Aza-cyclin derivatives and uses thereof

Abstract

This invention relates to a cyclic derivative and its uses. In particular, this invention relates to compounds of formula (I), pharmaceutical compositions thereof, and the use of compounds of formula (I) or pharmaceutical compositions thereof, said compounds being used for the prevention and / or treatment of MAT2A-mediated diseases, wherein the substituents in formula (I) are the same as defined in the specification.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more particularly to a cyclic derivative, including the preparation process, method, and use of the compound. Background Technology

[0002] Methionine adenosyltransferase 2A (MAT2A) is a key enzyme in the methionine metabolic pathway, catalyzing the synthesis of S-adenosylmethionine (SAM) from methionine and ATP. SAM acts as a methyl donor, participating in physiological processes such as epigenetic regulation, polyamine synthesis, and oxidative stress [DOI: 10.1021 / acs.jmedchem.2c00395]. Studies have shown that MAT2A is abnormally highly expressed in various tumor cells, promoting DNA methylation and inhibiting tumor suppressor gene expression by maintaining SAM levels in cancer cells, and participating in tumor cell proliferation, metastasis, and drug resistance formation [DOI: 10.1016 / j.drudis.2024.104189]. Furthermore, MAT2A is closely related to the pathological processes of non-tumor diseases such as metabolic syndrome and neurodegenerative diseases, making it an important target for innovative drug development.

[0003] Currently, some progress has been made in the development of inhibitors targeting MAT2A. Early-developed inhibitors, such as PF-9366 and FIDAS-5, while showing activity in in vitro experiments, suffer from insufficient selectivity, poor pharmacokinetic properties, toxicity risks, or limitations in single-therapeutic efficacy, thus restricting their clinical translation. Existing technologies have not yet fully resolved the issues of selectivity, efficacy, and safety in MAT2A-targeted therapy. Therefore, it remains necessary to develop new MAT2A inhibitors. Summary of the Invention

[0004] The present invention provides a compound of general formula (I), its stereoisomer or pharmaceutically acceptable salt thereof, which has good physicochemical properties, such as high solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety and low toxicity.

[0005] This invention relates to compounds represented by general formulas (I), (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), and (II-7), their stereoisomers, or pharmaceutically acceptable salts thereof:

[0006]

[0007] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0008] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl or 8-membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic alkyl, phenyl or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0009] In some implementations, R A1 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0010] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, or 9-10-membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0011] In some implementations, R A1 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl or C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0012] In some implementations, R A1 Methyl, ethyl, propyl, cyclobutyl, , , C 5-8 Polycyclic cycloalkyl, Optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0013] In some implementations, R A1 Methyl, ethyl, propyl, , , , , , , , , , , , , , , , , ;

[0014] In some implementations, R A1 Methyl, ethyl, propyl, cyclobutyl, , , Optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0015] In some implementations, R A1 Methyl, ethyl, propyl, , , , , ;

[0016] In some implementations, R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinone heteroaryl or -OC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0017] In some implementations, R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0018] In some implementations, R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0019] In some implementations, R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0020] In some implementations, R A2 R A3 Each is independently hydrogen;

[0021] In some implementations, R A2 R A3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits;

[0022] In some implementations, RA2 R A3 Together they form oxo groups, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2;

[0023] In some implementations, R B1 R B2 and R B3 Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -OC 3-8 cycloalkyl, -C≡CC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0024] In some implementations, R B1 and R B3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0025] In some implementations, R B1 It is hydrogen; R B3 It is hydrogen;

[0026] In some implementations, R B2 Hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0027] In some implementations, R B2 Halogen, SF5, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0028] In some implementations, R B2 The methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziretyl, -C≡C-cyclopropyl, -C≡C-cyclobutyl groups are selected from fluorine, chlorine, SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziretyl groups, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziretyl groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C1-3 Group substitution of haloalkyl subunits;

[0029] In some implementations, R B2 For example, fluorine, chlorine, SF5, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, , , ;

[0030] In some implementations, Z is O, S, or NR. Z ;

[0031] In some implementations, Z is O, S, or NR. Z ;

[0032] In some implementations, R Z Hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0033] In some implementations, R Z It can be hydrogen, deuterium, or methyl;

[0034] In some implementations, L stands for bond, -O-, -S-, -C 1-4 Alkylene-, -OC 1-4 alkylene-, -C 1-4 Alkylene O-, -C(O)-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)O-, -NR L C(O)-、-C(O)NR L -、-NR L -、C 3-4 Cycloalkyl, 3-4 membered heterocyclic alkyl, wherein the alkylene, cycloalkyl, or heterocyclic alkyl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0035] In some implementations, R L Hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0036] In some implementations, L represents a bond, -S(O)-, -S(O)O-, , , , ;

[0037] In some implementations, R1 is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamine group, -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted with 1-5 R groups, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0038] In some implementations, R1 is C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamine group, -NHCOC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may optionally be further substituted with 1-3 Rs, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0039] In some embodiments, R1 is a 5-6 membered heteroaryl group, optionally further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0040] In some implementations, R1 is , , , The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0041] In some implementations, R1 is , , , , , , , ;

[0042] In some implementations... for , , , , , , , , , , , , , ;

[0043] In some implementations, R B1 and R, R Z R and its connected atoms form C 5-8Cycloalkyl or 5-8 membered heterocycloalkyl, optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0044] In some implementations, R B1 and R, R Z R and its connected atoms form C 6-8 Cycloalkyl or 6-8-membered heterocycloalkyl, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0045] In some implementations, R a1 C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0046] In some implementations, R a1 C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heteroaryl, optionally further selected by 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0047] In some implementations, R a1 Cyclobutyl, cyclopentyl, , C 5-8 Polycyclic cycloalkyl, The molecule may be further selected from 1-3 groups selected from deuterium, halogen, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0048] In some implementations, R a1 C 5-8 Polycyclic cycloalkyl groups, preferably 5-8 membered bridged cycloalkyl groups, more preferably 5 membered bridged cycloalkyl groups;

[0049] In some implementations, R a1 C 3-6 Cycloalkyl, 5-membered bridged cycloalkyl, optionally further selected by 1-3 elements chosen from deuterium, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0050] In some implementations, R a1 Cyclobutyl, cyclopentyl, , Optionally further selected from 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0051] In some implementations, R a1 for , , , ;

[0052] In some implementations, Ra1 for , , , , , , , , , , , , , , , , ;

[0053] In some implementations, R a2 R a3 Together they form oxygen groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits;

[0054] In some implementations, R a2 R a3 Together they form oxo groups, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2;

[0055] In some implementations, R b2 For SF5, C 1-3 Alkyl, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-4 cycloalkyl, -C≡CC 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0056] In some implementations, R b2 The methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -C≡C-cyclopropyl, and -C≡C-cyclobutyl groups are selected from SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, and C. 1-3Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0057] In some implementations, R b2 SF5, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, , , ;

[0058] In some implementations, La is -S(O)-, -S(O)O-, or C. 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0059] In some embodiments, La is -S(O)-, -S(O)O-, cyclopropyl, cyclobutyl, oxetyl, or aziretyl, wherein the cyclopropyl, cyclobutyl, oxetyl, or aziretyl may optionally be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0060] In some implementations, La is -S(O)-, -S(O)O-, , , , ;

[0061] In some implementations, R 1a It is a 5-membered heteroaryl group, which can be further replaced by 1-3 Rs;

[0062] In some implementations, R 1a for , , can be further replaced by 1-3 R;

[0063] In some implementations, R 1a for , , , .

[0064] The first specific technical solution involves a compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof:

[0065]

[0066] in:

[0067] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0068] R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinone heteroaryl or -OC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0069] Or R A2 R A3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits;

[0070] R B1 R B2 and R B3 Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -OC 3-8 cycloalkyl, -C≡CC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0071] Z represents O, S, or NR. Z ;

[0072] R ZHydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0073] L represents a key, -O-, -S-, or -C. 1-4 Alkylene-, -OC 1-4 alkylene-, -C 1-4 Alkylene O-, -C(O)-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)O-, -NR L C(O)-、-C(O)NR L -、-NR L -、C 3-4 Cycloalkyl, 3-4 membered heterocyclic alkyl, wherein the alkylene, cycloalkyl, or heterocyclic alkyl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0074] R L Hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups;

[0075] R1 is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamine group, -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted with 1-5 R groups, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0076] Or, R B1 and R, R Z R and its connected atoms form C 5-8 Cycloalkyl or 5-8 membered heterocycloalkyl, optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits.

