = 8.6 Hz, 1H), 2.88 (t, J = 6.0 Hz, 2H), 2.26 – 2.16 (m, 1H), 1.98 – 1.87 (m, 3H).

[0178] Example 15

[0179]

[0180] The synthesis method was the same as that used for compound 1, resulting in compound 15. 1 H NMR (400 MHz, Chloroform-d)δ 8.39 (dd, J = 4.9, 1.7 Hz, 1H), 7.72 (s, 1H), 7.68 (dd, J = 7.9, 1.7 Hz,1H), 7.25 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.7 Hz, 1H), 7.13 – 7.06 (m, 2H), 5.21 – 5.11 (m, 1H), 4.10 (d, J = 9.0 Hz, 1H), 2.89 (t, J = 6.2 Hz, 2H), 2.31(s, 3H), 2.21 – 2.13 (m, 1H), 2.00 (s, 3H), 1.94 – 1.80 (m, 3H).

[0181] Example 16

[0182]

[0183] The synthesis method was the same as that used for compound 1, resulting in compound 16. 1H NMR (400 MHz, Chloroform-d)δ 8.29 (dd, J = 4.9, 1.6 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.82 (s, 1H), 7.64 (d,J = 7.9 Hz, 1H), 7.58 – 7.49 (m, 5H), 7.00 (dd, J = 7.9, 4.8 Hz, 1H), 5.23 –5.13 (m, 1H), 4.27 (d, J = 8.9 Hz, 1H), 2.88 – 2.69 (m, 2H), 2.20 – 2.10 (m,1H), 1.92 – 1.72 (m, 3H).

[0184] Example 17

[0185]

[0186] The synthesis method was the same as that used for compound 1, resulting in compound 17. 1 H NMR (400 MHz, Chloroform-d)δ 7.83 (d, J = 2.6 Hz, 1H), 7.57 (d, J = 4.8 Hz, 1H), 7.50 (dd, J = 4.9, 1.7Hz, 1H), 7.03 – 6.93 (m, 1H), 6.90 – 6.81 (m, 2H), 6.58 – 6.47 (m, 1H), 6.23 (dd, J = 7.9, 4.7 Hz, 1H), 4.41 – 4.30 (m, 1H), 4.23 (d, J = 8.4 Hz, 1H), 2.01 (t, J = 6.1 Hz, 2H), 1.40 – 1.26 (m, 1H), 1.17 – 0.99 (m, 3H).

[0187] Example 18

[0188]

[0189] The synthesis method was the same as that used for compound 1, resulting in compound 18. 1H NMR (400 MHz, Chloroform-d)δ 8.40 (dd, J = 4.7, 1.9 Hz, 1H), 7.75 (dd, J = 7.8, 1.7 Hz, 1H), 7.67 (d, J= 1.4 Hz, 1H), 7.53 – 7.46 (m, 1H), 7.41 (dd, J = 7.2, 1.6 Hz, 2H), 7.24 –7.18 (m, 1H), 7.12 (dd, J = 7.8, 4.7 Hz, 1H), 5.27 – 5.17 (m, 1H), 4.74 (d, J= 8.4 Hz, 1H), 3.01 – 2.82 (m, 2H), 2.30 – 2.15 (m, 1H), 2.01 – 1.87 (m, 3H).

[0190] Example 19

[0191]

[0192] The synthesis method was the same as that used for compound 1, resulting in compound 19. 1 H NMR (400 MHz, Chloroform-d)δ 8.30 (dd, J = 4.8, 1.7 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.73 (s,1H), 7.67 (dd, J = 8.0, 1.7 Hz, 2H), 7.51 (t, J = 8.0 Hz, 1H), 7.06 (dd, J =7.9, 4.8 Hz, 1H), 5.18 (dt, J = 9.0, 5.5 Hz, 1H), 4.54 (s, 1H), 2.81 (t, J =6.2 Hz, 2H), 2.23 – 2.12 (m, 2H), 1.98 – 1.81 (m, 3H).

[0193] Example 20

[0194]

[0195] The synthesis method was the same as that used for compound 1, resulting in compound 20. 1H NMR (400 MHz, Chloroform-d)δ 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.19 – 8.14 (m, 1H), 7.82 – 7.77 (m, 1H),7.73 (s, 1H), 7.69 (s, 1H), 7.60 – 7.52 (m, 2H), 7.39 (dd, J = 8.1, 1.5 Hz,1H), 7.32 (dd, J = 8.5, 4.2 Hz, 1H), 7.26 (dd, J = 7.9, 1.6 Hz, 1H), 7.11 (t,J = 8.0 Hz, 1H).

