Tricyclic compounds and their use

Abstract

The present invention provides a compound represented by formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. The compound according to the present invention has a potent MAT2A inhibitory effect and is useful as a medicament for treating and / or preventing MAT2A-mediated diseases, conditions, and pathologies, such as tumors. JPEG2025521737000116.jpg37170

Description

Technical Field

[0001] This application claims the priority of Chinese patent applications with application numbers 202210734328.0 filed with the China National Intellectual Property Administration on June 27, 2022, 202211120467.0 filed with the China National Intellectual Property Administration on September 15, 2022, and 202310135765.5 filed with the China National Intellectual Property Administration on February 20, 2023, and all of their contents are incorporated herein by reference.

[0002] The present invention relates to the technical field of medicine, and specifically to novel compounds having an inhibitory effect on MAT2A, and their use in the treatment and prevention of MAT2A-mediated diseases, disorders, and conditions, such as tumors.

Background Art

[0003] The full name of MAT2A is Methionine adenosyltransferase 2A, and it is also called S-Adenosylmethionine Synthase Isoform Type. MAT2A is expressed in all tissues including erythrocytes, brain, fetal liver, kidney, and pancreatic tissues, but it is not very abundant in adult liver tissues. When the expression of MAT2A and MAT2B increases, the growth, migration, and invasion of cancer cells occur. In short, when the expression of MAT2A and MAT2B decreases, apoptosis increases and cell growth, migration, and metastasis decrease.

[0004] MTAP is a methionine transferase that can catalyze the transfer of adenylate and plays an important role in the recycling synthesis of ATP. MTAP deficiency accounts for approximately 15% of all solid tumors. MTAP is deficient to varying degrees in various types of tumors. MTAP deficiency causes the accumulation of the enzyme substrate methylthioadenosine (MTA). An increase in MTA concentration partially inhibits the activity of PRMT5, while other methyltransferases are relatively unaffected. Inhibiting MAT2A reduces the methyl donor S-adenosylmethionine (SAM). On the other hand, since SAM is a substrate of PRMT5, PRMT5 is further inhibited, affecting mRNA splicing in tumor cells and causing DNA damage. Therefore, MAT2A inhibitors are effective against MTAP-deficient tumors.

[0005] Multiple patent documents such as WO2018039972, WO2019191470, WO2020139991, WO2020139992, WO2020243376, and WO2020123395 disclose MAT2A inhibitors.

Summary of the Invention

Problems to be Solved by the Invention

[0006] The present invention provides a MAT2A inhibitor compound having a novel structure or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, and also provides the use of this compound or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof in the treatment and prevention of MAT2A-mediated diseases, disorders, and conditions.

Means for Solving the Problems

[0007] Specifically, according to a first aspect, the present invention provides a compound represented by formula (I) having the following structure, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

Chemical formula

[0008] (wherein, ring A is selected from a carbocyclic group, C 5~10 carbocyclic group, C 6~14 aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, and each of the carbocyclic group, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more R R 1 is optionally substituted C 3~12 carbocyclic group, C 6~14 aryl, 5- to 14-membered heteroaryl, or 5- to 14-membered heterocyclyl, and each of the carbocyclic group, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more R a ; L is a bond, -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 )-, and the alkylene is optionally substituted by one or more R a1 ;

[0009] R a is, independently at each occurrence, deuterium, halogen, oxo, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 , -W-SR a1 , -W-C(O)R a4 , -W-C(O)OR a1 , -W-OC(O)R a1 , -W-OC(O)OR a1 , -W-C(O)NR a2 R a3 , -W-C(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-NRa2 C(O)NR a2 R a3 、 -W-S(O)R a4 、 -W-S(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, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, C 6~14 aryl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0010] R a1 is, in each occurrence, independently hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~14Aryl, 5- to 12-membered heteroaryl, or 3- to 20-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 6~14 aryl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, R a2 and R a3 is, independently at each occurrence, hydrogen, deuterium, C 1~6 alkyl, or C 1~6 alkoxy, wherein each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxy, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl, C 3~8 cycloalkyl, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, or when R a2 and R a3 are attached to the same nitrogen atom, R a2 and R a3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~14 aryl, 5- to 12-membered heteroaryl, R a4 is, independently at each occurrence, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~8Cycloalkyl, C 6~14 Aryl, 5 - to 12 - membered heteroaryl, or 3 - to 20 - membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 Alkyl, C 1~6 Alkoxy, phenyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, halophenyl,

[0011] X is N or CR 6 and R 2 , R 3 and R 6 are each independently hydrogen, deuterium, halogen, - CN, - OH, - SH, - NO2, - NH2, - W - OR b1 , - W - SR b1 , - W - C(O)R b4 , - W - C(O)OR b1 , - W - OC(O)R b1 , - W - OC(O)OR b1 , - W - C(O)NR b2 R b3 , - W - C(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 , - W - S(O)R b4 , - W - S(O)2R b4 , - W - SO2NR b2 R b3 , - W - NR b2 S(O)2R b4 , - W - OS(O)2R b4 , - W - NR b2S(O)2NR b2 R b3 、 -W-OS(O)2NR b2 R b3 、 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, C 6~14 aryl, 3 - to 12 - membered heterocyclyl, or 5 - to 16 - membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0012] R b1 is, in each occurrence, independently, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~14 aryl, or 3 - to 20 - membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 6~14 aryl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom, R b2 and R b3 are, in each occurrence, independently, hydrogen, deuterium, C 1~6alkyl, or C 1~6 is alkoxy, wherein each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxy, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl, C 3~8 cycloalkyl, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, or, when R b2 and R b3 are attached to the same nitrogen atom, R b2 and R b3 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~14 aryl, 5- to 12-membered heteroaryl, R b4 is, independently at each occurrence, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~8 cycloalkyl, C 6~14 aryl, or 3- to 20-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 6~14 aryl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl,

[0013] R 4 and R 5are each independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 -W-SR c1 -W-C(O)R c4 -W-C(O)OR c1 -W-OC(O)R c1 -W-OC(O)OR c1 -W-C(O)NR c2 R c3 -W-C(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 -W-S(O)R c4 -W-S(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, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, C 6~14 is selected from aryl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl has one or more Rc is optionally replaced by, or R 4 and R 5 are linked on the same, adjacent, or ring atoms separated by one atom, and together with the carbon and / or nitrogen atoms to which they are linked, form an optionally substituted C 3~10 cycloalkyl, C 6~14 aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, where said optionally substituted means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by substituents selected from R c , meaning that

[0014] R c is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-OC(O)OR c1 , -W-C(O)NR c2 R c3 , -W-C(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 , -W-S(O)R c4 , -W-S(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 Rc3 , -W-OS(O)2NR c2 R c3 , C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0015] R c1 is, in each occurrence, independently, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, C 6~14 aryl, or 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 6~14 aryl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom, R c2 and R c3 are, in each occurrence, independently, hydrogen, deuterium, C 1~6 alkyl, or C 1~6is an alkoxy, wherein each of said alkyl and alkoxy is halogen, deuterium, cyano, hydroxy, amino, carboxy, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 alkyl, C 3~8 cycloalkyl, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, optionally substituted by one or more substituents selected therefrom, or R c2 and R c3 when linked to the same nitrogen atom, R c2 and R c3 together with the nitrogen atom to which they are linked, form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C 6~14 aryl, 5- to 12-membered heteroaryl, R c4 is, independently at each occurrence, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~8 cycloalkyl, C 6~14 aryl, or 3- to 20-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 6~14 aryl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl,

[0016] W is a bond, C 1~3 alkylene, -OC 1~3 alkylene, -SC 1~3Selected from 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 heterocyclyl and heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3.)

[0017] In a further preferred embodiment, ring A is C 5~10 cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, In a further preferred embodiment, ring A is C 5~10 cycloalkyl, C6 aryl, 5- to 8-membered heteroaryl, 5- to 10-membered heterocyclyl, In a further preferred embodiment, ring A is C 5~10 cycloalkyl, 5- to 10-membered heterocyclyl, In a further preferred embodiment, ring A is selected from 5- to 10-membered heterocyclyl, In a further preferred embodiment, ring A is selected from 5- to 8-membered heterocyclyl,

[0018] In a further preferred embodiment, ring A is selected from 5- to 7-membered heterocyclyl, the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1 or 2, In a further preferred embodiment, ring A is selected from 5- to 6-membered heterocyclyl, the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1 or 2, In a further preferred embodiment, ring A is selected from 5- to 6-membered heterocyclyl, the heteroatoms are selected from N, and the number of heteroatoms is 1 or 2, In a further preferred embodiment, ring A is selected from 5-membered heterocyclyl, the heteroatoms are independently selected from O or N, and the number of heteroatoms is 1 or 2,

[0019] In a further preferred embodiment, ring A is selected from 5-membered heterocyclyl, the heteroatom is selected from N, and the number of heteroatoms is one or two, In a further preferred embodiment, ring A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0020] In a further preferred embodiment, X is selected from N or CH, In a further preferred embodiment, X is selected from N, In a further preferred embodiment, X is selected from CH.

[0021] In a further preferred embodiment, R 1 is optionally substituted C 3~10 cycloalkyl, C 5~10 bridged cycloalkyl, C 5~10 fused cycloalkyl, C 5~10 spirocycloalkyl, C 6~10Selected from aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, or 5- to 10-membered spiroheterocyclyl, each of the cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R a and is optionally substituted by In a further preferred embodiment, R 1 is optionally substituted C 3~6 cycloalkyl, C 5~10 fused cycloalkyl, C 5~10 spirocycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, or 5- to 10-membered spiroheterocyclyl, each of the cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R a and is optionally substituted by In a further preferred embodiment, R 1 is optionally substituted C 6~10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, 5- to 10-membered spiroheterocyclyl, each of the aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R a and is optionally substituted by

[0022] In a further preferred embodiment, R 1 is optionally substituted C 6~10Selected from aryl, 5- to 8-membered heteroaryl, 5- to 8-membered monocyclic heterocyclyl, 5- to 8-membered bridged heterocyclyl, 5- to 8-membered fused heterocyclyl, or 5- to 8-membered spiroheterocyclyl, each of said aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl being optionally substituted by one or more R a and being optionally substituted by In a further preferred embodiment, R 1 is selected from optionally substituted C6 aryl, 5- to 8-membered heteroaryl, or 5- to 8-membered monocyclic heterocyclyl, each of said aryl, heteroaryl, monocyclic heterocyclyl being optionally substituted by one or more R a and being optionally substituted by In a further preferred embodiment, R 1 is selected from optionally substituted C6 aryl, 5- to 6-membered heteroaryl, or 5- to 6-membered monocyclic heterocyclyl, each of said aryl, heteroaryl, monocyclic heterocyclyl being optionally substituted by one or more R a and the heteroatoms being independently selected from O, N, the number of heteroatoms being one or two,

[0023] In a further preferred embodiment, R 1 is selected from optionally substituted C6 aryl, or 5- to 6-membered heteroaryl, each of said aryl and heteroaryl being optionally substituted by one or more R a and the heteroatoms being independently selected from N, the number of heteroatoms being one or two, In a further preferred embodiment, R 1 is selected from phenyl, pyridyl, or imidazolyl optionally substituted by one or more R a and being optionally substituted by In a further preferred embodiment, R 1 is selected from pyridyl optionally substituted by one or more R a and being optionally substituted by

[0024] In a further preferred embodiment, R 1 is [Chemical formula] selected from In a further preferred embodiment, R 1 is [Chemical formula] selected from.

[0025] In a further preferred embodiment, L is a bond, -O-, -S-, -C 1~4 alkylene- or -OC 1~4 alkylene-, selected from, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2, In a further preferred embodiment, L is a bond, -O-, -S-, -C 1~2 alkylene-, or -OC 1~2 alkylene-, selected from, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2, In a further preferred embodiment, L is selected from a bond, -O-, -S-, methylene, or ethylene, wherein the methylene or ethylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2,

[0026] In a further preferred embodiment, L is selected from a bond, -O-, methylene, or ethylene, In a further preferred embodiment, L is selected from a bond or methylene, In a further preferred embodiment, L is selected from a bond.

