Tricyclic compound and application thereof

Abstract

The invention provides a compound as shown in a formula (I), or a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof. The compound disclosed by the invention has a relatively strong MAT2A inhibition effect, and has medical application of treating and / or preventing MAT2A-mediated diseases, symptoms and conditions, such as tumors and the like.

Description

[0001] This application is a divisional application of Chinese patent application No. 202380009530.X (filed on June 26, 2023, invention title: Tricyclic Compounds and Their Uses).

[0002] This application claims priority to Chinese patent applications filed on June 27, 2022, with application number 202210734328.0, September 15, 2022, with application number 202211120467.0, and February 20, 2023, with application number 202310135765.5, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of novel compounds with MAT2A inhibitory activity and their use in the treatment and prevention of diseases, symptoms and conditions mediated by MAT2A, such as tumors. Background Technology

[0004] MAT2A stands for Methionine adenosyltransferase 2A, also known as S-Adenosylmethionine Synthase Isoform Type.

[0005] MAT2A is expressed in all tissues, including erythrocytes, brain, fetal liver, kidney, and pancreatic tissue, but at a lower level in adult liver tissue. Higher MAT2A and MAT2B expression leads to cancer cell growth, migration, and invasion. Overall, lower MAT2A and MAT2B expression results in increased apoptosis and reduced cell growth, migration, and metastasis.

[0006] MTAP is a methionine transferase that catalyzes the transfer of adenosine nucleotides, playing a crucial role in ATP salvage synthesis. MTAP deficiency occurs in approximately 15% of all solid tumors. MTAP deficiency is present to varying degrees in different tumor types. MTAP deficiency leads to the accumulation of the enzyme substrate methionine (MTA). Increased MTA concentration partially inhibits PRMT5 activity, while other methyltransferases are relatively unaffected. Inhibition of MAT2A reduces the methyl donor S-adenosylmethionine (SAM), a substrate of PRMT5, further inhibiting PRMT5, affecting tumor cell mRNA splicing, and causing DNA damage. Therefore, MAT2A inhibitors can benefit MTAP-deficient tumors.

[0007] Several patents have disclosed MAT2A inhibitors, such as WO2018039972, WO2019191470, WO2020139991, WO2020139992, WO2020243376, and WO2020123395. Summary of the Invention

[0008] This invention provides a class of novel MAT2A inhibitor compounds or their tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and provides the use of such compounds or their tautomers, stereoisomers or pharmaceutically acceptable salts for the treatment and prevention of MAT2A-mediated diseases, symptoms and conditions.

[0009] Specifically, in a first aspect, the present invention provides a compound of formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, having the following structure:

[0010]

[0011] in,

[0012] Ring A is selected from C 5-10 carbonyl group, C 6-14 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic;

[0013] R 1 Selected from C (optional substitution) 3-12 carbonyl group, C 6-14 aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclic; wherein the carbocyclic, aryl, heteroaryl, or heterocyclic group is optionally surrounded by one or more R a Replaced;

[0014] L is selected from the following: -O-, -S-, -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -C(O)-, -C(O)O-, -OC(O)-, -N(R) a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-; the alkylene group is optionally surrounded by one or more R a1 Replaced;

[0015] R a Each occurrence is independently selected from deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1-W-OC(O)R a1 -W-OC(O)OR a1 -WC(O)NR a2 R a3 -WC(O)NR a2 OR a1 -W-OC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -W-NR a2 C(O)OR a1 -W-NR a2 C(O)NR a2 R a3 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 -W-OS(O)2R a4 -W-NR a2 S(O)2NR a2 R a3 -W-OS(O)2NR a2 R a3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0016] R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C6-14 aryl, 5-12-membered heteroaryl, 3-20-membered heterocyclic, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0017] R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R a2 and R a3 When R is attached to the same nitrogen atom, a2 and R a3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl;

[0018] R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14 aryl, 5-12-membered heteroaryl, 3-20-membered heterocyclic, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0019] X is N or CR 6 ;

[0020] R 2 R 3 and R 6 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-OC(O)NR b2 R b3 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)OR b1 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 -W-NR b2 S(O)2NR b2 R b3 -W-OS(O)2NR b2 R b3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0021] R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0022] R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R b2 and R b3 When R is attached to the same nitrogen atom, b2 and R b3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl;

[0023] R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0024] R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, and -W-OR. c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced;

[0025] R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NRc2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-12 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0026] R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0027] R c2 and R c3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R c2 and R c3 When R is attached to the same nitrogen atom, c2 and R c3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C.1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl;

[0028] R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0029] W is selected from key, C 1-3 Alkylene, -OC 1-3 Alkylene, -SC 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0030] Unless otherwise specified, the heteroatoms in the heterocyclic and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

[0031] In a further preferred embodiment, ring A is selected from C. 5-10 cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic;

[0032] In a further preferred embodiment, ring A is selected from C. 5-10 Cycloalkyl, C6 aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic;

[0033] In a further preferred embodiment, ring A is selected from C. 5-10 cycloalkyl groups, 5-10 membered heterocyclic groups;

[0034] In a further preferred embodiment, ring A is selected from 5-10 membered heterocyclic groups;

[0035] In a further preferred embodiment, ring A is selected from 5-8 membered heterocyclic groups;

[0036] In a further preferred embodiment, ring A is selected from 5-7 membered heterocyclic groups, and the heteroatom is independently selected from O or N, with one or two heteroatoms.

[0037] In a further preferred embodiment, ring A is selected from a 5-6 membered heterocyclic group, and the heteroatom is independently selected from O or N, with one or two heteroatoms.

[0038] In a further preferred embodiment, ring A is selected from a 5-6 membered heterocyclic group, the heteroatom is selected from N, and the number of heteroatoms is 1 or 2;

[0039] In a further preferred embodiment, ring A is selected from a 5-membered heterocyclic group, and the heteroatom is independently selected from O or N, with the number of heteroatoms being 1 or 2;

[0040] In a further preferred embodiment, ring A is selected from a 5-membered heterocyclic group, the heteroatom is selected from N, and the number of heteroatoms is 1 or 2;

[0041] In a further preferred embodiment, ring A is selected from...

[0042] In a further preferred embodiment, ring A is selected from...

[0043] In a further preferred embodiment, ring A is selected from...

[0044] In a further preferred embodiment, ring A is selected from...

[0045] In a further preferred embodiment, X is selected from N or CH;

[0046] In a further preferred embodiment, X is selected from N;

[0047] In a further preferred embodiment, X is selected from CH.

[0048] In a further preferred embodiment, R 1 Selected from C (optional substitution) 3-10 cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered monocyclic heterocyclic, 5-10 membered bridged heterocyclic, 5-10 membered fused heterocyclic, 5-10 membered spirocyclic heterocyclic; wherein the cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bridged cycloalkyl, fused heterocyclic and spirocyclic are optionally combined with one or more Ra Replaced;

[0049] In a further preferred embodiment, R 1 Selected from C (optional substitution) 3-6 cycloalkyl, C 5-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered monocyclic heterocyclic, 5-10 membered bridged heterocyclic, 5-10 membered fused heterocyclic, 5-10 membered spirocyclic heterocyclic; wherein the cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bridged heterocyclic, fused heterocyclic and spirocyclic are optionally combined with one or more R a Replaced;

[0050] In a further preferred embodiment, R 1 Selected from C (optional substitution) 6-10 Aryl, 5-10 member heteroaryl, 5-10 member monocyclic heterocyclic, 5-10 member bridged heterocyclic, 5-10 member fused heterocyclic, 5-10 member spirocyclic heterocyclic; wherein the aryl, heteroaryl, monocyclic, bridged, fused, and spirocyclic groups are optionally combined with one or more R a Replaced;

[0051] In a further preferred embodiment, R 1 Selected from C (optional substitution) 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered monocyclic heterocyclic, 5-8 membered bridged heterocyclic, 5-8 membered fused heterocyclic, 5-8 membered spirocyclic heterocyclic; wherein the aryl, heteroaryl, monocyclic, bridged, fused, and spirocyclic groups are optionally combined with one or more R a Replaced;

[0052] In a further preferred embodiment, R 1 Selected from optionally substituted C6 aryl, 5-8 membered heteroaryl, and 5-8 membered monocyclic heterocyclic groups; wherein the aryl, heteroaryl, or monocyclic heterocyclic group is optionally substituted with one or more R a Replaced;

[0053] In a further preferred embodiment, R 1 Selected from optionally substituted C6 aryl, 5-6 membered heteroaryl, and 5-6 membered monocyclic heterocyclic groups; wherein the aryl, heteroaryl, or monocyclic heterocyclic group is optionally substituted with one or more R a The heteroatoms are independently selected from O and N, with one or two heteroatoms respectively.

[0054] In a further preferred embodiment, R 1Selected from optionally substituted C6 aryl or 5-6 heteroaryl groups; wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. a The heteroatoms are independently selected from N, and the number of heteroatoms is 1 or 2.

[0055] In a further preferred embodiment, R 1 Selected from one or more R a The substituted phenyl, pyridyl, or imidazolyl groups;

[0056] In a further preferred embodiment, R 1 Selected from one or more R a The substituted pyridinyl group;

[0057] In a further preferred embodiment, R 1 Selected from

[0058] In a further preferred embodiment, R 1 Selected from

[0059] In a further preferred embodiment, L is selected from bond, -O-, -S-, -C 1-4 Alkylene- or -OC 1-4 Alkylene; the alkylene group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0060] In a further preferred embodiment, L is selected from bond, -O-, -S-, -C 1-2 Alkylene- or -OC 1-2 Alkylene; the alkylene group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0061] In a further preferred embodiment, L is selected from bond, -O-, -S-, methylene or ethylene; the methylene or ethylene may optionally be replaced by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2;

[0062] In a further preferred embodiment, L is selected from a bond, -O-, methylene, or ethylene;

[0063] In a further preferred embodiment, L is selected from a bond or a methylene group;

[0064] In a further preferred embodiment, L is selected from a key.

[0065] In a further preferred embodiment, Ra Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-OC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 -W-OS(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0066] In a further preferred embodiment, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-NR a2 R a3 -W-NRa2 C(O)R a4 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0067] In a further preferred embodiment, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy group; the alkyl, alkenyl, alkynyl, or alkoxy group may optionally be selected from one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Substituents of haloalkoxy groups;

[0068] In a further preferred embodiment, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -W-NR a2 C(O)R a4 -C 1-4 Alkyl, C 1-4 Alkyl group; wherein the alkyl or alkoxy group is optionally surrounded by one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0069] In a further preferred embodiment, R a Each occurrence is independently selected from deuterium, halogens, -OH, -NH2, -W-NR a2 C(O)R a4 C 1-4 Alkyl, C 1-4 Alkyl group; the alkyl group or alkoxy group may optionally be replaced by one or more radicals selected from deuterium, halogen, oxo group, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0070] In a further preferred embodiment, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, -W-NR a2 C(O)R a4 C 1-4 Halogenated alkyl group; the alkyl group or haloalkyl group may optionally be substituted with one or more deuterium groups;

[0071] In a further preferred embodiment, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -W-NR a2 C(O)R a4 The alkyl or haloalkyl group may optionally be substituted with one or more deuterium groups.

[0072] In a further preferred embodiment, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NHC(O)R a4 The alkyl group may optionally be substituted with one or more deuterium groups.

[0073] In a further preferred embodiment, R a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Alkoxy;

[0074] In a further preferred embodiment, R a Each time it appears, it is independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl or -NHC(O)-phenyl;

[0075] In a further preferred embodiment, R a Each time it appears, it is independently selected from Cl, methyl, methoxy, or -NHC(O)-phenyl;

[0076] In a further preferred embodiment, R a Each time it appears, it is independently selected from Cl, methyl, or -NHC(O)-phenyl.

[0077] In a further preferred embodiment, R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0078] In a further preferred embodiment, R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0079] In a further preferred embodiment, R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0080] In a further preferred embodiment, R a1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Substituents of alkyl groups;

[0081] In a further preferred embodiment, R a1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0082] In a further preferred embodiment, R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0083] In a further preferred embodiment, R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C1-4 Alkoxy group, wherein the alkyl group or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl groups, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0084] In a further preferred embodiment, R a2 and R a3 Each time it appears independently, it is hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy may be selected by one or more elements from halogen, deuterium, hydroxyl, or C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0085] In a further preferred embodiment, R a2 and R a3 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0086] In a further preferred embodiment, R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy or halophenyl groups; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0087] In a further preferred embodiment, R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0088] In a further preferred embodiment, R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0089] In a further preferred embodiment, R a4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0090] In a further preferred embodiment, R a4 Each time it appears, it is independently hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl is optionally selected by one or more of halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

[0091] In a further preferred embodiment, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3-WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12 aryl, 3-6 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0092] In a further preferred embodiment, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12 aryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0093] In a further preferred embodiment, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl; wherein the alkyl, alkoxy, cycloalkyl, or aryl group is optionally selected from one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0094] In a further preferred embodiment, R 2 Selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 The methyl, ethyl, isopropyl, methoxy, ethoxy, and propoxy groups are optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, and C. 1-4Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0095] In a further preferred embodiment, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, methyl, ethyl, isopropyl, -SO2NH2, -NHSO2H;

[0096] In a further preferred embodiment, R 2 Selected from hydrogen.

[0097] In a further preferred embodiment, R 6 Selected from hydrogen.

[0098] In a further preferred embodiment, R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12aryl, 3-6 membered heterocyclic, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0099] In a further preferred embodiment, R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 6- aryl, 3-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0100] In a further preferred embodiment, R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -WC(O)NR b2 R b3 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6- aryl, 3-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0101] In a further preferred embodiment, R 3 Selected from hydrogen, deuterium, halogens, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group; wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0102] In a further preferred embodiment, R 3 Selected from F, Cl, Br, -CF3, -CHF2-CH2, -CH2FCH3, -OCF3 or cyclopropane;

[0103] In a further preferred embodiment, R 3 Selected from Cl or -CF3;

[0104] In a further preferred embodiment, R 3 C selected from halogens, optionally substituted by one or more halogens 1-4 alkyl;

[0105] In a further preferred embodiment, R 3 Selected from halogens;

[0106] In a further preferred embodiment, R 3 Selected from Cl.

