Sf 5-containing quinoline derivatives and use thereof as p2x7 antagonists

Abstract

The present invention provides novel compounds capable of effectively antagonizing P2X7, which are compounds shown as the following formula (I), or stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs of the compounds shown as the formula.

Description

SF5-containing quinoline derivatives and their use as P2X7 antagonists Technical Field

[0001] The present invention relates to the field of biomedicine, specifically, the present invention relates to SF5-containing quinoline derivatives, more specifically, the present invention relates to SF5-containing quinoline derivatives and their use as P2X7 antagonists. Background Art

[0002] P2 receptors are cell membrane receptors that bind to extracellular nucleotides (such as ATP and ADP). These receptors are divided into two major families: ligand-gated ion channel receptors P2X and G-protein-coupled receptors P2Y. P2X receptors are divided into seven subtypes (P2X1-7). P2X7 receptors are closely associated with the development and progression of numerous diseases. Activation of P2X7 receptors can open ion channels on the cell membrane (allowing the influx of sodium and calcium ions and the efflux of potassium ions), activating multiple intracellular signaling pathways and releasing a variety of inflammatory cytokines, damaging the nervous system and inducing pain. Within the nervous system, P2X7 receptor activation primarily activates microglia, releasing inflammatory cytokines that damage the nervous system. Furthermore, upregulated P2X7 receptor expression can activate immune cells, promote inflammatory responses, increase tissue damage, and exacerbate pain. Studies have found that P2X7 receptors are overexpressed in various tumors and are closely associated with tumor progression, metastasis, and angiogenesis. Therefore, antagonizing P2X7 receptors can effectively prevent and treat the development and progression of various diseases, including pain, central nervous system disorders, immune disorders, and inflammatory diseases, and has important clinical applications. Summary of the Invention

[0003] The present invention aims to solve at least one of the technical problems existing in the prior art to a certain extent. Therefore, the present invention provides a SF5-containing quinoline derivative used as a P2X7 antagonist and its preparation method and use.

[0004] In the first aspect of the present invention, the present invention provides a compound as shown in formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound as shown in formula (I):

[0005] in:

[0006] X 1 、X 2 、X 3 、X 4 are each independently selected from CH, N;

[0007] R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3;

[0008] R 2 、R 3 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl; or, R 2 Can be used with R 3 Forming 3 to 6 membered rings;

[0009] R 4 are independently selected from halogen, n is an integer selected from 0, 1, 2, 3;

[0010] R 5 、R 6 are independently selected from hydrogen, halogen, hydroxy, cyano, -O-(C=O)-NR b1 R b2 , and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0011] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-Rb1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0012] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0013] According to certain embodiments of the present invention, the present invention provides a compound as represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

[0014] in:

[0015] X 1 、X 2 、X 3 、X 4 are each independently selected from CH, N;

[0016] R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3;

[0017] R 2 、R 3are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl; or, R 2 Can be used with R 3 Forming 3 to 6 membered rings;

[0018] R 4 are independently selected from halogen, n is an integer selected from 0, 1, 2, 3;

[0019] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0020] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0021] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0022] According to certain embodiments of the present invention, the present invention provides a compound as represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

[0023] in:

[0024] X 1 、X 2 、X 3 、X 4 are each independently selected from CH, N;

[0025] R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3;

[0026] R 2 、R 3 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl; or, R 2 Can be used with R 3 Forming 3 to 6 membered rings;

[0027] R 4 are independently selected from halogen, n is an integer selected from 0, 1, 2, 3;

[0028] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0029] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0030] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0031] According to certain embodiments of the present invention, in the compound represented by formula (I), X 1 、X 2 、X 3 and X 4 At least one of them is N and at most two of them are N; the undefined groups are as described in any scheme of the present invention.

[0032] According to certain embodiments of the present invention, in the compound represented by formula (I), X 4 N, X 1 、X 2 and X3 is CH; undefined groups are as described in any scheme of the present invention.

[0033] According to certain embodiments of the present invention, in the compound represented by formula (I), X 1 、X 4 N, X 2 and X 3 is CH; undefined groups are as described in any scheme of the present invention.

[0034] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 In the embodiment, the heteroatoms of the 5-6 membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; the undefined groups are as described in any embodiment of the present invention.

[0035] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 In the case of R a independently selected from -(C=O)-R a1 、-(C=O)-NR a1 R a2 When the R a1 and R a2 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0036] According to certain embodiments of the present invention, in the compound represented by formula (I), R 2 、R 3 In the embodiment, the 3- to 6-membered ring contains 0, 1, 2 or 3 heteroatoms selected from N, O, and S. When the number of heteroatoms is 2 or 3, the types of heteroatoms are 1, 2 or 3; the undefined groups are as described in any embodiment of the present invention.

[0037] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 In the case of R 5 and R 6 Each independently selected from 0, 1, 2 or 3 R b Substituted-(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 When the R c1 and R c2 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0038] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 、R 2 、R 3 、R 5 、R 6 In the C 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0039] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 、R 5 、R 6 In the C 3-6 The cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; undefined groups are as described in any embodiment of the present invention.

[0040] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from a 3- to 7-membered heterocycloalkyl group and a 3- to 7-membered heterocycloalkenyl group, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; and the undefined group is as described in any scheme of the present invention.

[0041] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 wherein the heteroatoms of the 5- to 8-membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; and the undefined groups are as described in any embodiment of the present invention.

[0042] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and the undefined groups are as described in any embodiment of the present invention.

[0043] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 In the case of R b independently selected from -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 When the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0044] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 wherein the 5-6 membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and undefined groups are as described in any embodiment of the present invention.

[0045] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from a 3- to 7-membered heterocycloalkyl group and a 3- to 7-membered heterocycloalkenyl group, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or two of N, O, and S, and the number of heteroatoms is one or two; and the undefined group is as described in any scheme of the present invention.

[0046] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 wherein the 5- to 8-membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and undefined groups are as described in any embodiment of the present invention.

[0047] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 、R 6 In the 3- to 6-membered heterocycloalkyl group, the heteroatoms are selected from one or two of N, O, and S, and the number of heteroatoms is one or two; the undefined groups are as described in any embodiment of the present invention.

[0048] According to certain embodiments of the present invention, in the compound represented by formula (I), when R 1 Selected from p R a When phenyl is substituted, p is 0, 1, 2 or 3, R a Independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0049] According to certain embodiments of the present invention, in the compound represented by formula (I), when R 1 Selected from p R a When the 5-6 membered heteroaryl is substituted, the 5-6 membered heteroaryl is selected from 6 membered heteroaryl, p is 0, 1, 2 or 3, R a Independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0050] According to certain embodiments of the present invention, in the compound represented by formula (I), when R a independently selected from -(C=O)-R a1 、-(C=O)-NR a1 R a2 When the R a1 and R a2 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0051] According to certain embodiments of the present invention, in the compound represented by formula (I), when R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, the C 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0052] According to certain embodiments of the present invention, in the compound represented by formula (I), when R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted-(C=O)-R c1 、-(C=O)-NR c1 R c2 and -NR c1 R c2 When the R c1 and R c2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; undefined groups are as described in any embodiment of the present invention.