[0027] In a further preferred embodiment, R ais, independently at each occurrence, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 , -W-SR a1 , -W-C(O)R a4 , -W-C(O)OR a1 , -W-OC(O)R a1 , -W-C(O)NR a2 R a3 , -W-OC(O)NR a2 R a3 , -W-NR a2 R a3 , -W-NR a2 C(O)R a4 , -W-S(O)R a4 , -W-S(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, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, and heteroaryl being optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, phenyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0028] In a further preferred embodiment, R a is, independently at each occurrence, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR a1 , -W-SR a1 , -W-C(O)R a4,-W-C(O)OR a1 ,-W-OC(O)R a1 ,-W-C(O)NR a2 R a3 ,-W-NR a2 R a3 ,-W-NR a2 C(O)R a4 ,-W-S(O)R a4 ,-W-S(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,C 1~6 alkoxy,C 1~6 alkylthio,C 3~10 cycloalkyl,a5- to 10-membered heterocyclyl,or a5- to 10-membered heteroaryl,each of said alkyl,alkenyl,alkynyl,alkoxy,alkylthio,cycloalkyl,heterocyclyl,and heteroaryl being optionally substituted by one or more substituents selected from deuterium,halogen,oxo,-CN,-OH,-NO2,-NH2,C 1~6 alkyl,C 1~6 alkoxy,C 1~6 haloalkyl,C 1~6 haloalkoxy,and is optionally substituted by one or more substituents selected from deuterium,halogen,oxo,-CN,-OH,-NO2,-NH2,C

[0029] In a more preferred embodiment,R a is,independently at each occurrence,deuterium,halogen,-CN,-OH,-SH,-NO2,-NH2,-W-OR a1 ,-W-SR a1 ,-W-C(O)R a4 ,-W-C(O)OR a1 ,-W-OC(O)R a1 ,-W-C(O)NR a2 R a3 ,-W-NR a2 R a3 ,-W-NR a2 C(O)R a4 ,-W-S(O)2R a4 ,-W-SO2NRa2 R a3 、 -W-NR a2 S(O)2R a4 、 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, or C 1~6 alkoxy, and each of said alkyl, alkenyl, alkynyl, and alkoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C In a further preferred embodiment, R a is, independently at each occurrence, deuterium, halogen, -CN, -OH, -NH2, -W-OR a1 、 -W-SR a1 、 -W-C(O)R a4 、 -W-C(O)OR a1 、 -W-OC(O)R a1 、 -W-NR a2 C(O)R a4 、 -C 1~4 alkyl, or C 1~4 alkoxy, and said alkyl or alkoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~4 alkyl, C 1~4 alkoxy, and is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C

[0030] In a further preferred embodiment, R a is, independently at each occurrence, deuterium, halogen, -OH, -NH2, -W-NR a2 C(O)R a4 、 C 1~4 alkyl, or C 1~4 alkoxy, and said alkyl or alkoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -OH, -NH2, C 1~4 alkyl, C 1~4 alkoxy, C 1~4Haloalkyl, C 1~4 Optionally substituted by one or more substituents selected from haloalkoxy, In a further preferred embodiment, R a Is, independently at each occurrence, deuterium, halogen, C 1~4 Alkyl, -W-NR a2 C(O)R a4 Or C 1~4 Haloalkyl, wherein the alkyl or haloalkyl is optionally substituted by one or more deuteriums,

[0031] In a further preferred embodiment, R a Is, independently at each occurrence, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, or -W-NR a2 C(O)R a4 Selected from, wherein the alkyl or haloalkyl is optionally substituted by one or more deuteriums, In a further preferred embodiment, R a Is, independently at each occurrence, deuterium, halogen, C 1~4 Alkyl, C 1~4 Alkoxy, or -NHC(O)R a4 Selected from, wherein the alkyl is optionally substituted by one or more deuteriums, In a further preferred embodiment, R a Is, independently at each occurrence, halogen, C 1~4 Alkyl, or C 1~4 Selected from alkoxy,

[0032] In a further preferred embodiment, R a Is, independently at each occurrence, deuterium, F, Cl, Br, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, or -NHC(O)-phenyl, In a further preferred embodiment, R ais independently selected from Cl, methyl, methoxy, or -NHC(O)-phenyl at each occurrence, In a further preferred embodiment, R a is independently selected from Cl, methyl, or -NHC(O)-phenyl at each occurrence.

[0033] In a further preferred embodiment, R a1 is independently hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and the heteroatoms are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3, In a further preferred embodiment, R a1 is independently hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatoms are independently selected from O, N, and the number of heteroatoms is 1 or 2,

[0034] In a further preferred embodiment, Ra1 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two, In a further preferred embodiment, R a1 is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, In a further preferred embodiment, R a1 is, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where each of said methyl, ethyl, and propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0035] In a further preferred embodiment, R a2 and R a3 are, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4Optionally substituted by one or more substituents selected from haloalkoxy, In a further preferred embodiment, R a2 and R a3 are, in each occurrence, independently hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy,

[0036] In a further preferred embodiment, R a2 and R a3 are, in each occurrence, independently hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy, In a further preferred embodiment, R a2 and R a3 are, in each occurrence, independently hydrogen, methyl, ethyl, or propyl, where each of said methyl, ethyl, and propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0037] In a further preferred embodiment, R a4 is, in each occurrence, independently hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~8 cycloalkyl, C 6~10Aryl, or a 3- to 10-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, the heteroatom is independently selected from O, N or S, and the number of heteroatoms is 1, 2 or 3, In a further preferred embodiment, R a4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or a 3- to 8-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and is optionally substituted by one or more substituents selected therefrom, the heteroatom is independently selected from O, N, and the number of heteroatoms is 1 or 2,

[0038] In a further preferred embodiment, R a4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, or C6 aryl, wherein each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, and is optionally substituted by one or more substituents selected therefrom, In a further preferred embodiment, R a4is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, where each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, and phenyl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, In a further preferred embodiment, R a4 is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl, where each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, and phenyl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy.

[0039] In a further preferred embodiment, R 2 is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 , -W-SR b1 , -W-C(O)R b4 , -W-C(O)OR b1 , -W-OC(O)R b1 , -W-OC(O)OR b1 , -W-C(O)NR b2 R b3 , -W-C(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 , -W-S(O)R b4 , -W-S(O)2R b4 , -W-SO2NR b2 R b3 , -W-NRb2 S(O)2R b4 、 -W-OS(O)2R b4 、 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~6 cycloalkyl, C 6~12 aryl, 3 - to 6 - membered heterocyclyl, or 5 - to 12 - membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and is optionally substituted by one or more substituents selected therefrom,

[0040] In a more preferred embodiment, R 2 is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 、 -W-SR b1 、 -W-C(O)R b4 、 -W-C(O)OR b1 、 -W-OC(O)R b1 、 -W-OC(O)OR b1 、 -W-C(O)NR b2 R b3 、 -W-C(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 、 -W-S(O)R b4 、 -W-S(O)2R b4 、 -W-SO2NR b2R b3 、 -W-NR b2 S(O)2R b4 、 -W-OS(O)2R b4 、 C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~6 cycloalkyl, C 6~12 is selected from aryl, 5- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and is optionally substituted by one or more substituents selected therefrom, the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two,

[0041] In a more preferred embodiment, R 2 is hydrogen, deuterium, halogen, -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, or C6 aryl, and each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy,

[0042] In a further preferred embodiment, R 2 is selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, -W-SO2NR b2 R b3 , or -W-NR b2 S(O)2R b4 and each of the methyl, ethyl, isopropyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, In a further preferred embodiment, R 2 is selected from hydrogen, deuterium, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, -SO2NH2, -NHSO2H, In a further preferred embodiment, R 2 is selected from hydrogen, In a further preferred embodiment, R 6 is selected from hydrogen.

[0043] In a further preferred embodiment, R 3 is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 , -W-SR b1 , -W-C(O)R b4 , -W-C(O)OR b1 , -W-OC(O)R b1 , -W-OC(O)OR b1 , -W-C(O)NR b2 R b3 , -W-C(O)NR b2 OR b1 , -W-NR b2 R b3 , -W-NR b2 C(O)R b4 , -W-NR b2C(O)NR b2 R b3 、 -W-S(O)R b4 、 -W-S(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, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~6 cycloalkyl, C 6~12 aryl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and is optionally substituted, the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two,

[0044] In a further preferred embodiment, R 3 is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR b1 、 -W-SR b1 、 -W-C(O)R b4 、 -W-C(O)OR b1 、 -W-OC(O)R b1 、 -W-OC(O)OR b1 、 -W-C(O)NR b2 R b3 、 -W-C(O)NR b2 OR b1 、 -W-NR b2 Rb3 、 -W-NR b2 C(O)R b4 、 -W-NR b2 C(O)NR b2 R b3 、 -W-S(O)R b4 、 -W-S(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, C 1~4 alkoxy, C 1~4 alkylthio, C 3~6 cycloalkyl, C 6~ aryl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C

[0045] In a more preferred embodiment, R 3 is hydrogen, deuterium, halogen, -CN, -OH, -NH2, -W-OR b1 、 -W-SR b1 、 -W-C(O)R b4 、 -W-C(O)OR b1 、 -W-OC(O)R b1 、 -W-C(O)NR b2 R b3 、 -W-NR b2 R b3 、 -W-NR b2 C(O)R b4 、 -W-NR b2C(O)NR b2 R b3 、 -W-S(O)R b4 、 -W-S(O)2R b4 、 C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C 6~ aryl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, and the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two, In a further preferred embodiment, R 3 is hydrogen, deuterium, halogen, -OH, -NH2, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, or 5- to 6-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, and heterocyclyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two,

[0046] In a further preferred embodiment, R 3 is selected from F, Cl, Br, -CF3, -CHF2-CH2, -CH2FCH3, -OCF3 or cyclopropyl, In a further preferred embodiment, R 3 is selected from Cl or -CF3, In a further preferred embodiment, R 3 is selected from halogen, C 1~4 alkyl optionally substituted by one or more halogens, In a further preferred embodiment, R 3 is selected from halogen, In a further preferred embodiment, R 3 is selected from Cl.

[0047] In a further preferred embodiment, R b1 is, in each occurrence, independently hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, In a further preferred embodiment, R b1 is, in each occurrence, independently hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or a 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy,

[0048] In a further preferred embodiment, R b1is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatoms are independently selected from O, N, and the number of heteroatoms is one or two, In a further preferred embodiment, R b1 is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, In a further preferred embodiment, R b1 is, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where each of said methyl, ethyl, and propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0049] In a further preferred embodiment, R b2 and R b3 are, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, or C 1~4 alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4Optionally substituted with one or more substituents selected from haloalkoxy, In a further preferred embodiment, R b2 and R b3 are, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, or C 1~4 alkoxy, where each of said alkyl and alkoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy,

[0050] In a further preferred embodiment, R b2 and R b3 are, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy, In a further preferred embodiment, R b2 and R b3 are, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where each of said methyl, ethyl, and propyl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0051] In a further preferred embodiment, R b4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~8 cycloalkyl, C 6~10Aryl, or a 3- to 10-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and the heteroatom is independently selected from O, N, or S, and the number of heteroatoms is one, two, or three, In a more preferred embodiment, R b4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or a 3- to 8-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatom is independently selected from O and N, and the number of heteroatoms is one or two,

[0052] In a more preferred embodiment, R b4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, or C6 aryl, wherein each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, In a more preferred embodiment, R b4is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, where said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, and is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C In a further preferred embodiment, R b4 is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted with one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy.

[0053] In a further preferred embodiment, R 4 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-OC(O)OR c1 , -W-C(O)NR c2 R c3 , -W-C(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 , -W-S(O)R c4 , -W-S(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 selected from aryl, 4- to 12-membered heterocyclyl, or 5- to 12-membered heteroaryl, wherein each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R c or R 4 and R 5 are linked on the same, adjacent, or separated by one atom ring atoms, and, together with the carbon atom and / or nitrogen atom to which they are attached, optionally substituted C 3~10 cycloalkyl, C 6~12 aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl to form, said optionally substituted means that the hydrogen in the group to be substituted is not substituted, or one or more substitutable sites of the group to be substituted are independently substituted by a substituent selected from R c which means that,

[0054] In a further preferred embodiment, R 4 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-OC(O)OR c1 , -W-C(O)NR c2 R c3 , -W-C(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 , -W-S(O)R c4 , -W-S(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 - to 10 - membered heterocyclyl, or 5 - to 12 - membered heteroaryl, wherein each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R c , or R 4 and R 5 are linked on the same, adjacent, or separated by one atom ring atoms, and together with the carbon atom and / or nitrogen atom to which they are linked, optionally substituted C 3~10 , cycloalkyl, C 6~12 , aryl, 5 - to 12 - membered heteroaryl, 5 - to 12 - membered heterocyclyl to form, said optionally substituted means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by a substituent selected from R c , the heteroatom is independently selected from O, N or S, and the number of heteroatoms is one, two or three,

[0055] , in a further preferred embodiment, R 4 and R 5are each independently hydrogen, deuterium, halogen, -CN, -OH, -NH2, -W-OR c1 -W-SR c1 -W-C(O)R c4 -W-C(O)OR c1 -W-OC(O)R c1 -W-C(O)NR c2 R c3 -W-OC(O)NR c2 R c3 -W-NR c2 R c3 -W-NR c2 C(O)R c4 -W-S(O)R c4 -W-S(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- to 10-membered heterocyclyl, or 5- to 12-membered heteroaryl, wherein each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R c and the heteroatoms are each independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3,

[0056] In a further preferred embodiment, R 4 and R 5 are each independently hydrogen, deuterium, halogen, -CN, -OH, -NH2, -W-OR c1 -W-SR c1 -W-C(O)R c4 -W-C(O)OR c1 -W-OC(O)R c1 -W-C(O)NR c2 R c3, -W-OC(O)NR c2 R c3 , -W-NR c2 R c3 , -W-NR c2 C(O)R c4 , -W-S(O)R c4 , -W-S(O)2R c4 , -W-SO2NR c2 R c3 , -W-NR c2 S(O)2R c4 , -W-OS(O)2R c4 , C 1~4 , C alkyl 1~4 , C alkoxy 1~4 , C alkylthio 3~6 , C cycloalkyl 4~6 , C cycloalkenyl, C6 aryl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, and each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R c , wherein the heteroatom is independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3

[0057] , in a further preferred embodiment, R 4 and R 5 are each independently hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 , -W-NR c2 R c3 , -W-SO2NR c2 R c3 , -W-C(O)R c4 , -W-S(O)2R c4 , C 1~4 , C alkyl 3~6 , C cycloalkyl, 4-10 membered heterocyclyl, C 6~12 , C aryl, or 5-10 membered heteroaryl, and said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted by one or more R c , or R4 and R 5 together with the carbon and / or nitrogen atoms to which they are attached, form an optionally substituted C 3~10 cycloalkyl, 5- to 12-membered heterocyclyl, where said optionally substituted means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by substituents selected from R c and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is one, two or three,