[0107] In a further preferred embodiment, R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0108] In a further preferred embodiment, R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0109] In a further preferred embodiment, Rb1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0110] In a further preferred embodiment, R b1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Substituents of alkyl groups;

[0111] In a further preferred embodiment, R b1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0112] In a further preferred embodiment, R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0113] In a further preferred embodiment, R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy group, wherein the alkyl group or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl groups, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0114] In a further preferred embodiment, R b2 and Rb3 Each time it appears independently, it is hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy may be selected by one or more elements from halogen, deuterium, hydroxyl, or C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0115] In a further preferred embodiment, R b2 and R b3 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0116] In a further preferred embodiment, R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 The substituents are substituted by haloalkoxy or halophenyl groups; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0117] In a further preferred embodiment, R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0118] In a further preferred embodiment, R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0119] In a further preferred embodiment, R b4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0120] In a further preferred embodiment, R b4 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or optionally one or more are selected from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

[0121] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 Rc3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-12 aryl, 4-12-membered heterocyclic, 5-12-membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced;

[0122] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3-W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, C 6-12 aryl, 4-10 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced by O, N or S; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0123] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C1-4 Alkylthio, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, C6 aryl, 4-10 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c The heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0124] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, C6 aryl, 4-10 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c The heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0125] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -OH, and -WC(O)NR. c2 R c3 -W-NR c2 Rc3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 aryl or 5-10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, phenyl, or heteroaryl group may optionally be surrounded by one or more R groups. c Replaced; or R 4 and R 5 Together with the attached carbon or nitrogen atom, they form an optionally substituted C. 3-10 Cycloalkyl, 5-12 membered heterocyclic groups; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced by O, N or S; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0126] In a further preferred embodiment, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -OH, and -WC(O)NR. c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 aryl or 5-6-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, phenyl, or heteroaryl group may optionally be surrounded by one or more R groups. c Replaced; or R 4 and R 5 Together with the attached carbon or nitrogen atom, they form an optionally substituted C. 3-10 Cycloalkyl, 5-12 membered heterocyclic groups; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced by O, N or S; the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3;

[0127] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4Alkoxy, 4-6 membered heterocyclic group; the alkyl, alkoxy, or heterocyclic group may optionally be R c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl or 5-10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be surrounded by one or more R groups. c The heteroatoms are independently selected from O and N, with one or two heteroatoms respectively.

[0128] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, 4-6 membered heterocyclic group; the alkyl, alkoxy, or heterocyclic group may optionally be R c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-10 aryl or 5-6-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group may optionally be surrounded by one or more R groups. c The heteroatoms are independently selected from O and N, with one or two heteroatoms respectively.

[0129] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, 4-6 membered heterocyclic alkyl; wherein the alkyl, alkoxy, or heterocyclic alkyl is optionally surrounded by one or more R c Replaced; R 5Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, or 9-10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by one or more R c Replaced;

[0130] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, 4-6 membered heterocyclic alkyl; wherein the alkyl, alkoxy, or heterocyclic alkyl is optionally surrounded by one or more R c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, or 5-6-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by one or more R c Replaced;

[0131] In a further preferred embodiment, R 4 The methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups are hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups optionally with one or more R groups. c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)Rc4 -WS(O)2R c4 methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, benzopyrazolyl; wherein the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, benzopyrazolyl is optionally modified by one or more R c Replaced;

[0132] In a further preferred embodiment, R 4 The methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups are hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups optionally with one or more R groups. c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, or pyrimidinyl; wherein the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, or pyrimidinyl is optionally modified by one or more R c Replaced;

[0133] In a further preferred embodiment, R 4 The methyl, ethyl, propyl, methoxy, ethoxy, aziridine, or pyrrolidinyl group is hydrogen, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, aziridine, or pyrrolidinyl group may optionally be modified by one or more R groups. c Replaced; R 5 Selected from hydrogen, halogens, -OH, -C 1-3 Alkylene-C(O)NR c2 R c3 -C 1-3 Alkylene-NR c2 R c3 -C1-3 Alkylene-SO2NR c2 R c3 -C(O)R c4 -S(O)2R c4 methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl; wherein the methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl are optionally modified by one or more R c Replaced;

[0134] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, methyl R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3,

[0135] In a further preferred embodiment, R 4 It is hydrogen, halogen, -OH or methyl; R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3,

[0136] In a further preferred embodiment, R 4 Hydrogen, deuterium, halogen, -OH, methyl R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3,

[0137] In a further preferred embodiment, R 4 It can be hydrogen, deuterium, halogen, -OH, or methyl; R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3,

[0138] In a further preferred embodiment, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-6 Alkyl, optionally with one or more R c Substituted phenyl groups, 9-10 membered bicyclic heteroaryl groups;

[0139] In a further preferred embodiment, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-4 Alkyl group, optionally with one or more halogens, -OH, C 1-4Alkyl-substituted phenyl groups, 9-10 membered bicyclic heteroaryl groups;

[0140] In a further preferred embodiment, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-4 Alkyl group, phenyl group optionally substituted with one or more -F, -Cl, -Br, -OH, methyl, ethyl, n-propyl, isopropyl, or 9-10 membered bicyclic heteroaryl group; wherein the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1, 2, or 3.

[0141] In a further preferred embodiment, R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-12 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0142] In a further preferred embodiment, R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3-W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-12 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0143] In a further preferred embodiment, R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3-W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0144] In a further preferred embodiment, R c Independently selected from deuterium, halogens, -CN, -OH, -SH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C6-12 aryl, 5-8 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 6-12 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0145] In a further preferred embodiment, R c Independently selected from deuterium, halogens, -CN, -OH, -SH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic, C6 aryl, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected by one or more elements from deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 6-12 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0146] In a further preferred embodiment, R c Independently selected from deuterium, halogens, -CN, -OH, -W-OR c1 -WC(O)NR c2 R c3 -W-NR c2R c3 -W-SO2NR c2 R c3 C 1-4 Alkyl, 4-8 membered heterocyclic group; wherein the heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0147] In a further preferred embodiment, R c Independently selected from deuterium, halogens, -CN, -OH, -W-OR c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 4-8 membered heterocyclic groups; wherein the heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogens, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0148] In a further preferred embodiment, R c Independently selected from -F, -Cl, -Br, -CH2-OH, -OH, -C(O)NH-CH3, -N(CH3)2, -SO2CH3, -SO2N(CH3)2, morpholinyl, methyl, ethyl, n-propyl, isopropyl;

[0149] In a further preferred embodiment, R c It is independently selected from -F, -Cl, -Br, -CH2-OH, -OH, -C(O)NH-CH3, -N(CH3)2, -SO2CH3, -SO2N(CH3)2, and morpholino.

[0150] In a further preferred embodiment, R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0151] In a further preferred embodiment, R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0152] In a further preferred embodiment, R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0153] In a further preferred embodiment, R c1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Substituents of alkyl groups;

[0154] In a further preferred embodiment, R c1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0155] In a further preferred embodiment, R c2 and R c3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups;

[0156] In a further preferred embodiment, R c2 and R c3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy group, wherein the alkyl group or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl groups, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0157] In a further preferred embodiment, R c2 and R c3 Each time it appears independently, it is hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy may be selected by one or more elements from halogen, deuterium, hydroxyl, or C. 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0158] In a further preferred embodiment, R c2 and R c3 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

[0159] In a further preferred embodiment, R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0160] In a further preferred embodiment, R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents are substituted by haloalkoxy groups; the heteroatoms are independently selected from O and N, with one or two heteroatoms;

[0161] In a further preferred embodiment, R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0162] In a further preferred embodiment, R c4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0163] In a further preferred embodiment, R c4 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or optionally one or more are selected from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

[0164] In a further preferred embodiment, W is selected from bonds, C 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0165] In a further preferred embodiment, W is selected from bonds, C 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2;

[0166] In a further preferred embodiment, W is selected from a bond, methylene, or ethylene, wherein the methylene or ethylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, or -NH2.

[0167] In a second aspect, the present invention provides a compound of formula (II), or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof:

[0168]

[0169] Among them, ring A is a 5-12 membered heteroaryl ring or a 5-12 membered heterocyclic group; R 1 R 2 R 3 R 4 R 5 L and X are defined as in the compound shown in formula (I) of this invention.

[0170] In a further preferred embodiment, L is a bond.

[0171] In a further preferred embodiment, R 5 The N atom is substituted at the position on the ring.

[0172] In a further preferred embodiment, ring A is selected from...

[0173] In a further preferred embodiment, ring A is selected from...

[0174] In a further preferred embodiment, ring A is selected from...

[0175] In a further preferred embodiment, ring A is selected from...

[0176] Thirdly, the present invention provides a compound of formula (III), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, having the following structure:

[0177]

[0178] Where X 1 Selected from C, N, O, or S; n 1 Selected from 0, 1, 2, 3; R 1 R 2 R 3 R 4 R 5 The definitions of L and X are as described in the compound of formula (I) of this invention.

[0179] In a further preferred embodiment, where n 1 Selected from 0, 1, or 2;

[0180] In a further preferred embodiment, L is selected from a key;

[0181] In a further preferred embodiment, X 1 Selected from C, N, or O;

[0182] In a further preferred embodiment, wherein, Selected from

[0183] In a further preferred embodiment, ring A is selected from...

[0184] Fourthly, the present invention provides a compound of formula (III-a), (III-b), (III-c), (III-d) or (III-e), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof, having the following structure:

[0185]

[0186] Where R 1 R 2 R 3 R 4 R 5 R 6 The definitions of L and X are as described in the compound shown in formula (I).

[0187] In a further preferred embodiment, L is selected from a key;

[0188] In a further preferred embodiment, R in formula (III-c) 5 The N atom is substituted at the position on the ring.

[0189] In a further preferred embodiment, ring A is selected from...

[0190] In a further preferred embodiment, X is selected from N or CH;

[0191] In a further preferred embodiment, L represents a bond;

[0192] In a further preferred embodiment, R 3 Selected from -Cl or -CF3;

[0193] In a further preferred embodiment, R 2 Selected from hydrogen;

[0194] In a further preferred embodiment, R 6 Selected from hydrogen;

[0195] In a further preferred embodiment, R 4 It is hydrogen; R 5 Selected from hydrogen, methyl, phenyl,

[0196] In a further preferred embodiment, R 1 Selected from one or more R a The substituted pyridinyl group;

[0197] In a further preferred embodiment, R a Each time it appears, it is independently selected from Cl, methyl, and methoxy;

[0198] In a further preferred embodiment, R 1 Selected from

[0199] Fifthly, the present invention provides a transisomer of a compound of formula (III-a), (III-b), (III-c), (III-d) or (III-e), or a pharmaceutically acceptable salt thereof of a transisomer:

[0200] Where R 1 R 2 R 3 R 4 R 5 R 6 L and X are as described in the compounds shown in formulas (III-a), (III-b), (III-c), (III-d), or (III-e) above, where L is a bond, R is a bond, and X is a bond. 1 At least one R a What it replaced.

[0201] Rotational isomers are stereoisomers produced by hindered rotation of a single bond axis, where the rotational barrier is high enough to allow the separation of individual rotational isomers. (LaPlante et al., J.Med.Chem., 54:7005(2011)). Compounds of formula (III-a), (III-b), (III-c), (III-d), or (III-e), wherein R 1 by one or more R a The substituted group is R on the quinazolinone ring. 1The bonds between them have a stereogenic axis. Due to the asymmetric nature of substitution on the rings connected by this bond, and due to the restricted rotation of this bond caused by steric hindrance, such compounds can form rotational isomers. Therefore, these compounds of formulas (III-a), (III-b), (III-c), (III-d), or (III-e) can form two rotational isomers, which, in certain cases, such as chromatography on a chiral stationary phase, can be separated into individual rotation-resistant isomers.

[0202] In a further preferred embodiment, the compound of formula (III-a), (III-b), (III-c), (III-d), or (III-e) may be provided as a mixture of two transisomers or as a single transisomer. It is separable and stable in solution at ambient and physiological temperatures. The absolute spatial structure of the transisomer can be determined by single-crystal X-ray crystallography.

[0203] In a further preferred embodiment, the compound of formula (III-a), (III-b), (III-c), (III-d), or (III-e) may be provided as a single transisomer or as a mixture of two transisomers of formula (III-a), (III-b), (III-c), (III-d), or (III-e) in any proportion.

[0204] In a further preferred embodiment, a compound of formula (III-a), (III-b), (III-c), (III-d), or (III-e) or a salt thereof, wherein only one transisomer is provided, or wherein only one transisomer is provided mixed with a small amount of other transisomers. If an absolute configuration is not assigned, the provided transisomer can be defined by the elution order relative to another transisomer during chromatography on a chiral stationary phase under specific conditions.

[0205] In a further preferred embodiment, the transisomers of formula (III-a), (III-b), (III-c), (III-d), or (III-e) are provided, wherein each transisomer of formula (III-a), (III-b), (III-c), (III-d), or (III-e) is provided substantially free of its complementary transisomers. As used herein, "substantially free" means providing a formula (I) compound having a transisomer purity of at least 95%, preferably at least 99%, and more preferably at least 99.5%.

[0206] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0207] Preferably, the compound provided by the present invention, or its tautomer, stereoisomer, transisomer, or pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220] In a sixth aspect, the present invention also aims to provide a method for preparing compounds of the above general formula or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

[0221] The method described below can be used, for example, to prepare the sample.

[0222] Method 1:

[0223]

[0224] 1.9 undergoes demethylation of the methoxy group to yield intermediate 1.10, which then undergoes a cyclization reaction to give the target compound 1.11. Alternatively, intermediate 1.9 undergoes demethylation of the methyl protecting group while simultaneously undergoing an in-situ cyclization reaction to give the target compound 1.11.

[0225] In a further preferred embodiment, compound 1.9 is prepared by the following steps:

[0226]

[0227] Starting with fluorinated arylcarboxylic acid (1.1), it is esterified with methanol to obtain intermediate 1.2. Then, bromination occurs at the benzylic position of the aromatic ring to obtain intermediate 1.3. Next, the bromine atom is replaced by a methoxy group to obtain compound 1.4. Esterification under alkaline conditions yields carboxyl-containing intermediate 1.5. The carboxyl group is then converted to an amide to obtain intermediate 1.6. Finally, under the action of oxalyl chloride, it reacts with R... 1 -L-NH2 reaction yields intermediate

[0228] 1.7, followed by a cyclization reaction under alkaline conditions to give intermediate 1.8, 1.8 reacts with phosphorus oxychloride, and then with R 5 The reaction with NH2 yielded intermediate 1.9.

[0229] Where R 1 R 2 R 3 R 4 R 5 L and X are as described in the compound of formula (III-a).

[0230] Method 2:

[0231]

[0232] 2.8 The target compound was obtained by cyclization with the action of methanesulfonyl chloride. 2.9

[0233] In a further preferred embodiment, compound 2.8 is prepared by the following steps:

[0234]

[0235] Starting with fluorinated and brominated arylcarboxylic acids (2.1), the carboxylic acid is converted into an amide intermediate 2.2, which is then reacted with R under the action of oxalyl chloride. 1 The reaction of -L-NH2 yields intermediate 2.3, followed by a cyclization reaction under alkaline conditions to give intermediate 2.4. 2.4 undergoes a Heck reaction with isobutyl acrylate to give compound 2.5, which is then reduced with sodium borohydride to give intermediate 2.6. This intermediate is then reacted with phosphorus oxychloride, followed by the addition of R5NH2 to give intermediate 2.7, which is then reduced with lithium aluminum hydride to give hydroxyl-containing intermediate 2.8.