[0053] According to certain embodiments of the present invention, in the compound represented by formula (I), when R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0054] According to certain embodiments of the present invention, in the compound represented by formula (I), R 1 Selected from unsubstituted or 1 R a Substituted phenyl, pyridyl, said R a is selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0055] According to certain embodiments of the present invention, in the compound represented by formula (I), R 2 and R 3 Each is independently selected from hydrogen, methyl, and ethyl; undefined groups are as described in any embodiment of the present invention.

[0056] According to certain embodiments of the present invention, in the compound represented by formula (I), R 4 are independently selected from fluorine and chlorine; undefined groups are as described in any embodiment of the present invention.

[0057] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 and R 6 Each independently selected from hydrogen, hydroxy, 0 or 1 R b Substituted with the following groups: C 1-6 Alkyl, -(C=O)-NR c1 R c2 , R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0058] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 and R 6 Each independently selected from hydrogen, hydroxyl, b Substituted C 1-6 Alkyl, the R b Selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0059] According to certain embodiments of the present invention, in the compound represented by formula (I), R 5 and R 6 Each independently selected from hydrogen, hydroxy, -O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0060] According to certain embodiments of the present invention, the compound is a compound represented by formula (II), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II):

[0061] in:

[0062] X 1 、X 4 are each independently selected from CH, N;

[0063] R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3;

[0064] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0065] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0066] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0067] According to certain embodiments of the present invention, the compound is a compound represented by formula (II-1), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II-1):

[0068] in:

[0069] X 1 、X 4 are each independently selected from CH, N;

[0070] R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3;

[0071] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0072] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0073] R b1 and Rb2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0074] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the embodiment, the heteroatoms of the 5-6 membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; the undefined groups are as described in any embodiment of the present invention.

[0075] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the case of R a independently selected from -(C=O)-R a1 、-(C=O)-NR a1 R a2 When the R a1 and R a2 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0076] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the C 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0077] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the C 3-6 The cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; undefined groups are as described in any embodiment of the present invention.

[0078] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1wherein the 5-6 membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and undefined groups are as described in any embodiment of the present invention.

[0079] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the case of R 1 Selected from p R a When phenyl is substituted, p is 0, 1, 2 or 3, R a Independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0080] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In the case of R 1 Selected from p R a When the 5-6 membered heteroaryl is substituted, the 5-6 membered heteroaryl is selected from 6 membered heteroaryl, p is 0, 1, 2 or 3, R a Independently selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0081] According to an embodiment of the present invention, in the compound represented by formula (II) or formula (II-1), R 1 In, R 1 Selected from unsubstituted or 1 R a Substituted phenyl, pyridyl, said R a is selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0082] According to an embodiment of the present invention, the compound is a compound represented by formula (III), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (III):

[0083] in:

[0084] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0085] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0086] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0087] According to an embodiment of the present invention, the compound is a compound represented by formula (III-1), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (III-1):

[0088] in:

[0089] R 5 、R 6 Each independently selected from hydrogen, halogen, hydroxyl, cyano and 0, 1, 2 or 3 R b Substituted with the following groups: C1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl;

[0090] R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S;

[0091] R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

[0092] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the case of R 5 and R 6 Each independently selected from 0, 1, 2 or 3 R b Substituted-(C=O)-Rc1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 When the R c1 and R c2 Each independently selected from hydrogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0093] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the C 1-6 The alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; undefined groups are as described in any embodiment of the present invention.

[0094] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the C 3-6 The cycloalkyl groups are independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; undefined groups are as described in any embodiment of the present invention.

[0095] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from a 3- to 7-membered heterocycloalkyl group and a 3- to 7-membered heterocycloalkenyl group, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one, two or three of N, O and S, and the number of heteroatoms is 1, 2 or 3; and the undefined group is as described in any scheme of the present invention.

[0096] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 wherein the heteroatoms of the 5- to 8-membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; and the undefined groups are as described in any embodiment of the present invention.

[0097] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1, 2, or 3; and the undefined groups are as described in any embodiment of the present invention.

[0098] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the case of R b independently selected from -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 When the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0099] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from a 3- to 7-membered heterocycloalkyl group and a 3- to 7-membered heterocycloalkenyl group, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or two of N, O, and S, and the number of heteroatoms is one or two; and the undefined group is as described in any scheme of the present invention.

[0100] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 wherein the 5- to 8-membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and undefined groups are as described in any embodiment of the present invention.

[0101] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the 3- to 6-membered heterocycloalkyl group, the heteroatoms are selected from one or two of N, O, and S, and the number of heteroatoms is one or two; the undefined groups are as described in any embodiment of the present invention.

[0102] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the case of R 5 and R6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, the C 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0103] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the case of R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted-(C=O)-R c1 、-(C=O)-NR c1 R c2 and -NR c1 R c2 When the R c1 and R c2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; undefined groups are as described in any embodiment of the present invention.

[0104] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In the case of R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0105] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R6 In, R 5 and R 6 Each independently selected from hydrogen, hydroxy, 0 or 1 R b Substituted with the following groups: C 1-6 Alkyl, -(C=O)-NR c1 R c2 , R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl; undefined groups are as described in any embodiment of the present invention.

[0106] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In, R 5 and R 6 Each independently selected from hydrogen, hydroxyl, b Substituted C 1-6 Alkyl, the R b Selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0107] According to an embodiment of the present invention, in the compound represented by formula (II), formula (II-1), formula (III) or formula (III-1), R 5 、R 6 In, R 5 and R 6 Each independently selected from hydrogen, hydroxy, -O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl, and isopropyl; the undefined group is as described in any embodiment of the present invention.

[0108] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), R 5 and R 6 Each independently selected from hydrogen, hydroxy, methyl, -CH2-OH, -(CH2)2-OH, Undefined groups are as described in any embodiment of the present invention.

[0109] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), R 5 and R 6 Each independently selected from hydrogen, hydroxy, -CH2-OH, -(CH2)2-OH, Undefined groups are as described in any embodiment of the present invention.

[0110] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), R 5 and R 6 Each is independently selected from hydrogen, hydroxyl, -CH2-OH, -(CH2)2-OH; undefined groups are as described in any embodiment of the present invention.

[0111] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), when R 5 and R 6 When one of them is -OH, the other is -CH2-OH or -(CH2)2-OH; the undefined group is as described in any embodiment of the present invention.

[0112] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), when R 5 and R 6 When one of them is -OH, the other is Undefined groups are as described in any embodiment of the present invention.

[0113] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), when R 5 and R 6When one of them is methyl, the other is -OH, -CH2-OH, Undefined groups are as described in any embodiment of the present invention.

[0114] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), when R 5 and R 6 When one of them is hydrogen, the other is

[0115] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), the group Selected from

[0116] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), the group Selected from Undefined groups are as described in any embodiment of the present invention.

[0117] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), the group Selected from Undefined groups are as described in any embodiment of the present invention.

[0118] According to certain embodiments of the present invention, in the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), the group Selected from Undefined groups are as described in any embodiment of the present invention.

[0119] According to certain embodiments of the present invention, the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) may be any of the following compounds or any of the following stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0120] According to certain embodiments of the present invention, the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) may be any of the following compounds or any of the following stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0121] According to certain embodiments of the present invention, the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1), or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I), formula (II), formula (II-1), formula (III) or formula (III-1) may be any of the following compounds or any of the following stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0122] In the second aspect of the present invention, the present invention also provides a pharmaceutical composition comprising the compound described in the first aspect, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect.