[0058] In a more preferred embodiment, R 4 and R 5 are each independently hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -W-C(O)R c4 -W-S(O)2R c4 C 1~4 alkyl, C 3~6 cycloalkyl, 4- to 10-membered heterocyclyl, C 6~12 aryl, or 5- to 6-membered heteroaryl, where said alkyl, cycloalkyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted by one or more R c or R 4 and R 5 together with the carbon and / or nitrogen atoms to which they are attached, form an optionally substituted C 3~10 cycloalkyl, 5- to 12-membered heterocyclyl, where said optionally substituted means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by substituents selected from R c and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is one, two or three,

[0059] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 alkoxy, a 4- to 6-membered heterocyclyl, and the alkyl, alkoxy, or heterocyclyl is optionally substituted by R c wherein R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -W-C(O)R c4 -W-S(O)2R c4 C 1~4 alkyl, C 3~6 cycloalkyl, a 4- to 10-membered heterocyclyl, C 6~10 aryl, or a 5- to 10-membered heteroaryl, and each of the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R c wherein the heteroatom is independently selected from O and N, and the number of heteroatoms is one or two, In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 alkoxy, a 4- to 6-membered heterocyclyl, and the alkyl, alkoxy, or heterocyclyl is optionally substituted by R c wherein R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -W-C(O)R c4 -W-S(O)2R c4 C 1~4 alkyl, C 3~6 cycloalkyl, a 4- to 10-membered heterocyclyl, C6~10 Selected from aryl or 5- to 6-membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R c The heteroatom is independently selected from O and N, and the number of heteroatoms is one or two,

[0060] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 alkoxy, 4- to 6-membered heterocycloalkyl, and said alkyl, alkoxy, heterocycloalkyl are optionally substituted by one or more R c R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 -W-NR c2 R c3 -W-SO2NR c2 R c3 -W-C(O)R c4 -W-S(O)2R c4 C 1~4 alkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or 9- to 10-membered heteroaryl, and each of said alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is optionally substituted by one or more R c In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 alkoxy, 4- to 6-membered heterocycloalkyl, and said alkyl, alkoxy, heterocycloalkyl are optionally substituted by one or more R c R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 -W-NR c2 R​c3 、 -W-SO2NR c2 R c3 、 -W-C(O)R c4 、 -W-S(O)2R c4 、 C 1~4 alkyl, C 3~6 cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each of said alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is optionally substituted by one or more R c ;

[0061] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, or pyrrolidinyl, wherein each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, and pyrrolidinyl is optionally substituted by one or more R c ; R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 、 -W-NR c2 R c3 、 -W-SO2NR c2 R c3 、 -W-C(O)R c4 、 -W-S(O)2R c4 、 methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, benzopyrazolyl, wherein said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, benzopyrazolyl is optionally substituted by one or more R c ;

[0062] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, or pyrrolidinyl, and each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, and pyrrolidinyl is optionally substituted by one or more R c ; R 5 is hydrogen, deuterium, halogen, -OH, -W-C(O)NR c2 R c3 、-W-NR c2 R c3 、-W-SO2NR c2 R c3 、-W-C(O)R c4 、-W-S(O)2R c4 、methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, or pyrimidinyl, and each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, and pyrimidinyl is optionally substituted by one or more R c ;

[0063] In a further preferred embodiment, R 4 is hydrogen, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, azetidinyl, or pyrrolidinyl, and each of said methyl, ethyl, propyl, methoxy, ethoxy, azetidinyl, and pyrrolidinyl is optionally substituted by one or more R c ; R 5 is hydrogen, halogen, -OH, -C 1~3 alkylene-C(O)NR c2 R c3 、-C 1~3 alkylene-NR c2 R c3 、-C 1~3Alkylene-SO2NR c2 R c3 、-C(O)R c4 、-S(O)2R c4 、 methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl, wherein said methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl are optionally substituted by one or more R c ;

[0064] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, methyl,

Chemical formula

Chemical formula

Chemical formula

[0065] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, methyl,

Chemical formula

Chemical formula

[0066] In a further preferred embodiment, R 4 is hydrogen, deuterium, halogen, -OH, or methyl, and R 5 is hydrogen, methyl, phenyl, benzoyl, -SO2CH3,

Chemical formula

[0067] In a further preferred embodiment, R 4 is hydrogen, and R 5 is hydrogen, C 1~6 alkyl, phenyl, selected from 9- to 10-membered bicyclic heteroaryl, wherein said phenyl and said heteroaryl are optionally substituted by one or more R c ; In a further preferred embodiment, R 4 is hydrogen, and R 5 is hydrogen, C 1~4 alkyl, phenyl, selected from 9- to 10-membered bicyclic heteroaryl, wherein said phenyl and said heteroaryl are optionally substituted by one or more halogen, -OH, C 1~4 alkyl; In a further preferred embodiment, R 4 is hydrogen, and R 5 is hydrogen, C 1~4 alkyl, phenyl, selected from 9- to 10-membered bicyclic heteroaryl, wherein said phenyl and said heteroaryl are optionally substituted by one or more -F, -Cl, -Br, -OH, methyl, ethyl, n-propyl, isopropyl, and the heteroatom in said heteroaryl is selected from N, and the number of heteroatoms is 1, 2, or 3.

[0068] In a further preferred embodiment, R c is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 ,-W-SR c1 ,-W-C(O)R c4 ,-W-C(O)ORc1 、 -W-OC(O)R c1 、 -W-OC(O)OR c1 、 -W-C(O)NR c2 R c3 、 -W-C(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 、 -W-S(O)R c4 、 -W-S(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, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, C 6~12 aryl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is independently deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C1~6 Haloalkyl, C 1~6 Optionally substituted with one or more substituents selected from haloalkoxy, halophenyl,

[0069] In a further preferred embodiment, R c is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-OC(O)OR c1 , -W-C(O)NR c2 R c3 , -W-C(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 , -W-S(O)R c4 , -W-S(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, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C3~10 Cycloalkenyl, C 6~12 selected from aryl, 3- to 12-membered heterocyclyl, or 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl being optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0070] In a further preferred embodiment, R c is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-OC(O)OR c1 , -W-C(O)NR c2 R c3 , -W-C(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 , -W-S(O)R c4 , -W-S(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, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, C 1~6 alkylthio, C 3~10 cycloalkyl, C 3~10 cycloalkenyl, 3- to 12-membered heterocyclyl, C 6~12 aryl, or 5- to 12-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~6 alkyl, C 6~14 aryl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom,

[0071] In a further preferred embodiment, R c is independently deuterium, halogen, -CN, -OH, -SH, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-C(O)NR c2 R c3 , -W-NR c2 R c3 , -W-NR c2 C(O)R c4 , -W-S(O)2R c4 , -W-SO2NR c2 R c3 , -W-NR c2 S(O)2Rc4 , C 1~4 alkyl, C 1~4 alkoxy, C 3~8 cycloalkyl, 4- to 8-membered heterocyclyl, C 6~12 aryl, or 5- to 8-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C 1~4 alkyl, C 6~12 aryl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and is optionally substituted by one or more substituents selected therefrom,

[0072] In a further preferred embodiment, R c is independently deuterium, halogen, -CN, -OH, -SH, -NH2, -W-OR c1 , -W-SR c1 , -W-C(O)R c4 , -W-C(O)OR c1 , -W-OC(O)R c1 , -W-C(O)NR c2 R c3 , -W-NR c2 R c3 , -W-NR c2 C(O)R c4 , -W-S(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- to 8-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1~4 alkyl, C 6~12 aryl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 optionally substituted with one or more substituents selected from haloalkoxy, the heteroatom is independently selected from O, N, and the number of heteroatoms is 1 or 2,

[0073] In a further preferred embodiment, R c is independently deuterium, halogen, -CN, -OH, -W-OR c1 , -W-C(O)NR c2 R c3 , -W-NR c2 R c3 , -W-SO2NR c2 R c3 , C 1~4 alkyl, a 4- to 8-membered heterocyclyl, the heterocyclyl being optionally substituted with one or more substituents selected from deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 haloalkoxy, the heteroatom is independently selected from O, N, and the number of heteroatoms is 1 or 2, In a further preferred embodiment, R c is independently deuterium, halogen, -CN, -OH, -W-OR c1 , -W-C(O)NR c2 R c3 , -W-NR c2 R c3 , -W-SO2NR c2 R c3 , a 4- to 8-membered heterocyclyl, the heterocyclyl being optionally substituted with one or more substituents selected from deuterium, halogen, -OH, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 haloalkoxy, the heteroatom is independently selected from O, N, and the number of heteroatoms is 1 or 2,

[0074] In a further preferred embodiment, R c is 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, In a further preferred embodiment, R c is independently selected from -F, -Cl, -Br, -CH2-OH, -OH, -C(O)NH-CH3, -N(CH3)2, -SO2CH3, -SO2N(CH3)2, morpholinyl.

[0075] In a further preferred embodiment, R c1 is independently, in each occurrence, hydrogen, deuterium, C 1~6 alkyl, C 1~6 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or a 3- to 10-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, C 1~6 haloalkoxy, In a further preferred embodiment, R c1 is independently, in each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C 6~10 aryl, or a 3- to 8-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy,

[0076] In a further preferred embodiment, R c1 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or a 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatom is independently selected from O, N, and the number of heteroatoms is one or two, In a further preferred embodiment, R c1 is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, In a further preferred embodiment, R c1 is, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where each of said methyl, ethyl, and propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0077] In a further preferred embodiment, R c2 and R c3 are, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, or C 1~4 alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C1~4 alkoxy, C 1~4 haloalkyl, C 1~4 optionally substituted by one or more substituents selected from haloalkoxy, In a further preferred embodiment, R c2 and R c3 are, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, or C 1~4 alkoxy, wherein each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy,

[0078] In a further preferred embodiment, R c2 and R c3 are, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C 1~4 alkyl, C 1~4 alkoxy, In a further preferred embodiment, R c2 and R c3 are, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, wherein each of said methyl, ethyl, and propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl.

[0079] In a further preferred embodiment, R c4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~8 cycloalkyl, C 6~10Aryl, or a 3- to 10-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~6 alkyl, C 1~6 alkoxy, phenyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, halophenyl, In a further preferred embodiment, R c4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, C6 aryl, or a 3- to 8-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, C 1~4 haloalkyl, C 1~4 haloalkoxy, and the heteroatoms are independently selected from O, N, and the number of heteroatoms is one or two,

[0080] In a further preferred embodiment, R c4 is, independently at each occurrence, hydrogen, deuterium, C 1~4 alkyl, C 1~4 alkoxy, C 3~6 cycloalkyl, or C6 aryl, wherein each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C 1~4 alkyl, C 1~4 alkoxy, In a further preferred embodiment, R c4is independently at each occurrence hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, wherein each of said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, and phenyl is selected from halogen, deuterium, hydroxy, amino, C 1~4 Alkyl, C 1~4 optionally substituted with one or more substituents selected from alkoxy; In a further preferred embodiment, R c4 is independently at each occurrence hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, wherein each of said methyl, ethyl, propyl, methoxy, ethoxy, and propoxy is selected from halogen, deuterium, hydroxy, amino, C 1~4 Alkyl, C 1~4 and optionally substituted with one or more substituents selected from alkoxy.

[0081] In a further preferred embodiment, W is a bond, C 1~3 alkylene, said alkylene being optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH; In a further preferred embodiment, W is a bond, C 1~3 alkylene, said alkylene being optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH; In a further preferred embodiment, W is selected from a bond, methylene, or ethylene, wherein said methylene or ethylene is optionally substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH2.

[0082] According to a second aspect, the present invention provides a compound of formula (II) or a tautomer, stereoisomer, or a pharma- ceutically acceptable salt thereof: [Chemical formula] (In the formula, ring A is a 5- to 12-membered heteroaryl ring or a 5- to 12-membered heterocyclyl, and R 1 , R 2 , R 3 , R 4 , R 5 , L, and X are as defined in the compound represented by formula (I) according to the present invention.)

[0083] In a further preferred embodiment, L is a bond. In a further preferred embodiment, the substitution position of R 5 is the N atom on the ring.

[0084] In a further preferred embodiment, ring A is [Chemical formula] selected from In a further preferred embodiment, ring A is [Chemical formula] selected from

[0085] In a further preferred embodiment, ring A is [Chemical formula] selected from In a further preferred embodiment, ring A is [Chemical formula] selected from.

[0086] According to a third aspect, the present invention provides a compound represented by formula (III) having the following structure, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. [Chemical formula]

[0087] (wherein X 1 is selected from C, N, O or S, n 1 is selected from 0, 1, 2, 3, R 1 , R 2 , R 3 , R 4 , R 5 , L and X are synonymous with the compound represented by formula (I) according to the present invention.)

[0088] In a further preferred embodiment, n 1 is selected from 0, 1 or 2, In a further preferred embodiment, L is selected from a bond, In a further preferred embodiment, X 1 is selected from C, N or O,

[0089] In a further preferred embodiment,

Chemical formula

Chemical formula

Chemical formula

[0090] According to a fourth aspect, the present invention provides a compound represented by formula (III-a), (III-b), (III-c), (III-d) or (III-e) having the following structure, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

Chemical formula

[0091] In a further preferred embodiment, L is selected from a bond In a further preferred embodiment, R in formula (III-c) 5 is substituted at the N atom on the ring.

[0092] In a further preferred embodiment, ring A is

Chemical formula

[0093] In a further preferred embodiment, R 4 is hydrogen, and R 5 is hydrogen, methyl, phenyl

Chemical formula

[0094] In a further preferred embodiment, R a is independently selected from Cl, methyl, methoxy at each occurrence In a further preferred embodiment, R 1 is [Chemistry] selected from.