[0196] Example 21

[0197]

[0198] The synthesis method was the same as that used for compound 1, resulting in compound 21. 1 H NMR (400 MHz, Chloroform-d)δ 8.03 (dd, J = 4.9, 1.9 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J = 7.4, 2.3 Hz,1H), 7.41 – 7.30 (m, 3H), 7.07 (d, J = 8.3 Hz, 1H), 6.50 – 6.42 (m, 2H), 6.37 (dd, J = 8.3, 2.4 Hz, 1H), 5.04 (q, J = 5.5 Hz, 1H), 4.87 – 4.66 (m, 2H), 4.13 (d, J = 7.1 Hz, 1H), 3.77 (d, J = 2.9 Hz, 6H), 3.43 – 3.28 (m, 2H), 2.25 – 2.14 (m, 1H), 2.13 – 2.03 (m, 1H).

[0199] Example 22

[0200]

[0201] Compound 21 (1 eq) was added to 15 mL of methanol, and dioxane hydrochloride solution (4 M, 5 eq) was added under ice bath conditions. The mixture was stirred for 5 hours at room temperature. After the reaction was completed, the pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 22. 1H NMR (400 MHz, Chloroform-d) δ 7.81 (dd, J = 4.9, 1.8 Hz, 1H), 7.74 – 7.69 (m, 1H), 7.56 (dd, J = 7.9, 1.8 Hz, 1H), 7.45 – 7.40 (m, 1H), 7.38 (dd, J = 8.0, 1.8 Hz,1H), 7.32 (t, J = 7.9 Hz, 1H), 6.49 (dd, J = 7.4, 5.0 Hz, 1H), 5.11 – 5.04(m, 1H), 5.02 (s, 1H), 4.50 (s, 1H), 3.47 – 3.26 (m, 2H), 2.23 – 2.01 (m,2H).

[0202] Example 23

[0203]

[0204] The synthesis method was the same as that used for compound 1, resulting in compound 22. 1 H NMR (400 MHz, Chloroform-d)δ 8.02 (dd, J = 5.1, 1.8 Hz, 1H), 7.70 (s, 1H), 7.59 (dd, J = 7.6, 2.1 Hz,1H), 7.41 – 7.30 (m, 3H), 6.47 (dd, J = 7.3, 5.0 Hz, 1H), 5.09 – 4.98 (m,1H), 4.21 (d, J = 7.1 Hz, 1H), 3.41 – 3.28 (m, 2H), 3.08 (s, 3H), 2.24 – 2.13(m, 2H).

[0205] Example 24

[0206]

[0207] The synthesis method was the same as that used for compound 1, resulting in compound 24. 1H NMR (400 MHz, Chloroform-d)δ 7.71 (d, J = 0.7 Hz, 1H), 7.58 (dd, J = 7.8, 1.9 Hz, 1H), 7.40 – 7.30 (m,2H), 7.29 – 7.24 (m, 1H), 7.17 (ddd, J = 8.7, 7.3, 1.7 Hz, 1H), 6.93 – 6.84(m, 1H), 6.81 (dd, J = 8.3, 1.2 Hz, 1H), 5.14 – 5.01 (m, 1H), 4.38 – 4.21 (m,2H), 4.20 – 4.06 (m, 1H), 2.34 – 2.19 (m, 2H).

[0208] Example 25

[0209]

[0210] The synthesis method was the same as that used for compound 1, resulting in compound 25. 1 H NMR (400 MHz, Chloroform-d)δ 8.02 (dd, J = 4.9, 1.9 Hz, 1H), 7.71 (d, J = 0.7 Hz, 1H), 7.60 (dd, J =7.6, 2.1 Hz, 1H), 7.41 – 7.32 (m, 3H), 6.47 (dd, J = 7.3, 4.9 Hz, 1H), 5.07 –4.99 (m, 1H), 4.17 (d, J = 7.2 Hz, 1H), 3.89 – 3.77 (m, 1H), 3.77 – 3.68 (m,1H), 3.64 – 3.54 (m, 2H), 3.49 (t, J = 5.5 Hz, 2H), 3.31 (s, 3H), 2.25 – 2.04 (m, 2H).

