Amino ester compounds and use thereof as p2x7 antagonist

Abstract

The present invention provides compounds represented by formula (I), and stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs thereof. The compounds can be used as P2X7 receptor antagonists.

Description

Amino ester compounds and their use as P2X7 antagonists

[0001] Priority Information

[0002] This application claims priority to and the benefit of Chinese Patent Application No. 202410789810.3, filed on June 18, 2024, Chinese Patent Application No. 202410931486.4, filed on July 11, 2024, and Chinese Patent Application No. 202411596682.7, filed on November 8, 2024, to the Chinese National Intellectual Property Office, and incorporates by reference the entire contents of each of the foregoing applications. TECHNICAL FIELD

[0003] The present application belongs to the field of medicine, and in particular, the present application relates to amino ester compounds, more particularly, the present application relates to amino ester compounds and their use as P2X7 antagonists. BACKGROUND

[0004] P2 receptors are a class of cell membrane receptors that bind to extracellular nucleotides such as ATP, ADP, etc. This class of receptors is divided into two families, ligand-gated ion channel receptors P2X and G protein-coupled receptors P2Y, among which P2X receptors are divided into seven subtypes (P2X1-7). P2X7 receptors are closely related to the occurrence and development of most diseases. Activation of P2X7 receptors can open ion channels on the cell membrane (sodium and calcium ions flow in and potassium ions flow out), activate various intracellular signaling pathways, release various inflammatory cytokines, damage the nervous system and induce pain. In the nervous system, activation of P2X7 receptors mainly activates microglia, releases inflammatory cytokines, and damages the nervous system. In addition, upregulation of P2X7 receptor expression can also activate immune cells, promote inflammatory reactions, increase tissue damage, and exacerbate pain. Studies have found that P2X7 receptors are overexpressed in various tumors and are closely related to tumor progression, metastasis, and angiogenesis. Therefore, antagonizing P2X7 receptors can effectively prevent and treat pain, central nervous system diseases, immune diseases, and inflammatory diseases, and has important clinical application value. SUMMARY

[0005] The present application aims to provide amino ester compounds for use as P2X7 antagonists, as well as their preparation methods and uses.

[0006] In a first aspect of the present application, the present application provides a compound represented by formula (I), a stereoisomer, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof:

[0007] wherein:

[0008] R 1 selected from p R aThe following groups are substituted: 6-15 aryl, 5-10 heteroaryl; p is an integer selected from 0, 1, 2, 3 and 4;

[0009] R 2 R 3 Each is independently selected from hydrogen, deuterium, and q R. b Replacement C 1-6 Alkyl group; q is an integer selected from 0, 1, 2, 3, R b Each is independently selected from halogens, -OH, -CN, -NH2, oxo (=O), C 1-6 Alkyl and -OC 1-6 alkyl;

[0010] Or, R 2 With R 3 In the equation, one is hydrogen, deuterium, or non-existent, and the other is related to R. 1 Formed by j R c Replacement of 3-7-membered rings; j is selected from 0, 1, 2, and 3;

[0011] R a and R c Each is independently selected from halogens, -OH, -CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated C 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, C 3-7 cycloalkyl, -OC 3-7 Cycloalkyl, -S(O)rR a1 -SF5, -NR a1 R a2 The R a1 and R a2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, where r is an integer selected from 0, 1, or 2;

[0012] R 4 Selected from hydrogen, deuterium, and fluorine;

[0013] R 5 Selected from hydrogen, deuterium, halogens, -OH, -CN and K-terminated R d The following groups are substituted: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R 51 -(C=O)-NR 51 R 52 and -NR 51 R 52 ;k is an integer selected from 0, 1, 2, 3, and 4, R 51and R 52 each independently selected from the group consisting of hydrogen, -OH, C 1-6 alkyl, C 1-6 alkyl, R d selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl and -O-C 1-6 alkyl;

[0014] R 6 and R 7 each independently selected from the group consisting of hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl;

[0015] or, R 6 , R 7 may form, together with the N atom to which they are attached, a 3-7 membered heterocyclic ring, said 3-7 membered heterocyclic ring being substituted with u R e ; u is selected from 0, 1, 2, 3, 4, 5 and 6, said R e each independently selected from the group consisting of halogen, -OH, oxo (=0), C 1-6 alkyl, -O-C 1-6 alkyl, halo C 1-6 alkyl, -O-halo C 1-6 alkyl;

[0016] m is selected from 0 and 1; n is selected from 0, 1 and 2.

[0017] said alkyl includes linear alkyl, branched alkyl;

[0018] said halogen is selected from fluorine, chlorine, bromine, iodine, preferably halogen is selected from fluorine, chlorine.

[0019] According to certain embodiments of the present application, the present application provides a compound represented by Formula (I), a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug thereof:

[0020] wherein:

[0021] R 1 selected from the group consisting of 6-15 membered aryl, 5-10 membered heteroaryl, substituted with p R a ; p is an integer selected from 0, 1, 2, 3 and 4;

[0022] R 2 , R 3 each independently selected from the group consisting of hydrogen or C b alkyl substituted with q R 1-6 alkyl; q is an integer selected from 0, 1, 2, 3, R b each independently selected from the group consisting of halogen, -OH, -CN, -NH2, oxo (=0), C1-6 alkyl and -O-C 1-6 alkyl;

[0023] or, R 2 and R 3 , one is hydrogen or is absent, the other forms, together with R 1 a 3-7 membered ring substituted by j R c ; j is an integer selected from 0, 1, 2 and 3;

[0024] R a and R c are each independently selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl, -O-C 1-6 alkyl, halogen-C 1-6 alkyl, -O-halogen-C 1-6 alkyl, C 3-7 cycloalkyl, -O-C 3-7 cycloalkyl, -S(O)r-R a1 , -SF5, -NR a1 R a2 ; R a1 and R a2 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, r is an integer selected from 0, 1, 2;

[0025] R 4 is selected from the group consisting of hydrogen, deuterium, fluorine;

[0026] R 5 is selected from the group consisting of hydrogen, halogen, -OH, -CN and the following groups substituted by k R d ; C 1-6 alkyl, -O-C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, -(C=O)-R 51 , -(C=O)-NR 51 R 52 and -NR 51 R 52 ; k is an integer selected from 0, 1, 2, 3 and 4, R 51 and R 52 are each independently selected from the group consisting of hydrogen, -OH, C 1-6 alkyl, C 1-6 alkyl substituted by hydroxyl, R d is selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl and -O-C 1-6 alkyl;

[0027] R 6 and R 7 are each independently selected from the group consisting of hydrogen, C 1-6alkyl, C 1-6 alkyl;

[0028] R 6 R 7 may form a 3-7 membered heterocyclic ring with the N atom to which they are attached, said 3-7 membered heterocyclic ring being substituted with u R e ; u is selected from 0, 1, 2, 3, 4, 5 and 6, said R e each independently is selected from halogen, -OH, oxo (=0), C 1-6 alkyl, -O-C 1-6 alkyl, haloC 1-6 alkyl, -O-haloC 1-6 alkyl;

[0029] m is selected from 0 and 1; n is selected from 0, 1 and 2.

[0030] said alkyl includes linear alkyl, branched alkyl;

[0031] said halogen is selected from fluorine, chlorine, bromine, iodine, preferably halogen is selected from fluorine, chlorine.

[0032] According to certain embodiments of the present application, in the compound of formula (I), R 1 , the heteroatom of said 5-10 membered heteroaryl is selected from 1 or 2 of N, O, S, the number of heteroatoms is 1, 2 or 3; the undefined groups are as described in any of the schemes of the present application.

[0033] According to certain embodiments of the present application, in the compound of formula (I), R 1 , said 5-10 membered heteroaryl is selected from thienyl, thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl; the undefined groups are as described in any of the schemes of the present application.

[0034] According to certain embodiments of the present application, in the compound of formula (I), R 1 , said 6-15 membered aryl is selected from phenyl, indenyl, naphthyl and azulenyl; the undefined groups are as described in any of the schemes of the present application.

[0035] According to certain embodiments of the present application, in the compound of formula (I), R 1 , said R a each independently is selected from fluorine, chlorine, -OH, -CN, C 1-6 alkyl, -SF5, -O-C 1-6 alkyl, haloC 1-6 alkyl, -O-haloC 1-6 alkyl, C 3-7cycloalkyl, -O-C 3-7 cycloalkyl, -S(O)r-R a1 , -NR a1 R a2 ; R a1 and R a2 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, r is an integer selected from 0, 1, 2; the C 1-6 alkyl, alone or as part of another group, is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl; the C 3-7 cycloalkyl, alone or as part of another group, is each independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the undefined groups are as described in any of the aspects of the application.

[0036] According to certain embodiments of the application, in the compound of formula (I), R 1 is selected from the group consisting of R a and p are as described in any of the preceding aspects of the application, and the undefined groups are as described in any of the aspects of the application.

[0037] According to certain embodiments of the application, in the compound of formula (I), R 1 is selected from the group consisting of R a and p are as described in any of the preceding aspects of the application, and the undefined groups are as described in any of the aspects of the application.

[0038] According to certain embodiments of the application, in the compound of formula (I), R 2 , R 3 , the C 1-6 alkyl, alone or as part of another group, is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl; the undefined groups are as described in any of the aspects of the application.

[0039] According to certain embodiments of the application, in the compound of formula (I), R 2 , R 3 are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl; the undefined groups are as described in any of the aspects of the application.