[0095] According to a fifth aspect, the present invention provides an atropisomer of a compound represented by formula (III-a), (III-b), (III-c), (III-d) or (III-e), or a pharmaceutically acceptable salt of the atropisomer, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , L and X are as defined for the compounds represented by formula (III-a), (III-b), (III-c), (III-d) or (III-e) above, where L is a bond, and R 1 is substituted by at least one R a .

[0096] An atropisomer is a stereoisomer resulting from restricted rotation about a single bond axis, where the rotational barrier is sufficiently high and separation of the individual rotational isomers is possible (LaPlante et al., J. Med. Chem., 54:7005 (2011)). In the compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e), R 1 is substituted by one or more R a , and there is a chiral axis in the bond between the quinazolinone ring and the group R 1 . Such compounds may form rotational isomers due to the asymmetry of the substitution on the ring linked to the bond and the restricted rotation of this bond caused by steric hindrance. Thus, these compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e) can form two rotational isomers, and the rotational isomers can be separated into individual atropisomers in certain cases such as chromatography on a chiral stationary phase.

[0097] In a further preferred embodiment, the compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e) can be provided as a mixture of two atropisomers or as a single atropisomer. At ambient temperature and physiological temperature, they are isolable and stable in solution. The absolute spatial structure of the atropisomers can be determined by single crystal X-ray crystallographic analysis.

[0098] In a further preferred embodiment, the compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e) can be provided as a single atropisomer or as a mixture containing two atropisomers of formula (III-a), (III-b), (III-c), (III-d) or (III-e) in any ratio.

[0099] In a further preferred embodiment, in the compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e) or salts thereof, only atropisomers are provided, or only atropisomers mixed with a small amount of other atropisomers are provided. In the case where no absolute configuration is assigned, the provided atropisomers can be defined by their elution order relative to other atropisomers during chromatography on a chiral stationary phase under specific conditions.

[0100] In a further preferred embodiment, for the atropisomers of the compounds of formula (III-a), (III-b), (III-c), (III-d) or (III-e), each atropisomer compound of formula (III-a), (III-b), (III-c), (III-d) or (III-e) substantially free of its complementary atropisomer can be provided. As used herein, "substantially free of" means providing a compound of formula (I) having an atropisomer purity of at least 95%, preferably at least 99%, more preferably at least 99.5%.

[0101] Based on common knowledge in the art, preferred examples of the present invention can be obtained by arbitrarily combining the above-preferred conditions.

[0102] Preferably, for the compound according to the present invention or its tautomer, stereoisomer, atropisomer, or pharmaceutically acceptable salt thereof, the compound has the following structure.

[0103] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0104] According to a sixth aspect, the present invention aims to provide a method for producing a compound represented by the above general formula or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof. The method can be produced, for example, by the method shown in the following scheme.

[0105] Method 1:

Chem.

[0106] Remove the methyl of methoxy from the above 1.9 to obtain intermediate 1.10, and finally, cause a ring-closing reaction to obtain the target compound 1.11. Alternatively, remove the methyl protecting group from intermediate 1.9 and cause an in situ ring-closing reaction to obtain the target compound 1.11.

[0107] In a more preferred embodiment, compound 1.9 can be produced by the following steps.

Chem.

[0108] Using fluorinated aryl carboxylic acid (1.1) as a starting material, form an ester with methanol to obtain intermediate 1.2. Next, perform a bromination reaction at the benzylic position of the aromatic ring to obtain intermediate 1.3. After that, replace the bromine atom with methoxy to obtain compound 1.4. Perform an ester decomposition reaction under alkaline conditions to obtain intermediate 1.5 containing carboxy. Then, convert the carboxy to an amide to obtain intermediate 1.6. Next, by the action of oxalyl chloride, react with R 1 -L-NH2 to obtain intermediate 1.7. Next, perform a ring-closing reaction under alkaline conditions to obtain intermediate 1.8. React 1.8 with phosphorus oxychloride, and then react with R 5 NH2 to obtain intermediate 1.9. Here, R 1 , R 2 , R 3 , R 4 , R 5 , L and X are synonymous with the compound represented by formula (III-a).

[0109] Method 2:

Chem.

[0110] In a more preferred embodiment, compound 2.8 can be produced by the following steps.

Chemical formula

[0111] Using fluorinated and brominated arylcarboxylic acid (2.1) as a starting material, the carboxylic acid is converted to amide intermediate 2.2, and then, by the action of oxalyl chloride, it reacts with R 1 -L-NH2 to obtain intermediate 2.3. Next, a cyclization reaction is carried out under alkaline conditions to obtain intermediate 2.4. After performing a Heck reaction between this intermediate 2.4 and isobutyl acrylate to obtain compound 2.5, the double bond is reduced with sodium borohydride to obtain intermediate 2.6. Then, it reacts with phosphorus oxychloride, and thereafter, R5NH2 is added to obtain intermediate 2.7. Next, it is reduced with lithium aluminum hydride to obtain intermediate 2.8 containing a hydroxy group. Here, R 1 、R 2 、R 3 、R 5 、L and X are synonymous with the compound represented by formula (III-b).

[0112] Method 3:

Chemical formula

[0113] In a more preferred embodiment, compound 3.5 can be produced by the following steps.

Chemical formula

[0114] Using 2,6-difluorobenzoic acid (3.1) as a starting material, the carboxylic acid is converted to an amide intermediate 3.2, and then, by the action of oxalyl chloride, it reacts with R 1 -L-NH2 to obtain an intermediate 3.3. Next, a ring-closing reaction is carried out under alkaline conditions to obtain an intermediate 3.4. The intermediate 3.4 is reacted with phosphorus oxychloride, and then an amine compound substituted with a hydroxy group at the end is added to obtain an intermediate 3.5. Here, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、and L are synonymous with the compound represented by formula (III-c).

[0115] Method 4:

Chemical formula

[0116] In a more preferred embodiment, compound 4.2 can be produced by the following steps.

Chemical formula

[0117] Using intermediate 3.4 as a starting material, a substitution reaction occurs with an acetal substituted with an amino group at the end to obtain intermediate 4.1. After that, it reacts with phosphorus oxychloride, and then an amine compound is added to obtain intermediate 4.2. Here, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、and L are synonymous with the compound represented by formula (III-d).

[0118] Method 5:

Chemical formula

[0119] In a more preferred embodiment, compound 5.12 can be produced by the following steps.

Chemical Structure

[0120] Using the above 5.1 as a starting material, react with phosphorus oxychloride to obtain intermediate 5.2, then react with potassium vinyltrifluoroborate to obtain intermediate 5.3. Next, perform a hydrolysis reaction under alkaline conditions to obtain compound 5.4 containing a carboxy fragment. After that, convert the carboxy group to an amide, and then react with p-toluenesulfonyl chloride to obtain intermediate 5.6. Then, under the action of oxalyl chloride, react with R 1 NH2 to obtain intermediate 5.7. Next, perform an intramolecular cyclization reaction of intermediate 5.7 under alkaline conditions to obtain intermediate 5.8. After that, oxidize the vinyl group of intermediate 5.8 to a formic acid fragment, and then convert the carboxy group of 5.9 to a methyl ester. Then, under the action of phosphorus oxychloride, react with R 5 NH2 to obtain intermediate 5.11. Next, reduce the methyl ester fragment to obtain intermediate 5.12. Here, R 1 、R 2 、R 3 、R 5 、L and X are synonymous with the compound represented by formula (III-a).

[0121] Method 6:

Chemical Structure

[0122] In a more preferred embodiment, compound 6.4 can be produced by the following steps.

Chemical formula

[0123] Method 7:

Chemical formula

[0124] The object of the present invention further includes the production of intermediates of compounds represented by the following general formula.

Chemical formula

[0125] According to another aspect of the present invention, there is further provided a pharmaceutical composition comprising the compound according to the present invention or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Furthermore, the pharmaceutical composition described in the present invention comprises the compound according to the present invention or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable auxiliary material.

[0126] The compound of the present invention or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof may be administered by any acceptable means of administration that provides a drug having similar uses in pure form or in the form of a suitable pharmaceutical composition. The pharmaceutical composition according to the present invention can be produced by combining the compound according to the present invention with a suitable pharmaceutically acceptable auxiliary material.

[0127] According to another aspect of the present invention, there is further provided the use of the compound according to the present invention or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present invention, in the manufacture of a drug for preventing and / or treating diseases, disorders, and conditions mediated by MAT2A. Furthermore, in the use according to the present invention, the diseases, disorders, and conditions are MTAP-deficient tumors.

[0128] According to another aspect of the present invention, there is further provided the use of the compound according to the present invention or a tautomer, stereoisomer thereof, or the pharmaceutical composition according to the present invention, in the manufacture of a drug for preventing and / or treating tumors. Furthermore, in the use according to the present invention, the tumors include solid tumors and hematological tumors, preferably, the solid tumors include gastrointestinal tumors, and more preferably, colorectal cancer. In some contexts in this field, the cancer may be referred to as a malignant tumor.

[0129] According to a further aspect, the present invention provides a method for preventing and / or treating a disease, disorder, and condition mediated by MAT2A, the method comprising administering to an individual in need thereof a compound according to the present invention or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention, preferably, the disease, disorder, and condition is a tumor, preferably, the disease, disorder, and condition is an MTAP-deficient tumor, more preferably, the tumor includes solid tumors and hematological tumors.

[0130] According to a further aspect, the present invention provides a compound according to the present invention or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention for preventing and / or treating a disease, disorder, and condition mediated by MAT2A, preferably, the disease, disorder, and condition is an MTAP-deficient tumor, preferably, the disease, disorder, and condition is a tumor, more preferably, the tumor includes solid tumors and hematological tumors. Further, in the use or method according to the present invention, the compound according to the present invention or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present invention is used in combination with one, two, or more other drugs having antitumor activity.

[0131] The present invention also provides a pharmaceutical composition comprising a compound according to the present invention or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof and one, two, or more other drugs having antitumor activity.

[0132] 〔Definitions〕 The terms "optionally", "optional", "optionally", or "optionally" mean that the event or situation described thereafter may occur, but does not necessarily have to occur, and this description includes both the case where the described event or situation occurs and the case where the described event or situation does not occur.

[0133] Unless otherwise specified, the term "optionally substituted" or "substituted at will" means that the substituents are independently hydroxy, halogen, hydroxy, amino, nitro, mercapto, cyano, azido, carboxy, -C(O)C 1~6 alkyl, -C(O)O-C 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, -NHC(O)-C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, C 3~10 cycloalkylsulfonyl, 3- to 10-membered heterocycloalkyl, C 6~14 aryl, 5- to 12-membered heteroaryl, meaning that one or more are selected therefrom. Here, the C 2~6 alkenyl, C 2~6 alkynyl, C 1~6 alkyl, C 1~6 alkoxy, C 3~10 cycloalkyl, C 3~10 cycloalkylsulfonyl, 3- to 10-membered heterocycloalkyl, C 6~14 aryl, or 5- to 12-membered heteroaromatic group may be optionally substituted by one or more of halogen, hydroxy, amino, cyano, C 1~6 alkyl, or C 1~6 alkoxy.

[0134] The term "oxo" means that two hydrogen atoms at the same substitution position are replaced by the same oxygen atom to form a double bond.

[0135] Unless otherwise specified, the term "carbocyclic group" refers to a saturated or partially unsaturated cyclic carbon-containing group such as a 4- to 6-membered (e.g., 5- to 6-membered) saturated carbocyclic ring and a 5- to 6-membered partially unsaturated carbocyclic ring. In one embodiment, the carbocyclic group is a 3- to 4-membered monocyclic, 3- to 5-membered monocyclic, 3- to 6-membered monocyclic, 3- to 8-membered monocyclic, 3- to 10-membered monocyclic, 5- to 8-membered monocyclic, 5- to 6-membered monocyclic, 4- to 12-membered bicyclic, or 10- to 15-membered tricyclic group. The carbocyclic ring includes a bridged ring or a spiro ring. Non-limiting examples of the carbocyclic group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]nonyl, tricyclo[5.3.1.1]dodecyl, adamantyl, or spiro[3.3]heptyl. The carbocyclic group may be optionally substituted. When substituted, the number of substituents is preferably 1 to 5, and the substituents are independently selected from F, Cl, Br, I, =O, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.

[0136] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group and includes a straight-chain or branched group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms (i.e., C 1~10 alkyl), more preferably 1 to 8 carbon atoms (C 1~8 alkyl), and even more preferably 1 to 6 carbon atoms (i.e., C 1~6 alkyl). For example, "C 1~6 alkyl" means that the group is alkyl and the number of carbon atoms in the carbon chain is 1 to 6 (specifically, 1, 2, 3, 4, 5, or 6). Examples include 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, and the like.

[0137] Unless otherwise specified, the term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. Alkenyl has 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2~10 alkenyl), more preferably 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), still more preferably 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), 2 to 5 carbon atoms (i.e., C 2~5 alkenyl), 2 to 4 carbon atoms (i.e., C 2~4 alkenyl), 2 to 3 carbon atoms (i.e., C 2~3 alkenyl), and may contain 2 carbon atoms (i.e., C2 alkenyl). For example, "C 2~6 alkenyl" means that the group is alkenyl and the number of carbon atoms on the carbon chain is 2 to 6 (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0138] Unless otherwise specified, the term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. Alkynyl has 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2~10 alkynyl), more preferably 2 to 8 carbon atoms (C 2~8 alkynyl), still more preferably 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), 2 to 5 carbon atoms (i.e., C 2~5 alkynyl), 2 to 4 carbon atoms (i.e., C 2~4 alkynyl), 2 to 3 carbon atoms (i.e., C 2~3 alkynyl), and contains 2 carbon atoms (i.e., C2 alkynyl). For example, "C 2~6"Alkynyl" means that the group is alkynyl and the number of carbon atoms on the carbon chain is 2 to 6 (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.