[0236] Where R 1 R 2 R 3 R 5 L and X are as described in the compound of formula (III-b).

[0237] Method 3:

[0238]

[0239] 3.5 The target compound was obtained by a substitution reaction under alkaline conditions. 3.6

[0240] In a further preferred embodiment, compound 3.5 is prepared by the following steps:

[0241]

[0242] Starting with substituted 2,6-difluorobenzoic acid (3.1), the carboxylic acid was converted into an amide intermediate 3.2, which was then reacted with R under the action of oxalyl chloride. 1 The reaction of -L-NH2 yields intermediate 3.3, which is then subjected to a cyclization reaction under alkaline conditions to give intermediate 3.4. Interaction of 3.4 with phosphorus oxychloride followed by the addition of an amine compound with a terminal hydroxyl group yields intermediate 3.5.

[0243] Where R 1 R 2 R 3 R 4 R 5 R 6 And L as shown in the compound of formula (III-c).

[0244] Method 4:

[0245]

[0246] 4.2 Under acidic conditions, the alkyl group was removed and a cyclization reaction occurred to give the target compound 4.3.

[0247] In a further preferred embodiment, compound 4.2 is prepared by the following steps:

[0248] Where alkyl represents C 1-6 alkyl.

[0249] Starting with 3.4, it undergoes a substitution reaction with a terminal amino-substituted acetal to give intermediate 4.1, which then reacts with phosphorus oxychloride, followed by the addition of an amine compound to give intermediate 4.2.

[0250] Where R 1 R 2 R 3 R 4 R 5 R 6 And L as shown in the compound of formula (III-d).

[0251] Method 5:

[0252]

[0253] The hydroxyl group of 5.12 is converted into the MsO fragment with strong leaving ability, and finally an intramolecular cyclization reaction occurs under alkaline conditions to obtain the target compound 5.14.

[0254] In a further preferred embodiment, compound 5.12 is prepared by the following steps:

[0255]

[0256] Starting from compound 5.1, it reacts with phosphorus oxychloride to give intermediate 5.2, then reacts with potassium vinyl boron trifluoride to give intermediate 5.3, followed by hydrolysis under alkaline conditions to give compound 5.4 containing a carboxyl group. The carboxyl group is then converted to an amide, which reacts with p-toluenesulfonyl chloride to give intermediate 5.6, and then reacts with R under the action of oxalyl chloride. 1 The reaction with NH2 yields intermediate 5.7, which then undergoes an intramolecular cyclization reaction under alkaline conditions to give intermediate 5.8. The vinyl group of 5.8 is then oxidized to a formic acid fragment, followed by the conversion of the carboxyl group of 5.9 to a methyl ester. Finally, under the action of phosphorus oxychloride, it reacts with R... 5 The reaction with NH2 yielded intermediate 5.11, which was then reduced to give intermediate 5.12.

[0257] Where R 1 R 2 R 3 R 5 L and X are as described in the compound of formula (III-a).

[0258] Method Six:

[0259]

[0260] 6.4 Reacts with phosphorus oxychloride and then with R 5 The reaction with NH2 yields intermediate 6.5, which is then reacted with the corresponding aldehyde R. 4 The CHO reaction yielded the target compound 6.6.

[0261] In a further preferred embodiment, compound 6.4 is prepared by the following steps:

[0262]

[0263] Starting from 6.1, the carboxyl group was converted to an amide to obtain intermediate 6.2, which was then reacted with R under the action of oxalyl chloride. 1 The -L-NH2 reaction yields intermediate 6.3, which is then subjected to a cyclization reaction under alkaline conditions to yield intermediate 6.4.

[0264] Where R 1 R 2 R 3 R 5 R 6 The compounds are as shown in formula (III-c).

[0265] Method Seven:

[0266]

[0267] Starting with intermediate 5.8, under the action of PyBop and DBU, it reacts with R 5 The NH2 reaction yielded the target compound 7.1.

[0268] Where R 1 R 2 R 3 R 5 L and X are as described in the compound of formula (III-e).

[0269] Note: The protection and deprotection reaction steps involved in this process have been omitted. The substituents are as defined in the general formula above.

[0270] The present invention also aims to provide intermediates for the preparation of compounds of the general formula shown below:

[0271]

[0272]

[0273] Among them, R 1 R 2 R 3 R 4 R 5 R 6 L and X are defined as in the compound shown in formula (I) of this invention, wherein alkyl represents C 1-6 alkyl.

[0274] In another aspect, the present invention provides a pharmaceutical composition comprising the compound described herein or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

[0275] Furthermore, the pharmaceutical composition of the present invention comprises the compound of the present invention or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0276] The compounds of the present invention, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, may be administered in pure form or as a suitable pharmaceutical composition by any acceptable route of administration of a medicament for similar use. The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients.

[0277] In another aspect, the present invention provides the use of the compounds described herein or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the prevention and / or treatment of diseases, symptoms, and conditions mediated by MAT2A.

[0278] Furthermore, in the use provided by the present invention, the disease, symptom, and condition are MTAP-deficient tumors.

[0279] In another aspect, the present invention provides the use of the compounds described herein or their tautomers, stereoisomers, or pharmaceutical compositions thereof in the preparation of medicaments for the prevention and / or treatment of tumors.

[0280] Furthermore, in the uses provided by this invention, the tumor includes solid tumors and hematologic malignancies; preferably, the solid tumor includes gastrointestinal tumors, and more preferably colorectal cancer. In certain contexts within the art, the cancer may also be referred to as a malignant tumor.

[0281] In another aspect, the present invention provides a method for preventing and / or treating diseases, symptoms, and conditions mediated by MAT2A, comprising administering to an individual in need a compound of the present invention or a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention; preferably, the disease, symptom, or condition is a tumor; preferably, the disease, symptom, or condition is a MTAP-deficient tumor; more preferably, the tumor includes solid tumors and hematologic malignancies.

[0282] Furthermore, this application provides compounds of the present invention or their tautomers, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention for the prevention and / or treatment of diseases, symptoms and conditions mediated by MAT2A; preferably, the diseases, symptoms and conditions are MTAP-deficient tumors; more preferably, the diseases, symptoms and conditions are tumors; more preferably, the tumors include solid tumors and hematologic malignancies. Further, the uses or methods provided by the present invention involve the use of compounds of the present invention or their tautomers, stereoisomers or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention in combination with another, two or more drugs having anti-tumor activity.

[0283] The present invention also provides a pharmaceutical composition comprising the compound of the present invention or its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, and another, two or more drugs having antitumor activity.

[0284] definition

[0285] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0286] Unless otherwise specified, "optional substitution" or "arbitrary substitution" means that the substituent is independently selected from one or more hydroxyl, halogen, amino, nitro, mercapto, cyano, azide, carboxyl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), -C(O)NH-C 1-6 Alkyl group, -NHC(O)-C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl groups; wherein, the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-12 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more of the alkoxy groups are substituted.

[0287] The term "oxo-substituent" refers to a double bond formed when two hydrogen atoms at the same substitution position are replaced by the same oxygen atom.

[0288] Unless otherwise specified, the term "carbocyclic group" refers to a saturated or partially unsaturated cyclic carbon-containing group, such as a 4-6 member (e.g., 5-6 member) saturated carbocyclic group and a 5-6 member partially unsaturated carbocyclic group. In one embodiment, the carbocyclic group is a 3-4 member monocyclic group, a 3-5 member monocyclic group, a 3-6 member monocyclic group, a 3-8 member monocyclic group, a 3-10 member monocyclic group, a 5-8 member monocyclic group, a 5-6 member monocyclic group, a 4-12 member bicyclic group, or a 10-15 member tricyclic system. The carbocyclic group includes bridged rings or spirocyclic groups. Non-limiting examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cyclohepttrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl, etc. The carbocyclic group may optionally be substituted. When substituted, the substituents are preferably 1 to 5, and said substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkoxy, hydroxyl, nitro, cyano, and amino.

[0289] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0290] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0291] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0292] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-7 carbon atoms (C 3-7 cycloalkyl groups), 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0293] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0294] Unless otherwise specified, the term "alkylthio" refers to -S-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, tert-butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, etc.

[0295] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0296] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 4 ring heteroatoms, comprising 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it comprises 3 to 12 ring atoms (3-12 membered heterocyclic group), more preferably 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused-ring group"), bridged ("heterobridged ring group" or "bridged ring heterocyclic group") or spiro-fused ("heterospirocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic system can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azahexacyclobutane, oxacyclobutane, and thiohexacyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrroliyl, dihydropyrroliyl, and pyrroliyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanecyclopentane, oxathiocyclopentane, dithiocyclopentane, and oxazolidin-2-one.Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing 2 heteroatoms include, but are not limited to, piperazineyl, morpholinyl, dithiadiazolinyl, and dioxazinanyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazineyl, thiadiazineyl, oxathiazineyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azirheptanyl, oxaheptanyl, and thiadiazeptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclooctyl, oxocyclooctyl, and thiocyclooctyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0297] Unless otherwise specified, "heterocyclic alkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms as above, i.e., containing 3 to 20 ring atoms ("3-20-membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 12 ring atoms ("3-12-membered heterocyclic alkyl"), more preferably containing 3 to 10 ring atoms ("3-10-membered heterocyclic alkyl"), even more preferably containing 3 to 8 ring atoms ("3-8-membered heterocyclic alkyl"), even more preferably containing 4 to 7 ring atoms ("4-7-membered heterocyclic alkyl"), even more preferably containing 5 to 10 ring atoms ("5-10-membered heterocyclic alkyl"), and even more preferably containing 5 to 6 ring atoms ("5-6-membered heterocyclic alkyl"). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an “unsubstituted heterocyclic alkyl”) or substituted with one or more substituents (an “substituted heterocyclic alkyl”). The “heterocyclic group” or “heterocyclic” section above has given some exemplary examples of “heterocyclic alkyl”, and also includes, but is not limited to, azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiohexyl, oxazolyl, dioxyl, dithiohexyl, thiazolyl, pyrroliyl, pyrazolyl, imidazolinidine, etc.

[0298] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring group." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyreneyl.

[0299] Unless otherwise specified, the term "heteroaryl" or "heteroary cycloyl" refers to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, or preferably a 5-10 member structure, or preferably a 5-8 member structure, more preferably a 5-6 member structure, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzo[] Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0300] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within the bounds of reasonable medical judgment, is suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0301] The compounds of this invention also include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15N; oxygen isotopes: 15 O、 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H) can enhance metabolic stability and prolong half-life, thereby providing therapeutic advantages through dose reduction. Isotopically labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, similar to the synthesis of non-isotopically labeled compounds. The compounds of this invention also include their "solvates" or "solvents," where, unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0302] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0303] The term "transisomer" refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is blocked or significantly slowed down due to spatial interactions with other parts of the molecule. The compounds of this invention include all transisomers as a single transisomer, or as a nonspecific mixture of each. If the rotational barrier around the single bond is high enough, and the interconversion between conformations is slow enough, then the separation and differentiation of isomers as different compounds can be allowed. For example, groups such as, but not limited to, the following R1 groups... It may exhibit limited rotation.

[0304] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0305] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0306] The compounds of this invention also include their “prodrugs,” the term “prodrug” meaning, unless otherwise specified, a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester (“prodrug”) to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0307] Preparation Examples, Examples, and other abbreviations used herein are:

[0308] DMF N,N-dimethylformamide

[0309] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0310] DIEA N,N-Diisopropylethylamine

[0311] SPhos 2-Bicyclohexylphosphine-2',6'-Dimethoxybiphenyl

[0312] PyBop 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate

[0313] The beneficial effects of this invention are as follows:

[0314] This invention designs a class of novel compounds, providing a new direction for the treatment of diseases such as tumors. Enzymatic assays show that the compounds of this invention have a strong inhibitory effect on MAT2A. They exhibit strong cell proliferation activity against HCT116 MTAP knockout cells and weaker cell proliferation activity against MTAP wild-type HCT116 cells, demonstrating good selectivity. They also exhibit good in vivo efficacy. Furthermore, human UGT1A1 enzyme activity assays indicate that the compounds of this invention have a low risk of inhibiting UGT1A1. Pharmacokinetic experiments show that the compounds of this invention have high oral bioavailability and good dose-exposure correlation. hERG assays show that the compounds of this invention have low cardiotoxicity. In addition, this invention studies a specific synthetic method, which is simple, convenient to operate, and conducive to large-scale industrial production and application. Detailed Implementation

[0315] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0316] The following are examples of the preparation of exemplary compounds of the present invention.

[0317] Example 1: 7-Chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A1)

[0318]

[0319] Step 1: Synthesis of methyl 4-chloro-2-fluoro-6-methylbenzoate

[0320] 4-Chloro-2-fluoro-6-methylbenzoic acid (8.44 g, 44.70 mmol) and dichloromethane (100 mL) were added to a 250 mL round-bottom flask, followed by oxaloyl chloride (8.51 g, 67.10 mmol) and DMF (0.2 mL). The mixture was stirred at room temperature. After the reaction was complete as monitored by TLC, the solvent was removed under reduced pressure, and methanol (200 mL) and 5M sodium methoxide (13.41 mL, 67.05 mmol) were added. The mixture was reacted for 0.5 h. After the reaction was complete, the solvent was removed under reduced pressure, and 100 mL of water was added. The mixture was extracted twice with 80 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The mixture was concentrated to obtain the target product, methyl 4-chloro-2-fluoro-6-methylbenzoate (8.43 g, 93% yield).

[0321] Step 2: Synthesis of methyl 2-(bromomethyl)-4-chloro-6-fluorobenzoate

[0322] The products from the previous step, methyl 4-chloro-2-fluoro-6-methylbenzoate (8.43 g, 41.70 mmol), NBS (9.66 g, 54.27 mmol), azobisisobutyronitrile (2.05 g, 12.50 mmol), and carbon tetrachloride (160 mL), were added to a 250 mL round-bottom flask, heated to 85 degrees Celsius, and the reaction was completed after 8 hours. The concentrate was then used directly in the next step.

[0323] Step 3: Synthesis of methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate

[0324] The concentrated product from the previous step, methyl 2-(bromomethyl)-4-chloro-6-fluorobenzoate, 5M sodium methoxide (12.51 mL, 62.55 mmol), and methanol (50 mL) were added to a 250 mL round-bottom flask. The mixture was stirred at room temperature, and the reaction was completed after 1 h. The solvent was removed under reduced pressure, 100 mL of water was added, and the mixture was extracted twice with 80 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The mixture was concentrated and purified by column chromatography to obtain methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate (5.1 g, two-step yield 53%).