[0040] According to certain embodiments of the application, in the compound of formula (I), R 2 , R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl; the undefined groups are as described in any of the aspects of the application.

[0041] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted by j R c , the 3-7 membered ring is selected from 3-7 membered cycloalkenyl and 3-7 membered heterocycloalkenyl, the 3-7 membered heterocycle comprising 1, 2 or 3 heteroatoms selected from N, O and S; the undefined groups are as described in any of the schemes of the application.

[0042] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted by j R c , the group is selected from represents a single or double bond, X 1 , X 2 and X 3 are each independently selected from CH, CH2, N, NH, O, S; ti and t2 are each independently selected from 0, 1 and 2; R a , R c , p, j and the other undefined groups are as described in any of the schemes of the application.

[0043] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted by j R c , the group is selected from X 1 , X 2 and X 3 are each independently selected from CH2, NH, O, S; ti and t2 are each independently selected from 0, 1 and 2; R a , R c , p, j and the other undefined groups are as described in any of the schemes of the application.

[0044] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted by j R c , the group is selected from X 1 , X 2 and X 3 are each independently selected from CH2, NH, O, S, and X 1 , X2 and X 3 at least one of X a , R c , p and j are as defined in claim 1 ; R a , R c , p, j and other undefined groups are as described in any of the aspects of the application.

[0045] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted with j R c , the group is selected from X 1 is independently selected from NH, O, S, X 2 and X 3 are each independently selected from CH2; t1 is 1 and t2 is 1 ; R a , R c , p, j and other undefined groups are as described in any of the aspects of the application.

[0046] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted with j R c , the group is selected from X 1 is independently selected from NH, O, S, X 2 and X 3 are each independently selected from CH2; t1 is 1 and t2 is 1 ; R a is independently selected from halogen, p is selected from 1 and 2; j is 0; undefined groups are as described in any of the aspects of the application.

[0047] According to certain embodiments of the application, in the compound of formula (I), when R 2 or R 3 forms a 3-7 membered ring with R 1 substituted with j R c , the group is selected from X 1 is independently selected from CH2, NH, O, S; R a , R c , j and other undefined groups are as described in any of the aspects of the application.

[0048] According to certain embodiments of the application, in the compound of formula (I), R 5 is selected from the group consisting of hydrogen, halogen, -OH, and C d alkyl substituted with k R 1-6 groups; k is selected from 0, 1, 2, 3, and 4, R d is selected from the group consisting of halogen, -OH, -CN, C 1-6 alkyl, and -O-C 1-6 alkyl; and the undefined groups are as described in any of the schemes of the application.

[0049] According to certain embodiments of the application, in the compound of formula (I), R 5 is selected from the group consisting of hydrogen, fluorine, chlorine, -OH, methyl, and ethyl; and the undefined groups are as described in any of the schemes of the application.

[0050] According to certain embodiments of the application, in the compound of formula (I), R 6 , R 7 , and R 1-6 is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl; and the undefined groups are as described in any of the schemes of the application.

[0051] According to certain embodiments of the application, in the compound of formula (I), R 6 , R 7 are each independently selected from the group consisting of hydrogen, methyl, ethyl; and the undefined groups are as described in any of the schemes of the application.

[0052] According to certain embodiments of the application, in the compound of formula (I), when R 6 , R 7 and the N atom to which they are jointly attached form a 3-7 membered heterocyclic ring, said 3-7 membered heterocyclic ring is a saturated ring; and the undefined groups are as described in any of the schemes of the application.

[0053] According to certain embodiments of the application, in the compound of formula (I), when R 6 , R 7 and the N atom to which they are jointly attached form a 3-7 membered heterocyclic ring, said 3-7 membered heterocyclic ring is a saturated ring containing only one N atom; and the undefined groups are as described in any of the schemes of the application.

[0054] According to certain embodiments of the application, in the compound of formula (I), when R 6 , R 7 and the N atom to which they are jointly attached form a 3-7 membered heterocyclic ring, said 3-7 membered heterocyclic ring is substituted with u R e groups; u is selected from 0, 1, 2, and 3, and the R e groups are each independently selected from the group consisting of halogen, -OH, oxo (=O), C1-3 alkyl, haloC 1-3 alkyl, -O-C 1-3 alkyl, -O-haloC 1-3 alkyl; the undefined groups are as described in any of the aspects of the application.

[0055] According to certain embodiments of the application, in the compound of formula (I), when R 6 , R 7 and the N atom to which they are jointly attached form a 3- to 7-membered heterocyclic ring, the group is selected from the undefined groups are as described in any of the aspects of the application.

[0056] According to certain embodiments of the application, in the compound of formula (I), R 1 is selected from the undefined groups are as described in any of the aspects of the application.

[0057] According to certain embodiments of the application, in the compound of formula (I), the group is selected from the undefined groups are as described in any of the aspects of the application.

[0058] According to certain embodiments of the application, in the compound of formula (I), the group is selected from the undefined groups are as described in any of the aspects of the application.

[0059] According to certain embodiments of the application, in the compound of formula (I), the group is selected from -NH2, the undefined groups are as described in any of the aspects of the application.

[0060] According to certain embodiments of the application, the compound is selected from the following structures:

[0061] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m and n are as defined in any of the aspects of the first aspect of the application.

[0062] According to certain embodiments of the application, the compound is selected from the following structures:

[0063] R a 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , m, n and p are defined as in any of the technical solutions of the first aspect of the application.

[0064] According to certain embodiments of the application, the compound is selected from the following structures:

[0065] wherein:

[0066] p is an integer selected from 0, 1, 2;

[0067] R 2 , R 3 are each independently selected from hydrogen, deuterium and C b alkyl substituted with q R 1-6 ; q is an integer selected from 0, 1, 2, 3, R b are each independently selected from halogen and C 1-6 alkyl;

[0068] R a are each independently selected from halogen, -OH, -CN, C 1-6 alkyl;

[0069] R 4 is selected from fluorine;

[0070] R 5 is selected from hydrogen, deuterium, halogen, -OH and C d alkyl substituted with k R 1-6 ; k is an integer selected from 0, 1, 2, 3 and 4, R d are selected from halogen, -OH and C 1-6 alkyl;

[0071] R 6 and R 7 are each independently selected from hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted with hydroxyl and / or halogen;

[0072] n is selected from 0, 1 and 2.

[0073] According to certain embodiments of the application, the compound is selected from the following structures:

[0074] wherein:

[0075] R 2 , R 3each independently selected from hydrogen and deuterium;

[0076] R a each independently selected from hydrogen, deuterium, C

[0077] R 5 selected from halogen, -OH, and C 1-6 alkyl;

[0078] R 6 and R 7 each independently selected from hydrogen, deuterium, C 1-6 alkyl.

[0079] According to certain embodiments of the present application, in the compound represented by formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4),

[0080] group selected from

[0081] According to certain embodiments of the present application, in the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (IV1), formula (IV2), formula (V1), formula (V2), formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4), R 5 selected from hydrogen, deuterium, C

[0082] According to certain embodiments of the present application, in the compound represented by formula (I), formula (II), formula (III), formula (IV), formula (IV1), formula (IV2), formula (V1), formula (V2), formula (VI-1), formula (VI-2), formula (VI-3), formula (VI-4), the group selected from -NH2and

[0083] According to certain embodiments of the present application, the present application provides a compound represented by the following formula:

[0084] According to certain embodiments of the present application, the compound represented by formula (I) includes:

[0085] According to certain embodiments of the present application, the compound represented by formula (I) includes:

[0086] In a second aspect of the present application, there is further provided a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound of formula (I) as described in the first aspect of the present application.

[0087] In the pharmaceutical composition, the compound of formula (I) or a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound of formula (I) can be in a therapeutically effective amount.

[0088] In a third aspect of the present application, there is further provided a use of a compound of formula (I) or a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound of formula (I) as described in the first aspect of the present application, or a pharmaceutical composition as described in the second aspect of the present application, the use comprising

[0089] antagonizing P2X7 receptor activity;

[0090] and / or, preventing and / or treating a condition or disorder mediated by P2X7 receptor antagonistic activity;

[0091] and / or, preparing a medicament, a pharmaceutical composition or a preparation for antagonizing P2X7 receptor activity, and / or preventing and / or treating a condition or disorder mediated by P2X7 receptor antagonistic activity.

[0092] According to certain embodiments of the present application, in the use of the third aspect of the present application, the condition or disorder is selected from the group consisting of pain, central diseases, immune diseases, inflammation and inflammation-related diseases.

[0093] In a fourth aspect of the present application, there is further provided a method for preventing and / or treating a condition or disorder mediated by P2X7 receptor antagonistic activity, the method comprising administering to a subject in need thereof a compound of formula (I) or a stereoisomer, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound of formula (I) as described in the first aspect of the present application, and / or a pharmaceutical composition as described in the second aspect of the present application.

[0094] According to certain embodiments of the present application, in the method of the fourth aspect of the present application, the condition or disorder is selected from the group consisting of pain, central diseases, immune diseases, inflammation and inflammation-related diseases.

[0095] Definitions and explanations of terms

[0096] Unless otherwise indicated, the definitions and explanations of terms recited in the present application specification and claims, including the definitions as examples, the exemplary definitions, the preferred definitions, the definitions recited in the tables, the definitions of the specific compounds in the examples, etc., can be combined and integrated with each other arbitrarily. The definitions and the compound structures after such combination and integration should belong to the scope recited in the present application specification.