[0123] In the pharmaceutical composition, the compound of the first aspect, or the pharmaceutical composition of the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of the first aspect may be a therapeutically effective dose.

[0124] In the third aspect of the present invention, the present invention further provides use of the compound of the first aspect, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound of the first aspect, or the pharmaceutical composition of the second aspect of the present invention in the preparation of a medicament for treating diseases mediated by P2X7 receptor antagonist activity.

[0125] According to certain embodiments of the present invention, in the use, the disease mediated by P2X7 receptor antagonism is selected from the following diseases: pain, central nervous system diseases, immune diseases, inflammation and inflammation-related diseases.

[0126] In the fourth aspect of the present invention, the present invention further provides the use of the compound described in the first aspect, or the stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound described in the first aspect, or the pharmaceutical composition described in the second aspect of the present invention in the treatment of P2X7 receptor-mediated related diseases.

[0127] According to certain embodiments of the present invention, in the use, the P2X7 receptor-mediated related diseases are selected from the following diseases: pain, central nervous system diseases, immune diseases, inflammation and inflammation-related diseases.

[0128] In a fifth aspect, the present invention further provides a method for preventing and / or treating P2X7 receptor-mediated diseases. According to an embodiment of the present invention, the method comprises administering to a subject a pharmaceutically acceptable dose of a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug of the compound of the first aspect, or the pharmaceutical composition of the second aspect of the present invention.

[0129] According to certain embodiments of the present invention, in the use, the P2X7 receptor-mediated related diseases are selected from the following diseases: pain, central nervous system diseases, immune diseases, inflammation and inflammation-related diseases.

[0130] Definitions and Explanations of Terms

[0131] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The resulting group definitions and compound structures shall fall within the scope of the description of this specification.

[0132] Unless otherwise defined, all technical and scientific terms herein have the same meanings as commonly understood by persons skilled in the art to which the claimed subject matter belongs. Unless otherwise indicated, all patents, patent applications, and publications cited herein are incorporated by reference in their entirety. If multiple definitions of a term are used herein, the definitions in this section shall prevail.

[0133] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR, IR and UV / Vis spectroscopy and pharmacological methods, are adopted. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceuticals and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, as well as in the treatment of patients. For example, the manufacturer's instructions for use of a test kit can be utilized, or reaction and purification can be implemented according to a manner well known in the art or the application's description. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description in a plurality of summaries and more specific documents cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0134] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents that would result from writing the formula from right to left. For example, CHO is equivalent to OCH. As used herein, Indicates the attachment site of a group.

[0135] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicates the relative configuration of a stereocenter.

[0136] When the numerical ranges described in the specification and claims of this application are understood as “integers”, they should be understood as recording the two endpoints of the range and each integer within the range. For example, “an integer from 1 to 6” should be understood as recording each integer of 1, 2, 3, 4, 5, and 6. When the numerical range is understood as a “number”, it should be understood as recording the two endpoints of the range and each integer within the range and each decimal within the range. For example, “a number from 1 to 10” should be understood as recording not only each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, but also at least the sum of each of these integers and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, and 0.9, respectively.

[0137] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that 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 problems or complications, commensurate with a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

[0139] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0140] The term "stereoisomer" refers to isomers resulting from the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformers. The stereochemical definitions and conventions used herein are generally those of SP 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.

[0141] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0142] When bonds to chiral carbon atoms in formulae of the present invention are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The diagrammatic representations of racemates and enantiomerically pure compounds herein are adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0143] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0144] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0145] With respect to a drug or pharmacologically active agent, the terms "effective dose," "effective amount," or "therapeutically effective amount" refer to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For oral dosage forms of the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0146] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0147] The term "solvate" refers to a compound of the present invention or a salt thereof including a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate.

[0148] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0149] As used herein, the term "treatment" refers to any agent used to obtain a desired pharmacological and / or physiological effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partially or completely curing a disease and / or the adverse effects caused by the disease. "Treatment" as used herein covers diseases in mammals, particularly humans, and includes: (a) preventing the occurrence of a disease or condition in an individual who is susceptible to the disease but has not yet been diagnosed with the disease; (b) inhibiting the disease, such as arresting the progression of the disease; or (c) alleviating the disease, such as alleviating the symptoms associated with the disease. "Treatment" as used herein covers any medication that administers a drug to an individual to treat, cure, alleviate, improve, reduce or inhibit the individual's disease, including but not limited to administering the drug herein to an individual in need.

[0150] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or C-14( 14C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0151] The term "C 1-6 "Alkyl" is understood to mean a linear or branched, saturated, monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. Such alkyl radicals are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc. or their isomers. In particular, the group has 1, 2 or 3 carbon atoms ("C1-C3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.

[0152] The term "C 3-6 "Cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic or bridged hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane.

[0153] The term "oxo" refers to =0. When oxo is substituted on a carbon chain, they together form a carbonyl moiety [-C(=O)-]. When oxo is substituted on a ring, one or more atoms on the ring are replaced by -C(O)-, for example, 2-pyridonyl.

[0154] The term "3- to 7-membered heterocyclic" substituent is understood to mean a monocyclic or bicyclic ring having 3 to 7 ring atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, and unless otherwise stated, they may be attached via carbon or nitrogen, wherein a -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide; "3- to 7-membered heterocyclic ring" includes "3- to 7-membered heterocycloalkyl" and "3- to 7-membered heterocycloalkenyl".

[0155] The term "3- to 6-membered heterocycloalkyl" or "3- to 7-membered heterocycloalkyl" is understood to mean a saturated monocyclic or bicyclic ring having 3 to 6 ring atoms or 3 to 7 ring atoms, wherein 1, 2 or 3 ring atoms are selected from N, O and S. Unless otherwise indicated, "3- to 6-membered heterocycloalkyl" and "3- to 7-membered heterocycloalkyl" may be attached to the remainder of the molecule via a carbon or heteroatom, wherein a -CH2- group is optionally replaced by -C(O)-; and wherein, unless otherwise indicated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted by an acetyl, formyl, methyl or methylsulfonyl group; and the ring is optionally substituted by one or more halogens. It should be understood that when the total number of S atoms and O atoms in the heterocyclyl group exceeds 1, these heteroatoms are not adjacent to each other.

[0156] The term "3-7 membered heterocycloalkenyl" is understood to mean a monocyclic or bicyclic ring system containing at least one carbon-carbon double bond (C=C), wherein the bicyclic ring system includes spirocyclic, fused and bridged rings, and any ring of the system is non-aromatic. Some of the ring atoms of the "3-7 membered heterocycloalkenyl" are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms can be optionally oxoed (i.e., C(=O), NO and S(O)p, where p is 1 or 2). In addition, heteroatoms can occupy the position at which the heterocycloalkenyl is connected to the rest of the molecule. The 3-7 membered heterocycloalkenyl includes 3-membered, 4-membered, 5-membered, 6-membered and 7-membered heterocycloalkenyls, etc. In some embodiments, the heterocycloalkenyl group is preferably a 3- to 6-membered heterocycloalkenyl group; examples of 3- to 6-membered heterocycloalkenyl groups include, but are not limited to, dihydrofuranyl, dihydrothiophenyl, 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.

[0157] The term "5-6 membered heteroaryl" is understood to mean a monovalent monocyclic aromatic ring radical having 5-6 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S. Examples of 5-6 membered heteroaryl radicals include, but are not limited to, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl and the like.