[0139] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably 3 to 12 carbon atoms (i.e., C 3~12 cycloalkyl), more preferably 3 to 10 carbon atoms (i.e., C 3~12 cycloalkyl), still more preferably 3 to 7 carbon atoms (C 3~7 cycloalkyl), 4 to 6 carbon atoms (C 4~6 cycloalkyl), 5 to 6 carbon atoms (C 5~6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0140] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, and the alkyl is as defined above, i.e., it contains 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically, 1, 2, 3, 4, 5, or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0141] Unless otherwise specified, the term "alkylthio" refers to -S-alkyl, where the alkyl is as defined above, i.e., containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative 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.

[0142] Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, I. The term "haloalkyl" means an alkyl as defined above in which one, two or more hydrogen atoms, or all hydrogen atoms, are substituted by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0143] Unless otherwise specified, the term "heterocyclyl" or "heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic non-aromatic substituent having ring carbon atoms and 1 to 4 ring heteroatoms, and containing 3 to 20 ring atoms, where 1, 2, or 3 or more of the ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3 to 12 ring atoms (3- to 12-membered heterocyclyl), more preferably 3 to 10 ring atoms (3- to 10-membered heterocyclyl), 3 to 8 ring atoms (3- to 8-membered group), 3 to 6 ring atoms (3- to 6-membered heterocyclyl), 4 to 6 ring atoms (4- to 6-membered heterocyclyl), 5 to 6 ring atoms (5- to 6-membered heterocyclyl). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyl includes spirocyclic, fused-ring, and bridged-ring heterocyclyl. "Heterocyclyl" is monocyclic ("monocyclic heterocyclyl") or fused ("fused heterocyclyl" or "hetero-fused cyl") or bridged ("hetero-bridged cyl" or "bridged heterocyclyl") or spiro-fused ("hetero-spiryl" or "spiro heterocyclyl") cyclic, e.g., bicyclic ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The bicyclic heterocyclyl may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes cyclic forms in which the heterocyclyl ring defined above is condensed with one or more carbocyclic groups and the point of attachment is on the carbocyclic ring or the heterocyclyl ring, or "heterocyclyl" includes cyclic forms in which the heterocyclyl ring defined above is condensed with one or more aryl groups or heteroaryl groups, or cyclic forms in which the cycloalkyl ring defined above is condensed with one or more heteroaryl groups, and the point of attachment is on the heterocyclyl ring or the cycloalkyl ring. In such cases, the number of members of the heterocyclyl cyclic form is the number of atoms in the cyclic form after condensation.In certain embodiments, each instance of a heterocyclyl may independently be optionally substituted, e.g., unsubstituted (a “non-substituted heterocyclyl”), or substituted with one or more substituents (a “substituted heterocyclyl”). Examples of 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiaranyl. Examples of 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Examples of 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrol-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and oxazolidin-2-one. Examples of 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Examples of 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxothiazinyl, and dioxazinanyl. Examples of 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azacyclooctanyl, oxacyclooctanyl, and thiacyclooctanyl.Examples of the 5-membered heterocyclyl group fused to the C6 aryl ring (also referred to as a 5,6-bicyclic heterocycle in this specification) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Examples of the 6-membered heterocyclyl group fused to the aryl ring (also referred to as a 6,6-bicyclic heterocycle in this specification) include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinoline.

[0144] Unless otherwise indicated, "heterocycloalkyl" refers to a monocyclic saturated "heterocyclyl" or "heterocycle" as defined above, with ring atoms as defined above, i.e., containing 3 to 20 ring atoms ("3- to 20-membered heterocycloalkyl"), the number of heteroatoms being 1 to 4 (1, 2, 3, or 4), preferably 1 to 3 (1, 2, or 3), and the heteroatoms each being independently selected from N, O, or S. Preferably, it contains 3 to 12 ring atoms ("3- to 12-membered heterocycloalkyl"), more preferably 3 to 10 ring atoms ("3- to 10-membered heterocycloalkyl"), even more preferably 3 to 8 ring atoms ("3- to 8-membered heterocycloalkyl"), even more preferably 4 to 7 ring atoms ("4- to 7-membered heterocycloalkyl"), even more preferably 5 to 10 ring atoms ("5- to 10-membered heterocycloalkyl"), and even more preferably 5 to 6 ring atoms ("5- to 6-membered heterocycloalkyl"). In certain embodiments, each example of heterocycloalkyl may independently be optionally substituted, e.g., unsubstituted ("unsubstituted heterocycloalkyl") or substituted with one or more substituents ("substituted heterocycloalkyl"). The above "heterocyclyl" or "heterocycle" moieties illustrate several exemplary "heterocycloalkyls", including, but not limited to, aziridinyl, oxiranyl, thiaranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathianyl, oxazolidinyl, dioxanyl, dithiocyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.

[0145] Unless otherwise specified, the term "aryl" or "aromatic ring group" means a monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms. The term "aryl" can be used interchangeably with the term "aromatic ring group". Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, or pyrenyl.

[0146] Unless otherwise specified, the term "heteroaryl" or "heteroaromatic ring group" means an aromatic monocyclic or polycyclic ring system having a structure of 5 to 14 members, or preferably 5 to 10 members, or preferably 5 to 8 members, more preferably 5 to 6 members, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, and the heteroatoms are independently selected from O, N or S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, 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.

[0147] Unless otherwise indicated, "pharmaceutically acceptable salts" or "medicinal salts" mean salts that, within the scope of reasonable medical judgment, are not associated with excessive toxicity, irritation, allergic reaction, etc. upon contact with mammalian, especially human, tissues and are commensurate with a reasonable benefit / risk ratio. For example, pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared alone during the final separation and purification of the compounds of the present invention or by reacting the free base or free acid with a suitable reagent.

[0148] The compounds of the present invention also include their "isotope derivatives". Unless otherwise indicated, "isotope derivatives" mean that the compounds of the present invention may exist in the form of isotope tracers or enriched forms and contain one or more atoms having an atomic weight or mass number different from the maximum number of atomic weights or mass numbers found in nature. Isotopes can be either radioactive isotopes or non-radioactive isotopes. Isotopes commonly used as isotope labels 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 15 N; oxygen isotopes: 15 O, 17 O, and 18 O, and sulfur isotope 35 S. These isotope-labeled compounds can be used to study the distribution of medicinal molecules in tissues. In particular 3 H and 13 C are more widely used because they are easy to label and detect. Deuterium ( 2Substitution with certain heavy isotopes, such as (H), improves metabolic stability and prolongs the half-life, resulting in a reduced dosage and a therapeutic advantage. Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques similar to non-isotopically labeled compounds. The compounds of the present invention also include their "solvates". Unless otherwise specified, the term "solvate" means the physical association of a compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In certain cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate can be present in a regular arrangement and / or a disordered arrangement. The solvate may contain a stoichiometric or non-stoichiometric amount of solvent molecules. "Solvate" includes both solvates isolable in the solution phase. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0149] Unless otherwise indicated, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and the like. 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 methods.

[0150] The term "atropisomer" refers to a conformational isomer that occurs when rotation around a single bond within a molecule is hindered or significantly slowed down due to steric interactions with other parts of the molecule. All atropisomers of the compounds of the present invention are included as a single atropisomer or as an unspecified mixture thereof. When the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, it becomes possible to separate the isomeric species as distinct compounds. For example, R1 groups such as the following [Chemical formula] are mentioned, but groups not limited to these may exhibit restricted rotation.

[0151] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert via a low energy barrier. When tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton transfer such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by partial reorganization of bonding electrons.

[0152] Unless otherwise specified, the structural formulas described in this specification include all isomeric forms (e.g., enantiomers, diastereomers, geometric isomers (or conformational isomers)). For example, R and S configurations containing chiral centers, (Z) and (E) isomers with double bonds, and (Z) and (E) conformational isomers, etc. Therefore, individual stereochemical isomers of the compounds of the present invention, or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

[0153] The compounds of the present invention also include their "prodrugs", which, unless otherwise indicated, refer to drugs that are converted into the parent drug in the body. Prodrugs are often useful in improving certain undesirable physical or biological properties. Physical properties are usually related to solubility (either too high or too low solubility in lipids or water) or stability, while the biological properties in question include too rapid metabolism or insufficient bioavailability, which may themselves be related to physicochemical properties. For example, they are biologically available by oral administration, while the parent is not. Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug is, but not limited to, any compound of the present invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility but beneficial once inside the cell. It is then metabolized and hydrolyzed to become the active carboxylic acid. Another example of a prodrug is a short peptide (polyamino acid) attached to an acid group, which is metabolized to reveal the active moiety.

[0154] The abbreviations used in the production examples, examples and other parts of this specification are as follows. DMF N,N-dimethylformamide DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIEA N,N-diisopropylethylamine SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl PyBop 1H-benzotriazol-1-yloxytrispyrrolidinylhexafluorophosphate

[0155] The beneficial effects of the present invention are as follows. The present invention designs compounds with novel structures and provides new directions for the treatment of tumors and other diseases. Enzyme tests have shown that the compounds of the present invention have a strong inhibitory effect on MAT2A. HCT116 MTAP knockout cells show high cell proliferation activity, while MTAP wild-type HCT116 cells show weaker cell proliferation activity, and this compound shows better selectivity. It exhibits excellent medicinal efficacy in vivo. Furthermore, human UGT1A1 enzyme activity tests have shown that the compounds of the present invention have a low risk of inhibiting UGT1A1. Pharmacokinetic experiments have shown that the compounds of the present invention have high oral bioavailability and a good dose-exposure correlation. hERG experiments have shown that the compounds of the present invention have little cardiotoxicity. Furthermore, the present invention studies a specific synthesis method that is simple in process, convenient to operate, and useful for large-scale industrial production and use.

Embodiments for Carrying Out the Invention

[0156] The present invention will be further described below based on specific examples. It should be understood that these examples are for explaining the present invention and do not limit the scope of the present invention. Experimental methods where specific conditions are not specified in the following examples usually follow conventional conditions or those proposed by the manufacturer. Unless otherwise defined, all technical terms and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art. Also, any methods and materials similar or equivalent to those described can be applied to the methods of the present invention. The preferred methods and materials shown in this specification are for illustrative purposes only. The following are production examples of exemplary compounds of the present invention.

Example

[0157] Example 1 7-Chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A1)

Chemical formula

[0158] Step 1: Synthesis of Methyl 4-chloro-2-fluoro-6-methylbenzoate To a 250 mL round-bottom flask, 4-chloro-2-fluoro-6-methylbenzoic acid (8.44 g, 44.70 mmol) and dichloromethane (100 mL) were added, then oxalyl chloride (8.51 g, 67.10 mmol) and DMF (0.2 mL) were added, and the mixture was stirred at room temperature for reaction. As a result of monitoring by TLC, when the reaction was completed, the solvent was removed under reduced pressure. Methanol (200 mL) and 5M sodium methoxide (13.41 mL, 67.05 mmol) were added and reacted for 0.5 h. After the reaction was completed, 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 the organic phase was washed successively with water and saturated sodium chloride solution, and then concentrated to obtain methyl 4-chloro-2-fluoro-6-methylbenzoate (8.43 g, yield 93%) as the target product.

[0159] Step 2: Synthesis of Methyl 2-(bromomethyl)-4-chloro-6-fluorobenzoate 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) from the product of the previous step were added to a 250 mL round-bottom flask, heated to 85 °C, and after 8 h, the reaction was terminated and the concentrated product was directly used in the next step.

[0160] Step 3: Synthesis of Methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate Methyl 2-(bromomethyl)-4-chloro-6-fluorobenzoate from the concentrated product of the previous step, 5M sodium methoxide (12.51 mL, 62.55 mmol), and methanol (50 mL) were added to a 250 mL round-bottom flask, stirred at room temperature, and after 1 h, the reaction was terminated. 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 combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate (5.1 g, two-step yield 53%).

[0161] Step 4: Synthesis of 4-chloro-2-fluoro-6-(methoxymethyl)benzoic acid Methyl 4-chloro-2-fluoro-6-(methoxymethyl)benzoate (4.60 g, 19.70 mmol) from the product of the previous step, 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 completion of the reaction, 100 mL of water was added, and the pH was adjusted to 4 - 5 with concentrated hydrochloric acid. The mixture was extracted twice with 80 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and 4-chloro-2-fluoro-6-(methoxymethyl)benzoic acid (4.24 g, yield 98.1%) was obtained as the target product. ESI-MS (m / z): 217.0 [M-H] - 。

[0162] Step 5: Synthesis of 4-chloro-2-fluoro-6-(methoxymethyl)benzamide The product of 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), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (11.06 g, 29.09 mmol), and DMF (35 mL) were added to a 100 mL round-bottom flask, and then N,N-diisopropylethylamine (5.0 g, 38.78 mmol) was added, and the reaction was carried out overnight at room temperature. After completion of the reaction, 200 mL of water was added, and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated under reduced pressure, and then purified by column chromatography to obtain 4-chloro-2-fluoro-6-(methoxymethyl)benzamide (2.50 g, yield 59%) of the target compound. ESI-MS (m / z): 218.0 [M+H] + .