[0097] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this application belongs. Unless otherwise stated, all references herein to the terms "about" and "comprise" or "comprises" are to be interpreted as meaning that the term "consisting of" or "consists of" can be substituted therefore. Unless otherwise stated, all patents, patent applications, published materials cited herein are incorporated by reference in their entirety.

[0098] Unless otherwise indicated, conventional methods of the applicable arts are employed, such as mass spectroscopy, NMR, IR and UV / Vis spectroscopy and pharmacological methods. Unless specifically defined, terms used in the description and appended claims of this application are intended to have the meanings commonly understood by those of ordinary skill in the art in analytical chemistry, organic synthetic chemistry, and medicinal and pharmaceutical chemistry. Standard techniques can be used for chemical syntheses, chemical analyses, pharmaceutical formulation, and delivery, and treatment of patients. For example, reactions and purification methodologies can be performed by manufacturers following manufacturers' instructions, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures can be readily implemented by the skilled artisan in light of the teachings of the present specification and can be used in conjunction with the examples described herein. In the present specification, groups and substituents are designated by their chemical names, as is conventional in the art. Where a group or substituent is described by a chemical name, it is understood that the group or substituent also includes the chemically equivalent groups and substituents that would result from writing the conventional chemical formula for the group or substituent from right to left. For example, CH2O is equivalent to OCH2.

[0099] Unless otherwise provided, the term "comprising" or "including" is an open expression that includes the indicated content, but does not exclude other content.

[0100] The numerical ranges recited in the specification and claims herein are inclusive of the integers within the recited range. For example, the numerical range of "1 to 6" should be interpreted as the inclusion of each integer from 0 to 6. The numerical range of "1 to 10" should be interpreted as the inclusion of each integer from 1 to 10, as well as each of the fractions 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, and 2.0.

[0101] The term "pharmaceutically acceptable" with respect to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0102] The term "pharmaceutically acceptable salt" means a salt of a pharmaceutically acceptable non-toxic acid or base, including inorganic acids and bases, and organic acids and bases.

[0103] In addition to pharmaceutically acceptable salts, salts of other acids and bases can be used in the preparation and purification of the compounds. They can serve as intermediates or be useful in the identification, characterization, or purification of the compounds of the application.

[0104] The term "stereoisomers" refers to isomers that have the same molecular formula but different structures, resulting from a difference in the arrangement of atoms in space. The term "stereoisomers" includes enantiomers, diastereomers, and geometric isomers. The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0105] Depending on the choice of starting materials and methods, the compounds according to the application can be present in the form of one of the possible isomers or as a mixture of them, for example, as pure optical isomers, or as mixtures of isomers, such as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. When describing compounds having optical activity, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to a single chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (-) are used to designate the sign of rotation of plane-polarized light by the compound, with (-) or L designating a levorotary compound. Compounds with the prefix (+) or D are dextrorotary. The stereoisomers are identical except that they are mirror images of one another. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, and such a racemic mixture or racemate can arise, for example, when a chemical reaction or process does not proceed with stereoselection or stereospecificity. Many geometric isomers of olefins, C=N double bonds, and the like can also exist in the compounds described herein, and all such isomers are contemplated in the present application. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds are understood to include both E and Z geometric isomers. If a compound contains a disubstituted cycloalkyl ring, the substituents on the ring can be in the cis- or trans- (or, alternatively, the Z- or E-) configuration.

[0106] A straight solid line bond and a straight dashed line bond represent the relative configuration of the stereocenters, e.g.: represent one of the configurations in while represents the other remaining configuration. Similarly, represent one of the configurations in respectively.

[0107] Unless otherwise indicated, a wedge solid line bond and a wedge dashed line bond represent the absolute configuration of a stereocenter.

[0108] When bonds to a chiral carbon in a formula of the application are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon, and the enantiomerically pure compounds and mixtures resulting therefrom, are included within the scope of the general formula. The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge bond and a dashed line bond represent the absolute configuration of a stereocenter.

[0109] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Compounds of the application containing asymmetrically substituted carbon atoms can be isolated in optically active form or as racemates. Resolution of racemic mixtures of the compounds can be achieved by any of the many methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving acid, which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional crystallization procedures are, for example, the D and L forms of an optically active acid, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the D and L forms of the various optically active mandelic acids, such as β- mandelic acid. Other resolving agents suitable for fractional crystallization procedures include the stereoisomerically pure forms of α-methyl- benzylamine (e.g., the S and R forms or the diastereomeric pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can be used as well as supercritical fluid chromatography (SFC). The choice of the particular method and elution conditions, as well as the choice of the chromatography column, can be made by one skilled in the art depending on the structure of the compound and the results of the test. Further, any enantiomer or diastereomer of a compound described herein can be obtained by stereochemically organized synthesis using optically pure starting materials or reagents of known configuration.

[0110] The term "pharmaceutical composition" denotes a mixture of one or more of the compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.

[0111] The term "effective dose," "effective amount," or "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to provide the intended effect, without being toxic to the organism. For oral dosage forms in the present application, an "effective amount" of one active agent in a composition means the amount needed to provide the intended effect in conjunction with another active agent in the composition. The determination of an effective amount is dependent on the age and general condition of the recipient, on the particular active agent, and an appropriate effective amount for a given case can be determined by one of ordinary skill in the art based on routine testing.

[0112] The term "active ingredient," "therapeutic agent," "active agent," or "active substance" means a chemical entity that is effective in treating a disorder, disease, or condition of interest.

[0113] The term "solvate" means a compound of the present application or a salt thereof, including where applicable a stoichiometric or non-stoichiometric amount of solvent, when the solvent is water, then the solvate is a hydrate.

[0114] The term "prodrug" means a compound of the present application which can be converted under physiological conditions or by solvolysis to a compound of the present application having the biological activity. A prodrug of the present application is prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present application wherein a hydroxy or amino group is bonded to any group which, when the prodrug of the compound of the present application is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino group, respectively.

[0115] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 2 H), carbon-14 ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0116] The term "oxo" means =0. When oxo is substituting on a carbon chain, two hydrogens on a methylene group are replaced by oxygen, which together form a carbonyl moiety [-C(=0)-]; when oxo is substituting on a ring, one or more atoms of the ring are replaced by =0, e.g., carbon, nitrogen and sulfur heteroatoms can optionally be replaced by oxo (i.e., C(=0), NO and S(0)p, p is 1 or 2), e.g., 2-pyridonyl.

[0117] The term "C 1-6 "alkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. Said alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, t-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 and the like or their isomers. In particular, said group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl. The term "C 3-7Cycloalkyl" means a saturated monocyclic or bicyclic ring having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[l. l. l]pentane, bicyclo[3.1.0]hexane.

[0118] The term "3-7 membered ring" substituent is understood to mean a monocyclic or bicyclic ring system having 3 to 7 ring atoms, wherein bicyclic ring systems include spiro, fused and bridged rings, and tricyclic ring systems include fused rings, any of which rings can be aromatic or non-aromatic, e.g., can be aryl, heteroaryl, can be saturated "3-7 membered ring alkyl or C 3-7 Cycloalkyl", "3-7 membered heterocycloalkyl", can also be unsaturated "3-7 membered ring alkenyl" and "3-7 membered heterocycloalkenyl". The term "3-7 membered heterocycle" is understood to mean a saturated or unsaturated monocyclic or bicyclic ring system having 3 to 7 ring atoms, wherein 1, 2 or 3 ring atoms are selected from N, O and S. Unless otherwise specified, the "3-7 membered heterocycle" can be attached to the rest of the molecule by carbon or nitrogen. "3-7 membered heterocycle" includes "3-7 membered heterocycloalkyl" and "3-7 membered heterocycloalkenyl".

[0119] The term "m-n membered heterocycloalkyl" is understood to mean a saturated monocyclic, bicyclic or tricyclic ring system having m to n ring atoms, wherein some of the ring atoms are selected from N, O and S. The "m to n membered heterocycloalkyl" can be attached to the rest of the molecule via carbon or nitrogen. It is understood that when the total number of S atoms and O atoms in the heterocycloalkyl group exceeds 1, these heteroatoms are not adjacent to each other. A non-limiting example is "3 to 6 membered heterocycloalkyl" or "3 to 7 membered heterocycloalkyl" which means a saturated monocyclic or bicyclic ring having 3 to 6 ring atoms or 3 to 7 ring atoms, wherein 1, 2 or 3 of the ring atoms are selected from N, O and S. The term "m-n membered heterocycloalkenyl" is understood to mean a monocyclic, bicyclic or tricyclic ring system having m to n ring atoms and comprising at least one carbon-carbon double bond (C=C), wherein the bicyclic ring systems include spiro, fused and bridged rings, and the tricyclic ring systems include fused rings, wherein some of the ring atoms are selected from N, O and S, the remainder being carbon atoms, and the heteroatoms can occupy the position of attachment of the heterocycloalkenyl group to the rest of the molecule. Any ring of this system is non-aromatic. A non-limiting example is "3-7 membered heterocycloalkenyl" which means a monocyclic or bicyclic ring system having 3-7 ring atoms and comprising at least one carbon-carbon double bond (C=C), wherein the bicyclic ring systems include spiro, fused and bridged rings, wherein 1, 2 or 3 of the ring atoms are heteroatoms independently selected from O, S and N. In addition, the 3-7 membered heterocycloalkenyl group includes 3 membered, 4 membered, 5 membered, 6 membered and 7 membered heterocycloalkenyl groups, etc. Examples of 3 to 7 membered heterocycloalkenyl groups include, but are not limited to, dihydrofuranyl, dihydrothienyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl and dihydrotetrazolyl, or isomers and stereoisomers thereof.