[0158] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0159] "Haloalkyl" refers to a saturated aliphatic hydrocarbon group, including branched and straight chains, having the specified number of carbon atoms, substituted with one or more halogens (e.g., -CvFw, where v = 1 to 3 and 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 heptachloropropyl. Beneficial effects

[0160] According to a specific example of the present invention, the compound of the present invention, its stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs have a good antagonistic effect on P2X7.

[0161] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention. DETAILED DESCRIPTION

[0162] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0163] Embodiments of the present invention provide compounds of formula (I), pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, cocrystals or prodrugs thereof, methods and intermediates for preparing compounds of formula (I) or pharmaceutically acceptable salts, tautomers, stereoisomers, hydrates, solvates, cocrystals or prodrugs thereof, pharmaceutical compositions, and uses of the compounds and pharmaceutical compositions of the present invention in preparing drugs.

[0164] The reaction solvents used in each reaction step described in the present invention are not particularly limited. Any solvent that can dissolve the starting materials to a certain extent and does not inhibit the reaction is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different ratios of solvent combinations equivalent to those described in the present invention are considered to be within the scope of the present invention.

[0165] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10-6 (ppm). The solvents used for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0166] Liquid chromatography-mass spectrometry (LC-MS) was performed on a Waters Acquity H-class UPLC-QDA mass spectrometer using an ACQUITY UPLC BEH C18, 2.1 x 50 mm, 1.7 μm column. Gradient elution conditions were: 95% to 5% solvent A1 and 5% to 95% solvent B1, followed by 95% B1 and 5% A1 for 0.5 min, at a flow rate of 1.0 mL / min. Percentages represent the volume percentage of a particular solvent relative to the total solvent volume. Solvent A1: 0.1% formic acid in water; Solvent B1: 0.1% formic acid in acetonitrile. Percentages represent the volume percentage of the solute relative to the total solvent volume.

[0167] The abbreviations of the present invention are defined as follows:

[0168] NCS: N-chlorosuccinimide

[0169] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0170] AD-mix-α:

[0171] SFC: Supercritical Fluid Chromatography

[0172] LiHMDS: Lithium bis(trimethylsilyl)amide

[0173] NaHMDS: sodium bis(trimethylsilyl)amide

[0174] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0175] NFSI: N-fluorobis(benzenesulfonamide)

[0176] M:mol / L

[0177] Example 1: Preparation of target compound I-1

[0178] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1)

[0179] The synthetic route of target compound I-1 is as follows:

[0180] Step 1: Synthesis of 2-chloro-4-(pentafluoromercapto)phenol (1A-2)

[0181] 4-(Pentafluoromercapto)phenol (1A-1) (9.50 g, 43.2 mmol) was dissolved in anhydrous acetonitrile (MeCN, 100 mL). N-chlorosuccinimide (NCS, 6.34 g, 47.5 mmol) and trifluoromethanesulfonic acid (TfOH, 7.12 g, 47.5 mmol) were then added at 0°C. The reaction was stirred at 35°C for 8 hours. After the starting material disappeared, the reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL x 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the compound 2-chloro-4-(pentafluoromercapto)phenol (1A-2) (crude product).

[0182] LC-MS, M / Z(ESI):252.8[MH] +

[0183] Step 2: Synthesis of 2-chloro-4-(pentafluoromercapto)phenyltrifluoromethanesulfonic acid anion (1A-3)

[0184] 2-Chloro-4-(pentafluoromercapto)phenol (1A-2) (9.00 g, 35.4 mmol) was dissolved in pyridine (50.0 mL). Trifluoromethanesulfonic anhydride (Tf2O, 11.0 g, 38.9 mmol) was then added at 0°C under nitrogen. The reaction was stirred at 25°C for 4 hours. After the starting material disappeared, the reaction solution was quenched with 1.00 M hydrochloric acid (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was collected, washed with 1.00 M hydrochloric acid (50.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 100:1 to 50:1) to obtain 2-chloro-4-(pentafluoromercapto)phenyltrifluoromethanesulfonic acid anion (1A-3).

[0185] LC-MS, M / Z (ESI): 385.0 [MH] +

[0186] Step 3: Synthesis of 2-chloro-4-(pentafluoromercapto)benzonitrile (1A-4)

[0187] 2-Chloro-4-(pentafluoromercapto)phenyl trifluoromethanesulfonic acid anion (1A-3) (9.00 g, 23.3 mmol) was dissolved in N,N-dimethylformamide (90.0 mL). Zinc cyanide (Zn(CN)2, 5.47 g, 46.6 mmol) and tetrakistriphenylphosphine palladium (2.69 g, 2.33 mmol) were then added under nitrogen. The mixture was then reacted at 120°C for 4 hours. After the starting material disappeared, the reaction solution was quenched with 1.00 M sodium bicarbonate (80.0 mL) and extracted with ethyl acetate (100 mL x 2). 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) = 100:1-10:1), and then separated and purified again by reverse phase column (solvent: A = water + 0.001 volume of ammonia water (30%), B = acetonitrile) to obtain compound 2-chloro-4-(pentafluoromercapto)benzonitrile (1A-4).

[0188] Step 4: Synthesis of 1-(2-chloro-4-(pentafluoromercapto)phenyl)methanamine (1A)

[0189] 2-Chloro-4-(pentafluoromercapto)benzonitrile (1A-4) (1.00 g, 3.79 mmol) was dissolved in methanol (100 mL). Raney nickel (250 mg, 2.92 mmol) was then added under argon to displace the hydrogen atmosphere. The mixture was then reacted at 50 psi and 25°C for 3 hours. After the starting material disappeared, the reaction solution was filtered, the filtrate was concentrated to dryness, and the crude product was separated and purified by high-performance liquid chromatography (HPLC column: Waters Xbridge 150*25 mm*5 μm; solvent: A = water + 0.05 vol ammonia (99%), B = acetonitrile; gradient: 28%-58% over 10 minutes) to obtain compound 1-(2-chloro-4-(pentafluoromercapto)phenyl)methanamine (1A).

[0190] LC-MS, M / Z(ESI):267.9[M+H] +

[0191] Step 5: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C)

[0192] 5-Fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B) (40.0 mg, 193 μmol) was dissolved in N,N-dimethylformamide (DMF, 2.00 mL). Triethylamine (TEA, 58.6 mg, 579 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 88.1 mg, 232 μmol), and 1-(2-chloro-4-(pentafluoromercapto)phenyl)methanamine (1A) (51.7 mg, 193 μmol) were then added. The reaction was stirred at 25°C for 8 hours. After the starting material disappeared, the reaction solution was diluted with water (5.00 mL) and extracted with ethyl acetate (10.0 mL x 2). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C).

[0193] LC-MS, M / Z(ESI):457.1[M+H] +

[0194] Step 6: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1)

[0195] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C) (50.0 mg, 109 μmol) was dissolved in methanol (0.50 mL), tert-butanol (0.50 mL), and water (0.50 mL). AD-mix-α (250 mg, 547 μmol) was then added, and the reaction was stirred at 25°C for 8 hours. After the starting material disappeared, the reaction solution was quenched with 1.00 M aqueous sodium sulfite solution (5.00 mL), then extracted with dichloromethane (5.00 mL × 3). 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 (chromatographic column: Waters Xbridge 150*25mm*5μm; solvent: A=water+0.05 volume of ammonia water (99%), B=acetonitrile; gradient: 20%-50%, 10 minutes), and lyophilized to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1).