[0163] Step 6: Synthesis of 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione The product of 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 for reaction. After the reaction was completed, the reaction solution was cooled to room temperature. Then, 2-methylpyridin-3-amine (149 mg, 1.37 mmol) was added to the reaction solution and reacted at room temperature for 3 hours. After the reaction was completed, 1 M potassium bis(trimethylsilyl)amide (5.48 mL, 5.48 mmol) was added to the reaction solution and stirred at room temperature for 4 hours for reaction. After the reaction was completed, 100 mL of water was added, and the pH was adjusted to 6 - 7 with acetic acid. The mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and then purified by column chromatography to obtain 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (310 mg, yield 68%) as the target product. ESI-MS (m / z): 332.1 [M+H] + 。

[0164] Step 7: Synthesis of 4-amino-7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one The product of the previous step, 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazoline-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, heated to 100 °C, and stirred for reaction. After the reaction was completed, the reaction solution was cooled to room temperature. Then, aqueous ammonia solution (5 mL) was added to the reaction solution and reacted at room temperature for 0.5 h. After the reaction was completed, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and then subjected to column chromatography to obtain 4-amino-7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (170 mg, yield 60%) as the target product. ESI-MS (m / z): 331.1 [M+H] + 。

[0165] Step 8: Synthesis of 4-amino-7-chloro-5-(hydroxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 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) from the product of the previous step were added to a 25 mL round-bottom flask and reacted overnight at room temperature. After the reaction was completed, 100 mL of water was added to the reaction solution, the pH was adjusted to about 7 with sodium hydroxide, and the mixture was extracted three times with 100 mL of dichloromethane. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and directly purified by column chromatography to obtain 4-amino-7-chloro-5-(hydroxymethyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, yield 70%) as the target product. ESI-MS (m / z): 317.1 [M+H] + 。

[0166] Step 9: Synthesis of 7-chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one 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) from the product of the previous step were added to a 25 mL round-bottom flask, and methanesulfonyl chloride (43 mg, 0.38 mmol) was added, followed by reaction overnight at room temperature. After completion of the reaction, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and directly purified by column chromatography to obtain 7-chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (40 mg, yield 42%) as the target product. ESI-MS (m / z): 299.1 [M+H] + ; 1 H NMR (600 MHz, DMSO) δ 9.39 (s, 1H), 8.57 (d, J = 3.9 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.30 (s, 1H), 6.17 (s, 1H), 4.85 (s, 2H), 2.21 (s, 3H). By the resolution method of A16, two individual atropisomers A1-P1 and A1-P2 were obtained. A1-P1, ESI-MS (m / z): 299.1 [M+H] + ; 11H NMR (600 MHz, DMSO) δ 9.39 (s, 1H), 8.57 (d, J = 3.9 Hz, 1H), 7.73 (d, J = 7.6 Hz, 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 1H NMR (600 MHz, DMSO) δ 9.39 (s, 1H), 8.57 (d, J = 3.9 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.47 - 7.40 (m, 1H), 7.30 (s, 1H), 6.17 (s, 1H), 4.85 (s, 2H), 2.21 (s, 3H).

[0167] Example 2 7-Chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A2)

Chemical formula

[0168] Step 1: Synthesis of 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 7-chloro-5-(methoxymethyl)-1-(2-methylpyridin-3-yl)quinazoline-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, heated to 100 °C, stirred, and reacted. After completion of the reaction, the reaction solution was cooled to room temperature. Then, an aqueous methylamine solution (5 mL) was added to the reaction solution, and the mixture was reacted at room temperature for 0.5 h. After completion of the reaction, 100 mL of water was added to the reaction solution, and the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazoline-2(1H)-one (104 mg, yield 100%) was obtained as the target product. ESI-MS (m / z): 345.1 [M+H] + 。

[0169] Step 2: Synthesis of 7-chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one 7-chloro-5-(methoxymethyl)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazoline-2(1H)-one (104 mg, 0.30 mmol), boron tribromide (500 μL), and dichloromethane (5 mL), the product from the previous step, were added to a 25 mL round-bottom flask and reacted overnight at room temperature. After completion of the reaction, 100 mL of water was added to the reaction solution, the pH was adjusted to about 7 with sodium hydroxide, the mixture was extracted twice with 100 mL of ethyl acetate. The combined organic phases were washed successively with water and saturated sodium chloride solution, concentrated, and then purified by column chromatography to obtain 7-chloro-4-methyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (35 mg, yield 37%) as the target product. ESI-MS (m / z): 313.1 [M+H] + 。 11H NMR (600 MHz, DMSO) δ 8.61 - 8.54 (m, 1H), 7.73 - 7.70 (m, 1H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.31 (s, 1H), 6.18 (s, 1H), 4.92 (s, 2H), 3.23 (s, 3H), 2.21 (s, 3H). By the resolution method of A16, two individual atropisomers A2-P1 and A2-P2 were obtained. A2-P1, ESI-MS (m / z): 313.1 [M+H] + 。 1 1H NMR (600 MHz, DMSO) δ 8.61 - 8.54 (m, 1H), 7.73 - 7.70 (m, 1H), 7.43 (dd, J = 7.8, 4.8 Hz, 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 1H NMR (600 MHz, DMSO) δ 8.61 - 8.54 (m, 1H), 7.73 - 7.70 (m, 1H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.31 (s, 1H), 6.18 (s, 1H), 4.92 (s, 2H), 3.23 (s, 3H), 2.21 (s, 3H).

[0170] Example 3 7-Chloro-4-phenyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A3)

Chemical Structure

[0171] According to the synthesis method of compound A2, using aniline etc. as synthetic raw materials, 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. ESI-MS (m / z): 375.1 [M+H] + 。 1 H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.80 (dd, J = 7.8, 1.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 7.41 (s, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.29 (s, 1H), 5.51 (s, 2H), 2.25 (s, 3H).

[0172] By the resolution method of A16, two individual atropisomers A3-P1 and A3-P2 were obtained. A3-P1, ESI-MS (m / z): 375.1 [M+H] + 。 1 H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.80 (dd, J = 7.8, 1.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 7.41 (s, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.29 (s, 1H), 5.51 (s, 2H), 2.25 (s, 3H). A3-P2, ESI-MS (m / z): 375.1 [M+H] + 。 11H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.80 (dd, J = 7.8, 1.2 Hz, 1H), 7.51 (t, J = 8.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 7.41 (s, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.29 (s, 1H), 5.51 (s, 2H), 2.25 (s, 3H).

[0173] Example 4 7-Chloro-4-benzoyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A4) [Chemical formula]

[0174] Compound A1 (27 mg, 0.09 mmol) and dichloromethane (5 mL) were added to a 25 mL round-bottom flask, and triethylamine (27 mg, 0.27 mmol) and benzoyl chloride (19 mg, 0.14 mmol) were added, followed by reaction at room temperature for 2 hours. After completion of the reaction, it was directly purified by column chromatography to obtain 7-chloro-4-benzoyl-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (25 mg, yield 64%) as the target product. ESI-MS (m / z): 403.1 [M+H] + . 11H NMR (600 MHz, DMSO) δ 8.60 (d, J = 3.7 Hz, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.75 (d, J = 7.3 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 7.46 - 7.45 (m, J = 7.9, 5.0 Hz, 2H), 6.36 (s, 1H), 5.43 (d, J = 5.0 Hz, 2H), 2.19 (s, 3H).

[0175] Example 5 7-Chloro-4-methyl-1-(2-chloropyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A16) [Chemical Structure Diagram]

[0176] According to the synthesis method of Compound A2, using methylamine etc. as synthetic raw materials, 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. ESI-MS (m / z): 333.0 [M + H] + ; 1 1H NMR (600 MHz, DMSO) δ 8.56 (dd, J = 4.8 Hz, 1.7 Hz, 1H), 8.04 (dd, J = 7.7 Hz, 1.7 Hz, 1H), 7.65 (dd, J = 7.7 Hz, 4.8 Hz, 1H), 7.34 (s, 1H), 6.38 (s, 1H), 4.93 (s, 2H), 3.23 (s, 3H). Compound A16 is an axial chiral compound containing two atropisomers, as shown in the following figure. [Chemical Structure Diagram]

[0177] Compound A16 was separated by supercritical fluid chromatography (SFC) (apparatus: SFC150, 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), and compound A16-P1 (the first elution isomer) and A16-P2 (the second elution isomer) were obtained in sequence. Next, this compound was analyzed by high performance liquid chromatography (apparatus: Waters e2695-2998, column: IG-3 (150 mm × 4.6 mm, 3 μm), mobile phase: n-hexane:ethanol = 30:70 of 0.1% diethylamine, flow rate: 1.0 mL / min, wavelength: 239 nm, column temperature: 30 °C). The retention time of compound A16-P1 was 4.89 min, and the retention time of compound A16-P2 was 7.73 min.

[0178] Compound A16-P1, ESI-MS (m / z): 333.0 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ 8.56 (dd, J = 4.8, 1.8 Hz, 1H), 8.05 (dd, J = 7.8, 1.8 Hz, 1H), 7.65 (dd, J = 7.7, 4.8 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 6.38 (d, J = 1.2 Hz, 1H), 4.93 (s, 2H), 3.23 (s, 3H). Compound A16-P2, ESI-MS (m / z): 333.0 [M+H] + ; 1 H NMR (600 MHz, DMSO-d6) δ 8.56 (dd, J = 4.8, 1.8 Hz, 1H), 8.05 (dd, J = 7.7, 1.8 Hz, 1H), 7.65 (dd, J = 7.7, 4.8 Hz, 1H), 7.34 (d, J = 1.2 Hz, 1H), 6.38 (d, J = 1.2 Hz, 1H), 4.93 (s, 2H), 3.23 (s, 3H).

[0179] Example 6 9-Chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazolin-2(1H)-one (B1)

Chem.

[0180] Step 1: 2-Bromo-4-chloro-6-fluorobenzamide 2-Bromo-4-chloro-6-fluorobenzoic acid (2.5 g, 10 mmol) was added to dichloromethane (100 mL), and oxalyl chloride (3.2 g, 25 mmol) and 2 drops of DMF were added under an ice bath, followed by stirring at room temperature for 1 hour. After completion of the reaction, the system was concentrated, dioxane (100 mL) was added, and aqueous ammonia (2.8 g, 50 mmol) was added dropwise under an ice bath, and then the temperature was raised to room temperature and stirred for reaction. After completion of the reaction, the reaction solution was added to water (300 mL), extracted 3 times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. 2-Bromo-4-chloro-6-fluorobenzamide (2 g, yield 80%) was obtained. ESI-MS (m / z): 251.9 [M+H] + .

[0181] Step 2: 2-Bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide 2-Bromo-4-chloro-6-fluorobenzamide (990 mg, 3.9 mmol) was added to tetrahydrofuran (10 mL), oxalyl chloride (541 mg, 4.3 mmol) was added, and the mixture was heated to 70 °C and stirred for 1 hour. After cooling, this mixture was added dropwise to a solution of 2-methylpyridin-3-amine (426 mg, 3.9 mmol) in tetrahydrofuran (10 mL), and then stirred at room temperature for reaction. After completion of the reaction, the reaction solution was poured into water (300 mL), extracted 5 times with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. 2-Bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide (1.4 g, yield 93%) was obtained. ESI-MS (m / z): 386.0 [M+H] + 。

[0182] Step 3: 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione 2-Bromo-4-chloro-6-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide (560 mg, 1.45 mmol) was added to tetrahydrofuran (30 mL), and 1 M potassium bis(trimethylsilyl)amide (2.9 mL, 2.9 mmol) was added dropwise under an ice bath, and then stirred under an ice bath for reaction. After completion of the reaction, water (200 mL) was added to the reaction solution, and the pH was adjusted to about 5 with acetic acid. After stirring for several minutes, it was extracted 3 times with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified with ethyl acetate and dried to obtain 5-bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (400 mg, yield 75%). ESI-MS (m / z): 366.0 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.65 (dd, J = 4.8 Hz, J = 1.8 Hz, 1H), 7.85 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 7.8 Hz, J = 4.8 Hz, 1H), 6.30 (d, J = 1.8 Hz, 1H), 2.28 (s, 3H).

[0183] Step 4: tert-Butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)acrylate 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (150 mg, 0.41 mmol) was added to DMF (5 mL), and tert-butyl acrylate (263 mg, 2.05 mmol), palladium acetate (18 mg, 0.082 mmol), tri-o-tolylphosphine (50 mg, 0.164 mmol), and potassium carbonate (113 mg, 0.8 mmol) were added. Under an argon atmosphere, the system was stirred and reacted at 140 °C. After the reaction was completed, the temperature was lowered, and the reaction solution was added to water (100 mL), and extracted 3 times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin-layer chromatography (the developing agent was dichloromethane:methanol = 20:1), and tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)acrylate (120 mg, yield 71%) was obtained. ESI-MS (m / z): 414.1 [M+H] + .