[0211] Example 26

[0212]

[0213] The synthesis method was the same as that used for compound 1, resulting in compound 26. 1H NMR (400 MHz, Chloroform-d)δ 7.91 (dd, J = 5.0, 1.8 Hz, 1H), 7.71 (s, 1H), 7.64 – 7.58 (m, 1H), 7.45 –7.31 (m, 3H), 6.52 (dd, J = 7.3, 5.0 Hz, 1H), 5.04 (q, J = 5.5 Hz, 1H), 4.44(d, J = 7.2 Hz, 1H), 3.80 – 3.64 (m, 3H), 3.51 (dt, J = 9.1, 4.6 Hz, 1H), 3.45 – 3.37 (m, 2H), 2.27 – 2.08 (m, 2H).

[0214] Example 27

[0215]

[0216] The synthesis method was the same as that used for compound 1, resulting in compound 27. 1 H NMR (400 MHz, Chloroform-d)δ 8.98 (s, 1H), 7.87 (s, 1H), 7.63 (dd, J = 7.9, 1.9 Hz, 1H), 7.41 (dd, J =8.0, 1.8 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.23 –7.14 (m, 2H), 7.13 – 7.08 (m, 1H), 5.07 – 4.87 (m, 2H), 2.87 – 2.67 (m, 2H),2.18 – 2.04 (m, 1H), 1.89 – 1.70 (m, 2H).

[0217] Example 28

[0218]

[0219] The synthesis method was the same as that used for compound 1, resulting in compound 28. 1H NMR (400 MHz, Chloroform-d)δ 8.79 (s, 1H), 7.88 (s, 1H), 7.63 (dd, J = 7.9, 1.9 Hz, 1H), 7.46 – 7.34 (m,2H), 7.31 (d, J = 6.8 Hz, 1H), 7.23 – 7.14 (m, 2H), 7.13 – 7.07 (m, 1H), 5.07 – 4.93 (m, 2H), 2.88 – 2.68 (m, 2H), 2.16 – 2.06 (m, 1H), 1.88 – 1.76 (m,2H).

[0220] Example 29

[0221]

[0222] Step 1: Synthesis of Intermediate 5. Intermediate 4 (1 g, 1 eq) and 2,3-dichloropyrazine (1.2 eq) were dissolved in DMF (30 mL), followed by the addition of DIPEA (2 eq). The reaction mixture was heated to 80 °C and stirred overnight. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with 20 mL of water, and extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 100:1~10:1) to obtain intermediate 5. LC-MS: ESI [M+H] + =261.1, 263.1.

[0223] Step 2: Synthesis of Compound 29. Intermediate 5 (500 mg, 1 eq), 2,3-dichlorophenylboronic acid (1.5 eq), Pd(dppf)Cl2 (5%), and potassium carbonate (2.5 eq) were added sequentially to a sealed tube. Then, 1,4-dioxane:water (7:3, 15 mL) was added. After purging with nitrogen three times, the reaction mixture was heated to 80 °C and stirred overnight. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 100:1~10:1) to obtain compound 29.

[0224] LC-MS:ESI[M+H] + =371.1, 373.1. 1H NMR (400 MHz, Chloroform-d) δ 8.43 –8.38 (m, 1H), 8.14 (dd, J = 2.9, 1.3 Hz, 1H), 7.97 (dd, J = 2.7, 1.1 Hz, 1H),7.70 – 7.52 (m, 2H), 7.37 – 7.28 (m, 2H), 7.12 – 7.01 (m, 1H), 5.48 (q, J =7.2 Hz, 1H), 4.37 (dd, J = 15.2, 8.5 Hz, 1H), 2.98 – 2.89 (m, 2H), 2.23 –2.07 (m, 1H), 2.03 – 1.87 (m, 3H).

[0225] Example 30

[0226]

[0227] Step 1: Synthesis of Intermediate 6. Intermediate 4 (1 g, 1 eq) and 4-chloro-5-bromopyrimidine (1.2 eq) were dissolved in DMF (30 mL), followed by the addition of DIPEA (2 eq). The reaction mixture was heated to 80 °C and stirred overnight. After the reaction was complete as monitored by TLC, it was cooled to room temperature, quenched with 20 mL of water, and extracted three times with ethyl acetate. The organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 100:1~10:1) to obtain intermediate 6. LC-MS: ESI [M+H] + =305.1, 307.1.