[0325] Step 4: Synthesis of 4-chloro-2-fluoro-6-(methoxymethyl)benzoic acid

[0326] The product from the previous step, methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate (4.60 g, 19.70 mmol), sodium hydroxide (3.10 g, 79.09 mmol), methanol (40 mL), and water (10 mL) were added to a 100 mL round-bottom flask and reacted at room temperature with stirring for 2 h. After the reaction was complete, 100 mL of water was added, the pH was adjusted to 4–5 with concentrated hydrochloric acid, and the mixture was extracted twice with 80 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The target product, 4-chloro-2-fluoro-6-(methoxymethyl)benzoic acid (4.24 g, yield 98.1%), was concentrated. ESI-MS (m / z): 217.0 [MH] - .

[0327] Step 5: Synthesis of 4-chloro-2-fluoro-6-(methoxymethyl)benzamide

[0328] The product from the previous step, 4-chloro-2-fluoro-6-(methoxymethyl)benzoic acid (4.24 g, 19.39 mmol), ammonium chloride (1.35 g, 25.21 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (11.06 g, 29.09 mmol), and DMF (35 mL) were added to a 100 mL round-bottom flask, followed by the addition of N,N-diisopropylethylamine (5.0 g, 38.78 mmol). The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the mixture was extracted twice with 200 mL of water and 100 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration under reduced pressure, the mixture was purified by column chromatography to obtain the target compound, 4-chloro-2-fluoro-6-(methoxymethyl)benzamide (2.50 g, 59% yield). ESI-MS (m / z): 218.0 [M+H] + .

[0329] Step 6: Synthesis of 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione

[0330] The product from the previous step, 4-chloro-2-fluoro-6-(methoxymethyl)benzamide (300 mg, 1.37 mmol), oxalyl chloride (174 μL, 2.06 mmol), and anhydrous tetrahydrofuran (10 mL), were added to a 50 mL round-bottom flask and heated to 80 °C. After the reaction was complete, the reaction solution was cooled to room temperature, and then 2-methylpyridin-3-amine (149 mg, 1.37 mmol) was added to the reaction solution, and the reaction was carried out at room temperature for 3 h. After the reaction was complete, 1 M bis(trimethylsilyl)amino potassium (5.48 mL, 5.48 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 4 h. After the reaction was complete, 100 mL of water was added, the pH was adjusted to 6-7 with acetic acid, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the organic phase was purified by column chromatography to obtain the target product 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (310 mg, yield 68%), ESI-MS (m / z): 332.1 [M+H]. + .

[0331] Step 7: Synthesis of 4-amino-7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0332] The products from the previous step—7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (286 mg, 0.86 mmol), phosphorus oxychloride (262 mg, 2.58 mmol), N,N-diisopropylethylamine (749 μL, 4.31 mmol), and anhydrous dioxane (10 mL)—were added to a 50 mL round-bottom flask and heated to 100 °C with stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and then 5 mL of ammonia solution was added. The reaction was allowed to proceed at room temperature for 0.5 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the organic phase was subjected to column chromatography to obtain the target product 4-amino-7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (170 mg, yield 60%), ESI-MS (m / z): 331.1 [M+H]. + .

[0333] Step 8: Synthesis of 4-amino-7-chloro-5-(hydroxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0334] The product from the previous step, 4-amino-7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (150 mg, 0.45 mmol), boron tribromide (750 μL), and dichloromethane (7.5 mL) were added to a 25 mL round-bottom flask and reacted overnight at room temperature. After the reaction was complete, 100 mL of water was added to the reaction solution, the pH was adjusted to approximately 7 with sodium hydroxide, and the mixture was extracted three times with 100 mL of dichloromethane. The organic phases were combined, washed successively with water and saturated sodium chloride solution, concentrated, and directly purified by column chromatography to obtain the target product, 4-amino-7-chloro-5-(hydroxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, yield 70%), ESI-MS (m / z): 317.1 [M+H]. + .

[0335] Step 9: Synthesis of 7-chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one

[0336] Take the product from the previous step, 4-amino-7-chloro-5-(hydroxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, 0.32 mmol), N-bromosuccinimide (64 mg, 0.38 mmol), triphenylphosphine (124 mg, 0.47 mmol), triethylamine (96 mg, 0.95 mmol), and dichloromethane (5 mL), and add them to a 25 mL round-bottom flask. Add methanesulfonyl chloride (43 mg, 0.38 mmol) and react at room temperature overnight. After the reaction was complete, 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution for extraction twice. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified directly by column chromatography to obtain the target product 7-chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (40 mg, yield 42%), ESI-MS (m / z): 299.1 [M+H]. + ; 1 H NMR(600MHz,DMSO)δ9.39(s,1H),8.57(d,J=3.9Hz,1H),7.73(d,J=7.6Hz,1 H),7.47–7.40(m,1H),7.30(s,1H),6.17(s,1H),4.85(s,2H),2.21(s,3H).

[0337] Following the A16 resolution method, two separate transisomers, A1-P1 and A1-P2, were obtained. A1-P1, ESI-MS (m / z): 299.1 [M+H] + ; 1H NMR (600MHz, DMSO) δ9.39(s,1H),8.57(d,J=3.9Hz,1H),7.73(d,J=7.6Hz,1H),7.47–7.40(m ,1H),7.30(s,1H),6.17(s,1H),4.85(s,2H),2.21(s,3H).A1-P2, ESI-MS(m / z): 299.1[M+H] + ; 1 H NMR(600MHz,DMSO)δ9.39(s,1H),8.57(d,J=3.9Hz,1H),7.73(d,J=7.6Hz,1 H),7.47–7.40(m,1H),7.30(s,1H),6.17(s,1H),4.85(s,2H),2.21(s,3H).

[0338] Example 2: 7-Chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A2)

[0339]

[0340] Step 1: Synthesis of 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0341] 7-Chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (100 mg, 0.30 mmol), phosphorus oxychloride (137 mg, 0.90 mmol), N,N-diisopropylethylamine (194 mg, 1.51 mmol), and anhydrous dioxane (5 mL) were added to a 50 mL round-bottom flask and heated to 100 °C with stirring. After the reaction was complete, the reaction solution was cooled to room temperature, and then 5 mL of aqueous methylamine solution was added to the reaction solution. The reaction was allowed to proceed at room temperature for 0.5 h. After the reaction was complete, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was then concentrated to obtain the target product 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (104 mg, 100% yield), ESI-MS (m / z): 345.1 [M+H]. + .

[0342] Step 2: Synthesis of 7-chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one

[0343] The product from the previous step, 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (104 mg, 0.30 mmol), boron tribromide (500 μL), and dichloromethane (5 mL) were added to a 25 mL round-bottom flask and reacted overnight at room temperature. After the reaction was complete, 100 mL of water was added to the reaction solution, the pH was adjusted to approximately 7 with sodium hydroxide, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the mixture was purified by column chromatography to obtain the target product, 7-chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (35 mg, yield 37%), ESI-MS (m / z): 313.1 [M+H]. + . 1 H NMR (600MHz, DMSO) δ8.61–8.54(m,1H),7.73–7.70(m,1H),7.43(dd,J=7.8,4 .8Hz,1H),7.31(s,1H),6.18(s,1H),4.92(s,2H),3.23(s,3H),2.21(s,3H).

[0344] Following the A16 resolution method, two separate transisomers, A2-P1 and A2-P2, were obtained. A2-P1, ESI-MS (m / z): 313.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.61–8.54(m,1H),7.73–7.70(m,1H),7.43(dd,J=7.8,4.8Hz,1H),7.31( s,1H),6.18(s,1H),4.92(s,2H),3.23(s,3H),2.21(s,3H).A2-P1, ESI-MS(m / z): 313.1[M+H] + . 1 H NMR (600MHz, DMSO) δ8.61–8.54(m,1H),7.73–7.70(m,1H),7.43(dd,J=7.8,4 .8Hz,1H),7.31(s,1H),6.18(s,1H),4.92(s,2H),3.23(s,3H),2.21(s,3H).

[0345] Example 3: 7-Chloro-4-phenyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A3)

[0346]

[0347] Following the synthetic method for compound A2, 7-chloro-4-phenyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (15 mg, yield 56%) was obtained using aniline and other raw materials. ESI-MS (m / z): 375.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(dd,J=4.8,1.3Hz,1H),8.08(d,J=8.0Hz,2H),7.80(dd,J=7.8,1.2Hz,1H),7.51(t,J=8. 0Hz,2H),7.47(dd,J=7.8,4.9Hz,1H),7.41(s,1H),7.25(t,J=7.4Hz,1H),6.29(s,1H),5.51(s,2H),2.25(s,3H).

[0348] Following the A16 resolution method, two separate transisomers, A3-P1 and A3-P2, were obtained. A3-P1, ESI-MS (m / z): 375.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(dd,J=4.8,1.3Hz,1H),8.08(d,J=8.0Hz,2H),7.80(dd,J=7.8,1.2Hz,1H),7.51(t,J=8.0Hz,2H),7.47(d d,J=7.8,4.9Hz,1H),7.41(s,1H),7.25(t,J=7.4Hz,1H),6.29(s,1H),5.51(s,2H),2.25(s,3H).A3-P2, ESI-MS(m / z): 375.1[M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(dd,J=4.8,1.3Hz,1H),8.08(d,J=8.0Hz,2H),7.80(dd,J=7.8,1.2Hz,1H),7.51(t,J=8. 0Hz,2H),7.47(dd,J=7.8,4.9Hz,1H),7.41(s,1H),7.25(t,J=7.4Hz,1H),6.29(s,1H),5.51(s,2H),2.25(s,3H).

[0349] Example 4: 7-Chloro-4-benzoyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A4)

[0350]

[0351] Compound A1 (27 mg, 0.09 mmol) and dichloromethane (5 mL) were added to a 25 mL round-bottom flask, followed by triethylamine (27 mg, 0.27 mmol) and benzoyl chloride (19 mg, 0.14 mmol). The mixture was reacted at room temperature for 2 h. After the reaction was complete, the product 7-chloro-4-benzoyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (25 mg, yield 64%) was directly purified by column chromatography. ESI-MS (m / z): 403.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.60(d,J=3.7Hz,1H),7.79(d,J=7.3Hz,2H),7.75(d,J=7.3Hz,1H),7.62(t,J=7.4Hz,1 H),7.51(t,J=7.7Hz,2H),7.46-7.45(m,J=7.9,5.0Hz,2H),6.36(s,1H),5.43(d,J=5.0Hz,2H),2.19(s,3H).

[0352] Example 5: 7-Chloro-4-methyl-1-(2-chloropyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A16)

[0353]

[0354] Following the synthetic method for compound A2, 7-chloro-4-methyl-1-(2-chloropyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (205 mg, yield 63%) was obtained using methylamine and other raw materials. ESI-MS (m / z): 333.0 [M+H] + ; 1 H NMR(600MHz,DMSO)δ8.56(dd,J=4.8Hz,1.7Hz,1H),8.04(dd,J=7.7Hz,1.7Hz,1H), 7.65(dd,J=7.7Hz,4.8Hz,1H),7.34(s,1H),6.38(s,1H),4.93(s,2H),3.23(s,3H).

[0355] Compound A16 is an axially chiral compound containing two trans-blocked isomers, as shown in the following formula:

[0356]

[0357] Compound A16 was separated by supercritical fluid chromatography (SFC) (instrument: SFC 150, column: Daicel CHIRALCEL AD, 250 mm * 30 mm, 10 μM, mobile phase: CO2:EtOH = 70:30, flow rate: 80 g / min, wavelength: 214 nm, temperature: 35 °C), yielding compounds A16-P1 (first eluting isomer) and A16-P2 (second eluting isomer). The two compounds were then analyzed by high-performance liquid chromatography (HPLC) using a Waters e2695-2998 instrument, column: IG-3 (150mm*4.6mm, 3μm), mobile phase: 0.1% diethylamine in n-hexane: ethanol = 30:70, flow rate: 1.0mL / min, wavelength: 239nm, column temperature: 30℃. The retention time of compound A16-P1 was 4.89 min, and the retention time of compound A16-P2 was 7.73 min.

[0358] Compound A16-P1, ESI-MS (m / z): 333.0 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.56 (dd, J=4.8, 1.8Hz, 1H), 8.05 (dd, J=7.8, 1.8Hz, 1H), 7.65 (dd, J=7.7,4.8Hz,1H),7.34(d,J=1.3Hz,1H),6.38(d,J=1.2Hz,1H),4.93(s,2H),3.23(s,3H).

[0359] Compound A16-P2, ESI-MS (m / z): 333.0 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.56 (dd, J=4.8, 1.8Hz, 1H), 8.05 (dd, J=7.7, 1.8Hz, 1H), 7.65 (dd, J=7.7,4.8Hz,1H),7.34(d,J=1.2Hz,1H),6.38(d,J=1.2Hz,1H),4.93(s,2H),3.23(s,3H).

[0360] Example 6: 9-Chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroaza [2,3,4-de]quinazolin-2(1H)-one (B1)

[0361]

[0362] Step 1: 2-Bromo-4-chloro-6-fluorobenzamide

[0363] 2-Bromo-4-chloro-6-fluorobenzoic acid (2.5 g, 10 mmol) was added to dichloromethane (100 mL), and oxaloyl chloride (3.2 g, 25 mmol) and two drops of DMF were added under ice bath conditions. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the system was concentrated, and dioxane (100 mL) was added. Ammonia water (2.8 g, 50 mmol) was added dropwise under ice bath conditions, and the mixture was then stirred at room temperature. After the reaction was complete, the reaction solution was added to water (300 mL), extracted three times with ethyl acetate, and the organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2-bromo-4-chloro-6-fluorobenzoamide (2 g, 80% yield). ESI-MS (m / z): 251.9 [M+H] + .

[0364] Step 2: 2-Bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide

[0365] 2-Bromo-4-chloro-6-fluorobenzamide (990 mg, 3.9 mmol) was added to tetrahydrofuran (10 mL), followed by oxalyl chloride (541 mg, 4.3 mmol). The mixture was heated to 70 °C and stirred for 1 hour. After cooling, this mixture was added dropwise to a tetrahydrofuran solution of 2-methylpyridin-3-amine (426 mg, 3.9 mmol) and stirred at room temperature. After the reaction was complete, the reaction solution was poured into water (300 mL), extracted five times with dichloromethane, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. 2-Bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)aminoformyl)benzamide (1.4 g, 93% yield) was obtained. ESI-MS (m / z): 386.0 [M+H] + .

[0366] Step 3: 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione

[0367] 560 mg (1.45 mmol) of 2-bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)aminocarbamoyl)benzamide was added to tetrahydrofuran (30 mL), and 1 M bis(trimethylsilylamino)potassium (2.9 mL, 2.9 mmol) was added dropwise under ice bath conditions, followed by stirring under ice bath conditions. After the reaction was complete, 200 mL of water was added to the reaction solution, and the pH was adjusted to approximately 5 with acetic acid. After stirring for several minutes, the mixture was extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified with ethyl acetate and dried to give 400 mg (75% yield) of 5-bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione. ESI-MS (m / z): 366.0 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ11.93(s,1H),8.65(dd,J=4.8Hz,J=1.8Hz,1H),7.85(dd,J=8.4Hz,J=1.8H z, 1H), 7.68 (d, J = 1.8Hz, 1H), 7.49 (dd, J = 7.8Hz, J = 4.8Hz, 1H), 6.30 (d, J = 1.8Hz, 1H), 2.28 (s, 3H).