[0184] Step 5: tert-Butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)propionate tert-Butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)acrylate (120 mg, 0.29 mmol) was added to tetrahydrofuran (5 mL), and methanol (1 mL) was added. Under an ice bath, sodium borohydride (55 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature to effect the reaction. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by thin-layer chromatography (the developing agent was dichloromethane:methanol = 20:1), to obtain tert-butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)propionate (100 mg, yield 83%). ESI-MS (m / z): 416.1 [M+H] + 。

[0185] Step 6: tert-Butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-5-yl)propionate tert-Butyl 3-(7-chloro-1-(2-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)propionate (100 mg, 0.24 mmol) was added to dioxane (10 mL), then phosphorus oxychloride (110 mg, 0.72 mmol) and DIEA (155 mg, 1.2 mmol) were added, and the mixture was heated to 100 °C and stirred for 1 h. After cooling, aqueous ammonia (0.2 mL) was added dropwise, and the mixture was stirred at room temperature for reaction. After completion of the reaction, water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by thin-layer chromatography (the developing agent was dichloromethane:methanol = 15:1), and tert-butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-5-yl)propionate (50 mg, yield 50%) was obtained. ESI-MS (m / z): 415.1 [M+H] + 。

[0186] Step 7: 4-Amino-7-chloro-5-(3-hydroxypropyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one tert-Butyl 3-(4-amino-7-chloro-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-5-yl)propionate (50 mg, 0.12 mmol) was added to tetrahydrofuran (5 mL), and lithium aluminum tetrahydride (13 mg, 0.36 mmol) was added under an ice bath. The mixture was stirred under an ice bath for reaction. After completion of the reaction, 1 mL of methanol was added to the reaction solution, and the mixture was concentrated. The product was separated and purified by thin-layer chromatography (the developing agent was dichloromethane:methanol = 10:1), and 4-amino-7-chloro-5-(3-hydroxypropyl)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (30 mg, yield 73%) was obtained. ESI-MS (m / z): 345.1 [M+H] + 。

[0187] Step 8: 9-Chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazolin-2(1H)-one 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), and methanesulfonyl chloride (9 mg, 0.087 mmol), triethylamine (18 mg, 0.18 mmol) and triphenylphosphine (33 mg, 0.132 mmol) were added. After stirring at room temperature for 1 hour, methanesulfonyl chloride (45 mg) and triethylamine (36 mg) were replenished batchwise, and the reaction mixture was stirred at room temperature overnight. After completion of the reaction, a small amount of methanol was added for quenching, and the mixture was concentrated and separated and purified by thin-layer chromatography with a developing solvent of dichloromethane:ethyl acetate:methanol = 5:5:1. The product layers were collected, combined, rinsed and concentrated. 9-Chloro-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydroazepino[2,3,4-de]quinazolin-2(1H)-one (3.5 mg, yield 12%) was obtained. ESI-MS (m / z): 327.1 [M+H] + ; 1 H NMR (600 MHz, CDCl3) δ 9.77 (br, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (dd, J1 = 7.8 Hz, J2 = 4.8 Hz, 1H), 7.00 (s, 1H), 6.24 (s, 1H), 3.65 - 3.62 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.26 - 2.23 (m, 2H).

[0188] By the resolution method of A16, two individual atropisomers B1-P1 and B1-P2 were obtained. B1-P1, ESI-MS (m / z): 327.1 [M+H] + ; 11H NMR (600 MHz, CDCl3) δ 9.77 (br, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (dd, J1 = 7.8 Hz, J2 = 4.8 Hz, 1H), 7.00 (s, 1H), 6.24 (s, 1H), 3.65 - 3.62 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.26 - 2.23 (m, 2H). B2 - P1, ESI - MS(m / z): 327.1[M + H] + ; 1 1H NMR (600 MHz, CDCl3) δ 9.77 (br, 1H), 8.66 (d, J = 4.8 Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.37 (dd, J1 = 7.8 Hz, J2 = 4.8 Hz, 1H), 7.00 (s, 1H), 6.24 (s, 1H), 3.65 - 3.62 (m, 2H), 3.05 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.26 - 2.23 (m, 2H).

[0189] Example 7 9 - chloro - 1 - (2 - methylpyridin - 3 - yl) - 5,6 - dihydro - 1H - [1,4]oxazepino[5,6,7 - de]quinazolin - 2(4H) - one (B2)

Chemical Structure

[0190] Step 1: 7-Chloro-5-fluoro-4-((2-hydroxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 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, followed by phosphorus oxychloride (292 mg, 1.92 mmol) and diisopropylethylamine (420 mg, 3.27 mmol). The mixture was stirred at 100 °C for 1 hour to allow the reaction to proceed. After cooling, aminoethanol (200 mg, 3.27 mmol) was added, and the mixture was stirred at room temperature to allow the reaction to proceed. After completion of the reaction, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 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] + ;

[0191] Step 2: 9-Chloro-1-(2-methylpyridin-3-yl)-5,6-dihydro-1H-[1,4]oxazepino[5,6,7-de]quinazolin-2(4H)-one The product of 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, and sodium hydride (23 mg, 0.57 mmol) was added while stirring under an ice bath. The mixture was stirred at room temperature to react. After completion of the reaction, 100 mL of water was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The combined organic phases were washed twice with 100 mL of water, then the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by thin layer chromatography to obtain 9-chloro-1-(2-methylpyridin-3-yl)-5,6-dihydro-1H-[1,4]oxazepino[5,6,7-de]quinazolin-2(4H)-one (13 mg, yield 13%). ESI-MS (m / z): 329.1 [M+H] + 。

[0192] Example 8 9-Chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinazolin-2(1H)-one (B3)

Chemical Structure

[0193] Step 1: 7-Chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2,4(1H,3H)-dione 5-Bromo-7-chloro-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (500 mg, 1.37 mmol), aminoacetaldehyde diethyl acetal (364 mg, 2.74 mmol), tris(dibenzylideneacetone)dipalladium (128 mg, 0.14 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (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 purging with nitrogen, the mixture was stirred at 100 °C for reaction. After completion of the reaction, the temperature was lowered, 100 mL of water was added, and the mixture was extracted twice with 200 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 7-chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (500 mg, yield 87%). ESI-MS (m / z): 419.1 [M+H] + 。

[0194] Step 2: 7-Chloro-5-((2,2-diethoxyethyl)amino)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one 7-chloro-5-((2,2-diethoxyethyl)amino)-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (200 mg, 0.48 mmol), the product of the previous step, and dioxane (10 mL) were added to a 100 mL round-bottom flask, and phosphorus oxychloride (218 mg, 1.44 mmol) and diisopropylethylamine (310 mg, 2.4 mmol) were added. The mixture was stirred at 100 °C for 1 hour to react. After cooling, an aqueous methylamine solution was added, and the mixture was stirred at room temperature to react. After the reaction was completed, 100 mL of water was added, and the mixture was extracted three times with 300 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and separated and 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] + 。

[0195] Step 3: 9-chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinazolin-2(1H)-one 7-chloro-5-((2,2-diethoxyethyl)amino)-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one (100 mg, 0.23 mmol), the product of the previous step, and acetonitrile (2 mL) were added to a 100 mL round-bottom flask, and concentrated hydrochloric acid (0.1 mL) was added. The mixture was stirred and reacted under sealed conditions at 80 °C. After the reaction was completed, the mixture was concentrated, and then 100 mL of ethyl acetate was added, and the mixture was washed twice with 100 mL of an aqueous sodium bicarbonate solution. After the organic phase was concentrated, 9-chloro-5-hydroxy-4-methyl-1-(2-methylpyridin-3-yl)-4,5,6,7-tetrahydro-[1,4]diazepino[5,6,7-de]quinazolin-2(1H)-one was purified by thin-layer chromatography. ESI-MS (m / z): 358.1 [M+H] + ; 11H NMR (600 MHz, DMSO-d6) δ 8.56 (d, J = 4.2 Hz, 1H), 7.69-7.68 (m, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.419 (t, J = 6.0 Hz, 1H), 6.35 (d, J = 1.2 Hz, 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 = 30 Hz, 3H).

[0196] By the splitting method of A16, two individual atropisomers B3-P1 and B3-P2 were obtained. B3-P1, ESI-MS (m / z): 358.1[M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ 8.56 (d, J = 4.2 Hz, 1H), 7.69-7.68 (m, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.419 (t, J = 6.0 Hz, 1H), 6.35 (d, J = 1.2 Hz, 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 = 30 Hz, 3H). B3-P2, ESI-MS (m / z): 358.1[M+H] + ; 1 1H NMR (600 MHz, DMSO-d6) δ 8.56 (d, J = 4.2 Hz, 1H), 7.69-7.68 (m, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.419 (t, J = 6.0 Hz, 1H), 6.35 (d, J = 1.2 Hz, 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 = 30 Hz, 3H).

[0197] According to the corresponding synthesis method, using the corresponding intermediate as the starting material, compounds A5 - A15, A17 - A18, A20 - A28, and A30 - A37 were prepared.

Table 11

Table 12

Table 13

Table 14

Table 15

Table 16

[0198] Example 39 2 - Methyl - 5 - (2 - methylpyridin - 3 - yl) - 7 - (trifluoromethyl) - 1,2 - dihydro - 2,3,5,6 - tetraazanaphthalen - 4(5H) - one (A19)

Chemical formula

[0199] Step 1: Synthesis of ethyl 4 - chloro - 2 - hydroxy - 6 - (trifluoromethyl)nicotinate Ethyl 2,4-dihydroxy-6-(trifluoromethyl)nicotinate (synthesized according to the literature "Org. Process Res. Dev., 2011, 15, 788 - 796") (50 g, 199.1 mmol) was added to a solution of DMF (62 mL) at room temperature and stirred well until dissolved. Then, the reaction flask was placed in ice water, and POCl3 (122.10 g, 796 mmol) was slowly added dropwise thereto at 0 °C. After the addition was complete, it was placed in an oil bath at 90 °C and reacted for 1 hour. As detected by LCMS, the reaction was carried out completely. A saturated solution of K2HPO4 (2.5 L) was prepared, and the reaction solution was slowly injected into it to quench the reaction. Then, it was extracted with dichloromethane, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (SiO2, DCM:MeOH = 1:0) to obtain ethyl 4-chloro-2-hydroxy-6-(trifluoromethyl)nicotinate (35 g).

[0200] Step 2: Synthesis of Ethyl 2-Hydroxy-6-(trifluoromethyl)-4-vinylnicotinate The product of the previous step (5 g) and potassium vinyltrifluoroborate (4.28 g) were added to a 100 mL PTFE sealed reactor. Next, H2O (10 mL) and dioxane (40 mL) were added, and while stirring at room temperature, SPhos (761 mg) and K3PO4 (11.81 g) were added, and Pd(OAc)2 (416 mg) was added under a nitrogen atmosphere. It was heated to 90 °C and reacted for 48 hours. As monitored by LCMS, the reaction was carried out completely. The reaction mixture was directly concentrated under reduced pressure to remove the solvent, and then purified by silica gel column (SiO2, DCM:MeOH = 1:0 - 10:1) to obtain ethyl 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinate (2.57 g).

[0201] Step 3: Synthesis of 2-Hydroxy-6-(trifluoromethyl)-4-vinylnicotinic Acid The product (18 g, 1 eq) from the previous step was added to a mixed solvent of MeOH (110 mL), THF (110 mL) and H2O (55 mL) at room temperature, and then NaOH (6.43 g, 3 eq) was added thereto. The reaction solution was heated to 60 °C and reacted for 16 hours. As a result of monitoring by LCMS, the reaction was completed. The reaction mixture was concentrated under reduced pressure to remove the solvent, and purified to obtain 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinic acid (7 g).

[0202] Step 4: Synthesis of 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinamide The product (7 g, 1 eq) from the previous step was dissolved in DCM (100 mL), and then oxalyl chloride (9.46 g) and DMF (0.4 g) were gradually added, and the reaction was carried out at room temperature for 1 hour. After sampling and adding methanol, when it was confirmed by TLC that the reaction was completed, the solvent was rotary evaporated from the reaction system, 500 mL of NH3.dioxane solution was added, and the reaction was carried out at room temperature for 1 hour. As a result of monitoring by LCMS, when the reaction was completed, the reaction solution was directly concentrated under reduced pressure to remove the solvent, and purified by silica gel column (SiO2, DCM:MeOH = 1:0 to 5:1) to obtain 2-hydroxy-6-(trifluoromethyl)-4-vinylnicotinamide (7 g).

[0203] Step 5: 3-Aminocarbonyl-6-(trifluoromethyl)-4-vinylpyridine-2-methyl p-toluenesulfonate The product (7 g) from the previous step was added to DCM (50 mL), and p-toluenesulfonyl chloride (TsCl, 8.6 g), triethylamine (TEA, 7.6 g) and DMAP (375 mg) were added, and the mixture was stirred at room temperature for 2 hours. As a result of monitoring by LCMS, the reaction was completed. Extraction was carried out with water (100 mL) and ethyl acetate, and the combined organic phases were concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (SiO2, PE:EA = 10:1 to pure DCM) to obtain 3-aminocarbonyl-6-(trifluoromethyl)-4-vinylpyridine-2-methyl p-toluenesulfonate (8.5 g) as the product.

[0204] Step 6: 3-(((2-Methylpyridin-3-yl)aminocarbonyl)aminocarbonyl)-6-(trifluoromethyl)-4-vinylpyridine-2-methyl p-toluenesulfonate The product (1.0 g) from the previous step was added to THF (40 mL), then oxalyl chloride (0.50 mL) was added, and then the temperature was raised to 80 °C and stirred for 1 hour. A sample was taken, quenched with methanol, and when the formation of the reaction intermediate state was confirmed, after cooling to room temperature, 3-amino-2-methylpyridine (400 mg) was added and stirred at room temperature for 1 hour. As a result of monitoring by LCMS, the reaction was completely carried out. An aqueous acetic acid solution was added to adjust the pH to acidic, extracted with H2O (100 mL) and ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and 3-(((2-methylpyridin-3-yl)aminocarbonyl)aminocarbonyl)-6-(trifluoromethyl)-4-vinylpyridine-2-methyl p-toluenesulfonate (4.5 g) of the crude product was obtained.