[0077] Specifically, in the second technical solution, the compound represented by the aforementioned general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein:

[0078] R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0079] In some implementations, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, or 9-10-membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0080] R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0081] Or R A2 R A3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits;

[0082] R B1 and R B3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups;

[0083] R B2 Hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0084] Z represents O, S, or NR. Z ;

[0085] R Z It can be hydrogen, deuterium, or methyl;

[0086] R1 is C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamine group, -NHCOC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may optionally be further substituted with 1-3 Rs, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0087] Or, R B1 and R, R Z R and its connected atoms form C 6-8 Cycloalkyl or 6-8-membered heterocycloalkyl, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0088] The remaining definitions are the same as those in the specific first technical solution.

[0089] Specifically, the third technical solution refers to the compound represented by the aforementioned general formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented as general formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), and (II-7):

[0090]

[0091] in:

[0092] R a1 C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0093] In some implementations, Ra1 Cyclobutyl, cyclopentyl, , C 5-8 Polycyclic cycloalkyl, The molecule may be further selected from 1-3 groups selected from deuterium, halogen, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0094] In some implementations, R a1 Cyclobutyl, cyclopentyl, , C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits;

[0095] In some implementations, R a1 C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heteroaryl, optionally further selected by 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R a1 Cyclobutyl, cyclopentyl, , Optionally further selected from 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits; in some embodiments, R a1 for , , , In some implementations, R a1 for , , , , , , , , , , , , In some implementations, R a1 for , , , , , , , , , , , , , , , , ;

[0096] R a2 R a3 Together they form oxygen groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits; in some embodiments, R a2 R a3 Together they form oxo groups, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2;

[0097] R b2 For SF5, C 1-3 Alkyl, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-4 cycloalkyl, -C≡CC 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R b2 The methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziridine, -C≡C-cyclopropyl, and -C≡C-cyclobutyl groups are selected from SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziridine groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R b2 SF5, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, , , ;

[0098] La is -S(O)-, -S(O)O-, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 The alkyl halide is substituted with a group; in some embodiments, La is -S(O)-, -S(O)O-, cyclopropyl, cyclobutyl, oxetyl, aziridine, wherein the cyclopropyl, cyclobutyl, oxetyl, aziridine are optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3Group substitution of the haloalkyl subunit; in some embodiments, La is -S(O)-, -S(O)O-, , , , ;

[0099] R 1a It is a 5-membered heteroaryl group, optionally further substituted with 1-3 Rs; in some embodiments, R 1a for , Optionally, it can be further replaced by 1-3 R; in some implementations, R 1a for , , , ;

[0100] The remaining definitions are the same as those of the specific first or second technical solution.

[0101] Specifically, in the fourth technical solution, the compound represented by the aforementioned general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:

[0102] R A1 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0103] In some implementations, R A1 Methyl, ethyl, propyl, cyclobutyl, , , C 5-8 Polycyclic cycloalkyl, The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0104] In some implementations, R A1 Methyl, ethyl, propyl, cyclobutyl, , , C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0105] In some implementations, R A1 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, or 9-10-membered heteroaryl, optionally further selected by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R A1 Methyl, ethyl, propyl, cyclobutyl, , , The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; and / or,

[0106] R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups; and / or,

[0107] R a2 R a3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits; and / or,

[0108] R B2 Halogen, SF5, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R B2 The methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziretyl, -C≡C-cyclopropyl, -C≡C-cyclobutyl groups are selected from fluorine, chlorine, SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziretyl groups, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, and aziretyl groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; and / or,

[0109] R1 is a 5-6 quinone heteroaryl group, optionally further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits;

[0110] The remaining definitions are the same as those for the specific first, second, or third technical solutions.

[0111] Specifically, in the fifth technical solution, the compound represented by the aforementioned general formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein:

[0112] R A1 Methyl, ethyl, propyl, , , , , , , , , , , , , , , , , In some implementations, R A1 Methyl, ethyl, propyl, , , , , , , , , , , , , In some implementations, R A1 Methyl, ethyl, propyl, , , , , ; and / or,

[0113] R A2 R A3 Each independently is hydrogen; and / or,

[0114] R a2 R a3 Together they form oxo groups, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2; and / or,

[0115] R B1 For hydrogen; and / or,

[0116] R B2 For example, fluorine, chlorine, SF5, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, , , ; and / or,

[0117] R B3 It is hydrogen;

[0118] The remaining definitions are the same as those for the specific first, second, third, or fourth technical solutions.

[0119] Specifically, in the sixth technical solution, the compound represented by the aforementioned general formula (I), its stereoisomers, or its pharmaceutically acceptable salts, wherein:

[0120] L represents the bond, -S(O)-, -S(O)O-, , , , ; and / or,

[0121] R1 is , , , The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; in some embodiments, R1 is... , , , , , , , In some implementations, R1 is , , , , , ;

[0122] In some implementations... for , , , , , , , , , , , , , In some implementations, for , , , , , , , , , , , ;

[0123] The remaining definitions are the same as those for the specific first, second, third, fourth, or fifth technical solutions.

[0124] Specifically, in the seventh technical solution, the general formula (I) is selected from the compounds in Table 1 below.

[0125] Table 1:

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132] .

[0133] Secondly, the present invention also provides a pharmaceutical composition comprising any of the compounds described in any of the foregoing technical solutions, their stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0134] Furthermore, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound described in any of the foregoing technical solutions, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0135] Furthermore, the present invention also provides the use of the compounds, stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described in any of the foregoing technical solutions in the preparation of a medicament, preferably the medicament being a medicament for the prevention and / or treatment of MAT2A-mediated diseases.

[0136] In some embodiments, the disease mediated by MAT2A is a tumor, preferably urothelial carcinoma, squamous NSCLC, non-small cell lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, and squamous esophageal cancer.

[0137] The present invention also provides a method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound described in any of the foregoing technical solutions, its stereoisomers or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is a tumor, preferably urothelial carcinoma, squamous NSCLC, non-small cell lung cancer, pancreatic cancer, head and neck cancer, gastric cancer and squamous esophageal cancer.

[0138] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, the mammals described in the present invention include humans.

[0139] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound, conjugate, or pharmaceutically acceptable salt thereof disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0140] In some embodiments, the pharmaceutical composition or formulation of the present invention contains a therapeutically effective amount of any of the compounds shown above, their stereoisomers, or their pharmaceutically acceptable salts.

[0141] The present invention further relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of any of the compounds shown above, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 24 mg, etc. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, in any of the above amounts of 0 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, or 1500 mg.

[0142] The present invention further relates to a method for treating a disease in mammals, the method comprising administering to a subject a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or multiple doses, and in some embodiments, the daily dose includes, but is not limited to, 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, etc. 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0143] This invention relates to a kit that may comprise a single-dose or multi-dose composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in any of the preceding claims of this invention, wherein the amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof is the same as that in the preceding pharmaceutical composition.

[0144] In this invention, the amount of the compound of the invention or its stereoisomer or pharmaceutically acceptable salt is converted in each case as a free base.

[0145] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0146] Synthetic route

[0147] Those skilled in the art can prepare the compounds of this invention using known organic synthesis techniques, with starting materials being commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from legitimate commercial sources, and suppliers include: Titan Technology, Energie Chemicals, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology, among others.

[0148] Indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service can selectively identify specific and similar reactants. These indexes are available in most public and university libraries, as well as online. Known but not commercially available chemicals can optionally be prepared by custom chemical synthesis plants, many of which offer custom synthesis services, including those listed above.

[0149] the term

[0150] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0151] The term "alkyl" refers to a saturated, straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C". 1-20 Alkyl group. The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 8 carbon atoms (i.e., C14-C ... 1-8 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkyl groups, most preferably alkyl groups having 1 to 3 carbon atoms (i.e., C14-C ... 1-3Alkyl groups). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point. When the alkyl group is substituted with a substituent, the substituent is no longer subject to further substitution.

[0152] The term "alkylene" refers to divalent straight-chain and branched saturated alkyl groups. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), etc.