[0196] LC-MS, M / Z(ESI):491.1[M+H] +

[0197] 1 H NMR (400MHz, CDCl3) δ8.51-8.63(m,1H),7.85(d,1H),7.69(m,1H),7.48-7.62(m,2H),7.30(m,1H),4.63-4 .76(m,2H),3.95-4.08(m,1H),3.69-3.89(m,2H),2.78-3.03(m,1H),2.37-2.61(m,1H),2.01-2.30(m,2H)

[0198] Example 2: Preparation of target compounds I-1-P1 and I-1-P2

[0199] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P1)

[0200] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P2)

[0201] The synthetic routes of target compounds I-1-P1 and I-1-P2 are as follows:

[0202] Step 1: Synthesis of 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P1) and 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P2)

[0203] The compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B) (2.50 g, 12.1 mmol) was subjected to chiral preparative separation and purification using supercritical fluid chromatography (SFC) (chromatographic column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 20% to 20%, 10 minutes), and then lyophilized to obtain the target compounds 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P1) with a retention time of 2.082 min and 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P2) with a retention time of 2.385 min.

[0204] Step 2: N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P1)

[0205] 5-Fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P1) (182 mg, 747 μmol) was dissolved in N,N-dimethylformamide (DMF, 5.00 mL), followed by the addition of triethylamine (TEA, 227 mg, 2.24 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 341 mg, 897 μmol), and 1-(2-chloro-4-(pentafluoromercapto)phenyl)methanamine (1A) (200 mg, 747 μmol). The reaction mixture was stirred at 25°C for 0.5 hours. After completion of the reaction, the reaction solution was diluted with water (20.0 mL) and extracted with ethyl acetate (25.0 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P1).

[0206] Step 3: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P1) and N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P2)

[0207] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P1) (240 mg, 525 μmol) was dissolved in methanol (5.00 mL), tert-butanol (5.00 mL), and water (10.0 mL). AD-mix-α (1.50 g, 2.63 mmol) was then added and stirred at 25°C for 8 hours. After the starting material disappeared, the reaction solution was quenched with 1 M sodium sulfite (20.0 mL) and extracted with dichloromethane (25.0 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was subjected to chiral preparative separation and purification using supercritical fluid chromatography (SFC) (chromatographic column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + isopropanol; gradient: 30% to 30%, 4.8 minutes), and then lyophilized to obtain the compound.

[0208] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P1), retention time: 1.663 min, LC-MS, M / Z (ESI): 491.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.56-8.64(m,1H),7.85(d,1H),7.68(m,1H),7.59(d,1H),7.51(d,1H),7.31(m,1H ),7.23-7.25(m,1H),4.67(d,2H),4.01(s,1H),3.67-3.92(m,2H),2.36-2.57(m,3H),1.98-2.13(m,1H).

[0209] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P2), retention time: 2.108 min, LC-MS, M / Z (ESI): 491.0 [M+H] + . 1H NMR(400MHz, CDCl3)δ:8.56(br d,1H),7.84(d,1H),7.67(m,1H),7.54-7.56(m,2H),7.27-7.33(m,1H),7.23-7.25( m,1H),4.70(d,2H),4.00(d,1H),3.70(d,1H),2.91-2.95(m,1H),2.06-2.22(m,3H).

[0210] Example 3: Preparation of target compounds I-1-P3 and I-1-P4

[0211] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P3)

[0212] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P4)

[0213] The synthetic routes of target compounds I-1-P3 and I-1-P4 are as follows:

[0214] Step 1: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P2)

[0215] 5-Fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxylic acid (1B-P2) (180 mg, 747 μmol) was dissolved in N,N-dimethylformamide (DMF, 5.00 mL), and triethylamine (TEA, 227 mg, 2.24 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 341 mg, 897 μmol) were added. The mixture was stirred at 25°C for 5 minutes, and then 1-(2-chloro-4-(pentafluoromercapto)phenyl) (1A) (200 mg, 747 μmol) was added. The reaction was stirred at 25°C for 0.5 hours. After completion of the reaction, the reaction solution was diluted with water (20.0 mL) and extracted with ethyl acetate (25.0 mL × 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V / V) = 2:1) to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P2).

[0216] Step 2: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P3) and N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P4)

[0217] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoline-5-carboxamide (1C-P2) (270 mg, 591 μmol) was dissolved in methanol (5.00 mL), tert-butanol (5.00 mL) and water (10.0 mL), and then AD-mix-α (1.50 g, 2.63 mmol) was added and stirred at 25 ° C for 8 hours until the starting material disappeared. The reaction solution was quenched with 1 M sodium sulfite (20.0 mL), then extracted with dichloromethane (25.0 mL × 2), the organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain the product, which was then subjected to chiral preparative separation and purification using supercritical fluid chromatography (SFC). The separation method was as follows (chromatographic column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); solvent: A = carbon dioxide, B = ammonia water (0.1%) + methanol; gradient: 30% to 30%, 2.6 minutes), and then lyophilized to obtain the compound.

[0218] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P3), retention time: 1.600 min, LC-MS, M / Z (ESI): 491.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.59(d,1H),7.85(d,1H),7.47-7.75(m,3H),7.27-7.31(m,1H),7.23-7.25(m,1H),4.66(d,2H),4.01(br s,1H),3.87(d,1H),3.72(d,1H),2.40-2.52(m,3H),2.01-2.11(m,1H).

[0219] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (target compound I-1-P4), retention time: 1.891 min, LC-MS, M / Z (ESI): 491.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ:8.57(br d,1H),7.85(d,1H),7.69(m,1H),7.53-7.62(m,2H),7.32(br m,1H),7.27-7.31(m,1H),4.71(d,2H),4.01(d,1H),3.79(br d,1H),3.71(d,1H),2.77-3.00(m,1H),2.03-2.28(m,3H).

[0220] Example 4: Preparation of target compounds I-2-P1, I-2-P2, I-2-P3, and I-2-P4

[0221] The synthetic routes of target compounds I-2-P1, I-2-P2, I-2-P3, and I-2-P4 are as follows:

[0222] Step 1: Synthesis of methyl 2-(3-chloropyrazin-2-yl)hex-5-enoate (2B-3)

[0223] Under nitrogen, lithium bis(trimethylsilyl)amide (LiHMDS, 1.00 M, 148 mL) was slowly added dropwise to a solution of 2,3-dichloropyrazine (2B-1) (10.0 g, 67.1 mmol) in toluene (100 mL) at 0°C. A solution of methyl hex-5-enoate (2B-2) (10.0 g, 78.0 mmol) in toluene (30.0 mL) was then added dropwise. The reaction was stirred at 25°C for 10 hours. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride (200 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to obtain methyl 2-(3-chloropyrazin-2-yl)hex-5-enoate (2B-3).

[0224] Step 2: Synthesis of 8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid methyl ester (2B-4)

[0225] Under nitrogen, palladium acetate (Pd(OAC) 2,466 mg, 2.08 mmol), Xantphos (1.20 g, 2.08 mmol), and triethylamine (TEA, 6.31 g, 62.3 mmol) were added to a solution of methyl 2-(3-chloropyrazin-2-yl)hex-5-enoate (2B-3) (5.00 g, 20.8 mmol) in acetonitrile (MeCN, 50.0 mL) and stirred at 100°C for 10 hours. After completion of the reaction, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 50:1-10:1) to obtain methyl 8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylate (2B-4).