[0368] Step 4: 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)tert-butyl acrylate

[0369] 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (150 mg, 0.41 mmol) was added to DMF (5 mL), followed by tert-butyl acrylate (263 mg, 2.05 mmol), palladium acetate (18 mg, 0.082 mmol), tri-o-methylphenylphosphine (50 mg, 0.164 mmol), and potassium carbonate (113 mg, 0.8 mmol). The system was stirred at 140 °C under an argon atmosphere. After the reaction was complete, the mixture was cooled and added to water (100 mL), and extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin-plate chromatography (developing solvent: dichloromethane:methanol = 20:1) to give tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)acrylate (120 mg, yield 71%). ESI-MS (m / z): 414.1 [M+H] + .

[0370] Step 5: tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)propionate

[0371] 120 mg (0.29 mmol) of tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)acrylate was added to tetrahydrofuran (5 mL), followed by methanol (1 mL). Sodium borohydride (55 mg, 1.45 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was concentrated and purified by thin-plate chromatography (eluent: dichloromethane:methanol = 20:1) to give 100 mg (83% yield) of tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)propionate. ESI-MS (m / z): 416.1 [M+H] + .

[0372] Step 6: tert-butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinazolin-5-yl)propionate

[0373] 100 mg (0.24 mmol) of tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dicarbonyl-1,2,3,4-tetrahydroquinazolin-5-yl)propionate was added to dioxane (10 mL), followed by phosphorus oxychloride (110 mg (0.72 mmol)) and DIEA (155 mg (1.2 mmol). The mixture was heated to 100 °C and stirred for 1 hour. After cooling, ammonia water (0.2 mL) was added dropwise, and the reaction was stirred at room temperature. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin-plate chromatography (developing solvent: dichloromethane:methanol = 15:1) to give tert-butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinazolin-5-yl)propionate (50 mg, yield 50%). ESI-MS (m / z): 415.1 [M+H] + .

[0374] Step 7: 4-amino-7-chloro-5-(3-hydroxypropyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0375] 50 mg (0.12 mmol) of tert-butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-carbonyl-1,2-dihydroquinazolin-5-yl)propionate was added to tetrahydrofuran (5 mL), and lithium aluminum hydride (13 mg (0.36 mmol)) was added under ice bath conditions. The mixture was stirred under ice bath conditions. After the reaction was complete, 1 mL of methanol was added to the reaction solution, and the mixture was concentrated and purified by thin-plate chromatography (developing solvent: dichloromethane:methanol = 10:1) to give 30 mg (73% yield) of 4-amino-7-chloro-5-(3-hydroxypropyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one. ESI-MS (m / z): 345.1 [M+H] + .

[0376] Step 8: 9-Chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroaza [2,3,4-de]quinazolin-2(1H)-one

[0377] 4-amino-7-chloro-5-(3-hydroxypropyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (30 mg, 0.087 mmol) was added to dichloromethane (10 mL), followed by methanesulfonyl chloride (9 mg, 0.087 mmol), triethylamine (18 mg, 0.18 mmol), and triphenylphosphine (33 mg, 0.132 mmol). The mixture was stirred at room temperature for 1 hour, followed by the addition of methanesulfonyl chloride (45 mg) and triethylamine (36 mg) in portions. The reaction mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was quenched with a small amount of methanol, concentrated, and purified by thin-layer chromatography using dichloromethane:ethyl acetate:methanol = 5:5:1 as the developing solvent. The product layers were collected, combined, washed, and concentrated to give 9-chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroazapyridine. [2,3,4-de]quinazolin-2(1H)-one (3.5 mg, yield 12%), ESI-MS (m / z): 327.1 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ9.77(br,1H),8.66(d,J=4.8Hz,1H),7.55(d,J=7.8Hz,1H),7.37(dd,J1=7.8Hz,J2=4.8 Hz,1H),7.00(s,1H),6.24(s,1H),3.65-3.62(m,2H),3.05(t,J=7.2Hz,2H),2.36(s,3H),2.26-2.23(m,2H).

[0378] Following the A16 resolution method, two separate transisomers, B1-P1 and B1-P2, were obtained. B1-P1, ESI-MS (m / z): 327.1 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ9.77(br,1H),8.66(d,J=4.8Hz,1H),7.55(d,J=7.8Hz,1H),7.37(dd,J1=7.8Hz,J2=4.8 Hz,1H),7.00(s,1H),6.24(s,1H),3.65-3.62(m,2H),3.05(t,J=7.2Hz,2H),2.36(s,3H),2.26-2.23(m,2H). B2-P1,ESI-MS(m / z): 327.1[M+H] + ; 1 H NMR (600MHz, CDCl3) δ9.77(br,1H),8.66(d,J=4.8Hz,1H),7.55(d,J=7.8Hz,1H),7.37(dd,J1=7.8Hz,J2=4.8 Hz,1H),7.00(s,1H),6.24(s,1H),3.65-3.62(m,2H),3.05(t,J=7.2Hz,2H),2.36(s,3H),2.26-2.23(m,2H).

[0379] Example 7: 9-Chloro-1-(2-methylpyridin-3-yl)-5,6-dihydro-1H-[1,4]oxazine [5,6,7-de]quinazolin-2(4H)-one (B2)

[0380]

[0381] Following the method for synthesizing 5-bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione, 7-chloro-5-fluoro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione was synthesized from 4-chloro-2,6-difluorobenzoic acid and 2-methylpyridin-3-amine. ESI-MS (m / z): 306.1 [M+H] + .

[0382] Step 1: 7-Chloro-5-fluoro-4-((2-hydroxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0383] 7-Chloro-5-fluoro-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (200 mg, 0.64 mmol) and dioxane (10 mL) were added to a 100 mL round-bottom flask. Phosphorus oxychloride (292 mg, 1.92 mmol) and diisopropylethylamine (420 mg, 3.27 mmol) were added. The mixture was stirred at 100 °C for 1 hour. After cooling, aminoethanol (200 mg, 3.27 mmol) was added, and the mixture was stirred at room temperature. After the reaction was complete, 100 mL of water and 300 mL of ethyl acetate were added for extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 7-chloro-5-fluoro-4-((2-hydroxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, yield 45%), ESI-MS (m / z): 349.1 [M+H]. + ;

[0384] Step 2: 9-Chloro-1-(2-methylpyridin-3-yl)-5,6-dihydro-1H-[1,4]oxazine [5,6,7-de]quinazolin-2(4H)-one

[0385] The product from the previous step, 7-chloro-5-fluoro-4-((2-hydroxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, 0.29 mmol) and N,N-dimethylformamide (5 mL), were added to a 100 mL round-bottom flask. Sodium hydride (23 mg, 0.57 mmol) was added with stirring in an ice bath, and the reaction was carried out at room temperature. After the reaction was complete, 100 mL of water and 200 mL of ethyl acetate were added for extraction twice. The organic phases were combined and washed twice with 100 mL of water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin-plate chromatography to obtain 9-chloro-1-(2-methylpyridin-3-yl)-5,6-dihydro-1H-[1,4]oxazine. [5,6,7-de]quinazolin-2(4H)-one (13 mg, yield 13%), ESI-MS (m / z): 329.1 [M+H] + .

[0386] Example 8: 9-Chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diaza [5,6,7-de]quinazolin-2(1H)-one (B3)

[0387]

[0388] Step 1: 7-Chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione

[0389] 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (500 mg, 1.37 mmol), aminoacetaldehyde diethanol condensate (364 mg, 2.74 mmol), tris(dibenzylacetone)palladium (128 mg, 0.14 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (174 mg, 0.28 mmol), sodium tert-butoxide (395 mg, 4.1 mmol), and toluene (10 mL) were added to a 100 mL round-bottom flask. After evacuating the flask with nitrogen, the mixture was stirred at 100 °C. After the reaction was complete, the mixture was cooled and 100 mL of water was added. The mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 7-chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (500 mg, yield 87%). ESI-MS (m / z): 419.1 [M+H] + .

[0390] Step 2: 7-Chloro-5-((2,2-diethoxyethyl)amino)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

[0391] Take the product from the previous step, 7-chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione (200 mg, 0.48 mmol) and dioxane (10 mL), and add them to a 100 mL round-bottom flask. Add phosphorus oxychloride (218 mg, 1.44 mmol) and diisopropylethylamine (310 mg, 2.4 mmol). Stir the mixture at 100 °C for 1 hour. After cooling, add an aqueous solution of methylamine and stir the mixture at room temperature. After the reaction was complete, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration and concentration, the solution was purified by column chromatography to obtain 7-chloro-5-((2,2-diethoxyethyl)amino)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, yield 48%), ESI-MS (m / z): 432.2 [M+H]. + .

[0392] Step 3: 9-Chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diaza [5,6,7-de]quinazolin-2(1H)-one

[0393] The product from the previous step, 7-chloro-5-((2,2-diethoxyethyl)amino)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, 0.23 mmol), and acetonitrile (2 mL) were added to a 100 mL round-bottom flask. Concentrated hydrochloric acid (0.1 mL) was added, and the mixture was stirred at 80 °C under a sealed environment. After the reaction was complete, the mixture was concentrated, and 100 mL of ethyl acetate was added. The mixture was then washed twice with 100 mL of sodium bicarbonate aqueous solution. The concentrated organic phase was purified by thin-plate chromatography to obtain 9-chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diaza [5,6,7-de]quinazolin-2(1H)-one, ESI-MS (m / z): 358.1 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.56(d,J=4.2Hz,1H),7.69-7.68(m,1H),7.65(t,J=7.2Hz,1H),7.419(t,J=6.0Hz,1H),6.35(d, J=1.2Hz,1H),5.25-5.23(m,2H),4.89(br,1H),3.64-3.59(m,1H),3.57-3.52(m,1H),3.16(s,3H),2.18(d,J=30Hz,3H).

[0394] Following the A16 resolution method, two separate transisomers, B3-P1 and B3-P2, were obtained. B3-P1, ESI-MS (m / z): 358.1 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.56(d,J=4.2Hz,1H),7.69-7.68(m,1H),7.65(t,J=7.2Hz,1H),7.419(t,J=6.0Hz,1H),6.35(d, J=1.2Hz,1H),5.25-5.23(m,2H),4.89(br,1H),3.64-3.59(m,1H),3.57-3.52(m,1H),3.16(s,3H),2.18(d,J=30Hz,3H). B3-P2, ESI-MS(m / z):358.1[M+H] + ; 1H NMR (600MHz, DMSO-d6) δ8.56(d,J=4.2Hz,1H),7.69-7.68(m,1H),7.65(t,J=7.2Hz,1H),7.419(t,J=6.0Hz,1H),6.35(d, J=1.2Hz,1H),5.25-5.23(m,2H),4.89(br,1H),3.64-3.59(m,1H),3.57-3.52(m,1H),3.16(s,3H),2.18(d,J=30Hz,3H).

[0395] Compounds A5-A15, A17-A18, A20-A28, and A30-A37 were prepared using the corresponding synthetic methods and intermediates as starting materials.

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402] Example 39: 2-Methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphth-4(5H)-one (A19)

[0403]

[0404] Step 1: Synthesis of ethyl 4-chloro-2-hydroxy-6-(trifluoromethyl)nicotinate

[0405] Ethyl 2,4-dihydroxy-6-(trifluoromethyl)nicotinic acid (synthesized according to the literature "Org. Process Res.Dev., 2011, 15, 788–796") (50 g, 199.1 mmol) was added to a DMF (62 mL) solution at room temperature. After thorough stirring and dissolution, the reaction flask was placed in ice water, and POCl3 (122.10 g, 796 mmol) was slowly added dropwise at 0 °C. After the addition was complete, the flask was placed in an oil bath at 90 °C for 1 h. The reaction was confirmed to be complete by LCMS. A saturated solution of K2HPO4 (2.5 L) was prepared, and the reaction solution was slowly poured into it to quench the reaction. The solution was then extracted with dichloromethane, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (SiO2, DCM:MeOH = 1:0) to obtain ethyl 4-chloro-2-hydroxy-6-(trifluoromethyl)nicotinic acid (35 g).

[0406] Step 2: Synthesis of ethyl 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinate

[0407] The product from the previous step (5 g) and potassium vinyltrifluoroborate (4.28 g) were added to a 100 mL tetrafluoroethylene flask, followed by 10 mL of H₂O and 40 mL of dioxane. SPhos (761 mg) and K₃PO₄ (11.81 g) were added with stirring at room temperature, and Pd(OAc)₂ (416 mg) was added under a nitrogen atmosphere. The mixture was heated to 90 °C and reacted for 48 h. The reaction was monitored by LCMS until complete. The reaction mixture was directly concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography (SiO₂, DCM:MeOH = 1:0 to 10:1) to obtain ethyl 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinate (2.57 g).

[0408] Step 3: Synthesis of 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinic acid

[0409] The product from the previous step (18 g, 1 eq.) was added at room temperature to a mixed solvent of MeOH (110 mL), THF (110 mL), and H₂O (55 mL), followed by the addition of NaOH (6.43 g, 3 eq.). The reaction mixture was heated to 60 °C and reacted for 16 h. The reaction was monitored by LCMS until complete. The solvent was removed from the reaction mixture under reduced pressure, and the mixture was purified to give 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinic acid (7 g).

[0410] Step 4: Synthesis of 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinamide

[0411] The product from the previous step (7 g, 1 eq.) was dissolved in DCM (100 mL), and then oxalyl chloride (9.46 g) and DMF (0.4 g) were slowly added. The reaction was carried out at room temperature for 1 hour. A sample was taken and methanol was added for TLC to confirm that the reaction was complete. The reaction system was then evaporated to dryness, and 500 mL of NH3·dioxane solution was added. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by LCMS to ensure complete reaction. The reaction solution was then concentrated under reduced pressure to remove the solvent. The solution was purified by silica gel column chromatography (SiO2, DCM:MeOH = 1:0 to 5:1) to obtain 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinamide (7 g).

[0412] Step 5: 3-Aminocarbonyl-6-(trifluoromethyl)-4-vinylpyridine-2-methyl p-toluenesulfonic acid

[0413] The product from the previous step (7 g) was added to DCM (50 mL), along with p-toluenesulfonyl chloride (TsCl, 8.6 g), triethylamine (TEA, 7.6 g), and DMAP (375 mg). The mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The mixture was extracted with water (100 mL) and ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (SiO2, PE:EA = 10:1 to pure DCM) to obtain the product p-toluenesulfonic acid 3-aminocarbonyl-6-(trifluoromethyl)-4-vinylpyridine-2-methyl ester (8.5 g).