[0153] The term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and even further such as 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl. The alkenyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the alkenyl group is substituted by a substituent, the substituent is not further substituted.

[0154] The term "alkenyl" refers to divalent straight-chain and branched alkenyl groups. Examples of alkenyl groups include, but are not limited to, -CH=CH-, -CH=C(CH3)-, etc.

[0155] The term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically comprising 2 to 18 carbon atoms, further comprising 2 to 8 carbon atoms, further comprising 2 to 6 carbon atoms, and further comprising 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 3-octyynyl, 3-nonynyl, and 4-decynyl. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable linker. When the alkynyl group is substituted by a substituent, the substituent is not further substituted.

[0156] The term "ynynyl" refers to divalent straight-chain and branched ynynyl groups. Examples of ynynyl groups include, but are not limited to, -C≡C-.

[0157] The term "heterocycle" or "heterocyclic group" refers to a substituted or unsubstituted, saturated or unsaturated aromatic or non-aromatic ring, which, unless otherwise specified, contains 1 to 3 heteroatoms selected from N, S, O, Si, P, B, and Se, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles, and bicyclic spirocyclic heterocycles, etc. Unless otherwise specified, it is a 3- to 12-membered heterocycle, more preferably a 4- to 12-membered heterocycle, more preferably a 4- to 10-membered heterocycle, and even more preferably a 4- to 7-membered heterocycle. Its definition includes heterocyclic alkyl groups and heteroaryl groups. The N and S in the heterocyclic group ring can be oxidized to various oxidation states. Heterocyclic groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, azirropropyl, oxacyclobutyl, azirrobutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxohexyl, azirroheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazoleyl, piperidinyl, piperinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, and dioxinyl. Hydrofuranyl, dihydropyranyl, dithiapentylcycloyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydroimidazoyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazoyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, and oxaspiro[3.3]heptyl, etc.

[0158] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C64. 3-20 Cycloalkyl group. The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C12). 3-12 cycloalkyl groups, more preferably cycloalkyl groups having 3 to 8 carbon atoms (i.e., C14-C ... 3-8 Cycloalkyl groups, more preferably cycloalkyl groups having 3 to 6 carbon atoms (i.e., C164-C ... 3-6 (Cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, and cyclooctyl, etc. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0159] The term "spirocycloalkyl" refers to a polycyclic group in which the monocyclic rings share a single carbon atom (called the spiro atom). It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. It has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Spirocycloalkyl. The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C14). 6-14 Spirocycloalkyl, more preferably spirocycloalkyl having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Spirocycloalkyl. Based on the number of spiroatoms shared between rings, spirocycloalkyl is classified into monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocycloalkyl.

[0160] The term "fused-cycloalkyl" refers to a polycyclic aromatic hydrocarbon group in which each ring in a system shares an adjacent pair of carbon atoms with the other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20 Fused cyclic alkyl groups. They may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, the fused cyclic alkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Fused cyclic alkyl groups, more preferably fused cyclic alkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Fused cyclic alkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused cyclic alkyl groups based on the number of constituent rings. Bicyclic or tricyclic fused cyclic alkyl groups are preferred, and ternary / quadrivalent, ternary / quinary, ternary / sixary, quadrivalent / quadrivalent, quadrivalent / quinary, quadrivalent / sixary, quinary / trivalent, quinary / quadrivalent, quinary / quinary, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, quinary / quadrivalent, quinary / sixary, quinary / sevenary, quinary / trivalent, or quinary / sixary bicyclic fused cyclic alkyl groups are more preferred.

[0161] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C atoms). 5-20Bridged cycloalkyl groups. They contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. Preferably, the bridged cycloalkyl group has 6 to 14 ring atoms (i.e., C14). 6-14 Bridged cycloalkyl groups, more preferably bridged cycloalkyl groups having 7 to 10 ring atoms (i.e., C14-C ... 7-10 Bridged cycloalkyl groups are classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups based on the number of rings, with bicyclic or tricyclic bridged cycloalkyl groups being preferred.

[0162] The cycloalkyl group includes polycyclic cycloalkyl groups that can be fused to an aryl, heteroaryl, or heterocyclic alkyl ring, wherein the ring attached to the parent structure is a cycloalkyl group, for example including C 5-6 Cycloalkylphenyl, C 5-6 cycloalkyl 5-6-membered heteroaryl, C 5-6 The cycloalkyl group is preferably a 5-6 membered heterocycloalkyl group, such as cyclopentyl 5-membered heterocycloalkyl, cyclopentyl 6-membered heterocycloalkyl, cyclopentyl 5-membered heteroaryl, cyclopentyl 6-membered heteroaryl, cyclohexyl 5-membered heterocycloalkyl, cyclohexyl 6-membered heterocycloalkyl, cyclohexyl 5-membered heteroaryl, or cyclohexyl 6-membered heteroaryl. The cycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point. When the cycloalkyl group is substituted by a substituent, the substituent is not further substituted.

[0163] The term "cycloalkylene" refers to divalent straight-chain and branched cycloalkyl groups. Examples of cycloalkylene groups include, but are not limited to, those mentioned above. , wait.

[0164] The term "heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocyclic alkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocyclic alkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of N, S, O, Si, P, B, and Se, but excluding the ring moiety of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heterocyclic alkyl group preferably has 3 to 10 ring atoms (i.e., 3-10 membered heterocyclic alkyl groups), wherein it contains 1 to 4 heteroatoms selected from N, O and S atoms; more preferably it has 3 to 8 ring atoms (i.e., 3-8 membered heterocyclic alkyl groups), wherein it contains 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms; and even more preferably it has 4 to 7 ring atoms (i.e., 4-7 membered heterocyclic alkyl groups), wherein it contains 1 to 4, 1 to 3 or 1 to 2 heteroatoms selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocyclic alkyl groups include: azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazoyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxocyclopentyl, 2,2-difluoro-1,3-dioxocyclopentyl, cyclopentanone, 2,2-difluorocyclopentanone, acrylonitrile, oxacyclopentyl, or azirropentyl. Non-limiting examples of the polycyclic heterocyclic alkyl groups include: spiroheterocyclic alkyl, fused heterocyclic alkyl, and bridged heterocyclic alkyl.

[0165] The term "spiroheteroalkyl" refers to a polycyclic heterocyclic alkyl group that shares a single atom (called a spiro atom) between monocyclic rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered spiroheteroalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of N, S, O, Si, P, B, and Se, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The spiroheteroalkyl group is preferably a spiroheteroalkyl group having 6 to 14 ring atoms (i.e., 6-14-membered spiroheteroalkyl), more preferably a spiroheteroalkyl group having 7 to 10 ring atoms (i.e., 7-10-membered spiroheteroalkyl). The spiroheterocyclic alkyl groups are classified into monospirocyclic alkyl groups, bispirocyclic alkyl groups, or polyspirocyclic alkyl groups based on the number of shared spiroatoms between the rings. Monospirocyclic alkyl groups or bispirocyclic alkyl groups are preferred, and more preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocyclic alkyl groups. Non-limiting examples include: , , wait.

[0166] The term "fused heterocyclic alkyl" or "heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which each ring in a system shares an adjacent pair of atoms with other rings in the system. This group has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered fused heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of N, S, O, Si, P, B, and Se, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a fully conjugated π-electron system. The fused heterocyclic alkyl is preferably a fused heterocyclic alkyl with 6 to 14 ring atoms (i.e., 6-14-membered fused heterocyclic alkyl), more preferably a fused heterocyclic alkyl with 7 to 10 ring atoms (i.e., 7-10-membered fused heterocyclic alkyl). Based on the number of constituent rings, they are classified as bicyclic, tricyclic, tetracyclic, or polycyclic heterocyclic alkyl groups, preferably bicyclic or tricyclic fused heterocyclic alkyl groups, and more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic fused heterocyclic alkyl groups. Non-limiting examples include: , , wait.