[0228] Step 2: Synthesis of Compound 30. Intermediate 6 (500 mg, 1 eq), 2,3-dichlorophenylboronic acid (1.5 eq), Pd(dppf)Cl2 (5%), and potassium carbonate (2.5 eq) were added sequentially to a sealed tube. Then, 1,4-dioxane:water (7:3, 15 mL) was added. After purging with nitrogen three times, the reaction mixture was heated to 100 °C and stirred overnight. The reaction solution was filtered through diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH / DCM = 100:1~10:1) to obtain compound 30.

[0229] LC-MS:ESI[M+H] + =371.1, 373.1. 1H NMR (400 MHz, Chloroform-d) δ 8.48 (d,J = 2.2 Hz, 1H), 8.26 – 8.17 (m, 1H), 7.81 (d, J = 3.7 Hz, 1H), 7.60 – 7.38(m, 1H), 7.34 (td, J = 7.8, 1.7 Hz, 1H), 7.25 – 7.07 (m, 2H), 6.96 (ddd, J =25.4, 7.8, 4.7 Hz, 1H), 5.63 – 5.47 (m, 1H), 5.13 (dd, J = 36.0, 8.6 Hz, 1H), 2.82 – 2.69 (m, 2H), 2.13 – 1.99 (m, 1H), 1.94 – 1.70 (m, 3H).

[0230] Bioactivity testing and evaluation

[0231] The following specific experimental examples demonstrate the beneficial effects of the present invention.

[0232] 1. Tests on the antagonistic activity of compounds against P2X7 receptors

[0233] Experimental Methods: As is well known to those skilled in the art, the P2X7 receptor (P2X7R) is primarily regulated by ATP. High concentrations of ATP (0.5–1 mM and above) can stimulate P2X7R activation, leading to the opening of the receptor pores. These open macropores allow the uptake of hydrophilic solutes with molecular weights up to 900 Da (such as ethidium bromide, propidium iodide (PI), or luciferin), which are normally impermeable to the intracellular environment, by organic dyes. In this experiment, PI was used as the fluorescent dye, and a PI dye uptake experiment was conducted.

[0234] Cells stably expressing human and mouse P2X7R (mP2X7-HEK293, hP2X7-HEK293) were constructed on HEK293 (human embryonic kidney cells 293) via lentiviral transfection, and an in vitro cell-based detection method was established: ATP was used to induce P2X7R activation in cells, and a fluorescent dye was added for labeling. The antagonistic activity of drugs against hP2X7R (human P2X7R) and mP2X7R (mouse P2X7R) was tested. Positive reference compound JNJ-55308942 (catalog number: HY-123857) was purchased from MedChemExpress Shanghai. Materials: PI, ATP, DMEM medium.

[0235]

[0236] Preparation of drug solutions: 1) Prepare a stock solution of 10 mmol / L of the compound using 100% DMSO; 2) Prepare a stock solution of PI using sterile PBS using 1 mg / ml; 3) Prepare a stock solution of ATP using sterile PBS using 600 mM.

[0237] Methods: mP2X7R-HEK293 and hP2X7R-HEK293 cells (2×10⁻⁶) were used to prepare mP2X7R-HEK293 cells. 5 The compounds (pI, ATP) were seeded in 96-well black transparent flat-bottomed microplates at concentrations of 100 μL / well and incubated at 37℃, 25% CO2 for 24 hours. Then, the compounds, PI, and ATP were diluted to their target concentrations using DMEM medium and added to the wells (100 μL / well). The plates were incubated in the dark for 2 hours, then the medium was removed and pre-chilled PBS (100 μL / well) was added. Fluorescence was immediately measured using a microplate reader (Ex / Em = 535 / 617 nM). The target concentrations of PI and ATP were 0.05 g / mL and 3 mM, respectively. The raw data for each well were read and recorded, and the data were converted accordingly to calculate the antagonistic activity of each compound against hP2X7R and mP2X7R.

[0238] Experimental results: The results are shown in Table 1. The effective concentration of the compounds in Table 1 is 1 μM. Antagonism rate ≥80% is represented by "+++", 50% ≤ antagonism rate <80% is represented by "++", antagonism rate <50% is represented by "+", and " / " was not tested.