[0414] Step 6: 3-(((2-methylpyridin-3-yl)aminocarbonyl)aminocarbonyl)-6-(trifluoromethyl)-4-vinylpyridine-2-methyl ester of p-toluenesulfonic acid

[0415] The product from the previous step (1.0 g) was added to THF (40 mL), followed by oxaloyl chloride (0.50 mL), and then the mixture was heated to 80 °C and stirred for 1 h. A sample was taken, and the reaction intermediate was confirmed by quenching with methanol. After cooling to room temperature, 3-amino-2-methylpyridine (400 mg) was added, and the mixture was stirred at room temperature for one hour. The reaction was monitored by LCMS to ensure complete reaction. The pH was adjusted to acidic by adding acetic acid aqueous solution, and the mixture was extracted with H2O (100 mL) and ethyl acetate. The organic phases were combined and concentrated under reduced pressure to obtain crude p-toluenesulfonic acid 3-(((2-methylpyridin-3-yl)aminocarbonyl)aminocarbonyl)-6-(trifluoromethyl)-4-vinylpyridine-2-methyl ester (4.5 g).

[0416] Step 7: 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyridino[2,3-d]pyrimidine 2,4-(1H,3H)-dione

[0417] The product from the previous step (4.5 g) was added to acetonitrile (ACN, 50 mL), followed by DBU (3.9 mL), and stirred at room temperature for 1 h. The reaction was monitored by LCMS until complete. The pH was adjusted to acidic by adding aqueous acetic acid, and the product was directly concentrated under reduced pressure to obtain the crude product. The crude product was purified by prep-TLC (ethyl acetate: dichloromethane = 1:4) to obtain 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyridino[2,3-d]pyrimidine 2,4-(1H,3H)-dione (280 mg).

[0418] Step 8: Synthesis of 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyridine[2,3-d]pyrimidine-5-carboxylic acid

[0419] 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyridin [2,3-d]pyrimidine-2,4(1H,3H)-dione (472 mg, 1.356 mmol.) was added to a solution of 1,4-dioxane (20 mL) and water (10 mL) at room temperature. After thorough stirring and dissolution, 10 drops of 1N sulfuric acid solution were added, followed by potassium permanganate (1.07 g, 6.781 mmol.). The mixture was then placed in an oil bath at 50 °C and reacted for 1 h. The reaction was confirmed to be complete by LC-MS. The mixture was cooled to room temperature, and 20 mL of methanol was added and stirred for 0.5 h. The filter cake was then filtered through diatomaceous earth, washed with methanol, and the filtrate was concentrated to obtain the product, which was directly used in the next step of ESI-MS (m / z): 367.0 [M+H]. + .

[0420] Step 9: Synthesis of methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyridine[2,3-d]pyrimidine-5-carboxylic acid ester

[0421] The product from the previous step was dissolved in dichloromethane (100 mL), oxalyl chloride (256 mg, 2.034 mmol) was added, and DMF (1 drop) was added. The mixture was stirred at room temperature for 2 h. The reaction was checked by TLC to confirm completion. Methanol (20 mL) was added, and stirring was continued for 0.5 h. The reaction was checked by TLC to confirm completion. The reaction mixture was directly concentrated under reduced pressure to remove the solvent, and then passed through a silica gel column (SiO2). 2, DCM:MeOH = 1:0 to 50:1) purification yielded methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyridine[2,3-d]pyrimidine-5-carboxylate (428 mg, two-step yield 83%). ESI-MS (m / z): 381.1 [M+H] + .

[0422] Step 10: Synthesis of methyl 1-(2-methylpyridin-3-yl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyridine[2,3-d]pyrimidine-5-carboxylic acid ester

[0423] Methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyridine[2,3-d]pyrimidine-5-carboxylic acid ester (209 mg, 0.549 mmol) was dissolved in 1,4-dioxane (10 mL), followed by the addition of N,N-diisopropylethylamine (708 mg, 5.490 mmol) and phosphorus oxychloride (501 mg, 3.294 mmol). The reaction mixture was heated to 100 °C and reacted for 1 h. The reaction was monitored by LCMS until complete. The reaction mixture was then cooled to room temperature, and N,N-diisopropylethylamine (708 mg, 105.490 mmol) and methylamine hydrochloride (185 mg, 2.745 mmol) were added. The reaction was carried out at room temperature for 2 h, and the reaction was monitored by LCMS until complete. The system was not treated before proceeding to the next step. ESI-MS (m / z): 394.1 [M+H] + .

[0424] Step 11: Synthesis of 1-(2-methylpyridin-3-yl)-5-(hydroxymethyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

[0425] The previous step's system was added to methanol (10 mL), and sodium borohydride (208 mg, 5.490 mmol) was added in portions under ice bath conditions. The reaction was carried out at room temperature for 0.5 hours. The reaction was monitored by LCMS until complete. 100 mL of water was added, and the mixture was extracted twice with 80 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent. The solution was purified by silica gel column chromatography (SiO2, DCM:MeOH = 1:0 to 20:1) to obtain 1-(2-methylpyridin-3-yl)-5-(hydroxymethyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (28.4 mg, 14% yield in two steps), ESI-MS (m / z): 366.1 [M+H]. + .

[0426] Step 12: Synthesis of 2-methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphth-4(5H)-one

[0427] 1-(2-methylpyridin-3-yl)-5-(hydroxymethyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one (28 mg, 0.078 mmol) was added to DCM (5 mL), followed by triethylamine (24 mg, 0.233 mmol) and methanesulfonyl chloride (18 mg, 0.155 mmol). The mixture was stirred at room temperature for 0.5 h. The reaction was monitored by LCMS until complete. The crude product was directly concentrated under reduced pressure and purified by silica gel column chromatography (SiO2, DCM:MeOH = 20:1) to obtain the product 5-(2-methylpyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphth-4(5H)-one (11 mg, yield 42%). ESI-MS (m / z): 348.1 [M+H] + . 1 HNMR (600MHz, DMSO) δ8.53 (d, J = 4.9 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.41-7.38 (m, 1H), 5.10 (d, J = 4.5 Hz, 2H), 3.29 (s, 3H), 2.19 (s, 3H).

[0428] Following the A16 resolution method, two separate transisomers, A19-P1 and A19-P2, were obtained. A19-P1, ESI-MS (m / z): 348.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.53 (d, J = 4.9 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.41-7.38 (m, 1H), 5.10 (d, J = 4.5 Hz, 2H), 3.29 (s, 3H), 2.19 (s, 3H). A19-P2, ESI-MS(m / z): 348.1[M+H] + . 1 H NMR (600MHz, DMSO) δ8.53 (d, J = 4.9 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.41-7.38 (m, 1H), 5.10 (d, J = 4.5 Hz, 2H), 3.29 (s, 3H), 2.19 (s, 3H).

[0429] Example 40: 5-(2-chloropyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphth-4(5H)-one (A29)

[0430]

[0431] Following the synthetic method for compound A19, 5-(2-chloropyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphth-4(5H)-one (10 mg, yield 36%) was obtained from 3-amino-2-chloropyridine and methylamine as starting materials. ESI-MS (m / z): 368.1 [M+H] + , 1 H NMR (600MHz, CDCl3) δ8.50 (d, J = 5.04, 1H), 7.76 (d, J = 5.16, 1H), 7.51 (s, 1H), 7.44 (t, J = 5.16, 1H), 4.93 (s, 2H), 3.44 (s, 3H).

[0432] Following the A16 resolution method, two separate transisomers, A29-P1 and A29-P2, were obtained. A29-P1, ESI-MS (m / z): 368.1 [M+H] + , 1 H NMR (600MHz, CDCl3) δ8.50 (d, J = 5.04, 1H), 7.76 (d, J = 5.16, 1H), 7.51 (s, 1H), 7. 44(t,J=5.16,1H),4.93(s,2H),3.44(s,3H).A29-P2, ESI-MS(m / z): 368.1[M+H] + , 1 H NMR (600MHz, CDCl3) δ8.50 (d, J = 5.04, 1H), 7.76 (d, J = 5.16, 1H), 7.51 (s, 1H), 7.44 (t, J = 5.16, 1H), 4.93 (s, 2H), 3.44 (s, 3H).

[0433] Example 41: 7-chloro-4-(2-methyl-2H-indazol-5-yl)-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A38)

[0434]

[0435] Following the synthetic method for compound A2, 7-chloro-4-(2-methyl-2H-indazole-5-amine), 1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (5 mg, yield 60%) was obtained using 2-methyl-2H-indazole-5-yl)-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one as starting materials. ESI-MS (m / z): 429.1 [M+H]+ . 1 H NMR (600MHz, DMSO) δ8.61(d,J=4.8Hz,1H),8.44(s,1H),8.28(d,J=1.8Hz,1H),8.02(dd,J=9.3,2.1Hz,1H),7.79(d,J=6.6H z,1H),7.74(d,J=9.4Hz,1H),7.47(dd,J=7.8,4.9Hz,1H),7.41(s,1H),6.28(s,1H),5.55(s,2H),4.20(s,3H),2.26(s,3H).

[0436] Following the A16 resolution method, two separate transisomers were obtained, namely A38-P1 and A38-P2. A38-P1, ESI-MS (m / z): 429.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(d,J=4.8Hz,1H),8.44(s,1H),8.28(d,J=1.8Hz,1H),8.02(dd,J=9.3,2.1Hz,1H),7.79(d,J=6.6Hz,1H),7.74(d,J= 9.4Hz,1H),7.47(dd,J=7.8,4.9Hz,1H),7.41(s,1H),6.28(s,1H),5.55(s,2H),4.20(s,3H),2.26(s,3H).A38-P2, ESI-MS(m / z): 429.1[M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(d,J=4.8Hz,1H),8.44(s,1H),8.28(d,J=1.8Hz,1H),8.02(dd,J=9.3,2.1Hz,1H),7.79(d,J=6.6H z,1H),7.74(d,J=9.4Hz,1H),7.47(dd,J=7.8,4.9Hz,1H),7.41(s,1H),6.28(s,1H),5.55(s,2H),4.20(s,3H),2.26(s,3H).

[0437] Example 42: 7-Chloro-4-(4-chlorophenyl)-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A39)

[0438]

[0439] Following the synthetic method for compound A2, 7-chloro-4-(4-chlorophenyl)-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (15 mg, yield 50%) was obtained using p-chloroaniline, 3-amino-2-methylpyridine, etc. as raw materials. ESI-MS (m / z): 409.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.61(dd,J=4.8,1.3Hz,1H),8.12(d,J=9.0Hz,2H),7.82–7.77(m,1H),7.58( d,J=9.0Hz,2H),7.47(dd,J=7.8,4.8Hz,1H),7.41(s,1H),6.31(s,1H),5.50(s,2H),2.25(s,3H).

[0440] Following the A16 resolution method, two separate transisomers were obtained, namely A39-P1 and A39-P2. A39-P1, ESI-MS (m / z): 409.1 [M+H] + . 1 H NMR(600MHz, DMSO)δ8.61(dd,J=4.8,1.3Hz,1H),8.12(d,J=9.0Hz,2H),7.82–7.77(m,1H),7.58(d,J=9.0Hz,2H),7 .47(dd,J=7.8,4.8Hz,1H),7.41(s,1H),6.31(s,1H),5.50(s,2H),2.25(s,3H).A39-P2, ESI-MS(m / z): 409.1[M+H] + . 1 HNMR(600MHz,DMSO)δ8.61(dd,J=4.8,1.3Hz,1H),8.12(d,J=9.0Hz,2H),7.82–7.77(m,1H),7.58( d,J=9.0Hz,2H),7.47(dd,J=7.8,4.8Hz,1H),7.41(s,1H),6.31(s,1H),5.50(s,2H),2.25(s,3H).

[0441] Example 43: 7-Chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrole[2,3,4-de]quinazolin-2(1H)-one (A40)

[0442]

[0443] Following the synthetic method for compound A1, 7-chloro-1-(2-methoxypyridin-3-yl)-4-methyl-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (17 mg, yield 50%) was obtained using 2-methoxypyridin-3-amine, methylamine, etc. as raw materials. ESI-MS (m / z): 329.1 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.30(d,J=3.8Hz,1H),7.77(d,J=7.1Hz,1H),7.28(s,1 H),7.19-7.17(m,1H),6.25(s,1H),4.90(s,2H),3.80(s,3H),3.21(s,3H).

[0444] Following the A16 resolution method, two separate transisomers were obtained, namely A40-P1 and A40-P2. A40-P1, ESI-MS (m / z): 329.1 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.30(d,J=3.8Hz,1H),7.77(d,J=7.1Hz,1H),7.28(s,1H),7.19-7.17(m ,1H),6.25(s,1H),4.90(s,2H),3.80(s,3H),3.21(s,3H).A40-P2, ESI-MS(m / z):329.1[M+H] + . 1 H NMR(600MHz,DMSO)δ8.30(d,J=3.8Hz,1H),7.77(d,J=7.1Hz,1H),7.28(s,1 H),7.19-7.17(m,1H),6.25(s,1H),4.90(s,2H),3.80(s,3H),3.21(s,3H).

[0445] Example 44: 4-Methyl-1-(2-methylpyridin-3-yl)-8-(trifluoromethyl)-5,6-dihydro-1H-pyrimidino[4,5,6-ij][2,7]naphthidin-2(4H)-one (C1)

[0446]

[0447] 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyrido[2,3-d]pyrimidine 2,4-(1H,3H)-dione (100 mg, 0.287 mmol) was added to DMF (3 mL), followed by methylamine hydrochloride (58.16 mg, 0.861 mmol) and PyBop (448.26 mg, 0.861 mmol). Finally, DBU (219 mg, 1.44 mmol) was added, and the reaction mixture was stirred at 20 °C for 16 hours. LC-MS detected the main peak as the product peak. The reaction mixture was purified by preparative liquid chromatography to obtain the product (11.4 mg, yield 11%). ESI-MS (m / z): 362.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ=8.52-8.47(m,1H),7.65-7.55(m,2H),7.40-7.33(m,1H),3.85-3.76(m,2H),3.28-3.19(m,5H),2.14(s,3H).

[0448] Following the A16 resolution method, two separate transisomers were obtained, namely C1-P1 and C1-P2. C1-P1, ESI-MS (m / z): 362.1 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ=8.52-8.47(m,1H),7.65-7.55(m,2H),7.40-7.33(m,1H),3 .85-3.76(m,2H),3.28-3.19(m,5H),2.14(s,3H).C1-P2, ESI-MS(m / z):362.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ=8.52-8.47(m,1H),7.65-7.55(m,2H),7.40-7.33(m,1H),3.85-3.76(m,2H),3.28-3.19(m,5H),2.14(s,3H).

[0449] Compounds B4-B72 and C2-C23 were prepared using the corresponding synthetic methods and intermediates as starting materials.

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469] The following are the experimental results and data on the effects of the compounds of this invention.