[0226] Step 3: Synthesis of 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid methyl ester (2B-5)

[0227] Under nitrogen, sodium bis(trimethylsilyl)amide (NaHMDS, 1.00 M, 2.95 mL) was slowly added dropwise to a solution of 8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid methyl ester (2B-4) (500 mg, 2.46 mmol) in tetrahydrofuran (THF, 20.0 mL) at -78 ° C. The reaction was stirred at -78 ° C. for 2 hours, and then a solution of N-fluorobisbenzenesulfonamide (NFSI, 931 mg, 2.95 mmol) in tetrahydrofuran (3.00 mL) was added. The reaction was stirred at -78 ° C. for 1 hour and then at 25 ° C. for 1 hour. After completion of the reaction, the reaction solution was quenched with saturated ammonium chloride (30.0 mL), and then extracted with ethyl acetate (30.0 mL×3). The organic phases were combined, washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V / V) = 50:1-10:1) to obtain compound 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid methyl ester (2B-5).

[0228] Step 4: Synthesis of 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid (2B)

[0229] To a solution of methyl 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylate (2B-5) (100 mg, 450 μmol) in tetrahydrofuran (2.00 mL) and water (1.00 mL) was added lithium hydroxide (LiOH, 37.8 mg, 900 μmol), and the reaction was stirred at 10°C for 12 hours. After completion of the reaction, the reaction solution was diluted with water (10.0 mL) and adjusted to pH 2 with 1.00 M dilute hydrochloric acid. The mixture was then extracted with dichloromethane / isopropanol (5 / 1, 10.0 mL x 5). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to afford 5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid (2B), which was used directly in the next step.

[0230] Step 5: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (2C)

[0231] 5-Fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxylic acid (2B) (100 mg, 480 μmol) was dissolved in N,N-dimethylformamide (DMF, 5.00 mL), followed by the addition of triethylamine (TEA, 146 mg, 1.44 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 237 mg, 623 μmol), and 1-(2-chloro-4-(sulfur pentafluoride)phenyl)methanamine (1A) (129 mg, 480 μmol). The reaction was stirred at 10°C for 1 hour. After completion of the reaction, the reaction solution was diluted with water (10.0 mL) and extracted with ethyl acetate (10.0 mL × 3). The organic phase was collected, washed with water (10.0 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified on a silica gel plate (petroleum ether:ethyl acetate (V / V) = 1:1) to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (2C).

[0232] Step 6: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (target compound I-2)

[0233] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-methylidene-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (2C) (90.0 mg, 197 μmol) was dissolved in methanol (5.00 mL), tert-butanol (5.00 mL), and water (5.00 mL), and then AD-mix-α (500 mg, 983 μmol) was added. The reaction was stirred at 20°C for 10 hours. After completion of the reaction, the reaction solution was quenched with saturated aqueous sodium sulfite solution (20.0 mL) and then extracted with dichloromethane (20.0 mL × 3). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by silica gel plate (ethyl acetate:methanol (V / V) = 20:1) to obtain compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (target compound I-2).

[0234] LC-MS, M / Z(ESI):492.1[M+H] + . 1H NMR(400MHz, CDCl3)δ8.54-8.69(m,2H),7.82(d,1H),7.65-7.77(m,2H),4.59-4.88(m,2H),3 .82-4.08(m,1H),3.72-3.80(m,1H),2.97-3.22(m,1H),2.27-2.76(m,2H),2.01-2.23(m,2H)

[0235] Step 7: Synthesis of N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (target compounds I-2-P1, I-2-P2, I-2-P3, I-2-P4)

[0236] The compound N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (I-2) was separated and purified by chiral preparative chromatography using supercritical fluid chromatography (SFC). The separation method was as follows (chromatographic column: DAICEL CHIRALPAKAD (250mm*30mm, 10μm); solvent: A = carbon dioxide, B = ammonia (0.1%) + ethanol; gradient: 28% to 28%, 3.8 minutes), and then lyophilized to obtain the target compound.

[0237] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (I-2-P1), retention time: 1.444 min, LC-MS, M / Z (ESI): 492.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.56-8.73(m,2H),7.81(s,1H),7.67(s,2H),7.29-7.32(m,1H),4.56-4.84(m,2H),3.81 -3.88(m,1H),3.73-3.80(m,2H),2.89-3.02(m,1H),2.60-2.78(m,1H),2.44-2.59(m,2H),2.06-2.21(m,1H).

[0238] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (I-2-P2), retention time: 1.590 min, LC-MS, M / Z (ESI): 492.1 [M+H] + ,1 H NMR(400MHz, CDCl3)δ8.63(dd,2H),7.81(s,1H),7.67(s,2H),7.28-7.33(m,1H),4.59-4.83(m,2H),3 .82-3.89(m,1H),3.72-3.81(m,2H),2.88-3.03(m,1H),2.60-2.79(m,1H),2.44-2.59(m,2H),2.13(br dd,1H).

[0239] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (I-2-P3), retention time: 1.806 min, LC-MS, M / Z (ESI): 492.1 [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.65(d,1H),8.57(s,1H),7.82(d,1H),7.64-7.76(m,2H),7.30(br d,1H),4.58-4.87(m,2H),4.06(d,1H),3.75(d,1H),2.98-3.24(m,1H),2.27-2.41(m,1H),2.04-2.24(m,2H).

[0240] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoxaline-5-carboxamide (I-2-P4), retention time: 2.464 min, LC-MS, M / Z (ESI): 492.1 [M+H] + , 1 H NMR(400MHz, CDCl3)δ8.65(d,1H),8.58(s,1H),7.82(d,1H),7.65-7.77(m,2H),7.28-7.31(m,1H),4 .60-4.91(m,2H),4.06(d,1H),3.75(d,1H),2.98-3.23(m,1H),2.28-2.40(m,1H),2.06-2.22(m,2H).

[0241] Example 5: Preparation of target compound I-3

[0242] Methyl N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-3)

[0243] The synthetic route of target compound I-3 is as follows:

[0244] Step 1: Synthesis of N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl(2,2,2-trichloroacetyl)carbamate (3A)

[0245] N-((2-chloro-4-(pentafluoromercapto)phenyl)methyl)-5-fluoro-8-hydroxy-8-(hydroxymethyl)-5,6,7,8-tetrahydroquinoline-5-carboxamide (I-1-P4) (120 mg, 244 μmol) was dissolved in dichloromethane (DCM, 1.00 mL), and 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 completion of the reaction, the reaction solution was concentrated to obtain compound N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (3A), which was used directly in the next step.

[0246] LC-MS, M / Z(ESI):680.0[M+H] +

[0247] Step 2: Methyl N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamate (target compound I-3)

[0248] N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl (2,2,2-trichloroacetyl)carbamate (3A) (170 mg, 250 μmol) was dissolved in methanol (MeOH, 2.00 mL), and then an aqueous potassium carbonate solution (K2CO3.2 M, 313 μL) was added dropwise at 0°C. The reaction was stirred at 0°C for 1 hour. After completion of the reaction, the reaction solution was diluted with water (20.0 mL) and extracted with ethyl acetate (20.0 mL*3). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18150*25mm*10μm; solvent: A=water+0.05 volume formic acid (99%), B=acetonitrile; gradient: 25%-55%, 15 minutes), and then lyophilized to obtain compound N-((2-chloro-4-(pentafluoromercapto)benzyl)carbamoyl)-5-fluoro-8-hydroxy-5,6,7,8-tetrahydroquinolin-8-yl)carbamic acid methyl ester (I-3).