[0239] Table 1. Antagonistic activity of the compounds against hP2X7R and mP2X7R at 1 μM

[0240]

[0241] Experimental conclusion: The compounds of this invention have significant antagonistic activity against hP2X7R (human P2X7R) and mP2X7R (mouse P2X7R).

Claims

1. A compound of formula I or a pharmaceutically acceptable form thereof, characterized in that: The structure of Formula I is as follows: Mode in: Ring A is selected from 6-10 aryl or 5-10 heteroaryl; In ring A, the 5-10 membered heteroaryl group contains 1-3 heteroatoms selected from N, S, and O; R1 is selected from hydrogen, deuterium, cyano, hydroxyl, halogen, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 hydroxyl-substituted alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered halocycloalkyl groups, -NR 1a R 1b or -C(O)NHR 1c ; R 1a Selected from hydrogen, deuterium, or C 1-4 Alkyl; R 1b Selected from hydrogen, deuterium, or C 1-4 Alkyl; R 1c Selected from hydrogen, deuterium, or C 1-4 alkyl; n1 is selected from 0, 1, 2, 3 or 4; Ring B is selected from substituted or unsubstituted 5-10 aryl or 5-10 membered heteroaryl rings; In ring B, the 5-10 membered heteroaromatic ring contains 1-4 heteroatoms selected from N, S, and O, and contains at least one N; In ring B, the substituents of the substituted 5-10 membered heteroaromatic ring are selected from deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl; Structural unit Selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , or ; n4 is selected from 0, 1, 2, 3, or 4; n5 is selected from 0, 1, 2, 3, or 4; R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl; R 4a R 4c Independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl; R 3b Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; R 4b Selected from hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl; R 3b R 4b In this context, the 3-6 membered heterocyclic alkyl group and the 5-10 membered heteroaryl group contain 1-3 heteroatoms selected from N, S, and O; R 3b R 4b In, the replaced C 1-6 Alkyl, substituted C 2-6 alkenyl, substituted C 2-6 alkynyl, substituted C 2-6 The substituents of the alkyl carbonyl group are independently selected from deuterium, cyano, hydroxyl, amino, halogen, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuteroxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl; R 3b R 4b In this context, the substituents of the substituted 3-6 membered cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted 6-10 membered aryl, and substituted 5-10 membered heteroaryl are independently selected from deuterium, cyano, hydroxyl, amino, halogen, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuterated methoxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl. The pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, nitrogen oxides, isotope-labeled substances, metabolites, or prodrugs.

2. The compound according to claim 1, or a pharmaceutically acceptable form thereof, characterized in that: Ring A is selected from 6-10 aryl or 6-10 heteroaryl; in ring A, the 5-10 heteroaryl contains 1-2 heteroatoms selected from N, S, and O; Preferably, ring A is selected from phenyl, naphthyl, pyridyl, quinolinyl, or isoquinolinyl; More preferably, ring A is selected from , , , , or .

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable form thereof, characterized in that: R1 is selected from hydrogen, deuterium, cyano, hydroxyl, fluorine, chlorine, bromine, and C. 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered fluorocycloalkyl groups, -NR 1a R 1b or -C(O)NHR 1c ;R 1a Selected from hydrogen, deuterium, methyl, or ethyl; R 1b Selected from hydrogen, deuterium, methyl, or ethyl; R 1c Selected from hydrogen, deuterium, methyl, or ethyl; Preferably, R1 is selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, N-methylamino, N,N-dimethylamino or -C(O)NHCH3; More preferably, R1 is selected from hydrogen, fluorine, chlorine, methyl or fluoromethyl.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable form thereof, characterized in that: Structural unit Selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

5. The compound according to claim 1, or a pharmaceutically acceptable form thereof, characterized in that: Ring B is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; n2 is selected from 0, 1, 2, 3, or 4; n3 is selected from 0, 1, 2, 3, or 4; R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl; R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered halocycloalkyl; R 2c Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl, 3-6 membered cycloalkyl or 3-6 membered halocycloalkyl.