[0470] Experimental Example 1: Enzyme Test

[0471] The inhibitory effect of the test compound on the MAT2A enzyme activity was determined using the MAT2A inhibitor enzyme screening kit (BPS Bioscience).

[0472] 1) Dissolve the test compound in DMSO, mixing thoroughly until completely dissolved. Dilute all compounds to an initial concentration of 2 mM with DMSO, and then serially dilute 3-fold to create 10 concentration gradients. Perform replicates on each well, adding the compound 1:100 to the reaction system during detection (final concentration maximum 20 μM). Prepare a 100× positive control (1 mM AGI-24512) and a 100× negative control (100% DMSO).

[0473] 2) Using an Echo 550 pipette system, transfer 200 nL of the diluted compound to each well of the reaction plate (Corning 3702). Seal the reaction plate with sealing film and centrifuge at 1000 g for 1 minute. The final concentration of DMSO is 1%.

[0474] 3) Prepare 1×MAT2A enzyme reaction buffer: Add 1 volume of 5×MAT2A enzyme reaction buffer to 4 volumes of water and mix thoroughly.

[0475] 4) Prepare 2×MAT2A enzyme solution using 1× enzyme reaction buffer.

[0476] 5) Add 10 μL of 2×MAT2A enzyme solution to each well of the 384-reaction plate (Corning3702) and seal the plate with sealing film.

[0477] 6) Centrifuge at 1000g for 60 seconds, then incubate at room temperature for 30 minutes.

[0478] 7) Prepare a mixture of 2×L-Methionine and ATP using 1×MAT2A enzyme reaction buffer.

[0479] 8) Add 10 μL of a mixture of 2×L-Methionine and ATP to each well of a 384-reaction plate (Corning 3702), and seal the plate with sealing film. The total reaction volume is 20 μL.

[0480] 9) Centrifuge at 1000g for 60 seconds, then incubate at room temperature for 60 minutes.

[0481] 10) Prepare the detection buffer, Colorimetric Detection Rebgent.

[0482] 11) Add 20 μL of detection buffer to each well, centrifuge at 1000g for 30 seconds, and react at room temperature for 15 minutes.

[0483] 12) The fluorescence signal at 630 nm was measured using a multi-functional microplate reader (PerkinElmer, Nivo).

[0484] Experimental results show that the compounds of this invention have strong MAT2A inhibitory activity. Exemplary compounds are shown in the table below:

[0485] Compound numbering <![CDATA[Enzyme inhibitory activity (IC 50 : nM)]]> Compound numbering <![CDATA[Enzyme inhibitory activity (IC 50 : nM)]]> A1 A A2 A B3 B A3 A A16 A A38 A A39 A A40 B C1 A A19 C A16-P2 A B1 C B2 C A29 C

[0486] A represents IC 50 < 50nM, where B represents 50nM <IC 50 < 100nM, C represents IC 50 >100nM.

[0487] Experimental Example 2. Test for Inhibition of Cell Proliferation

[0488] The specific operating procedure is as follows: Tumor cells were treated with the compound for 5 days, and the effect of the test compound on tumor cell proliferation was evaluated. HCT116-MTAP was then... - / - Wild-type control HCT116-WT (colorectal cancer cells) cells were seeded at a density of 600 cells / well in 384-well culture plates, and different concentrations of the test compound were added simultaneously (20 μM starting, 10 concentration gradients). The cells were incubated at 37°C, 5% CO2, and saturated humidity for 5 days.

[0489] Cell proliferation was assessed using an ATP-based cell proliferation assay kit (Cell Titer Glo, Promega Corporation). Cells were equilibrated at room temperature for 30 minutes and then treated with Cell Titer Glo reagent. The culture dishes were then covered with aluminum foil and agitated for 15 minutes to ensure thorough mixing and lysis. Chemiluminescence detection was performed using a multi-plate reader (Envision 2105, PerkinElmer). Blank wells and DMSO control wells were prepared.

[0490] The inhibition rate (IR) of the detected compound is calculated using the following formula:

[0491] IR (%) = [1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)] × 100%

[0492] Using GraphPad Prism for plotting, data analysis, and IC (Integrated Circuits) 50 calculate.

[0493] The compounds of the present invention were tested in the above assays, and their IC50 inhibitory activity against cell proliferation was determined. 50 As shown in the table below.

[0494]

[0495] The results showed that the test compound exhibited strong cell proliferation inhibitory activity against HCT116 MTAP knockout cells and weak cell proliferation inhibitory activity against MTAP wild-type HCT116 cells, indicating good selectivity.

[0496] Note: When the maximum inhibition rate is <50%, the result is expressed as IC50. 50 > Maximum initial concentration.

[0497] Experimental Example 3. Human UGT1A1 Enzyme Activity Assay

[0498] The specific procedure for determining the inhibitory activity of the compound against UGT1A1 is as follows:

[0499] 1) Add 1 μL of 2 mM control compound (atazanavir), 1 μL of 440 μM test compound or 1 μL of dimethyl sulfoxide (solvent control) to the culture plate, add the master reaction solution containing 0.01 mg / mL UGT1A1 (Corning, 456411), 0.5 μM substrate bilirubin, and Tris buffer, and pre-incubate in a 37°C water bath for 10 min. The final concentration of the control compound is 10 μM, and the final concentration of the test compound is 2.2 μM.

[0500] 2) The reaction was started by adding 20 μL of UDPGA solution with a final concentration of 2 mM, reacted at 37 °C for 5 min, and then stopped by adding 400 μL of cold acetonitrile containing the internal standard.

[0501] 3) Vortex the sample for 5 minutes, centrifuge at 3220g for 40 minutes at 4°C. Then transfer 100 μL of the supernatant to a new 96-well plate for LC-MS / MS analysis of metabolite formation. The % inhibition rate is calculated by comparing the reduction in metabolite formation (peak area quantification) between the test drug and the control group.

[0502] UGT1A1 participates in the metabolism of bilirubin in the body. When UGT1A1 is inhibited, bilirubin metabolism is impaired, ultimately leading to elevated bilirubin levels in the body. The IC50 of the above-mentioned compounds of this invention on UGT1A1... 50 A concentration greater than 50 μM indicates a low risk of the compound of this invention inhibiting UGT1A1. Example 4. Pharmacokinetic Study in Mice

[0503] Laboratory animals: CD-1 mice (male, 22-25g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0504] Experimental procedure: The test compound was administered intravenously or by gavage to male CD-1 mice (22-25g). Plasma samples were collected at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The compound concentration was detected by LC-MS / MS, and its plasma clearance rate (Cl) and elimination half-life (T) were investigated. 1 / 2 Peak time T max Peak concentration C max Pharmacokinetic parameters such as area under the curve (AUC), apparent volume of distribution (Vss), and absolute bioavailability (F) are used.

[0505] Assay Method: Acetonitrile / water (1:1) was used as the stock solution for diluting the analyte to obtain the required series of working solution concentrations. 10 μL of working solution (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng / mL) was added to 10 μL of blank CD1 mouse plasma to achieve a total volume of 20 μL for calibration standards ranging from 1 to 10000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng / mL). Five quality control (QC) samples (2 ng / mL, 5 ng / mL, 10 ng / mL, 800 ng / mL, 8000 ng / mL) were prepared on the day of analysis in the same manner as the calibration standards. 20 μL of standard, 20 μL of QC sample, and 20 μL of unknown sample (10 μL of unknown sample plasma and 10 μL of blank solution) were added to 200 μL of IS mixture containing acetonitrile to precipitate proteins. The samples were then vortexed for 3 min. After centrifugation at 4700 rpm for 15 min at 4 °C, the supernatant was diluted with ultrapure water at a ratio of 1:2 (v / v), and 10 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0506] Pharmacokinetic results show that the compounds of the present invention have high absolute oral bioavailability (preferred compounds can reach more than 70%), moderate clearance rate, and good dose-exposure correlation.

[0507] Experimental Example 5: hERG Test

[0508] The potential inhibitory effect of the test sample on the hERG channel was assessed using an automated patch-clamp system. This study used a CHO cell line stably expressing the hERG gene and used cisapride as a positive control.

[0509] The CHO-hERG-DUO cell line, stably expressing the hERG channel, was purchased from B'SYS GmbH. Cells were cultured in F12 (HAM) medium, 10% FBS, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin, and 100 μg / mL G418. Cells were passaged three times a week and maintained approximately 80% confluence.

[0510] The test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 mM; then the stock solution was continuously diluted with DMSO at a ratio of 1:3 (3.33, 1.11 and 0.37 mM); the final concentrations of the compound were 30, 10, 3.33, 1.11 and 0.37 μM.

[0511] A baseline was established using a blank solvent. After the hERG current stabilized for at least 5 minutes, the working solution of the compound was infused. The hERG current was recorded for at least 5 minutes to reach a steady state, followed by 5 captures. If a steady state was not reached within 10 minutes, the average peak current of the last 5 captures was used to replace the steady-state value. The experiment was performed twice (n=2) to detect the hERG current suppression at 5 compound concentrations to determine the IC50.

[0512] Use the following formula to calculate the current suppression percentage.

[0513]

[0514] Calculate IC using Graphpad Prism 8.0 50 .

[0515] The experimental results show that the preferred compounds of the present invention have no significant inhibitory effect on hERG channels within the detection concentration range of this experiment, IC50... 50 A value greater than 30 μM indicates that the compounds of this invention have a low risk of cardiotoxicity.

[0516] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, having the following structure: in, Ring A is selected from C 5-10 carbonyl group, C 6-14 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; R 1 Selected from C (optional substitution) 3-12 carbonyl group, C 6-14 aryl, 5-14 membered heteroaryl, 5-14 membered heterocyclic; wherein the carbocyclic, aryl, heteroaryl, or heterocyclic group is optionally surrounded by one or more R a Replaced; L is selected from the following: -O-, -S-, -C 1-4 Alkylene-, -OC 1-4 Alkylene-, -C(O)-, -C(O)O-, -OC(O)-, -N(R) a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-; the alkylene group is optionally surrounded by one or more R a1 Replaced; R a Each occurrence is independently selected from deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -W-OC(O)OR a1 -WC(O)NR a2 R a3 -WC(O)NR a2 OR a1 -W-OC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -W-NR a2 C(O)OR a1 -W-NR a2 C(O)NR a2 R a3 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 -W-OS(O)2R a4 -W-NR a2 S(O)2NR a2 R a3 -W-OS(O)2NR a2 R a3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-14 aryl, 5-12-membered heteroaryl, 3-20-membered heterocyclic, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R a2 and R a3 When R is attached to the same nitrogen atom, a2 and R a3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl; R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14 aryl, 5-12-membered heteroaryl, 3-20-membered heterocyclic, wherein the alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; X is N or CR 6 ; R 2 R 3 and R 6 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-OC(O)NR b2 R b3 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)OR b1 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 -W-NR b2 S(O)2NR b2 R b3 -W-OS(O)2NR b2 R b3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R b2 and R b3 When R is attached to the same nitrogen atom, b2 and R b3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl; R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, and -W-OR. c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-14 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced; R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-12 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; R c2 and R c3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl, C 3-8 cycloalkyl, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; or when R c2 and R c3 When R is attached to the same nitrogen atom, c2 and R c3 Together with the nitrogen atoms they are attached to, they form groups that are halogenated, hydroxyl, amino, nitro, mercapto, cyano, oxo, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 One or more of the following: aryl, 5-12 heteroaryl, or any substituted 3-10 heterocyclic alkyl or 5-12 heteroaryl; R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 6-14 aryl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-14 Aryl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; W is selected from key, C 1-3 Alkylene, -OC 1-3 Alkylene, -SC 1-3 Alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2; Unless otherwise specified, the heteroatoms in the heterocyclic and heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.

2. The compound according to claim 1, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: Ring A is selected from C 5-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclic; preferably, ring A is selected from C. 5-10 Cycloalkyl, C6 aryl, 5-8 membered heteroaryl, 5-10 membered heterocyclic; preferably, ring A is selected from C6. 5-10 Cycloalkyl, 5-10 membered heterocyclic group; preferably, ring A is selected from 5-10 membered heterocyclic group; preferably, ring A is selected from 5-8 membered heterocyclic group; preferably, ring A is selected from 5-7 membered heterocyclic group, the heteroatom is independently selected from O or N, and the number of heteroatoms is 1 or 2; preferably, ring A is selected from Preferably, ring A is selected from Preferably, ring A is selected from 3. The compound according to claim 1 or 2, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: X is selected from N or CH; preferably, X is selected from N; preferably, X is selected from CH.

4. The compound according to any one of claims 1 to 3, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 1 Selected from C (optional substitution) 3-10 cycloalkyl, C 5-10 Bridged cycloalkyl, C 5-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered monocyclic heterocyclic, 5-10 membered bridged heterocyclic, 5-10 membered fused heterocyclic, 5-10 membered spirocyclic heterocyclic; wherein the cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bridged cycloalkyl, fused heterocyclic and spirocyclic are optionally combined with one or more R a Replaced; preferred, R 1 Selected from C (optional substitution) 3-6 cycloalkyl, C 5-10 fused cycloalkyl, C 5-10 Spirocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, 5-10 membered monocyclic heterocyclic, 5-10 membered bridged heterocyclic, 5-10 membered fused heterocyclic, 5-10 membered spirocyclic heterocyclic; wherein the cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclic, bridged heterocyclic, fused heterocyclic and spirocyclic are optionally combined with one or more R a Replaced; preferred, R 1 Selected from C (optional substitution) 6-10 Aryl, 5-10 member heteroaryl, 5-10 member monocyclic heterocyclic, 5-10 member bridged heterocyclic, 5-10 member fused heterocyclic, 5-10 member spirocyclic heterocyclic; wherein the aryl, heteroaryl, monocyclic, bridged, fused, and spirocyclic groups are optionally combined with one or more R a Replaced; preferred, R 1 Selected from C (optional substitution) 6-10 Aryl, 5-8 membered heteroaryl, 5-8 membered monocyclic heterocyclic, 5-8 membered bridged heterocyclic, 5-8 membered fused heterocyclic, 5-8 membered spirocyclic heterocyclic; wherein the aryl, heteroaryl, monocyclic, bridged, fused, and spirocyclic groups are optionally combined with one or more R a Replaced; preferred, R 1 Selected from optionally substituted C6 aryl, 5-8 membered heteroaryl, and 5-8 membered monocyclic heterocyclic groups; wherein the aryl, heteroaryl, or monocyclic heterocyclic group is optionally substituted with one or more R a Replaced; preferred, R 1 Selected from optionally substituted C6 aryl, 5-6 membered heteroaryl, and 5-6 membered monocyclic heterocyclic groups; wherein the aryl, heteroaryl, or monocyclic heterocyclic group is optionally substituted with one or more R a Replaced; preferred, R 1 Selected from optionally substituted C6 aryl or 5-6 heteroaryl groups; wherein the aryl or heteroaryl group is optionally substituted with one or more R groups. a Replaced; preferred, R 1 Selected from one or more R a The substituted phenyl, pyridyl, or imidazolyl groups; preferably, R 1 Selected from one or more R a The substituted pyridinyl group; preferably, R 1 Selected from Preferred, R 1 Selected from 5. The compound according to any one of claims 1 to 4, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: L is selected from the following: -O-, -S-, -C 1-4 Alkylene- or -OC 1-4 Alkylene; the alkylene group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2; preferably, L is selected from bond, -O-, -S-, -C 1-2 Alkylene- or -OC 1-2 Alkylene; the alkylene group may optionally be substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2; preferably, L is selected from bond, -O-, -S-, methylene or ethylene; the methylene or ethylene group may optionally be substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2; preferably, L is selected from bond, -O-, methylene or ethylene; preferably, L is selected from bond or methylene; preferably, L is selected from bond.