[0167] The term "bridged heterocyclic alkyl" refers to a polycyclic heterocyclic alkyl group in which any two rings share two non-directly connected atoms, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20-membered bridged heterocyclic alkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from heteroatoms of N, S, O, Si, P, B, and Se, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The bridged heterocyclic alkyl is preferably a bridged heterocyclic alkyl with 6 to 14 ring atoms (i.e., 6-14-membered bridged heterocyclic alkyl), more preferably a bridged heterocyclic alkyl with 7 to 10 ring atoms (i.e., 7-10-membered bridged heterocyclic alkyl). Based on the number of constituent rings, they are classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic alkyl groups, preferably bicyclic or tricyclic bridged heterocyclic alkyl groups. Non-limiting examples include: , wait.

[0168] The heterocyclic alkyl group includes polycyclic heterocyclic alkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic alkyl group, such as 5-6 membered heterocyclic alkyl phenyl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, 5-6 membered heterocyclic alkyl 5-6 membered heteroaryl, and 5-6 membered heterocyclic alkyl 5-6 membered C 5-6 Cycloalkyl groups, preferably 5-membered heterocycloalkyl with 5-membered heterocycloalkyl, 5-membered heterocycloalkyl with 6-membered heterocycloalkyl, 5-membered heterocycloalkyl with 5-membered heteroaryl, 5-membered heterocycloalkyl with 6-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heterocycloalkyl, 6-membered heterocycloalkyl with 5-membered heteroaryl, 6-membered heterocycloalkyl with 6-membered heteroaryl, etc. The heterocycloalkyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the heterocycloalkyl group is substituted by a substituent, the substituent is no longer further substituted.

[0169] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) having a conjugated π-electron system, having 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms (i.e., C atoms). 6-14 Aryl group). The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C64). 6-12 Aryl), more preferably aryl having 6 to 10 carbon atoms (i.e., C10). 6-10 Aryl), further preferably phenyl or naphthyl, most preferably phenyl. The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracene, phenanthryl, etc.

[0170] The aryl group includes polycyclic systems that can be fused to heterocyclic alkyl or cycloalkyl rings, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 membered heterocycloalkyl, preferably benzoC 4-6 Cycloalkyl, benzo4-6 membered heterocycloalkyl, further preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazahexyl, benzooxetyl, benzooxetyl, benzooxetyl, benzoazapentyl, benzooxetyl, benzooxetyl, benzoazahexetyl The aryl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is no longer further substituted.

[0171] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14-membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) of the ring atoms are heteroatoms selected from N, S, O, Si, P, B, and Se, preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding the -OO-, -OS-, or -SS- ring moieties, and the remaining ring atoms are carbon. The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., 5-10-membered heteroaryl). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 member heteroaryl group). Non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 member heteroaryl group with a 5-6 member heteroaryl group or a 5-10 member heteroaryl group with a C-shaped ring. 6-10 Aryl or C 6-10 The compounds are aryl 5-10-membered heteroaryl groups, more preferably 5-6-membered heteroaryl 5-6-membered heteroaryl, 5-6-membered heteroaryl phenyl, or phenyl 5-6-membered heteroaryl. Non-limiting examples include: indolyl, indazole, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophene, thiophene-phenyl, quinazolinyl, benzothiazolyl, carbazole, thiophene-pyridyl, pyridothiophene, pyridopyrrole, benzo-γ-pyranone, pyrido-γ-pyranone. , wait.

[0172] The heteroaryl group includes a polycyclic system fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl rings with C positrons. 3-8 Cycloalkyl, 5-6-membered heteroaryl, 3-8-membered heterocycloalkyl, 5-6-membered heteroarylphenyl, preferably 5-6-membered heteroaryl-C 4-6 Cycloalkyl, 5-6-membered heteroaryl, and 4-6-membered heterocycloalkyl, 5-6-membered heteroarylphenyl. The heteroaryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linker. When the heteroaryl group is substituted by a substituent, the substituent is not further substituted. Non-limiting examples include: , wait.

[0173] The term "alkoxy" refers to -O- (alkyl) or -O- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkoxy group). The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C14). 1-8 Alkoxy groups, more preferably alkoxy groups having 1 to 6 carbon atoms (i.e., C14-C6 ... 1-6 Alkoxy groups, preferably alkoxy groups having 1 to 3 carbon atoms (i.e., C464-C ... 1-3 Alkoxy groups. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, etc. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable linking point. When the alkoxy group is substituted by a substituent, the substituent is not further substituted.

[0174] The term "alkathioyl" refers to -S- (alkyl) or -S- (unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as above and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C atoms). 1-10 Alkylthio group). The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C12). 1-8 Alkylthioyl), more preferably alkylthioyl groups having 1 to 6 carbon atoms (i.e., C14-C ... 1-6 Alkylthio group), preferably alkylthio group with 1 to 3 carbon atoms (i.e., C12-C ... 1-3 Alkylthioyl groups. Non-limiting examples include: methylthioyl, ethylthioyl, propylthioyl, butylthioyl, cyclopropylthioyl, cyclobutylthioyl, cyclopentylthioyl, cyclohexylthioyl, etc. The alkylthioyl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable linking point. When the alkylthioyl group is substituted by a substituent, the substituent is not further substituted.

[0175] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms, preferably fluorine, chlorine or bromine atoms.

[0176] The term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2 2-chlorofluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, etc.

[0177] The term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, etc.; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2 -Chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0178] The term "alkyl subunit" refers to a divalent free alkyl structure formed by the loss of two hydrogen atoms, wherein the alkyl group is as defined above. Non-limiting examples include: methyl subunits ( ), β-subunit ( ), 1-methylethylidene ( ).

[0179] The term "halogenated alkyl subunit" refers to an alkyl subunit substituted with one or more halogens, wherein the alkyl subunit is as defined above. Non-limiting examples include: fluoromethyl subunits (...). ), difluoromethyl subunit ( ).

[0180] The term "thiol" refers to -SH. The term "hydroxyl" refers to -OH. The term "nitro" refers to -NO2. The term "amino" refers to -NH2. The term "cyano" refers to -CN.

[0181] The term "carboxyl" refers to -C(O)OH. The term "aldehyde" refers to -CHO. The term "oxo" or "oxoyl group" refers to =O. The term "carbonyl" refers to C=O. The term "aminoacyl" refers to -C(O)NH2. The term "sulfonyl" refers to -S(O)2. The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above. The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein the alkoxy group is as defined above. The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group is as defined above. The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above. The term "alkylamine" refers to an alkyl group -NH-, wherein the alkyl group is as defined above. The term "alkenyl" refers to a divalent straight-chain and branched alkenyl group. The term "alkynyl" refers to a divalent straight-chain and branched alkynyl group.

[0182] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. Those skilled in the art will understand that the foregoing term “comprising” encompasses the meaning of “consisting of.”

[0183] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0184] When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each numerical value and range encompassed within a wider range.

[0185] In this article, "Z" and "-Z-" both refer to the same specific group and can be used interchangeably.

[0186] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C2-C8" or "C2-8 "Covering a range of 2-8 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., and C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can cover any subrange and point value contained therein, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C..." 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 For example, stating "C1-C6" or "C..." 1-6 "The term 'covers' the range of 1-6 carbon atoms and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, and C1, C2, C3, C4, C5, C6, etc. Similarly, the expression 'ternary to decaary' should be understood to include any subrange within this range and each point value, such as ternary to pentary, ternary to hexaary, ternary to octary, quaternary to pentary, quaternary to hexaary, quaternary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, pentary to octary, octary to octary, quinary to decaary, etc., and tri-, quadri-, quinary, quinary, quinary, quinary, octary, quinary, octary, quinary, decaary, etc. Other similar expressions in this text should also be understood in a similar manner."

[0187] The different expressions used in this article, such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", and "X is A, B and C", all express the same meaning, that is, X can be any one or more of A, B, and C.

[0188] The terms “optional” or “optionally” mean that an event or condition described below may or may not occur, including both the occurrence and non-occurrence of the event or condition. For example, “optionally (al) alkyl-substituted cycloalkyl” means that an alkyl group may but is not required to be present, and this description includes cases where the cycloalkyl group is substituted with an alkyl group and cases where the cycloalkyl group is not substituted with an alkyl group.