[0120] The term "6-15 membered aryl" is understood to mean a monocyclic, bicyclic or tricyclic aromatic ring group having 6-15 ring atoms. The term "5-10 membered heteroaryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 5-10 ring atoms, in particular 5 or 6 carbon atoms, and comprising 1-5 heteroatoms independently selected from N, O and S. Preferably, 1-3 monovalent monocyclic, bicyclic or tricyclic aromatic ring groups independently selected from N, O and S, and, in each case additionally, can be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxazinyl, etc.

[0121] The term "halo" or "halogen" is fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups including a specified number of carbon atoms, substituted by one or more halogens (e.g., -CvFw, where v = 1 to 3, w = 1 to (2v + 1)). Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptafluoropropyl.

[0122] The term "amino" denotes the substituent -NH2. Advantages

[0123] According to a specific example of the present application, the compound represented by the formula (I) of the present application, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof has a good antagonistic effect on P2X7.

[0124] According to a specific example of the present application, the compound of the present application has a good antagonistic effect on P2X7 and has excellent pharmacokinetic properties.

[0125] Additional aspects and advantages of the application will be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following and / or can be learned by practice of the application.

[0126] DETAILED DESCRIPTION

[0127] The present application will be illustrated below with reference to Examples. Those skilled in the art will appreciate that the following Examples are intended to illustrate the present application and should not be construed as limiting the scope of the present application. In the Examples, unless otherwise specified, the techniques or conditions are performed according to the techniques or conditions described in the literature or according to the product manual. Unless otherwise specified, the reagents or instruments used are conventional products that can be commercially available.

[0128] The present application provides a compound represented by the formula (I), a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a method for preparing a compound represented by the formula (I) or a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, and intermediates, a pharmaceutical composition, and the use of the compound and the pharmaceutical composition of the present application in the manufacture of a medicament.

[0129] The reaction solvent used in each reaction step described in the present application is not particularly limited, and any solvent that can dissolve the starting material to some extent and does not inhibit the reaction is included in the present application. In addition, many similar modifications, equivalent replacements, or different proportions of the solvent, the solvent combination, and the solvent combination described in the present application are considered to be included in the scope of the present application.

[0130] The abbreviations used in the present application are defined as follows:

[0131] Symbols or units:

[0132] IC 50 : half maximal inhibitory concentration, the concentration at which the maximum inhibition is reached by 50%; M: mol / L, for example n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M solution in n-hexane) indicates a solution of n-butyllithium in n-hexane with a molar concentration of 2.5 mol / L; N: normality, for example 2N hydrochloric acid indicates a 2 mol / L hydrochloric acid solution

[0133] Reagents:

[0134] DCM: dichloromethane MeOH: methanol DMF: N,N-dimethylformamide HATU: 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate TEA: triethylamine

[0135] AD-mix-α: SFC: supercritical fluid chromatography

[0136] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).

[0137] LC-MS method 1: determined by Waters Acquity H-class Uplc-QDA or Aglient 1260IIPrime iQ mass spectrometer, using ACQUITY UPLC BEH C18, 2.1*50mm, 1.7μm column. Gradient elution conditions: 95-5% solvent A1 and 5-95% solvent B1 at a flow rate of 1.0 mL / min, then 95% B1 and 5% A1 for 0.5 min, the percentage is the volume percentage of a certain solvent in the total solvent volume. Among them, solvent A1: 0.1% formic acid aqueous solution; solvent B1: 0.1% formic acid acetonitrile or ethanol solution. The percentage is the volume percentage of the solute in the solution.

[0138] LC-MS method two: measured by Aglient 1260 HPLC system and Aglient 1260 IPremier IQ mass spectrometer, using YMCC18 EXRS 2.1*33 mm, 3 um column. Gradient elution condition: 95-5% solvent A1 and 5-95% solvent B1 within 1.1 min at a flow rate of 1.2 mL / min, then 95% B1 and 5% A1 for 0.4 min, 1.51 min when A1 is 95% and B1 is 5%. The percentage is the volume percentage of a certain solvent in the total solvent volume. Among them, solvent A1: 0.1% formic acid aqueous solution, solvent B1: 0.1% formic acid acetonitrile or ethanol solution. The percentage is the volume percentage of the solute in the solution.

[0139] Example 1: Preparation of compound I-1

[0140] Methyl N-((2,4-dichlorobenzylcarbamoyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)carbamate (target compound I-1)

[0141] The synthetic route of the target compound I-1 is as follows:

[0142] First step: synthesis of N-(2,4-dichlorobenzyl)-5-fluoro-8-methylidene-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-1B)

[0143] Dissolve 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-1A) (160 mg, 0.8 mmol) in N,N-dimethylformamide (8.0 mL), then add triethylamine (236 mg, 2.3 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (360 mg, 0.9 mmol) and 2,4-dichlorobenzylamine (0.2 g, 0.8 mmol), and stir the reaction at 25°C for 8 hours. After the raw material disappears, dilute the reaction liquid with water (20.00 mL), then extract with ethyl acetate (30.0 mL x 2), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound N-(2,4-dichlorobenzyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-1B). LC-MS, M / Z (ESI): 365.1 [M+H] +

[0144] Second step: synthesis of N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-1C)

[0145] N-(2,4-dichlorobenzyl)-5-fluoro-8-methylen-5,6,7,8-tetrahydroquinoline-5- carboxamide (I-1B) (157.0 mg, 430 μmol) was dissolved in methanol (2.0 mL), tert-butyl alcohol (2.0 mL) and water (2.0 mL), then AD-mix-α (1.0 g, 2.1 mmol) was added, the reaction was stirred at 25 °C for 8 hours. After the disappearance of the raw material, the reaction was quenched with 1.00 M aqueous sodium sulfite solution (20.0 mL), then extracted with dichloromethane (20.0 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-1C). LC-MS, M / Z (ESI): 399.1 [M+H] +

[0146] Step 3: Synthesis of N-((2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinoline-8-yl)methyl-(2,2,2-trichloroacetyl)carbamate (I-1D)

[0147] N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-1C) (97 mg, 244 μmol) was dissolved in dichloromethane (1.0 mL), then 2,2,2-trichloroacetyl isocyanate (50.7 mg, 269 μmol) was added dropwise at 0 °C, the reaction was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction was concentrated to obtain compound N-((2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinoline-8-yl)methyl-(2,2,2- trichloroacetyl)carbamate (I-1D), which was directly used in the next step. LC-MS, M / Z (ESI): 586.0 [M+H] +

[0148] Step 4: Synthesis of methyl N-((2,4-dichlorobenzylcarbamoyl)-5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinoline-8-yl)carbamate (target compound I-1)

[0149] N-(2,4-dichlorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (I-1D) (146 mg, 250 μmol) was dissolved in methanol (2.0 mL), then potassium carbonate aqueous solution (2 M, 313 μL) was added dropwise at 0 °C, the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was diluted with water (20.0 mL), then extracted with ethyl acetate (20.0 mL x 3), the organic phase was combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography, the separation method was (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 15 min), then methyl N-((2,4-dichlorobenzylcarbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-1) was obtained. LC-MS, M / Z (ESI): 442.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H), 7.95 (s, 1H), 7.60-7.47 (m, 1H), 7.32 (s, 1H), 7.29-7.19 (m, 1H), 7.15 (d, 1H), 4.46 (d, 2H), 4.36 (s, 1H), 4.20 (dd, 1H), 2.65-2.42 (m, 1H), 2.37-2.03 (m, 3H).

[0150] Example 2: Preparation of compound I-2

[0151] Methyl N-((2-chloro-4-fluorobenzylcarbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-2)

[0152] The synthetic route of target compound I-2 is shown as follows:

[0153] First step: synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2B)

[0154] Dissolve 5-fluoro-8-methylenyl-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-1A) (1.0 g, 5 mmol) in N,N-dimethylformamide (20.0 mL), then add triethylamine (1.5 g, 15 mmol) and 2-(7-azabenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.1 g, 5.5 mmol) and 2-chloro-4-fluorobenzylamine (0.8 g, 5 mmol), and stir the reaction at 25 °C for 8 hours. After the raw material disappears, dilute the reaction with water (20.00 mL), then extract with ethyl acetate (30.0 mL x 2), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separation on a silica gel plate (petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylenyl-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2B). LC-MS, M / Z (ESI): 349.1 [M+H] +

[0155] Second step: synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2C)

[0156] Dissolve N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylenyl-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-1B) (0.7 g, 2 mmol) in methanol (5.0 mL), tert-butyl alcohol (10.0 mL), and water (10.0 mL), then add AD-mix-α (6.2 g, 8 mmol), and stir the reaction at 25 °C for 8 hours. After the raw material disappears, quench the reaction with 1.00 M aqueous sodium sulfite solution (20.0 mL), then extract with dichloromethane (20.0 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by separation on a silica gel column (petroleum ether: ethyl acetate (V / V) = 1:1) to obtain compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2C). LC-MS, M / Z (ESI): 383.1 [M+H] +

[0157] Third step: synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2C1) & (I-2C2) & (I-2C3) & (I-2C4)

[0158] Compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8- (hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-2C) (55.0 mg), purified by chiral prep separation, separation method was (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: [A = CO2, B = EtOH (0.1% NH3-H2O)]; B%: 28%, isocratic elution mode), to give compound (I-2C1) with retention time of 1.656 min. LC-MS, M / Z (ESI): 383.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H), 7.55 (d, 1H), 7.44-7.43 (m, 1H), 7.27-7.21 (m, 1H), 7.19 (td, 2H), 7.00 (td, 1H), 5.00 (d, 1H), 4.68-4.59 (m, 2H), 4.00 (d, 1H), 3.69 (t, 2H), 2.94-2.85 (m, 1H), 2.22-2.01 (m, 3H).