[0249] LC-MS, M / Z(ESI):534.2[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.60-8.70(m,1H),7.82-7.91(m,1H),7.65-7.75(m,1H),7.48-7.60( m,2H),7.29-7.36(m,1H),7.18-7.26(m,1H),4.61-4.73(m,3H),4.38-4.56(m,2H),3.40(br s,1H),2.51-2.80(m,1H),2.20-2.43(m,3H).

[0250] Example 6:

[0251] Compounds I-4, I-5, I-6 and I-7 were prepared by methods similar to those in Examples 2 to 5. The prepared I-4, I-5, I-6 and I-7 were subjected to mass spectrometry analysis. The results are shown in the table below.

[0252] Test Example 1: FLIPR method to determine the antagonistic activity of compounds against hP2X7

[0253] The inhibitory effect of compounds on hP2X7 calcium flux was determined in HEK293 cells stably overexpressing the human P2X7 receptor. Calcium flux signals were detected using the FLIPR Calcium 6 Assay Kit (Molecular Devices, R8191) and the FLIPR TETRA System (Molecular Devices). Stably transfected cells were cultured at 37°C, 5% CO2, detached and counted using TrypLE™ Express (cell viability >85%), and seeded at a density of 20,000 cells / well in a 384-well plate. 30 μL of the solution was added per well and incubated overnight in the incubator. To prepare the 2× dye buffer, dilute the dye in assay buffer (1× HBSS containing 20 mM HEPES, pH 7.4) and add probenecid to a final concentration of 5 mM. The cell culture plate was removed from the incubator, the medium was removed, and 10 μL of assay buffer and 10 μL of 2× dye were added to each well. Place the cell plate on a shaker at 600 rpm and incubate for 2 minutes. Incubate at 37°C for 2 hours, then at 25°C for an additional 15 minutes. Prepare a 10 mM stock solution of the test compound in DMSO and serially dilute it in DMSO in a 384-well plate. Transfer the compound to a new 384-well plate using an Echo Acoustic Pipetting System (Labcyte) at varying concentrations, using 90 nL per well. Add 30 μL / well of dilution buffer to the 384-well plate to obtain a 3× compound solution. Shake the compound plate on a plate shaker for 2 minutes.

[0254] The cell plate, compound plate, and pipette tips were placed in the FLIPR instrument. The instrument transferred the 3× compound solution to the cell plate at a volume of 10 μl / well. The plate was then read for 160 seconds with a 1-second interval to obtain data in the agonist mode. The cell plate was then stored in the dark at 25°C for 30 minutes. The EC value of the control agonist (BzATP) was calculated using the data. 80 Prepare 4×EC in assay buffer. 80 The concentration of BzATP was added to a new 384-well compound plate at a volume of 30 μl / well. After incubation at 25°C in the dark for 30 minutes, the cell plate, compound plate containing BzATP and pipette tips were placed in the FLIPR instrument. The FLIPR instrument added 4×EC 80 The concentration of BzATP was transferred to the cell plate. The plate was then read for 160 seconds with a 1 second interval to obtain the data of the antagonistic mode. The inhibition rate was calculated according to the following formula: Inhibition rate (%) = 100-(test value-low control mean) / (high control mean-low control mean)*100. The low control group was the one with EC added. 80BzATP and the highest concentration of positive control (JNJ-47965567, a commercially available P2X7 antagonist), the high control group was only added with EC 80 The IC was calculated by curve fitting using XLift based on the inhibition rate of different compound concentrations. 50 value.

[0255] The experimental results are shown in Table 1, which indicate that the compounds of the present invention have excellent antagonistic activity against human P2X7.

[0256] Table 1 Antagonistic activity of test compounds against hP2X7

[0257] Test Example 2: Pharmacokinetics test in mice

[0258] Mouse pharmacokinetic studies were conducted using three male ICR mice weighing 20-30 g, fasted overnight, and administered 10 mg / kg (Compound I-1-P4) by oral gavage. Blood samples were collected before dosing and at 5, 15, and 30 minutes, as well as 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 6000 g / min for 3 minutes at 2-8°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 10-fold volume of a 50% methanol-acetonitrile solution containing an internal standard. The mixture was vortexed for 5 minutes and centrifuged at 4000 rpm at 4°C for 10 minutes. The supernatant was mixed with 1-fold volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0259] The experimental results are shown in Table 2, which indicate that the compound of the present invention has good pharmacokinetic properties in mice.

[0260] Table 2 Results of mouse pharmacokinetic tests

[0261] Test Example 3: Pharmacokinetics test in rats

[0262] For a pharmacokinetic study in rats, three male SD rats weighing 180-240 g were fasted overnight and administered 10 mg / kg (Compound I-1-P4) by oral gavage. Blood was collected before dosing and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were centrifuged at 8000 rpm for 6 minutes at 4°C, and plasma was collected and stored at -20°C. Plasma was collected at each time point and mixed with 3-5 times the volume of acetonitrile solution containing the internal standard. The mixture was vortexed for 1 minute and centrifuged at 13000 rpm for 10 minutes at 4°C. The supernatant was mixed with 3 times the volume of water, and an appropriate amount of the mixture was analyzed by LC-MS / MS. Key pharmacokinetic parameters were analyzed using a non-compartmental model using WinNonlin 7.0 software.

[0263] The experimental results are shown in Table 3, which indicate that the compound of the present invention has good pharmacokinetic properties in rats.

[0264] Table 3 Pharmacokinetic test results in rats

[0265] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0266] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I): in: X 1 、X 2 、X 3 、X 4 are each independently selected from CH, N; R 1 Selected from p R a substituted phenyl or 5-6 membered heteroaryl, said R a independently selected from halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -(C=O)-R a1 、-(C=O)-NR a1 R a2 , cyano, C 3-6 Cycloalkyl; said R a1 and R a2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 Alkyl; p is an integer selected from 0, 1, 2, 3; R 2 、R 3 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 haloalkyl; or, R 2 Can be used with R 3 Forming 3 to 6 membered rings; R 4 are independently selected from halogen, n is an integer selected from 0, 1, 2, 3; R 5 、R 6 are independently selected from hydrogen, halogen, hydroxy, cyano, -O-(C=O)-NR b1 R b2 , 0, 1, 2 or 3 R b Substituted with the following groups: C 1-6 Alkyl, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, -(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 ; the R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 Alkyl, -OC 1-6 alkyl; R b Independently selected from halogen, hydroxy, C 1-6 Alkyl, -OC 1-6 Alkyl, cyano, -NR b1 R b2 、-(C=O)-R b1 、-(C=O)-NR b1 R b2 、-O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 、-S(O)mR b1 , phenyl, 5- to 8-membered heteroaryl, m is independently 0, 1 or 2, and the heteroatoms of the 5- to 8-membered heteroaryl are selected from one or more of N, O, and S; R b1 and R b2 are independently selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl; or, R b1 、R b2 The N atom to which they are commonly connected may form a 3- to 7-membered heterocyclic ring, wherein the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or more of N, O, and S, and the 3- to 7-membered heterocyclic ring is unsubstituted or substituted by 1 to 6 substituents independently selected from the following: halogen, hydroxyl, C 1-6 Alkyl, -OC 1-6 alkyl.