[0189] The terms "substitution" and "substituted" refer to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Furthermore, when a structural unit is substituted, even if the structural unit is marked with a hydrogen atom, it does not mean that the hydrogen atom cannot be substituted, but rather that any position in the structural unit including the hydrogen atom can be substituted. For example, structural unit... Substitution means that any position, including the hydrogen atom on the nitrogen atom, can be substituted. Combinations of substituents and / or variables are only permitted if such combinations form a stable compound. When describing the absence of a substituent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing each carbon atom in a group as optionally being replaced by a heteroatom, the condition is that it does not exceed the normal valence of all atoms in the group under the current condition, and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 Aryl, 5-12 heteroaryl, -CO-(C 3-8 cycloalkyl), -CO- (3-8 membered heterocycloalkyl), -CO- (C 5-12 aryl), -CO- (5-12 membered heteroaryl), hydroxyl, C 1-6 Alkoxy, C 5-12 aryloxy groups, thiol groups, C 1-6 Alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 Alkyl carbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, amino groups, phosphonic acids, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C1-6 Alkyl)2、-HC(=O)NH(C 1-6 Alkyl groups), -NHC(=O)NH2, -CH=N(C 1-6 Alkyl group), -CH=NO(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl groups, etc.

[0190] If a substituent is described as "optionally...substituted," the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted by one or more of the substituents in the list, one or more hydrogen atoms on that atom or group may be substituted by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "unsubstituted." Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable position of the substituent.

[0191] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0192] When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of a compound, their definition is independent for each occurrence in each case. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0193] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of linking in the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes the cases of AMWB and AWMB, with AMWB being preferred.

[0194] The compounds of this invention can exist in specific geometric or stereoisomeric forms. All such compounds of this invention, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, are within the scope of this invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of this invention. All such isomers and mixtures thereof are included within the scope of this invention. In some embodiments, the preferred compounds are those isomers exhibiting superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of this invention, or racemic mixtures or diastereomer mixtures, are also included within the scope of this invention. Purification and separation of such substances can be achieved using standard techniques known in the art.

[0195] All hydrogen atoms described in this invention can be replaced by their isotope deuterium, and any hydrogen atom in the compounds of the embodiments of this invention can also be replaced by a deuterium atom.

[0196] The compounds of this invention include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, respectively. 2 H (deuterium, D) 3 H (tritium, T) 11 C 13 C 14 C 15 N、 17 O、 18 O、 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl、 82 Br、 123 I, 124 I, 125 I, 129 I and 131 Grade I, with deuterium as the preferred grade.

[0197] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0198] In the compounds of this invention, when a position is specifically designated as deuterium D, that position should be understood as having a deuterium abundance at least 1000 times greater than the native abundance (which is 0.015%) (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 1000 times greater than the native abundance of deuterium (i.e., at least 15% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 2000 times greater than the native abundance of deuterium (i.e., at least 30% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3000 times greater than the native abundance of deuterium (i.e., at least 45% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3340 times greater than the natural deuterium abundance (i.e., at least 50.1% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 3500 times greater than the natural deuterium abundance (i.e., at least 52.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4000 times greater than the natural deuterium abundance (i.e., at least 60% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 4500 times greater than the natural deuterium abundance (i.e., at least 67.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5000 times greater than the natural deuterium abundance (i.e., at least 75% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 5500 times greater than the natural deuterium abundance (i.e., at least 82.5% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6000 times greater than the natural deuterium abundance (i.e., at least 90% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6333.3 times greater than the natural deuterium abundance (i.e., at least 95% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6466.7 times greater than the natural deuterium abundance (i.e., at least 97% deuterium doping). In some embodiments, the deuterium abundance of each designated deuterium atom is at least 6600 times greater than the natural deuterium abundance (i.e., at least 99% deuterium doping). In some implementations, the abundance of deuterium in each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% deuterium doping).

[0199] The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0200] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention that is safe and effective when used in mammals and has the intended biological activity.

[0201] The term "pharmaceutical composition" refers to a composition containing one or more compounds described in this invention, or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and enabling it to exert its biological activity.

[0202] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0203] The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0204] As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and / or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

[0205] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom. The term "neuropsychiatric disorders" is a collective term for neurological and psychiatric disorders, encompassing both neurological and / or psychiatric conditions.

[0206] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0207] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0208] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0209] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0210] The following detailed description of the invention is intended to illustrate non-limiting technical solutions, enabling other skilled personnel in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled personnel in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Detailed Implementation

[0211] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the technical solutions by those skilled in the art based on the above description are still within the scope of protection of this invention.

[0212] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments.-6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0213] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0214] The HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C). 18 100 × 4.6mm, 3.5 μM);

[0215] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm-0.20 mm in diameter, and the silica gel plates used for thin-layer chromatography separation and purification are 0.4 mm-0.5 mm in diameter.

[0216] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0217] When the compounds or intermediates of this application have one or more chiral centers, in the case of synthesizing compounds that produce a mixture of enantiomers or diastereomers, the desired enantiomers or diastereomers (or mixtures rich in the desired enantiomers or mixtures rich in the desired diastereomers) can be obtained using conventional chiral resolution methods. Conventional methods that can be employed include chromatography (e.g., HPLC) or supercritical fluid chromatography on asymmetric resins. Examples of suitable resins include, but are not limited to, Chiralcel OJ-H, Chiralpak AD-H, Chiralpak IA, and Chiralpak AS-H. The eluent is concentrated to obtain a rich mixture.

[0218] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0219] Synthetic route of Example 1:

[0220]

[0221] Synthetic route of Example 2:

[0222]

[0223] The following embodiments are synthesized according to or with reference to the above-described route:

[0224] Table 2

[0225]

[0226] Example 21

[0227]

[0228] Step 1: At room temperature, compound 21A (15.8 g, 78 mmol) was dissolved in carbon tetrachloride (300 mL), followed by the sequential addition of N-bromosuccinimide (18.0 g, 101 mmol) and 2,2-azobisisobutyronitrile (3.84 g, 23 mmol). The reaction mixture was purged three times under a nitrogen atmosphere and stirred at 85 °C for 60 hours. After the reaction was complete, the reaction solution was cooled to room temperature, concentrated, and dissolved in tetrahydrofuran. DIPEA and diethyl phosphite were added, and the mixture was stirred at room temperature for one hour. Water and ethyl acetate were added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography to give compound 21B (20.3 g, 92% yield). LCMS (ESI): m / z = 281.0 [M+H] + .

[0229] Step 2: At room temperature, compound 21B (20.0 g, 71 mmol) was dissolved in methanol (200 mL). A 5M sodium methoxide solution in methanol (42.6 mL, 213 mmol) was slowly added dropwise at room temperature. The reaction mixture was purged three times under a nitrogen atmosphere and stirred at room temperature for 1 hour. After the reaction was complete, water and ethyl acetate were added. The mixture was extracted three times with ethyl acetate, washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography to give compound 21C (12.5 g, 76% yield). LCMS (ESI): m / z = 233.0 [M+H] + .

[0230] Step 3: At room temperature, compound 21C (10.0 g, 43 mmol) was dissolved in methanol (150 mL) and water (40 mL). NaOH (6.88 g, 172 mmol) was added at room temperature. The reaction mixture was purged three times under a nitrogen atmosphere and stirred at room temperature for 16 hours. After the reaction was complete, water was added to the reaction solution, and the pH was adjusted to 4-5 with 2 M dilute hydrochloric acid. The mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the residue. The residue was slurried with (PE / EA = 5 / 1) to give compound 21D (8.5 g, 90% yield). LCMS (ESI): m / z = 219.0 [M+H] + .

[0231] Step 4: At room temperature, compound 21D (9.7 g, 44.4 mmol) was dissolved in N,N-dimethylformamide (200 mL), followed by the sequential addition of ammonium chloride (3.08 g, 57.7 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (25.3 g, 66.6 mmol), and finally N,N-diisopropylethylamine (23.19 mL, 133 mmol). The reaction mixture was purged three times under a nitrogen atmosphere and stirred at room temperature for 16 hours. After the reaction was complete, water and ethyl acetate were added, followed by three extractions with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography to give compound 21E (8.5 g, 90% yield). LCMS (ESI): m / z = 218.0 [M+H] + .

[0232] Step 5: At room temperature, 21E (300 mg, 1.38 mmol) was dissolved in a sealed tube containing 20 mL of 1,4-dioxane. Oxaloyl chloride (0.58 mL, 6.89 mmol) was added. The reaction mixture was stirred at 80 °C for 2 hours. After complete reaction, the sample was analyzed. The mixture was cooled to room temperature, and 230 mg (1.79 mmol) of 1,4-dioxane (2 mL) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for another 3 hours. After the reaction was complete, the mixture was dried under nitrogen, dissolved in tetrahydrofuran, and dried again. The residue was purified by silica gel column chromatography to give compound 21F (350 mg, 68% yield). LCMS (ESI): m / z = 372.0 [M+H] + .