[0159] (I-2C2) with retention time of 2.048 min. LC-MS, M / Z (ESI): 383.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H), 7.55 (d, 1H), 7.44-7.43 (m, 1H), 7.27-7.21 (m, 1H), 7.19 (td, 2H), 7.00 (td, 1H), 5.00 (d, 1H), 4.68-4.59 (m, 2H), 4.00 (d, 1H), 3.69 (t, 2H), 2.94-2.85 (m, 1H), 2.22-2.01 (m, 3H).

[0160] (I-2C3) with retention time of 1.588 min. LC-MS, M / Z (ESI): 383.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H), 7.55 (d, 1H), 7.44-7.43 (m, 1H), 7.27-7.21 (m, 1H), 7.19 (td, 2H), 7.00 (td, 1H), 5.00 (d, 1H), 4.68-4.59 (m, 2H), 4.00 (d, 1H), 3.69 (t, 2H), 2.94-2.85 (m, 1H), 2.22-2.01 (m, 3H).

[0161] Retention time 1.866 min. LC-MS, M / Z (ESI): 383.1 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.55 (d, 1H), 7.55 (d, 1H), 7.44 - 7.43 (m, 1H), 7.27 - 7.21 (m, 1H), 7.19 (td, 2H), 7.00 (td, 1H), 5.00 (d, 1H), 4.68 - 4.58 (m, 2H), 3.99 (d, 1H), 3.70 (t, 2H), 2.96 - 2.81 (m, 1H), 2.22 - 2.03 (m, 3H).

[0162] Fourth step: synthesis of N-((2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl-(2,2,2-trichloroacetyl)carbamate (I-2D4)

[0163] N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-2C4) (382.1 mg, 1 mmol) was dissolved in dichloromethane (5.0 mL), then 2,2,2-trichloroacetyl isocyanate (224.4 mg, 1.2 μmol) was added dropwise at 0 °C, the reaction was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction liquid was concentrated to obtain compound N-((2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl-(2,2,2-trichloroacetyl)carbamate (I-2D4), which was directly used in the next step. LC-MS, M / Z (ESI): 586.0 [M+H] +

[0164] Fifth step: synthesis of methyl N-((2-chloro-4-fluorobenzylcarbamoyl)-5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-2)

[0165] N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (I-2D4) (150 mg, 263 μmol) was dissolved in methanol (5.0 mL), then potassium carbonate aqueous solution (2 M, 400 μL) was added dropwise at 0 °C, the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was diluted with water (10.0 mL), then extracted with ethyl acetate (10.0 mL x 3), the organic phase was combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography, the separation method was (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 15 min), then methyl N-((2-chloro-4-fluorobenzylcarbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-2) was obtained. LC-MS, M / Z (ESI): 326.1 [M+H] + . 1 H NMR (400 MHz, dmso) δ 9.14 (s, 1H), 8.63 (d, 1H), 7.58 (d, 1H), 7.49 - 7.30 (m, 2H), 7.24 (td, 1H), 6.39 (s, 1H), 5.36 (s, 1H), 4.62 - 4.28 (m, 3H), 4.21 (d, 1H), 2.72 - 2.49 (m, 1H), 2.30 - 2.03 (m, 2H), 1.92 (d, J = 13.9 Hz, 1H).

[0166] Example 3: Preparation of target compounds I-3P1 and I-3P2

[0167] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (target compound I-3P1)

[0168] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (target compound I-3P2)

[0169] The synthetic route of target compounds I-3P1 and I-3P2 is shown below:

[0170] First step: synthesis of 5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C2)

[0171] Compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C1). Retention time 1.835 min.

[0172] Compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C1). Retention time 1.835 min.

[0173] Compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C1). Retention time 1.835 min.

[0174] Second step: synthesis of (2-chloro-4-fluorophenyl)methane-d2-amine (I-3B)

[0175] Compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C1). Retention time 1.835 min. +

[0176] Third step: synthesis of N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-3D)

[0177] Dissolve 5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C2) (520 mg, 2.51 mmol) in dichloromethane (20.0 mL), then add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.15 g, 3.01 mmol), triethylamine (762 mg, 7.53 mmol, 1.05 mL), stir the reaction at 25 °C for 0.5 h, then add (2-chloro-4-fluorophenyl)methane-d2-amine (I-3B) (506.95 mg, 3.14 mmol), stir the reaction at 25 °C for 1 h. After the reaction is completed, dilute the reaction with water (20.0 mL), then extract with dichloromethane (10.0 mL x 3), wash the combined organic phase with brine (30.0 mL), dry over sodium sulfate, filter, and concentrate. Purify the crude product by silica gel plate separation (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain compound N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-3D). LC-MS, M / Z (ESI): 351.1 [M+H] +

[0178] Fourth step: synthesis of N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-3E)

[0179] Dissolve N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-3D) (600 mg, 1.71 mmol) in methanol (10.0 mL), tert-butyl alcohol (10.0 mL), and water (30.0 mL), then add AD-mix-α (3.00 g, 8.55 mmol), stir the reaction at 25 °C for 10 h. After the reaction is completed, quench the reaction with saturated aqueous sodium sulfite solution (200 mL), then extract with dichloromethane (50.0 mL x 3), collect the organic phase, dry over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 5:1-0:1) to obtain compound N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-3E). LC-MS, M / Z (ESI): 385.1 [M+H] +

[0180] Step 5: Synthesis of (5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (1-3F)

[0181] N-((2-chloro-4-fluorophenyl)methyl-d2)-5-fluoro-8-hydroxy-8-(hydroxymethyl)- 5,6,7,8-tetrahydroquinoline-5-carboxamide (1-3E) (550 mg, 1.43 mmol) was dissolved in dichloromethane (10.0 mL), then 2,2,2-trichloroacetyl isocyanate (296 mg, 1.57 mmol) was added dropwise at 0 °C, the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction was concentrated to obtain compound (5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (1-3F) (820 mg, crude), which was used directly in the next step. LC-MS, M / Z (ESI): 572.1 [M+H] +

[0182] Step 6: Synthesis of (5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl carbamate (1-3G)

[0183] (5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (1-3F) (820 mg, 1.43 mmol,) was dissolved in dichloromethane (10.0 mL), then neutral alumina (3.65 g, 35.8 mmol) was added at 0 °C, the reaction was stirred at 25 °C for 10 h. After the reaction was completed, the reaction was diluted with methanol (20.0 mL), then filtered, the filter cake was washed with dichloromethane (20.0 mL) and methanol (20.0 mL), the filtrate was combined and concentrated to obtain crude product. The crude product was separated and purified by high performance liquid chromatography, the separation method was (column: Phenomenex luna C18 150*40mm*15um; solvent: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 18%-48%, 15 min), to obtain compound (5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (1-3G). LC-MS, M / Z (ESI): 428.1 [M+H] +

[0184] Step 7: Synthesis of 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl carbamate (Target Compound I-3P1) and 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (Target Compound I-3P2)

[0185] Compound 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy- 5,6,7,8-tetrahydroquinolin-8-yl)methyl carbamate (I-3G) (350 mg, 818 pmol) was purified by chiral prep separation with the separation method of (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um; solvent: A = carbon dioxide, B = ammonia (0.1%) + acetonitrile / ethanol; gradient: 50%~50%, 3.3 min), to give compounds:

[0186] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (I-3P1). Retention time was 1.512 min. LC-MS, M / Z (ESI): 428.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.61-8.68 (m, 1H), 7.51 (d, 1H), 7.39-7.45 (m, 1H), 7.29 (d, 1H), 7.19-7.26 (m, 2H), 6.98-7.07 (m, 1H), 4.26-4.38 (m, 2H), 4.19 (s, 1H), 2.72-2.99 (m, 1H), 2.17-2.44 (m, 3H).

[0187] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl carbamate (I-3P2). Retention time was 1.740 min. LC-MS, M / Z (ESI): 428.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.64 (dt, 1H), 7.50-7.58 (m, 1H), 7.39-7.45 (m, 1H), 7.28-7.32 (m, 1H), 7.20 (dd, 1H), 7.10-7.16 (m, 1H), 7.00 (td, 1H), 4.55-4.75 (m, 2H), 4.34-4.55 (m, 2H), 3.43 (s, 1H), 2.55-2.72 (m, 1H), 2.16-2.41 (m, 3H).