2. The compound of formula (I) according to claim 1, or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: X 1 、X 2 、X 3 and X 4 At least one of them is N, and at most two of them are N; preferably, X 4 N, X 1 、X 2 and X 3 CH, or X 1 、X 4 N, X 2 and X 3 For CH.

3. The compound of formula (I) according to claim 1, or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 wherein the heteroatoms of the 5-6 membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; (2)R 1 In the case of R a independently selected from -(C=O)-R a1 、-(C=O)-NR a1 R a2 When the R a1 and R a2 Each independently selected from hydrogen, hydroxyl, C 1-6 alkyl; (3)R 2 、R 3 wherein the 3- to 6-membered ring contains 0, 1, 2 or 3 heteroatoms selected from N, O and S. When the number of heteroatoms is 2 or 3, the number of heteroatoms is 1, 2 or 3; (4)R 5 、R 6 In the case of R 5 and R 6 Each independently selected from 0, 1, 2 or 3 R b Substituted-(C=O)-R c1 、-(C=O)-NR c1 R c2 、-NR c1 R c2 When the R c1 and R c2 Each independently selected from hydrogen, hydroxyl, C 1-6 alkyl; (5)R 1 、R 2 、R 3 、R 5 、R 6 In the C 1-6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; (6)R 1 、R 5 、R 6 In the C 3-6 Cycloalkyl is each independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (7)R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from 3- to 7-membered heterocycloalkyl and 3- to 7-membered heterocycloalkenyl, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; (8)R 5 、R 6 wherein the heteroatoms of the 5- to 8-membered heteroaryl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1 or 2; (9)R 5 、R 6 wherein the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or two of N, O, and S, and the number of heteroatoms is 1, 2, or 3; (10)R 5 、R 6 In the case of R b independently selected from -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 When the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 alkyl.

4. The compound of formula (I) according to claim 3, or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 wherein the 5-6 membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; (2)R 5 、R 6 wherein the 3- to 7-membered heterocyclic ring is selected from a 3- to 7-membered heterocycloalkyl group and a 3- to 7-membered heterocycloalkenyl group, and the heteroatoms of the 3- to 7-membered heterocyclic ring are selected from one or two of N, O, and S, and the number of heteroatoms is one or two; (3)R 5 、R 6 wherein the 5- to 8-membered heteroaryl group is selected from furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; (4)R 5 、R 6 In the 3- to 6-membered heterocycloalkyl group, the heteroatoms are selected from one or two of N, O, and S, and the number of heteroatoms is one or two.

5. The compound of formula (I) according to claim 3, or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1) When R 1 Selected from p R a When phenyl is substituted, p is 0, 1, 2 or 3, R a independently selected from fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; (2) When R 1 Selected from p R a When the 5-6 membered heteroaryl is substituted, the 5-6 membered heteroaryl is selected from 6 membered heteroaryl, p is 0, 1, 2 or 3, R a independently selected from fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; (3) When R a independently selected from -(C=O)-R a1 、-(C=O)-NR a1 R a2 When the R a1 and R a2 Each independently selected from hydrogen, hydroxyl, C 1-6 alkyl; (4) When R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from halogen, hydroxyl, C 1-6 Alkyl, the C 1-6 Alkyl is selected from methyl, ethyl, n-propyl, isopropyl; (5) When R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted-(C=O)-R c1 、-(C=O)-NR c1 R c2 and -NR c1 R c2 When the R c1 and R c2 Each is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl; (6) When R 5 and R 6 Each independently is 0, 1, 2 or 3 R b Substituted C 1-6 When alkyl, the R b Each independently selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl and isopropyl.

6. The compound of formula (I) according to claim 3, or its stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, characterized in that: The compound represented by formula (I) satisfies one or more of the following conditions: (1)R 1 Selected from unsubstituted or 1 R a Substituted phenyl, pyridyl, said R a is selected from fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl; (2)R 2 and R 3 Each independently selected from hydrogen, methyl, ethyl; (3)R 4 independently selected from fluorine and chlorine; (4)R 5 and R 6 Each independently selected from hydrogen, hydroxy, 0 or 1 R b Substituted with the following groups: C 1-6 Alkyl, -(C=O)-NR c1 R c2 , R c1 and R c2 Each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl; (5)R 5 and R 6 Each independently selected from hydrogen, hydroxyl, b Substituted C 1-6 Alkyl, the R b Selected from hydroxyl, -O-(C=O)-R b1 、-O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 Alkyl is selected from methyl, ethyl, n-propyl, isopropyl; (6)R 5 and R 6 Each independently selected from hydrogen, hydroxy, -O-(C=O)-NR b1 R b2 , the R b1 and R b2 are each independently selected from hydrogen, C 1-6 Alkyl, C substituted by hydroxyl and / or halogen 1-6 Alkyl, alone or as part of another group 1-6 The alkyl group is selected from methyl, ethyl, n-propyl and isopropyl.

7. The compound according to claim 1, characterized in that The compound is a compound represented by formula (II), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II): Among them, X 1 、X 4 、R 1 、R 5 、R 6 The definition is as stated in claim 1.

8. The compound according to claim 1, characterized in that The compound is a compound represented by formula (II-1), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (II-1): Among them, X 1 、X 4 、R 1 、R 5 、R 6 The definition is as stated in claim 1.

9. The compound according to claim 1, characterized in that The compound is a compound represented by formula (III), or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (III): Among them, R 5 、R 6 The definition is as stated in claim 1.

10. The compound according to any one of claims 6 to 9, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that: R 5 and R 6 Each independently selected from hydrogen, hydroxy, methyl, -CH2-OH, -(CH2)2-OH, Preferably, when R 5 and R 6 When one of them is -OH, the other is -CH2-OH or -(CH2)2-OH; preferably, when R 5 and R 6 When one of them is -OH, the other is Preferably, when R 5 and R 6 When one of them is methyl, the other is -OH, -CH2-OH, Preferably, when R 5 and R 6 When one of them is hydrogen, the other is 11. The compound according to claim 10, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that: Group Selected from 12. The compound according to any one of claims 6 to 8, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, characterized in that: Group Selected from 13. The compound according to claim 1, characterized in that It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

14. The compound according to claim 1, characterized in that It is a compound represented by the following formula, or a stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof:

15. A pharmaceutical composition, characterized in that A compound according to any one of claims 1 to 14 comprising an effective dose.

16. Use of the compound according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, in the preparation of a medicament for treating a disease mediated by P2X7 receptor antagonism.

17. Use of the compound according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, in treating diseases mediated by P2X7 receptor antagonism.

18. The use according to claim 16 or 17, characterized in that The disease mediated by P2X7 receptor antagonism is selected from the following diseases: pain, central nervous system disease, immune disease, inflammation and inflammation-related disease.

19. A method for treating diseases mediated by P2X7 receptors, characterized in that: include: Administering a pharmaceutically acceptable dose of the compound according to any one of claims 1 to 14, or the pharmaceutical composition according to claim 15, to a subject.

20. The method according to claim 19, characterized in that The disease mediated by P2X7 receptor antagonism is selected from the following diseases: pain, central nervous system disease, immune disease, inflammation and inflammation-related disease.

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