[0233] Step 6: At room temperature, compound 21F (200 mg, 0.54 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and 1.0 M bis(trimethylsilylamino)potassium (1.07 mL, 1.07 mmol) was slowly added dropwise. The reaction mixture was purged three times under a nitrogen atmosphere, and stirred at room temperature for 16 hours. After the reaction was complete, water and ethyl acetate were added, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and the residue was purified by silica gel column chromatography to give compound 21G (125 mg, 66% yield). LCMS (ESI): m / z = 352.0 [M+H] + .

[0234] Step 7: At room temperature, compound 21G (200 mg, 0.57 mmol) was dissolved in a dry sample vial containing 1,4-dioxane (10 mL). Phosphorus oxychloride (435 mg, 2.84 mmol) and N,N-diisopropylethylamine (367 mg, 2.84 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 16 hours, cooled to room temperature, and then slowly added dropwise to a solution of 3-aminocyclobutanone hydrochloride (345 mg, 2.84 mmol) and N,N-diisopropylethylamine (1 mL) in tetrahydrofuran (20 mL) under an ice-water bath. The mixture was then heated to room temperature and stirred for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give compound 21H (190 mg, yield 79.80%). LC-MS (ESI): m / z = 419.0 [M+H] + .

[0235] Step 8: At room temperature, compound 21H (190 mg, 0.45 mmol) was dissolved in a single-necked flask containing 10 mL of dry dichloromethane. Boron tribromide (1.96 g, 7.84 mmol) was slowly added dropwise at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, the pH was adjusted to 7 with 1 M NaOH solution, and the mixture was extracted with ethyl acetate (2 x 30 mL). The organic phase was washed with saturated brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was then subjected to Prep-HPLC to prepare compound 21 (14 mg, yield 7.98%). LC-MS (ESI): m / z = 387.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.59-8.58 (m, 1H),8.09-8.06 (m, 1H), 7.70-7.67 (m, 1H), 7.41-7.40 (m, 1H), 6.45-6.44 (m, 1H),5.18 (s, 2H), 5.07-5.01 (m, 1H), 3.80-3.73 (m, 2H), 3.51-3.48 (m, 2H).

[0236] Example 22

[0237]

[0238] Step 1: At room temperature, compound 21G (340 mg, 0.97 mmol) was dissolved in dichloromethane (15 mL), and boron tribromide (4.18 g, 16.70 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was poured into ice water (50 mL), the pH was adjusted to 8 with 2M sodium hydroxide solution, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and subjected to silica gel column chromatography to give compound 22A (240 mg, yield 73.52%). LCMS (ESI): m / z = 338.0 [M+H] + .

[0239] Step 2: At room temperature, compound 22A (100 mg, 0.30 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and phosphorus oxychloride (227 mg, 1.48 mmol) and N,N-diisopropylethylamine (191 mg, 1.48 mmol) were added. The reaction mixture was reacted at 100 °C for 8 hours. After cooling to room temperature, the above solution was added dropwise to a solution of 3-methylenecyclobutylamine hydrochloride (123 mg, 1.48 mmol) in tetrahydrofuran (5 mL) and N,N-diisopropylethylamine (0.5 mL). After the reaction was complete, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was washed with saturated sodium chloride aqueous solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and purified by reverse-phase extraction to obtain compound 22. Further separation by SFC yielded compounds 22-1 (9.15 mg, 8.03% yield) and 22-2 (9.03 mg, 7.93% yield). SFC analysis method: Instrument: Waters UPCC; Column: ChiralPak OD, 100×4.6mm ID, 3µm; Mobile phase: MeOH (0.1% DEA); Flow rate: 80 mL / min; Column temperature: 35 ℃; Absorption wavelength: 214 nm. Retention time: Compound 22-1: 1.230 min; Retention time: Compound 22-2: 1.638 min. LCMS (ESI): m / z = 385.0 [M+H] + .

[0240] 22-1: 1 H NMR (400 MHz, DMSO-d6) δ 8.57-8.55 (m, 1H), 8.07-8.02 (m,1H), 7.70-7.60 (m, 1H), 7.38-7.34 (m, 1H), 6.41 (s, 1H), 5.11 (s, 2H), 4.94(s, 2H), 4.81-4.73 (m, 1H), 3.30-3.22 (m, 2H), 3.10-2.98 (m, 2H);

[0241] 22-2: 1H NMR (400 MHz, DMSO-d6) δ 8.58-8.54 (m, 1H), 8.07-8.02 (m,1H), 7.68-7.61 (m, 1H), 7.38-7.34 (m, 1H), 6.41 (s, 1H), 5.11 (s, 2H), 4.94 (s, 2H), 4.82-4.70 (m, 1H), 3.30-3.25 (m, 2H), 3.10-2.97 (m, 2H).

[0242] Example 23

[0243]

[0244] Step 1: At room temperature, compound 22A (200 mg, 0.59 mmol) was dissolved in anhydrous 1,4-dioxane (3 mL), and N,N-diisopropylethylamine (382 mg, 2.96 mmol) and phosphorus oxychloride (453 mg, 2.96 mmol) were added. The reaction mixture was reacted at 100 °C for 15 hours. After cooling to room temperature, the above solution was added dropwise to a solution of bicyclo[1.1.1]pentane-1-amine hydrochloride (142 mg, 1.18 mmol) and N,N-diisopropylethylamine (0.3 mL) in N,N-dimethylformamide (1 mL). After the reaction was complete, the reaction solution was diluted with methanol (10 mL), then concentrated at low temperature. The residue was purified by reverse-phase preparation to give compound 23 (20 mg, yield 8.78%). Compound 23 was further resolved by SFC to obtain compounds 23-1 (4.1 mg) and 23-2 (3.9 mg). SFC analysis method: Instrument: Waters AcQuity UPCC; Column: ChiralPak OJ-3, 4.6*100mm 3µm; Mobile phase: MeOH (0.1%DEA); Flow rate: 3.0 mL / min; Column temperature: 40 ℃; Absorption wavelength: 214 nm. Retention time: Compound 23-1: 1.185 min. Retention time: Compound 23-2: 1.587 min. LC-MS (ESI): m / z = 385.0 / 387.0 [M+H] + .

[0245] 23-1: 11H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.56 (m, 1H), 8.09 - 8.05 (m, 1H), 7.70 - 7.66 (m, 1H), 7.42 - 7.29 (m, 1H), 6.49 - 6.33 (m, 1H), 5.05 - 4.90 (m, 2H), 2.61 (s, 1H), 2.30 (s, 6H);

[0246] 23 - 2: 1 1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.51 (m, 1H), 8.13 - 8.00 (m, 1H), 7.73 - 7.64 (m, 1H), 7.39 - 7.31 (m, 1H), 6.60 - 6.28 (m, 1H), 5.06 - 4.86 (m, 2H), 2.61 (s, 1H), 2.30 (s, 6H).

[0247] Example 24

[0248]

[0249] Step 1: At room temperature, compound 22A (200 mg, 0.59 mmol) was dissolved in anhydrous 1,4-dioxane (5 mL), and N,N-diisopropylethylamine (382 mg, 2.96 mmol) and phosphorus oxychloride (453 mg, 2.96 mmol) were added. The reaction mixture was reacted at 100 °C for 3 hours. After cooling to room temperature, the above reaction solution was added dropwise to a solution of 3-fluorobicyclo[1.1.1]pentane-1-amine hydrochloride (142 mg, 1.18 mmol) and N,N-diisopropylethylamine (0.5 mL) in N,N-dimethylformamide (2 mL). After the reaction was complete, the reaction solution was diluted with methanol (10 mL), then concentrated at low temperature, and the residue was purified by reverse-phase preparation to obtain compound 24. Compound 24 was further resolved by SFC to give compounds 24-1 (17.45 mg, yield 7.32%) and 24-2 (13.7 mg, yield 5.74%). SFC analysis method: Instrument: Waters AcQuityUPCC; Column: ChiralPak OJ-3, 4.6*100mm 3µm; Mobile phase: MeOH (0.1% DEA); Flow rate: 3.0 mL / min; Column temperature: 40 ℃; Absorption wavelength: 214 nm. Retention time: Compound 24-1: 1.139 min. Retention time: Compound 24-2: 1.578 min. LC-MS (ESI): m / z = 403.0 / 405.0 [M+H] + .