[0188] Example 4: Preparation of target compounds I-4P1 and I-4P2

[0189] 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8- yl carbamate (target compound I-4P1)

[0190] 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8- yl carbamate (target compound I-4P2)

[0191] The synthetic route of target compounds I-4P1 and I-4P2 is shown below:

[0192] First step: Synthesis of 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C2)

[0193] Compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-1A) (2.50 g, 12.1 mmol), purified by chiral preparative separation, separation method (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 20% ~ 20%, 10 minutes), to give the following compounds:

[0194] 5-fluoro-8-methylen-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C1). Retention time 1.835 min.

[0195] 5-fluoro-8-methylen-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C2). Retention time 1.974 min.

[0196] Second step: Synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylen-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-4A)

[0197] Dissolve 5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (I-3C2) (180 mg, 869 μmol) in dichloromethane (2.00 mL), then add O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (396 mg, 1.04 mmol), N,N-diisopropylethylamine (337 mg, 2.61 mmol, 454 μL) and 2-chloro-4-fluorobenzylamine (139 mg, 869 μmol), stir the reaction at 25 °C for 1 hour. After the reaction is completed, dilute the reaction with water (10.0 mL), then extract with dichloromethane (10.0 mL x 3), dry the combined organic phases over sodium sulfate, filter, concentrate, and purify the crude product by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 20:1-5:1) to obtain compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-4A).

[0198] Third step: synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-4B)

[0199] Dissolve N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-methylene-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-4A) (750 mg, 2.15 mmol) in methanol (5.00 mL) and dichloromethane (5.00 mL), then cool to -70 °C, pass ozone gas for 15 minutes at -70 °C, then remove excess ozone by passing nitrogen gas for 15 minutes, then slowly drop dimethyl sulfide (670 mg, 10.8 mmol) into the reaction at -70 °C, stir the reaction at 25 °C for 3 hours. After the reaction is completed, concentrate the reaction to obtain the crude product. Purify the crude product by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 5:1-0:1) to obtain compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-4B). LC-MS, M / Z (ESI): 351.1 [M+H] +

[0200] Fourth step: synthesis of N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-4C)

[0201] Dissolve (R)-N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-oxo-5,6,7,8-tetrahydroquinoline-5- carboxamide (I-4B) (250 mg, 713 μmol) in tetrahydrofuran (5.00 mL), then add methyl magnesium bromide (3.00 M, 356 μL) dropwise at -70 °C under nitrogen protection, stir the reaction at -70 °C for 3 hours, then stir at 25 °C for 10 hours. After the reaction is completed, quench the reaction with saturated aqueous ammonium chloride solution (20.0 mL), then extract with ethyl acetate (20.0 mL x 3), dry the combined organic phase with sodium sulfate, filter, and concentrate. Purify the crude product by high performance liquid chromatography, separation method: (column: Waters Xbridge 150*25mm*5um; solvent: A = water + 0.05 volume of ammonia water (30%), B = acetonitrile; gradient: 26%-56%, 11 minutes), to obtain compound N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline-5- carboxamide (I-4C). LC-MS, M / Z (ESI): 367.1 [M+H] + .

[0202] Step 5: Synthesis of 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl (2,2,2-trichloroacetyl)carbamate (I-4D)

[0203] Dissolve N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-methyl-5,6,7,8-tetrahydroquinoline- 5-carboxamide (I-4C) (30.0 mg, 81.8 μmol) in dichloromethane (2.00 mL), then add 2,2,2- trichloroacetyl isocyanate (17.0 mg, 90.0 μmol) dropwise at 0 °C, stir the reaction at 0 °C for 2 hours. After the reaction is completed, concentrate the reaction to obtain compound 5-((2-chloro-4- fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl (2,2,2- trichloroacetyl)carbamate (I-4D) (crude), which is used directly in the next step. LC-MS, M / Z (ESI): 554.2 [M+H] +

[0204] Step 6: Synthesis of 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl carbamate (target compound I-4P1) and 5-((2-chloro-4-fluorobenzyl) carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8-yl carbamate (target compound I-4P2)

[0205] Dissolve 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl (2,2,2-trichloroacetyl)carbamate (I-4D) (45.0 mg, 81.1 µmol) in dichloromethane (3.00 mL), then add neutral alumina (124 mg, 1.22 mmol) dropwise at 0 °C, and stir the reaction at 25 °C for 10 hours. After the reaction is completed, dilute the reaction with methanol (10.0 mL), then filter, wash the filter cake with dichloromethane (10.0 mL) and methanol (10.0 mL), and concentrate the filtrate to obtain a crude product. Purify the crude product by high performance liquid chromatography, using the following separation method (column: Waters Xbridge 150*25mm*5µm; solvent: A = water + 0.05 volume ammonium bicarbonate (99%), B = acetonitrile; gradient: 25%-55%, 9 minutes) to obtain compound:

[0206] 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8- yl carbamate (I-4P1), retention time: 0.911 min. LC-MS, M / Z (ESI): 410.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.61-8.67 (m, 1H), 7.40-7.48 (m, 2H), 7.29-7.35 (m, 1H), 7.17-7.24 (m, 2H), 7.01 (td, 1H), 4.44-4.76 (m, 4H), 3.13 (td, 1H), 2.48-2.67 (m, 1H), 2.30-2.42 (m, 1H), 2.12-2.23 (m, 1H), 1.74 (s, 3H).

[0207] 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-methyl-5,6,7,8-tetrahydroquinolin-8- yl carbamate (I-4P2), retention time: 0.937 min. LC-MS, M / Z (ESI): 410.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.65-8.69 (m, 1H), 7.72 (dd, 1H), 7.33-7.41 (m, 1H), 7.29-7.32 (m, 1H), 7.20-7.26 (m, 1H), 7.09 (dd, 1H), 6.92 (td, 1H), 4.37-4.75 (m, 4H), 2.84-2.96 (m, 1H), 2.56-2.70 (m, 1H), 2.13-2.30 (m, 2H), 1.79 (s, 3H).

[0208] Example 5: Preparation of target compound I-5

[0209] 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl methylcarbamate (target compound I-5)

[0210] The synthetic route of target compound I-5 is shown below:

[0211] First step: synthesis of 4-nitrophenyl methylcarbamate (I-5B)

[0212] Methylamine hydrochloride (335 mg, 4.96 mmol) was dissolved in dichloromethane (10.0 mL), then triethylamine (1.51 g, 14.9 mmol, 2.07 mL) and p-nitrophenyl chloroformate (I-5A) (1.00 g, 4.96 mmol) were added dropwise at 0 °C, and the reaction was stirred at 0 °C for 1 h. After the reaction was completed, the reaction solution was diluted with dichloromethane (20.0 mL), then washed with water (20.0 mL x 3), and the organic phase was dried over sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column separation (petroleum ether: ethyl acetate (V / V) = 50:1-3:1) to obtain compound 4-nitrophenyl methylcarbamate (I-5B). LC-MS, M / Z (ESI): 197.1 [M+H] +

[0213] Second step: synthesis of 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8- hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl methylcarbamate (target compound I-5)

[0214] N-(2-chloro-4-fluorobenzyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8- tetrahydroquinoline-5-carboxamide (I-2C4) (100 mg, 261 μmol) was dissolved in dichloromethane (5.00 mL), then 1.8-diazabicyclo[5.4.0]undec-7-ene (99.4 mg, 653 μmol, 98.4 μL) and 4-nitrophenyl methylcarbamate (I-5B) (56.4 mg, 287 μmol) were added dropwise at 0 °C, the reaction was stirred at 25 °C for 10 h. After the reaction was completed, the reaction solution was concentrated, and the crude product was separated and purified by high performance liquid chromatography, the separation method was (chromatographic column: Waters Xbridge 150*25mm*5μm; solvent: A = water + 0.05 volume of ammonia water (30%), B = acetonitrile; gradient: 22%-52%, 11 min), to obtain compound 5-((2-chloro-4-fluorobenzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8- tetrahydroquinolin-8-yl)methyl methylcarbamate (I-5). LC-MS, M / Z (ESI): 440.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.57-8.69 (m, 1H), 7.53 (dt, 1H), 7.38-7.44 (m, 1H), 7.24-7.27 (m, 1H), 7.19 (dd, 1H), 7.09-7.17 (m, 1H), 7.00 (td, 1H), 4.53-4.76 (m, 3H), 4.36-4.52 (m, 2H), 3.36-3.49 (m, 1H), 2.79 (d, 3H), 2.55-2.70 (m, 1H), 2.15-2.45 (m, 3H).

[0215] Example 6: Preparation of target compounds I-6P1 and I-6P2

[0216] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl)carbamate (target compound I-6P1)

[0217] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl)carbamate (target compound I-6P2)

[0218] The synthesis route of target compounds I-6P1 and I-6P2 refers to the synthesis of reference compounds I-4P1 and I-4P2, and (2-chloro-4-fluorophenyl)methane-d2-amine (I-3B) is replaced for 2-chloro-4-fluorobenzylamine.

[0219] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl) carbamate (Target compound I-6P1), Retention time: 0.923 min. LC-MS, M / Z (ESI): 410.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.61 - 8.67 (m, 1H), 7.40 - 7.48 (m, 2H), 7.29 - 7.35 (m, 1H), 7.17 - 7.24 (m, 2H), 7.01 (td, 1H), 4.44 - 4.76 (m, 2H), 3.13 (td, 1H), 2.48 - 2.67 (m, 1H), 2.30 - 2.42 (m, 1H), 2.12 - 2.23 (m, 1H), 1.74 (s, 3H).