6. The compound according to claim 5, or a pharmaceutically acceptable form thereof, characterized in that: R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 2c Selected from hydrogen, deuterium, and C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Hydroxyl-substituted alkyl groups, 3-6 membered cycloalkyl groups, or 3-6 membered fluorocycloalkyl groups; Preferred, R 2a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl; R 2b Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl; R 2c Selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, cyclopropyl, cyclobutyl, fluorocyclopropyl or fluorocyclobutyl; More preferably, structural unit Selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

7. The compound according to claim 1, or a pharmaceutically acceptable form thereof, characterized in that: R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 4a R 4c Independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 hydroxylated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Hydroxyl-substituted alkoxy, 3-6 membered cycloalkyl, or 3-6 membered fluorocycloalkyl; R 3b Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, substituted or unsubstituted C 2-4 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl; R 4b Selected from hydrogen, substituted or unsubstituted C 1-4 Alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 Alkyne group, substituted or unsubstituted C 2-4 Alkyl carbonyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted 6 membered aryl, substituted or unsubstituted 5-6 membered heteroaryl; R 3b R 4b In this context, the 3- to 6-membered heterocyclic alkyl groups are selected from... , , , , or ; R 3b R 4b In this context, the 5-6 heteroaryl group is selected from pyridinyl, pyrimidinyl, pyrroleyl, furanyl, thiophenyl, pyrazolyl, or oxazolyl; R 3b R 4b In, the replaced C 1-4 Alkyl, substituted C 2-4 alkenyl, substituted C 2-4 alkynyl, substituted C 2-4 The substituents of the alkyl carbonyl group are independently selected from deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuteroxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl; R 3b R 4b In this context, the substituents of the substituted 3-6 membered cycloalkyl, substituted 4-6 membered heterocycloalkyl, substituted 6 membered aryl, and substituted 5-6 membered heteroaryl are independently selected from deuterium, cyano, hydroxy, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, carboxyl, methoxycarbonyl, methoxy, fluoromethoxy, deuterated methoxy, N-methylamino, N,N-dimethylamino, -C(O)NHCH3, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, phenyl, methoxy-substituted phenyl, pyridyl, methoxy-substituted pyridyl, pyrimidinyl, or 1-methyl-1H-pyrazolyl. Preferred, R 3a Selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl, or fluorocyclobutyl; R 4a R 4c It is independently selected from hydrogen, deuterium, cyano, hydroxyl, amino, fluorine, chlorine, bromine, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, methoxy, fluoromethoxy, deuterated methoxy, hydroxy-substituted methoxy, ethoxy, fluoroethoxy, deuterated ethoxy, hydroxy-substituted ethoxy, cyclopropyl, cyclobutyl, fluorocyclopropyl or fluorocyclobutyl; R 3b Selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, acetyl, propionyl, fluoroacetyl, fluoropropionyl, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R 4b Selected from hydrogen, deuterium, methyl, fluoromethyl, deuterated methyl, hydroxymethyl, ethyl, fluoroethyl, deuterated ethyl, hydroxyethyl, n-propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, acetyl, propionyl, fluoroacetyl, fluoropropionyl, cyclopropyl, cyclobutyl, fluorocyclopropyl, fluorocyclobutyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; More preferably, structural unit Selected from the following groups: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , or .

8. The compound according to any one of claims 1 to 7, characterized in that: The compound is selected from: 。 9. A pharmaceutical composition, characterized in that: Its active ingredient contains the compound of any one of claims 1 to 8 or a pharmaceutically acceptable form thereof, supplemented by a pharmaceutically acceptable carrier.

10. Use of the compound of any one of claims 1 to 8 or a pharmaceutically acceptable form thereof, or the pharmaceutical composition of claim 9, in the preparation of a P2X7 receptor antagonist or in the preparation of a medicament for the prevention and / or treatment of diseases associated with abnormal P2X7R activity, preferably, wherein the P2X7R-related diseases are inflammation and inflammation-related diseases, kidney disease, respiratory diseases, cancer, pain disorders, central nervous system diseases, radiation-induced brain injury, radiation-induced cerebral ischemia, myocardial injury, diabetes, obesity, gout, depression, lupus erythematosus, atherosclerosis, or allergic asthma; preferably, the inflammation and inflammation-related diseases are rheumatoid arthritis, endotoxic shock, Crohn's disease, or colitis; the pain disorders are headache, migraine, trigeminal neuralgia, atypical facial pain, arthralgia, bone pain, neuropathic pain syndrome, or pain caused by cancer invasion; the central nervous system diseases are Alzheimer's disease, Parkinson's syndrome, epilepsy, cerebral arteriosclerosis, myasthenia gravis, multiple sclerosis, amyotrophic lateral sclerosis, or other demyelinating syndromes.

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