[0250] 24-1: 1 H NMR (400 MHz, DMSO-d6) δ 8.61 – 8.56 (m, 1H), 8.09 – 8.04 (m,1H), 7.72 – 7.66 (m, 1H), 7.37 (s, 1H), 6.45 (s, 1H), 5.00 (s, 2H), 2.69 –2.65 (m, 6H).

[0251] 24-2: 1 H NMR (400 MHz, DMSO-d6) δ 8.61 – 8.57 (m, 1H), 8.09 – 8.05 (m,1H), 7.72 – 7.65 (m, 1H), 7.37 (s, 1H), 6.45 (s, 1H), 5.00 (s, 2H), 2.69 –2.65 (m, 6H).

[0252] Biological testing evaluation

[0253] I. MAT2A Activity Inhibition Experiment

[0254] The compounds were serially diluted using DMSO in a 384 PP Plate compound dilution plate. A specific volume of the compound was transferred to a 384 reaction microplate using ECHO. Proteins and substrates were diluted with reaction buffer containing 50 mM Tris-HCl (pH 8.0), 50 mM KCl, 10 mM MgCl2, 0.05% BSA, 0.01% Trition X-100, and 5% Glycerol. A specific volume of MAT2A enzyme solution was added to each well of the 384 reaction microplate, and incubated at 25°C for a specified time. Wells containing DMSO and enzyme served as high controls, while wells containing the same amounts of DMSO and buffer served as low controls. A specific volume of L-Methionine and ATP mixed solution was added to each well, and incubated at 25°C for a specified time. A specific volume of malachite green solution was added to each well, and incubated at 25°C for a specified time. The OD 620 nm signal was read using a BMG microplate reader. The percentage of inhibition of the compound-treated wells was normalized between high and low control (%inhibition rate = (signal value High control - signal value compound) / (signal value High control - signal value Low control) * 100). Four-parameter IC50 curves were then fitted and analyzed using Prism 8.0.

[0255] The compounds of the present invention, such as the compounds in the examples, have an IC50 of less than 1000 nM for their inhibitory activity against MAT2A. 50 IC50 values ​​for some preferred compounds 50 <500 nM, IC50 of some preferred compounds 50 <200 nM, IC50 of some preferred compounds 50 <100 nM, IC50 of some preferred compounds 50 <50 nM. The IC50 values ​​for some specific compounds are shown in Table 1, where AA indicates 0 nM < IC50. 50 ≤50 nM, A means 50 nM < IC 50 ≤200 nM, B means 200 nM < IC 50 ≤500nM, C represents IC 50 >500nM.

[0256] Table 1. Inhibition results of compounds on MAT2A activity

[0257]

[0258] Conclusion: The compounds of the present invention, such as the compounds in the examples, have significant inhibitory activity against MAT2A.

[0259] II. Evaluation of the inhibitory activity of the compounds on the proliferation of HCT116 and HCT116 MTAP KO cells

[0260] The HCT116 and HCT116 MTAP KO cell lines were used to screen compounds for their inhibitory activity on cell proliferation.

[0261] HCT116 and HCT116 MTAP KO cells were passaged separately. Once the cells reached the logarithmic growth phase, the cell suspension was collected, centrifuged at 1000 rpm for 5 min, and the supernatant was discarded. After resuspending and counting, the cells were seeded evenly at an appropriate density into 96-well plates and incubated overnight at 37°C with 5% CO2. The next day, a certain volume of the diluted compound was added to the corresponding cell wells, and the plates were incubated at 37°C for a certain period. CellCounting-Lite 2.0 Luminescent Cell Viability Assay reagent was then added to each well of the cell culture plate, and the plates were shaken at 200 rpm for 2 min at room temperature and incubated for a certain period before BMG readings were detected. Data were then exported, with DMSO cell wells serving as negative controls and wells containing only culture medium serving as positive controls. The percentage of inhibition in the compound-treated wells was standardized between the negative and positive controls (%inhibition rate = (signal value - negative control - signal value - compound) / (signal value - negative control - signal value - positive control) * 100). Then, data analysis software was used for fitting to calculate the IC of the compound. 50 .

[0262] Table 2. Results of the inhibitory activity of the compounds on the proliferation of HCT116 MTAP KO cells.

[0263]

[0264] A represents 0 nM < IC 50 ≤100 nM, B means 100 nM < IC 50 ≤500 nM, C represents IC 50 >500nM.

[0265] Table 3 Results of the inhibitory activity of the compounds on the proliferation of HCT116 cells

[0266]

[0267] AA represents IC 50 >10000 nM, A means 1000 nM < IC 50≤10000 nM, B means 0 nM < IC 50 ≤1000nM.

[0268] Conclusion: The compounds of the present invention, such as those in the examples, have good inhibitory activity against HCT116 MTAP KO cells, but show little or no inhibition against HCT116 cells. In other words, the compounds of the present invention, such as those in the examples, exhibit good selectivity in in vitro cell proliferation inhibition experiments.

[0269] III. Mouse Pharmacokinetic Tests

[0270] 1. Experimental animals: Male CD-1 ICR mice, 25-40g. Purchased from Sichuan Vital River Laboratory Animal Technology Co., Ltd.

[0271] 2. Experimental Design: On the day of the experiment, mice were randomly divided into two groups according to their body weight: an intravenous group and a gavage group. Mice were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0272] Before and after administration of isoflurane anesthesia, 0.06 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Plasma was collected by centrifugation at C for 10 min. Blood collection time points for the intravenous and gavage groups were: 5, 15, 30 min, 1, 2, 4, 7, and 24 h. All samples were stored at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0273] Table 4. Pharmacokinetic parameters of the tested compounds in mouse plasma

[0274]

[0275] Note: For IV and IG, the solvent is 5% DMA + 5% Solutol + 90% Saline.

[0276] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in mice.

[0277] IV. Rat Pharmacokinetic Test

[0278] 1. Experimental animals: Male SD rats, approximately 220 g in size, 6-8 weeks old. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0279] 2. Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to their body weight. They were fasted for 12-14 hours before drug administration but allowed free access to water. They were fed 4 hours after drug administration.

[0280] Before and after administration of isoflurane anesthesia, 0.15 mL of blood was drawn via the orbital cavity and placed in an EDTAK2 centrifuge tube. The centrifuge was then incubated at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0281] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in rats.

[0282] V. Pharmacokinetic Testing in Beagle Dogs

[0283] 1. Experimental animals: Male beagle dogs, approximately 8-11 kg, 6 dogs per compound. Purchased from Beijing Mars Biotechnology Co., Ltd.

[0284] 2. Experimental Method: On the day of the experiment, beagle dogs were randomly divided into groups according to their weight. They were fasted for 12-14 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0285] Blood samples of 1 mL were collected via jugular or limb veins before and after drug administration and placed in EDTAK2 centrifuge tubes. The plasma was collected by centrifugation at 5000 rpm and 4 °C for 10 min. All samples were stored at -80 °C before analysis and quantitative analysis was performed using LC-MS / MS.

[0286] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in beagle dogs.

[0287] VI. Pharmacokinetic Tests in Monkeys

[0288] 1. Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0289] 2. Experimental Methods: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted for 14-18 hours before administration but allowed free access to water. They were fed 4 hours after administration.

[0290] Before and after drug administration, 1.0 mL of blood was collected via venous sampling from each of the four limbs and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm for 4 hours. o Centrifuge at 1°C for 10 min and collect plasma. Store all samples at -80°C before analysis. o C. Quantitative analysis of the sample was performed using LC-MS / MS.

[0291] Conclusion: The compounds of the present invention, such as the compounds in the examples, have favorable pharmacokinetic characteristics in monkeys.