[0220] 5-(((2-chloro-4-fluorophenyl)methyl-d2)carbamoyl-5-fluoro-8-methyl-5,6,7,8- tetrahydroquinolin-8-yl) carbamate (Target compound I-6P1), Retention time: 0.923 min. LC-MS, M / Z (ESI): 410.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.65 - 8.69 (m, 1H), 7.72 (dd, 1H), 7.33 - 7.41 (m, 1H), 7.29 - 7.32 (m, 1H), 7.20 - 7.26 (m, 1H), 7.09 (dd, 1H), 6.92 (td, 1H), 4.37 - 4.75 (m, 2H), 2.84 - 2.96 (m, 1H), 2.56 - 2.70 (m, 1H), 2.13 - 2.30 (m, 2H), 1.79 (s, 3H).

[0221] Example 7: Preparation of target compound I-8

[0222] Methyl (N-((2-chloro-4-fluorobenzylcarbamoyl)-5,8-difluoro-5,6,7,8- tetrahydroquinolin-8-yl)carbamate (Target compound I-8)

[0223] The synthetic route of target compound I-8 is shown below:

[0224] Compound I-2C4 (400 mg, 0.9 mmol) was dissolved in dichloromethane (10.0 mL), diethylamine sulfide trifluoride (DAST) (320 mg, 2.0 mmol) was added at -20 °C, and stirred for 8 hours. The reaction was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 mL x 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography, the separation method was (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: A = water + 0.05 volume of formic acid (99%), B = acetonitrile; gradient: 25%-55%, 15 minutes), then methyl (N-((2-chloro-4-fluorobenzylcarbamoyl)-5,8-difluoro-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-8) was obtained. LC-MS, M / Z (ESI): 444.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, 1H), 7.85 (s, 1H), 7.60-7.47 (m, 1H), 7.32 (s, 1H), 7.29-7.29 (m, 1H), 7.15 (d, 1H), 4.46 (d, 2H), 4.36 (s, 2H), 2.68-2.52 (m, 2H), 2.37-2.13 (m, 2H).

[0225] Example 8: Preparation of target compound I-9

[0226] (N-((2,4-dichloro-benzylcarbamoyl)-5,8-difluoro-5,6,7,8-tetrahydroquinolin-8-yl)amino methylate (target compound I-9)

[0227] The synthetic route of target compound I-9 is shown below:

[0228] Compound I-1 (440 mg, 1.0 mmol) was dissolved in dichloromethane (10.0 mL), diethylamine sulfide trifluoride (DAST) (320 mg, 2.0 mmol) was added at -20 °C, and stirred for 8 hours. The reaction was diluted with water (20.00 mL), then extracted with ethyl acetate (30.0 mL x 2), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography, the separation method was (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A = water + 0.05 volume formic acid (99%), B = acetonitrile; gradient: 25%-55%, 15 minutes), then methyl (N-((2,4-dichloro-benzylcarbamoyl)-5,8-difluoro-5,6,7,8-tetrahydro-quinolin-8-yl)carbamate (target compound I-9) was obtained. LC-MS, M / Z (ESI): 444.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, 1H), 7.95 (s, 1H), 7.60-7.47 (m, 1H), 7.32 (s, 1H), 7.29-7.19 (m, 1H), 7.15 (d, 1H), 4.46 (d, 2H), 4.36 (s, 2H), 2.68-2.42 (m, 2H), 2.37-2.03 (m, 2H).

[0229] Test Example 1: Determination of the antagonistic activity of compounds on hP2X7 by FLIPR method

[0230] The determination of the inhibitory effect of compounds on hP2X7 calcium flow was carried out in HEK293 stable transfected cells overexpressing human P2X7 receptors, using the FLIPR Calcium 6 Assay Kit (Molecular Devices, R8191) and the FLIPR TETRA system (Molecular Devices) to detect calcium flow signals. The stable transfected cells were cultured in a 37 °C, 5% CO2 incubator, and TrypLE Express (Gibco, 12604036) was used to detach the cells. The cells were resuspended in a 384-well plate at a density of 50,000 cells / well, and incubated for 24 hours. The cells were then incubated with 10 μM probenecid for 30 minutes, and then the test compounds were added. After 5 minutes, ATP was added to induce calcium flow, and the calcium flow signals were detected by the FLIPR TETRA system. TMExpress cells were detached and counted (cell viability > 85%) and seeded into 384-well plates at a density of 20,000 cells / well in a volume of 30 μL per well and incubated overnight in an incubator. Prepare 2x dye buffer: dilute dye in assay buffer (1x HBSS with 20 mM HEPES, pH 7.4) with a final concentration of 5 mM probenecid. Remove cell culture plates from the incubator and remove the culture medium, add 10 μL assay buffer and 10 μL of 2x dye per well. Place the cell plates on a shaker at 600 rpm for 2 minutes. Incubate for 2 hours at 37°C and then for an additional 15 minutes at 25°C. Prepare test compounds as 10 mM stock solutions in DMSO and serially diluted in DMSO in a 384-well plate. Transfer different concentrations of compounds into a new 384-well plate using an Echo acoustic liquid handling system (Labcyte) at 90 nL per well. Add 30 μL / well of dilution buffer to the 384-well plate to obtain 3x compound solutions. Place the compound plate on a shaker for 2 minutes.

[0231] Place the cell plate, compound plate and tips into the FLIPR instrument and transfer the 3x compound solutions into the cell plate at a volume of 10 μL / well. Perform a plate read for 160 seconds at 1 second intervals to obtain agonist mode data and then store the cell plate in the dark at 25°C for 30 minutes. Calculate the EC 80 concentration of BzATP in assay buffer into a new 384-well compound plate at a volume of 30 μL / well. After incubation for 30 minutes at 25°C in the dark, place the cell plate, compound plate with BzATP and tips into the FLIPR instrument. Transfer the 4x EC 80 concentration of BzATP into the cell plate at a volume of 10 μL / well. Perform a plate read for 160 seconds at 1 second intervals to obtain antagonist mode data. Calculate the inhibition as follows: Inhibition (%) = 100 - (test value - low control mean) / (high control mean - low control mean)*100. Where the low control group is with EC 80 concentration of BzATP and the highest concentration of positive control (JNJ-47965567) and the high control group is with EC 80 concentration of BzATP only. Calculate the IC 80 values from the inhibition of different concentrations of compounds using XLift for curve fitting. 50

[0232] The results of the experiments show that the compounds exhibit excellent antagonistic activity against human P2X7.

[0233] ​Table 1 Antagonistic activity of test compounds on hP2X7

[0234] Test Example 2: Mouse pharmacokinetic test

[0235] The mouse pharmacokinetic test was performed on 3 male ICR mice, 20-30 g, which were fasted overnight and orally administered with 10 mg / kg. Blood was collected before administration and at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours after administration. The blood sample was centrifuged at 6000 g / min at 2-8°C for 3 minutes, and the plasma was collected and stored at -20°C. The plasma at each time point was mixed with 10 times the amount of 50% methanol acetonitrile solution containing an internal standard, vortexed for 5 minutes, centrifuged at 4000 rpm for 10 minutes at 4°C, mixed with 1 times the amount of water, and an appropriate amount of the mixture was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software using a non-compartment model.

[0236] The experimental results show that the compound of the present application has good pharmacokinetic characteristics in mice.

[0237] Test Example 3: Rat pharmacokinetic test

[0238] The rat pharmacokinetic test was performed on 3 male SD rats, 180-240 g, which were fasted overnight and orally administered with 10 mg / kg. Blood was collected before administration and at 15, 30 minutes and 1, 2, 4, 6, 8, 24 hours after administration. The blood sample was centrifuged at 8000 rpm for 6 minutes at 4°C, and the plasma was collected and stored at -20°C. The plasma at each time point was mixed with 3-5 times the amount of acetonitrile solution containing an internal standard, vortexed for 1 minute, centrifuged at 13000 rpm for 10 minutes at 4°C, mixed with 3 times the amount of water, and an appropriate amount of the mixture was subjected to LC-MS / MS analysis. The main pharmacokinetic parameters were analyzed by WinNonlin 7.0 software using a non-compartment model.

[0239] The experimental results show that the compound of the present application has good pharmacokinetic characteristics in rats.

[0240] Table 3 Rat pharmacokinetic test results

[0241] In the description of the specification, the description of the terms "one embodiment", "some embodiments", "an example", "a specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in connection with the embodiment or example are contained in at least one embodiment or example of the present application. In the specification, the illustrative description of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any suitable manner in any one or more embodiments or examples. In addition, the person skilled in the art can combine and combine the different embodiments or examples described in the specification and the features of the different embodiments or examples without contradiction.

[0242] Although the embodiments of the present application have been shown and described above, it is understood that the above-described embodiments are exemplary and are not to be construed as limiting the present application, and those skilled in the art can make changes, modifications, replacements and variations to the above-described embodiments within the scope of the present application.