6. The compound according to any one of claims 1 to 5, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-OC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 -W-OS(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; preferably, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -WS(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 5-10 membered heterocyclic, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -WC(O)NR a2 R a3 -W-NR a2 R a3 -W-NR a2 C(O)R a4 -WS(O)2R a4 -W-SO2NR a2 R a3 -W-NR a2 S(O)2R a4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy group; the alkyl, alkenyl, alkynyl, or alkoxy group may optionally be selected from one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R a Each occurrence is independently selected from deuterium, halogen, -CN, -OH, -NH2, -W-OR a1 -W-SR a1 -WC(O)R a4 -WC(O)OR a1 -W-OC(O)R a1 -W-NR a2 C(O)R a4 -C 1-4 Alkyl, C 1-4 Alkyl group; wherein the alkyl or alkoxy group is optionally surrounded by one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R a Each occurrence is independently selected from deuterium, halogens, -OH, -NH2, -W-NR a2 C(O)R a4 C 1-4 Alkyl, C 1-4 Alkyl group; the alkyl group or alkoxy group may optionally be replaced by one or more radicals selected from deuterium, halogen, oxo group, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, -W-NR a2 C(O)R a4 C 1-4 Halogenated alkyl; the alkyl or haloalkyl group may optionally be substituted with one or more deuterium atoms; preferably, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -W-NR a2 C(O)R a4 The alkyl or haloalkyl group is optionally substituted with one or more deuterium atoms; preferably, R a Each time it appears, it is independently selected from deuterium, halogen, and C. 1-4 Alkyl, C 1-4 Alkoxy, -NHC(O)R a4 The alkyl group may optionally be substituted with one or more deuterium atoms; preferably, R a Each time it appears, it is independently selected from halogens and C. 1-4 Alkyl, C 1-4 Alkoxy; preferably, R a Each time it appears, it is independently selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, or -NHC(O)-phenyl; preferably, R a Each time it appears, it is independently selected from Cl, methyl, methoxy, or -NHC(O)-phenyl.

7. The compound according to any one of claims 1 to 6, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituent is a haloalkoxy group; the heteroatom is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3; preferably, R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R a1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R a1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Alkyl substituents are used; preferably, R a1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

8. The compound according to any one of claims 1 to 7, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R a2 and R a3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy group, wherein the alkyl group or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl groups, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R a2 and R a3 Each time it appears independently, it is hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy may be selected by one or more elements from halogen, deuterium, hydroxyl, or C. 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R a2 and R a3 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

9. The compound according to any one of claims 1 to 8, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 The substituents are halogenated alkoxy or halogenated phenyl groups; the heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3; preferably, R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R a4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R a4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R a4 Each time it appears, it is independently hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl is optionally selected by one or more of halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

10. The compound according to any one of claims 1 to 9, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12 aryl, 3-6 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12 aryl, 5-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R 2 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl; wherein the alkyl, alkoxy, cycloalkyl, or aryl group is optionally selected from one or more radicals selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R 2 Selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 The methyl, ethyl, isopropyl, methoxy, ethoxy, and propoxy groups are optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R 2 Selected from hydrogen, deuterium, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, -SO2NH2, -NHSO2H; preferably, R 2 Selected from hydrogen.

11. The compound according to any one of claims 1 to 10, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, C 6-12 aryl, 3-6 membered heterocyclic, 5-10 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, heteroaryl are optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -W-OC(O)OR b1 -WC(O)NR b2 R b3 -WC(O)NR b2 OR b1 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 -W-SO2NR b2 R b3 -W-NR b2 S(O)2R b4 -W-OS(O)2R b4 C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 6- aryl, 3-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R 3 Selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, -W-OR b1 -W-SR b1 -WC(O)R b4 -WC(O)OR b1 -W-OC(O)R b1 -WC(O)NR b2 R b3 -W-NR b2 R b3 -W-NR b2 C(O)R b4 -W-NR b2 C(O)NR b2 R b3 -WS(O)R b4 -WS(O)2R b4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6- aryl, 3-6 membered heterocyclic, 5-6 membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R 3 Selected from hydrogen, deuterium, halogens, -OH, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 5-6 membered heterocyclic group; wherein the alkyl, alkoxy, cycloalkyl, or heterocyclic group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R 3 Selected from F, Cl, Br, -CF3, -CHF2-CH2, -CH2FCH3, -OCF3 or cyclopropane; preferably, R 3 Selected from Cl or -CF3; preferably, R 3 C selected from halogens, optionally substituted by one or more halogens 1-4 Alkyl; preferably, R 3 Selected from halogens; preferably, R 3 Selected from Cl.

12. The compound according to any one of claims 1 to 11, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R b1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R b1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Alkyl substituents are used; preferably, R b1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

13. The compound according to any one of claims 1 to 12, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R b2 and R b3 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy group, wherein the alkyl group or alkoxy group is optionally selected from one or more halogens, deuterium, hydroxyl groups, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R b2 and R b3 Each time it appears independently, it is hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy may be selected by one or more elements from halogen, deuterium, hydroxyl, or C. 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R b2 and R b3 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

14. The compound according to any one of claims 1 to 13, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; preferably, R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R b4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R b4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R b4 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or optionally one or more are selected from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

15. The compound according to any one of claims 1 to 14, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, C 6-12 aryl, 4-12-membered heterocyclic, 5-12-membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced; preferably, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, C 6-12 aryl, 4-10 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c Replaced; or R 4 and R 5 A ring atom attached to a carbon or nitrogen atom of the same, adjacent, or spaced one atom apart forms an optionally substituted C atom. 3-10 cycloalkyl, C 6-12 Aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclic; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced; preferably, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -CN, -OH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, C 4-6 Cycloalkenyl, C6 aryl, 4-10 membered heterocyclic, 5-12 membered heteroaryl; wherein the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclic, or heteroaryl group is optionally surrounded by one or more R c The heteroatom is replaced; the heteroatom is independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3; preferably, R 4 and R 5 Each element is independently selected from hydrogen, deuterium, halogens, -OH, and -WC(O)NR. c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-10 membered heterocyclic groups, C 6-12 aryl or 5-10-membered heteroaryl; the alkyl, cycloalkyl, heterocyclic, phenyl, or heteroaryl group may optionally be surrounded by one or more R groups. c Replaced; or R 4 and R 5 Together with the attached carbon or nitrogen atom, they form an optionally substituted C. 3-10 Cycloalkyl, 5-12 membered heterocyclic groups; the optional substitution means that the hydrogen on the substituted group is not substituted or one or more substituted sites of the substituted group are independently selected from R. c The substituents are replaced; Preferred, R 4 Hydrogen, deuterium, halogen, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, 4-6 membered heterocyclic alkyl; wherein the alkyl, alkoxy, azacyclic butyl or pyrrolidinyl is optionally surrounded by one or more R c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 C 1-4 Alkyl, C 3-6 Cycloalkyl, 4-6-membered heterocycloalkyl, phenyl, or 9-10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group is optionally surrounded by one or more R c Replaced; Preferred, R 4 The methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups are hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, aziridine, or pyrrolidinyl groups optionally with one or more R groups. c Replaced; R 5 Selected from hydrogen, deuterium, halogens, -OH, -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -WC(O)R c4 -WS(O)2R c4 methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, benzopyrazolyl; wherein the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidine, phenyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, benzopyrazolyl is optionally modified by one or more R c Replaced; Preferred, R 4 The methyl, ethyl, propyl, methoxy, ethoxy, aziridine, or pyrrolidinyl group is hydrogen, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, aziridine, or pyrrolidinyl group may optionally be modified by one or more R groups. c Replaced; R 5 Selected from hydrogen, halogens, -OH, -C 1-3 Alkylene-C(O)NR c2 R c3 -C 1-3 Alkylene-NR c2 R c3 -C 1-3 Alkylene-SO2NR c2 R c3 -C(O)R c4 -S(O)2R c4 methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl; wherein the methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl are optionally modified by one or more R c Replaced; Preferred, R 4 Hydrogen, deuterium, halogen, -OH, methyl R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3, Preferred, R 4 It is hydrogen, halogen, -OH or methyl; R 5 Selected from hydrogen, methyl, phenyl, benzoyl, -SO2CH3, Preferred, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-6 Alkyl, optionally with one or more R c Substituted phenyl, 9-10 membered bicyclic heteroaryl; preferably, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-4 Alkyl group, optionally with one or more halogens, -OH, C 1-4 Alkyl-substituted phenyl groups, 9-10 membered bicyclic heteroaryl groups; preferably, R 4 It is hydrogen; R 5 Selected from hydrogen, C 1-4 Alkyl group, phenyl group optionally substituted with one or more -F, -Cl, -Br, -OH, methyl, ethyl, n-propyl, or isopropyl groups, or 9-10 membered bicyclic heteroaryl group; wherein the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1, 2, or 3.

16. The compound according to any one of claims 1 to 15, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-12 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; Preferred, R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-12 aryl, 3-12-membered heterocyclic, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; Preferred, R c Independently selected from deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -WC(O)NR c2 R c3 -WC(O)NR c2 OR c1 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-NR c2 C(O)OR c1 -W-NR c2 C(O)NR c2 R c3 -WS(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 -W-OS(O)2R c4 -W-NR c2 S(O)2NR c2 R c3 -W-OS(O)2NR c2 R c3 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, 3-12 membered heterocyclic groups, C 6-12 aryl, 5-12-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 6-14 Aryl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups; Preferred, R c Independently selected from deuterium, halogens, -CN, -OH, -SH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-12 aryl, 5-8 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 6-12 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups; Preferred, R c Independently selected from deuterium, halogens, -CN, -OH, -SH, -NH2, -W-OR c1 -W-SR c1 -WC(O)R c4 -WC(O)OR c1 -W-OC(O)R c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -WS(O)2R c4 -W-SO2NR c2 R c3 -W-NR c2 S(O)2R c4 C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-8 membered heterocyclic, C6 aryl, 5-6 membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, heteroaryl is optionally selected by one or more elements from deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-4 Alkyl, C 6-12 Aryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups; Preferred, R c Independently selected from deuterium, halogens, -CN, -OH, -W-OR c1 -WC(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 C 1-4 Alkyl, 4-8 membered heterocyclic group; wherein the heterocyclic group is optionally surrounded by one or more elements selected from deuterium, halogen, -OH, C 1-4 Alkyl C 1-4 Haloalkyl, C 1-4 Substituents of haloalkoxy groups; Preferred, R c It is independently selected from -F, -Cl, -Br, -CH2-OH, -OH, -C(O)NH-CH3, -N(CH3)2, -SO2CH3, -SO2N(CH3)2, morpholino, methyl, ethyl, n-propyl, and isopropyl.

17. The compound according to any one of claims 1 to 16, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 The substituents of the haloalkoxy group are replaced; preferably, R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 6-10 aryl, 3-8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more of halogen, deuterium, cyano, hydroxyl, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R c1 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 5-6 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or heterocyclic groups. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R c1 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally selected by one or more elements from halogen, deuterium, hydroxyl, amino, C. 1-4 Alkyl substituents are used; preferably, R c1 Each time it appears, it is independently hydrogen, methyl, ethyl, or propyl, wherein methyl, ethyl, or propyl is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, or C. 1-4 Alkyl groups are substituted.

18. The compound according to any one of claims 1 to 17, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that... R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 cycloalkyl, C 6-10 aryl, 3-10 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, phenyl, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy or halophenyl groups; preferably, R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, 3-8 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, aryl, or heterocyclic group is optionally selected by one or more elements chosen from halogen, deuterium, hydroxyl, amino, C6, alkyl, alkyl, alkyl, alkyl, or C6. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 The substituents of the haloalkoxy group are replaced; preferably, R c4 Each time it appears, it is independently hydrogen, deuterium, or carbon. 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C6 aryl, wherein the alkyl, alkoxy, cycloalkyl, and aryl groups are optionally selected from one or more halogens, deuterium, hydroxyl, amino, C6 alkyl, ... 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R c4 Each time it appears independently of hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropane, cyclobutane, or phenyl is optionally selected by one or more from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted; preferably, R c4 Each time it appears independently as hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy; wherein methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or optionally one or more are selected from halogen, deuterium, hydroxyl, amino, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

19. The compound according to any one of claims 1 to 18, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: W is selected from key, C 1-3 The alkylene group is optionally substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2; preferably, W is selected from bond, C 1-3 The alkylene group is optionally substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2; preferably, W is selected from bond, methylene or ethylene, the methylene or ethylene group being optionally substituted with one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, -NH2.

20. A transisomer of a compound of formula (III-a), (III-b), (III-c), (III-d) or (III-e), or a pharmaceutically acceptable salt thereof of a transisomer: Where R 1 R 2 R 3 R 4 R 5 R 6 And X is as described in the compound of formula (I) according to claims 1-18, wherein L is a bond, R is a bond, and X is a bond. 1 At least one R a What it replaced.

21. A transisomer of the compound according to claim 20 or a pharmaceutically acceptable salt of the transisomer thereof: preferably, R 1 Selected from one or more R a The substituted pyridinyl group; preferably, R a Each occurrence is independently selected from Cl, methyl, and methoxy; more preferably, R 1 Selected from 22. Selected from the following compounds, or their tautomers, stereoisomers, transisomers, or pharmaceutically acceptable salts thereof:

23. A pharmaceutical composition, characterized in that: It comprises the compound of any one of claims 1 to 22 or its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients.

24. Use of the compound of any one of claims 1 to 22, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 23, in the preparation of a medicament for the prevention and / or treatment of diseases, symptoms, and conditions mediated by MAT2A, preferably said diseases, symptoms, and conditions being MTAP-deficient tumors, more preferably, said tumors including solid tumors and hematologic malignancies; said solid tumors including colorectal cancer.

25. Use of the compound of any one of claims 1 to 22, or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 23, in the preparation of a medicament for the prevention and / or treatment of tumors.

26. A pharmaceutical composition, characterized in that: The pharmaceutical composition includes any one of claims 1 to 22, or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 23, as well as another, two, or more drugs having antitumor activity.

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