[0292] VII. hERG Potassium Ion Channel Function Test

[0293] 1. Experimental platform: Electrophysiological manual patch-clamp system

[0294] 2. Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channels

[0295] 3. Experimental Methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch-clamp technique. Glass microelectrodes were fabricated from glass electrode blanks (BF150-86-10, Sutter) using a stretching device. The tip resistance after perfusion with electrode fluid was approximately 2-5 MΩ. The glass microelectrodes were inserted into the amplifier probe to connect to the patch-clamp amplifier. Clamping voltage and data recording were controlled and recorded using pClamp 10 software via computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80 mV to induce hERG potassium current (Ik). hERG The step voltage was applied from -80 mV to +20 mV over 2 s, then repolarized to -50 mV for 1 s before returning to -80 mV. This voltage stimulation was applied every 10 s, and the drug administration process began after the hERG potassium current stabilized (at least 1 minute). Each test concentration of the compound was administered for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0296] 4. Data Processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0297] Inhibition % = [1 – (I / Io)]×100%

[0298] Where Inhibition % represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current before and after drug administration, respectively.

[0299] Compound IC 50 The following equations were fitted and calculated using GraphPad Prism 5 software:

[0300] Y=Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0301] Where X is the Log value of the detected concentration of the test sample, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0302] Conclusion: The compounds of the present invention, such as the compounds in the examples, do not inhibit the hERG potassium channel current.

[0303] VIII. CYP450 Enzyme Inhibition Test

[0304] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) after sample processing, and the changes in CYP enzyme activity were measured. The IC50 values ​​were calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0305] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no inhibitory activity against the five isoenzymes of human liver microsomal cytochrome P450 (CYP).

[0306] IX. Liver microsomal stability test

[0307] This experiment used liver microsomes from five genera—human, monkey, dog, rat, and mouse—as in vitro models to evaluate the metabolic stability of the test substance.

[0308] At 37°C, 1 µM of the test substance was co-incubated with microsomal protein and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. T1 / 2 was obtained by using the ln value of the drug residue in the incubation system and the incubation time. The intrinsic clearance rate of liver microsomes CLint(mic) and intrinsic clearance rate of liver CLint(Liver) were further calculated.

[0309] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibit good metabolic stability in liver microsomal stability tests.

[0310] 10. Caco-2 Permeability Test

[0311] The experiment used monolayers of Caco-2 cells, incubated in triple parallel in 96-well Transwell plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4±0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. After incubation at 37±1°C for 2 hours, the cell plate was removed, and a suitable amount of sample was transferred from both the apical and basal sides to a new 96-well plate. Acetonitrile containing an internal standard was then added to precipitate the protein. The samples were analyzed using LC MS / MS to determine the concentrations of the compound of the present invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side of the monolayer cells, and from the basal side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0312] Table 5. Caco-2 test results of the compounds of this invention.

[0313]

[0314] Conclusion: The compounds of the present invention, such as the compounds in the examples, exhibited good permeability in the Caco-2 permeability test.

Claims

1. A compound of general formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof: in: R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 quinone heteroaryl or -OC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; Or R A2 R A3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits; R B1 R B2 and R B3 Each of these can be independently represented as hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl, 5-8 quinone heteroaryl, -OC 3-8 cycloalkyl, -C≡CC 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further selected from 1 to 5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; Z represents O, S, or NR. Z ; R Z Hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; L represents a key, -O-, -S-, or -C. 1-4 Alkylene-, -OC 1-4 alkylene-, -C 1-4 Alkylene O-, -C(O)-, -C(O)O-, -OC(O)-, -S(O)-, -S(O)O-, -NR L C(O)-、-C(O)NR L -、-NR L -、C 3-4 Cycloalkyl, 3-4 membered heterocyclic alkyl, wherein the alkylene, cycloalkyl, or heterocyclic alkyl group is optionally further selected from 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; R L Hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 1-3 Halogenated alkyl groups; R1 is C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamine group, -NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-8 Aryl or 5-8-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is optionally further substituted with 1-5 R groups, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits; Or, R B1 and R, R Z R and its connected atoms form C 5-8 Cycloalkyl or 5-8 membered heterocycloalkyl, optionally further composed of 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits.

2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R A1 It can be hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic alkyl, phenyl, or heteroaryl groups are optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; Or R A2 R A3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits; R B1 and R B3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups; R B2 Hydrogen, deuterium, halogen, hydroxyl, cyano, amino, oxo, SF5, SCF3, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 alkylamine group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; Z represents O, S, or NR. Z ; R Z It can be hydrogen, deuterium, or methyl; R1 is C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamine group, -NHCOC 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl may optionally be further substituted with 1-3 Rs, wherein R is deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits; Or, R B1 and R, R Z R and its connected atoms form C 6-8 Cycloalkyl or 6-8-membered heterocycloalkyl, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits.

3. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, General formula (I) is further shown in general formulas (II-1), (II-2), (II-3), (II-4), (II-5), (II-6), and (II-7): in: R a1 C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; preferably cyclobutyl, cyclopentyl, , C 5-8 Polycyclic cycloalkyl, The molecule may be further selected from 1-3 groups selected from deuterium, halogen, cyano, amino, oxo, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Halogenated alkyl subunits; R a2 R a3 Together they form oxygen groups, C 1-3 alkyl subunits, C 1-3 Halogenated alkyl subunits; R b2 For SF5, C 1-3 Alkyl, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-4 cycloalkyl, -C≡CC 3-4 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 The alkyl halide group is substituted, preferably with SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, azirone, -C≡C-cyclopropyl, or -C≡C-cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, or azirone group is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; La is -S(O)-, -S(O)O-, C 3-4 Cycloalkyl, 3-4 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 The alkyl halide is substituted with a group, preferably -S(O)-, -S(O)O-, cyclopropyl, cyclobutyl, oxetyl, or aziridine, wherein the cyclopropyl, cyclobutyl, oxetyl, or aziridine is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; R 1a It is a 5-membered heteroaryl group, optionally further substituted with 1-3 Rs, preferably , , can be further replaced by 1-3 Rs.

4. The compound according to claim 3, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R A1 C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, C 5-8 Polycyclic cycloalkyl groups, optionally further composed of 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Substitution of the alkyl halide group; preferably methyl, ethyl, propyl, cyclobutyl, , , C 5-8 Polycyclic cycloalkyl, The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; and / or, R A2 R A3 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy groups; and / or, R a2 R a3 Together they form oxygen groups, C 1-6 alkyl subunits, C 1-6 Halogenated alkyl subunits; and / or, R B2 Halogen, SF5, C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, -OC 3-6 cycloalkyl, -C≡CC 3-6 Cycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl group is optionally further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 The alkyl halide group is substituted, preferably with fluorine, chlorine, SF5, methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, aziretyl, -C≡C-cyclopropyl, or -C≡C-cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, oxetyl, or aziretyl group is optionally further substituted with 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits; and / or, R1 is a 5-6 quinone heteroaryl group, optionally further divided by 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits.

5. The compound according to claim 4, its stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that, R A1 Methyl, ethyl, propyl, , , , , , , , , , , , , , , , , ; and / or, R A2 R A3 Each independently is hydrogen; and / or, R a2 R a3 Together they form oxo groups, =CH2, =CF2, =CHF, =CH(CH3), =CF(CH3), =C(CH3)2; and / or, R B1 For hydrogen; and / or, R B2 For example, fluorine, chlorine, SF5, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, , , ; and / or, R B3 It is hydrogen.

6. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that, L represents the bond, -S(O)-, -S(O)O-, , , , ; and / or, R1 is , , , The group may be further selected from 1-3 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 1-3 alkyl subunits or C 1-3 Group substitution of haloalkyl subunits, preferably , , , , , , , ; The preferred one for , , , , , , , , , , , , , .

7. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, characterized in that, It is selected from one of the structures in Table 1.

8. A pharmaceutical composition comprising a therapeutically effective dose of the compound of any one of claims 1-7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

9. The pharmaceutical composition according to claim 7, comprising 1-1500 mg of the compound of any one of claims 1-7, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

10. Use of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-7, or the pharmaceutical composition according to claim 8 or 9, in the preparation of a medicament, preferably a medicament for the prevention and / or treatment of MAT2A-mediated diseases.

11. The use according to claim 10, wherein the MAT2A-mediated disease is a tumor, preferably urothelial carcinoma, squamous NSCLC, non-small cell lung cancer, pancreatic cancer, head and neck cancer, gastric cancer, and squamous esophageal cancer.

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