Claims

The compounds shown in formula (I), their stereoisomers, solvates, pharmaceutically acceptable salts, or prodrugs: in: R 1 Selected from p R a The following groups are substituted: 6-15 aryl, 5-10 heteroaryl; p is an integer selected from 0, 1, 2, 3 and 4; R 2 R 3 Each is independently selected from hydrogen, deuterium, and q R. b Replacement C 1-6 Alkyl group; q is an integer selected from 0, 1, 2, 3, R b Each is independently selected from halogens, -OH, -CN, -NH2, oxo (=O), C 1-6 Alkyl and -OC 1-6 alkyl; Or, R 2 With R 3 In the equation, one is hydrogen, deuterium, or non-existent, and the other is related to R. 1 Formed by j R c Replacement of 3-7-membered rings; j is selected from 0, 1, 2, and 3; R a and R c Each is independently selected from halogens, -OH, -CN, and C. 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated C 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, C 3-7 cycloalkyl, -OC 3-7 Cycloalkyl, -S(O)rR a1 -SF5, -NR a1 R a2 The R a1 and R a2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, where r is an integer selected from 0, 1, or 2; R 4 Selected from hydrogen, deuterium, and fluorine; R 5 Selected from hydrogen, deuterium, halogens, -OH, -CN and K-terminated R d The following groups are substituted: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R 51 -(C=O)-NR 51 R 52 and -NR 51 R 52 ;k is an integer selected from 0, 1, 2, 3, and 4, R 51 and R 52 Each is independently selected from hydrogen, -OH, and C. 1-6 Alkyl groups, C groups substituted with hydroxyl groups 1-6 Alkyl, R d Selected from halogens, -OH, -CN, C 1-6 Alkyl and -OC 1-6 alkyl; R 6 and R 7 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl groups, C groups substituted with hydroxyl groups and / or halogens 1-6 alkyl; Or, R 6 R 7 The N atoms that can be connected with it can form a 3-7 membered heterocycle, which is then connected by u R atoms. e Replacement; u is selected from 0, 1, 2, 3, 4, 5, and 6, wherein R e Each is independently selected from halogens, -OH, oxo (=O), and C. 1-6 Alkyl, -OC 1-6 Alkyl, Halogenated C 1-6 Alkyl, -O-halogenated C 1-6 alkyl; m is selected from 0 and 1; n is selected from 0, 1 and 2. The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, R 1 In this context, the heteroatoms of the 5-10 member heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is one, two, or three. And / or, R 1 In this context, the 5-10 heteroaryl group is selected from thienyl, thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolithyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl. And / or, R 1 In this context, the 6-15 aryl group is selected from phenyl, indene, naphthyl, and azulel; And / or, R 1 In, the R a Each is independently selected from fluorine, chlorine, -OH, -CN, and C. 1-6 Alkyl, -SF5, -OC 1-6 Alkyl, Halogenated C 1-6 Alkyl, -O-halogenated C 1-6 Alkyl, C 3-7 cycloalkyl, -OC 3-7 Cycloalkyl, -S(O)rR a1 -NR a1 R a2 The R a1 and R a2 Each is independently selected from hydrogen and C. 1-6 Alkyl group, where r is an integer selected from 0, 1, 2; the C group alone or as part of other groups. 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and the C group, alone or as part of other groups, is also included. 3-7 The cycloalkyl groups are individually cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; And / or, R 1 Selected from And / or, R 1 Selected from The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, R 2 R 3 In, the C, either alone or as part of other groups 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; And / or, R 2 R 3 Each is independently selected from hydrogen, deuterium, methyl, and ethyl; And / or, when R 2 Or R 3 With R 1 Formed by j R c When the substituted 3-7 membered ring is used, the 3-7 membered ring is selected from 3-7 membered cyclic alkenyl and 3-7 membered heterocyclic alkenyl, and the 3-7 membered heterocyclic ring includes 1, 2 or 3 heteroatoms, and the heteroatoms are selected from N, O and S. The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, When R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from Indicates a single or double bond, X 1 X 2 and X 3 Each is independently selected from CH, CH2, N, NH, O, and S; t1 and t2 are independently selected from 0, 1, and 2 respectively; R a R c The definitions of p and j are as described in claim 1; And / or, when R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from X 1 X 2 and X 3 Each is independently selected from CH2, NH, O, and S; t1 and t2 are independently selected from 0, 1, and 2; R a R c The definitions of p and j are as described in claim 1; And / or, when R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from X 1 X 2 and X 3 Each is independently selected from CH2, NH, O, and S, and X 1 X 2 and X 3 At least one of them is selected from NH, O, and S; t1 and t2 are each independently selected from 0, 1, and 2; R a R c The definitions of p and j are as described in claim 1; And / or, when R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from X 1 Independently selected from NH, O, S, X 2 and X 3 Each is independently selected from CH2; t1 is 1, t2 is 1; R a R c The definitions of p and j are as described in claim 1; And / or, when R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from X 1 Independently selected from NH, O, S, X 2 and X 3 Each is independently selected from CH2; t1 is 1, t2 is 1; R a Each element is independently selected from halogens, p is selected from 1 and 2; j is 0; And / or, when R 2 Or R 3 With R 1 Formed by j R c When 3-7 membered rings are substituted, the group Selected from X 1 Independently selected from CH2, NH, O, S; R a R c The definitions of j are as described in claim 1. The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, R 5 Selected from hydrogen, halogens, -OH and K-type R d Replacement C 1-6 Alkyl; k is selected from 0, 1, 2, 3, and 4, R d Selected from halogens, -OH, -CN, C 1-6 Alkyl and -OC 1-6 alkyl; And / or, R 5 Selected from hydrogen, fluorine, chlorine, -OH, methyl and ethyl. The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, R 6 R 7 In, the C, either alone or as part of other groups 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl; And / or, R 6 R 7 Each is independently selected from hydrogen, methyl, and ethyl; And / or, when R 6 R 7 When the N atoms connected to it form a 3-7 membered heterocycle, the 3-7 membered heterocycle is a saturated ring; And / or, when R 6 R 7 When the N atom connected to it forms a 3-7 membered heterocycle, the 3-7 membered heterocycle is a saturated ring containing only one N atom; And / or, when R 6 R 7 When the N atoms connected to it form a 3-7 membered heterocycle, the 3-7 membered heterocycle is affected by u R atoms. e Replacement; u is selected from 0, 1, 2, and 3, wherein R e Each is independently selected from halogens, -OH, oxo (=O), and C. 1-3 Alkyl, Halogenated C 1-3 Alkyl, -OC 1-3 Alkyl, -O-halogenated C 1-3 alkyl; And / or, when R 6 R 7 When the N atom it is connected to forms a 3- to 7-membered heterocycle, the group Selected from The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 Selected from (2) Group Selected from (3) Group Selected from -NH2, The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, wherein, The compound is selected from the following structures: R 1 R 2 R 3 R 4 R 5 R 6 R 7 m and n have the definitions described in claim 1. The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, wherein, The compound is selected from the following structures: R a R 2 R 3 R 4 R 5 R 6 R 7 m, n, and p have the definitions described in claim 1. The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, wherein, The compound is selected from the following structures: in: p is an integer selected from 0, 1, and 2; R 2 R 3 Each is independently selected from hydrogen, deuterium, and q R. b Replacement C 1-6 Alkyl group; q is an integer selected from 0, 1, 2, 3, R b Each is independently selected from halogens and C. 1-6 alkyl; R a Each is independently selected from halogens, -OH, -CN, and C. 1-6 alkyl; R 4 Selected from fluorine; R 5 Selected from hydrogen, deuterium, halogens, -OH and K-terminated R d The following groups are substituted: C 1-6 Alkyl group; k is an integer selected from 0, 1, 2, 3, and 4, R d Selected from halogens, -OH and C 1-6 alkyl; R 6 and R 7 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl groups, C groups substituted with hydroxyl groups and / or halogens 1-6 alkyl; n is selected from 0, 1, and 2. The compound of claim 1, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, wherein, The compound is selected from the following structures: in: R 2 R 3 Each is independently selected from hydrogen and deuterium; R a Each is independently selected from fluorine and chlorine; R 5 Selected from halogens, -OH and C 1-6 alkyl; R 6 and R 7 Each is independently selected from hydrogen, deuterium, and C. 1-6 alkyl. The compound of claim 11, its stereoisomers, solvates, pharmaceutically acceptable salts or prodrugs, wherein, Group Selected from And / or, R 5 Selected from fluorine and -OH; and / or, groups Selected from -NH2 and The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound shown in formula (I) is selected from the following structures: The compound of formula (I) as described in claim 1, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, wherein, The compound shown in formula (I) is selected from the following structures: A pharmaceutical composition wherein, The compound of formula (I) according to any one of claims 1 to 14 contains an effective dose, including its stereoisomer, solvate, pharmaceutically acceptable salt, or prodrug. The use of the compound of formula (I) according to any one of claims 1 to 14, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, or the pharmaceutical composition according to claim 15, wherein, The uses include: Antagonizes P2X7 receptor activity; And / or, prevent and / or treat conditions or disorders mediated by P2X7 receptor antagonistic activity; And / or, to prepare a medicine, pharmaceutical composition or preparation for antagonizing P2X7 receptor activity, and / or for preventing and / or treating conditions or disorders mediated by P2X7 receptor antagonistic activity. The use as described in claim 16, wherein, The symptoms or disorders mentioned are selected from pain, central nervous system diseases, immune diseases, inflammation and inflammation-related diseases. A method for preventing and / or treating conditions or disorders mediated by P2X7 receptor antagonistic activity, wherein, The method comprises administering to a subject in need the compound of formula (I) of any one of claims 1 to 14, its stereoisomer, solvate, pharmaceutically acceptable salt or prodrug, and / or the pharmaceutical composition of claim 15. The method of claim 18, wherein, The symptoms or disorders mentioned are selected from pain, central nervous system diseases, immune diseases, inflammation and inflammation-related diseases.

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