[0205] Step 7: 1-(2-Methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione The product (4.5 g) from the previous step was added to acetonitrile (ACN, 50 mL), then DBU (3.9 ml) was added, and stirred at room temperature for 1 hour. As a result of monitoring by LCMS, the reaction was completely carried out. An aqueous acetic acid solution was added to adjust the pH to acidic, and directly concentrated under reduced pressure to obtain a crude product. It was purified by prep-TLC (ethyl acetate:dichloromethane = 1:4) to obtain 1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyrido[2,3-d]pyrimidine-2,4-(1H,3H)-dione (280 mg) of the product. Step 8: Synthesis of 1-(2-Methylpyridin-3-yl)-2,4-dioxy-7-(trifluoromethyl)-1,2,3,4-tetrahydropyridine[2,3-d]pyrimidine-5-carboxylic acid 1-(2-Methylpyridin-3-yl)-7-(trifluoromethyl)-5-vinylpyrido[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 stirring well to dissolve, 10 drops of 1N sulfuric acid solution were added dropwise, and potassium permanganate (1.07 g, 6.781 mmol) was added. Then it was placed in an oil bath at 50 °C and reacted for 1 hour. As detected by LCMS, the reaction was completed. The temperature was lowered to room temperature, 20 mL of methanol was added, and it was stirred for 0.5 hour. Then, the filter cake was filtered through diatomaceous earth, washed with methanol, and the filtrate was concentrated. The obtained product was used directly in the next step. ESI-MS (m / z): 367.0 [M+H] + 。

[0206] Step 9: Synthesis of methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate The product from the previous step was dissolved in dichloromethane (100 mL), oxalyl chloride (256 mg, 2.034 mmol) was added, 1 drop of DMF was added, and it was stirred at room temperature for 2 hours. As detected by TLC, the reaction was completed. Methanol (20 mL) was added, and it was stirred for an additional 0.5 hour. When detected by TLC and the reaction was completed, the reaction mixture was directly concentrated under reduced pressure to remove the solvent. Then, it was purified by silica gel column (SiO2, DCM:MeOH = 1:0 to 50:1) to obtain methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate (428 mg, two-step yield 83%). ESI-MS (m / z): 381.1 [M+H] + 。

[0207] Step 10: Synthesis of methyl 1-(2-methylpyridin-3-yl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidine-5-carboxylate Methyl 1-(2-methylpyridin-3-yl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate (209 mg, 0.549 mmol) was dissolved in 1,4-dioxane (10 mL). Next, N,N-diisopropylethylamine (708 mg, 5.490 mmol) and phosphorus oxychloride (501 mg, 3.294 mmol) were added thereto, and the reaction solution was heated to 100 °C and reacted for 1 hour. As a result of monitoring by LCMS, the reaction was completed. The reaction was cooled to room temperature, N,N-diisopropylethylamine (708 mg, 105.490 mmol) and methylamine hydrochloride (185 mg, 2.745 mmol) were added, and the reaction was carried out at room temperature for 2 hours. As a result of monitoring by LCMS, the reaction was completed. The system was used for the next step without treatment. ESI-MS (m / z): 394.1 [M+H] + 。

[0208] Step 11: Synthesis of 1-(2-methylpyridin-3-yl)-5-(hydroxymethyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one The system from the previous step was added to methanol (10 mL), and sodium borohydride (208 mg, 5.490 mmol) was added batchwise under an ice bath, and the reaction was carried out at room temperature for 0.5 hour. As a result of monitoring by LCMS, when the reaction was completed, 100 mL of water was added, and extraction was carried out twice with 80 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to remove the solvent, and purified by silica gel column (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, two-step yield 14%). ESI-MS (m / z): 366.1 [M+H] + 。

[0209] Step 12: Synthesis of 2-Methyl-5-(2-methylpyridin-3-yl)-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphthalen-4(5H)-one 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), and triethylamine (24 mg, 0.233 mmol) and methanesulfonyl chloride (18 mg, 0.155 mmol) were added, followed by stirring at room temperature for 0.5 h. As monitored by LCMS, when the reaction was completed, it was directly concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column (SiO2, DCM:MeOH = 20:1) to give 5-(2-methylpyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphthalen-4(5H)-one (11 mg, yield 42%). ESI-MS (m / z): 348.1 [M+H] + 。 1 H NMR (600 MHz, DMSO) δ 8.53 (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).

[0210] By the resolution method of A16, two individual atropisomers A19-P1 and A19-P2 were obtained. A19-P1, ESI-MS (m / z): 348.1 [M+H] + 。 1 H NMR (600 MHz, DMSO) δ 8.53 (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 1H NMR (600 MHz, DMSO) δ 8.53 (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).

[0211] Example 40 5-(2-Chloropyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphthalen-4(5H)-one (A29)

Chemical Structure

[0212] According to the synthesis method of compound A19, using 3-amino-2-chloropyridine and methylamine as raw materials, the product 5-(2-chloropyridin-3-yl)-2-methyl-7-(trifluoromethyl)-1,2-dihydro-2,3,5,6-tetraazanaphthalen-4(5H)-one (10 mg, yield 36%) was obtained. ESI-MS (m / z): 368.1 [M+H] + 、 1 1H NMR (600 MHz, CDCl3) δ 8.50 (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).

[0213] By the resolution method of A16, two individual atropisomers A29-P1 and A29-P2 were obtained. A29-P1, ESI-MS (m / z): 368.1 [M+H] + 、 11H NMR (600 MHz, CDCl3) δ 8.50 (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 1H NMR (600 MHz, CDCl3) δ 8.50 (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).

[0214] 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) [Chemical Structure]

[0215] According to the synthesis method of compound A2, using 2-methyl-2H-indazol-5-amine, 3-amino-2-methylpyridine, etc. as starting materials, 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 (5 mg, yield 60%) was obtained. ESI-MS (m / z): 429.1 [M+H] + . 11H NMR (600 MHz, DMSO) δ 8.61 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 9.3, 2.1 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 5.55 (s, 2H), 4.20 (s, 3H), 2.26 (s, 3H).

[0216] By the splitting method of A16, two individual atropisomers A38-P1 and A38-P2 were obtained. A38-P1, ESI-MS (m / z): 429.1 [M+H] + 。 1 1H NMR (600 MHz, DMSO) δ 8.61 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 9.3, 2.1 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.47 (dd, J = 7.8, 4.9 Hz, 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] + 。 11H NMR (600 MHz, DMSO) δ 8.61 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.02 (dd, J = 9.3, 2.1 Hz, 1H), 7.79 (d, J = 6.6 Hz, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.47 (dd, J = 7.8, 4.9 Hz, 1H), 7.41 (s, 1H), 6.28 (s, 1H), 5.55 (s, 2H), 4.20 (s, 3H), 2.26 (s, 3H).

[0217] Example 42 7-Chloro-4-(4-chlorophenyl)-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A39) [Chemical Structure]

[0218] According to the synthesis method of Compound A2, using p-chloroaniline, 3-amino-2-methylpyridine, etc. as starting materials, 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. ESI-MS (m / z): 409.1 [M+H] + . 1 1H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.82 - 7.77 (m, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.8 Hz, 1H), 7.41 (s, 1H), 6.31 (s, 1H), 5.50 (s, 2H), 2.25 (s, 3H).

[0219] By the splitting method of A16, two individual atropisomers A39-P1 and A39-P2 were obtained. A39-P1, ESI-MS (m / z): 409.1 [M+H] + 。 1 H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.82 - 7.77 (m, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.8 Hz, 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 H NMR (600 MHz, DMSO) δ 8.61 (dd, J = 4.8, 1.3 Hz, 1H), 8.12 (d, J = 9.0 Hz, 2H), 7.82 - 7.77 (m, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.47 (dd, J = 7.8, 4.8 Hz, 1H), 7.41 (s, 1H), 6.31 (s, 1H), 5.50 (s, 2H), 2.25 (s, 3H).

[0220] Example 43 7-Chloro-1-(2-methylpyridin-3-yl)-4,5-dihydropyrrolo[2,3,4-de]quinazolin-2(1H)-one (A40)

Chemical Structure

[0221] According to the synthesis method of compound A1, using 2-methoxypyridin-3-amine, methylamine, etc. as synthetic raw materials, 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. ESI-MS (m / z): 329.1 [M+H] + 。1 1H NMR (600 MHz, DMSO) δ 8.30 (d, J = 3.8 Hz, 1H), 7.77 (d, J = 7.1 Hz, 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).

[0222] By the splitting method of A16, two individual atropisomers A40 - P1 and A40 - P2 were obtained. A40 - P1, ESI - MS (m / z): 329.1[M + H] + 。 1 1H NMR (600 MHz, DMSO) δ 8.30 (d, J = 3.8 Hz, 1H), 7.77 (d, J = 7.1 Hz, 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 1H NMR (600 MHz, DMSO) δ 8.30 (d, J = 3.8 Hz, 1H), 7.77 (d, J = 7.1 Hz, 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).

[0223] Example 44 4 - Methyl - 1 - (2 - methylpyridin - 3 - yl) - 8 - (trifluoromethyl) - 5,6 - dihydro - 1H - pyrimido[4,5,6 - ij][2,7]naphthyridin - 2(4H) - one (C1)

Chemical Structure

[0224] 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), and then methylamine hydrochloride (58.16 mg, 0.861 mmol) and PyBop (448.26 mg, 0.861 mmol) were added to the reaction solution. Finally, DBU (219 mg, 1.44 mmol) was added, and then the reaction solution was stirred at 20 °C for 16 hours. As a result detected by LC-MS, the main peak was the peak due to the product. The reaction solution 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 (400 MHz, 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).

[0225] By the resolution method of A16, two individual atropisomers C1-P1 and C1-P2 were obtained. C1-P1, ESI-MS (m / z): 362.1 [M+H] + 。 1 H NMR (400 MHz, 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 (400 MHz, 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).

[0226] By the corresponding synthesis method, using the corresponding intermediate as the starting material, compounds B4 - B72 and C2 - C23 are produced. [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32]

Table 33

Table 34

[0227] The effect tests and data of the compounds of the present invention are shown below.

[0228] Test Example 1 Enzyme Test Using an enzyme screening kit for MAT2A inhibitors (BPS Bioscience), the inhibitory effect of the test compound on MAT2A enzyme activity was measured. 1) The test compound was dissolved in DMSO and mixed well until the test compound was completely dissolved. All compounds were diluted to an initial concentration of 2 mM with DMSO and then diluted to a total of 10 concentration gradients at a three-fold dilution factor. In replicate wells, they were added to the reaction system at a ratio of 1:100 during detection (maximum final concentration: 20 μM). 100× positive control (1 mM AGI-24512) and 100× negative control (100% DMSO) were prepared.

[0229] 2) Using an Echo 550 pipetting system, 200 nL of the diluted compound was transferred to each well of a reaction plate (Corning 3702). The reaction plate was sealed with a sealing film and centrifuged at 1000 g for 1 minute. The final concentration of DMSO was 1%. 3) 1× MAT2A enzyme reaction buffer was prepared. That is, 4 volumes of water were added to 1 volume of 5× MAT2A enzyme reaction buffer and mixed well. 4) 2× MAT2A enzyme solution was prepared using 1× enzyme reaction buffer.

[0230] 5) 10 μL of 2× MAT2A enzyme solution was added to each well of a 384-well reaction plate (Corning 3702), and the plate was sealed with a sealing film. 6) Centrifuged at 1000 g for 60 seconds and incubated at room temperature for 30 minutes. 7) Using 1×MAT2A enzyme reaction buffer, a mixture of 2×L-methionine and ATP was prepared. 8) 10 μL of the mixture of 2×L-methionine and ATP was added to each well of a 384-well reaction plate (Corning 3702), and the plate was sealed with a sealing film. The total volume of the reaction system was 20 μL.

[0231] 9) Centrifuged at 1000 g for 60 seconds and incubated at room temperature for 60 minutes. 10) Detection buffer Colorimetric Detection Rebgent was prepared. 11) 20 μL of the detection buffer was added to each well, centrifuged at 1000 g for 30 seconds, and reacted at room temperature for 15 minutes. 12) Using a multi-functional microplate reader (PerkinElmer, Nivo), the fluorescence signal at 630 nm was measured.

[0232] The experimental results show that the compounds of the present invention have a strong MAT2A inhibitory effect. Exemplary compounds are shown in the following table.

Table 35

[0233] Test Example 2 Test for cell growth inhibition The specific operation procedure is as follows. Tumor cells were treated with the compound for 5 days, and the effect of the test compound on the growth of tumor cells was evaluated. HCT116-MTAP - / - Cells and wild-type control HCT116-WT (colorectal cancer cells) were seeded in a 384-well culture plate at a density of 600 cells / well, and different concentrations of the test compound were added simultaneously (starting from 20 μM, 10 concentration gradients). The cells were incubated at 37 °C, 5% CO2, and saturated humidity for 5 days.

[0234] Cell proliferation was detected using an ATP-based cell proliferation detection kit (Cell Titer Glo, Promega Corporation). After equilibration of the cells at room temperature for 30 minutes, they were treated with Cell Titer Glo reagent. The culture dishes were then covered with aluminum foil and shaken for 15 minutes to ensure complete mixing and lysis. Chemiluminescence detection was performed using a multifunctional microplate reader (Envision 2105, PerkinElmer). Blank wells (without cells) and DMSO control wells were set up.

[0235] The inhibition rate (IR) of the test compound was calculated using the following formula. IR(%) = [1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)] × 100% Plots were made and data were analyzed using GraphPad Prism to calculate the IC 50 value.

[0236] The compounds of the present invention were tested in the above assay, and their IC 50 values for inhibiting cell proliferation are shown in the following table.

Table 36

[0237] As a result, the test compounds showed strong cell growth inhibitory activity against HCT116 MTAP knockout cells, weak cell growth inhibitory activity against MTAP wild-type HCT116 cells, and good selectivity. Note: When the maximum inhibition rate < 50%, IC 50 > the highest starting concentration.

[0238] Test Example 3 Test of human UGT1A1 enzyme activity The specific procedure for measuring the enzyme inhibitory activity of compounds against UGT1A1 is as follows. 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, and then add the main reaction solution containing UGT1A1 (Corning, 456411) at a final concentration of 0.01 mg / mL, 0.5 μM substrate bilirubin, and Tris buffer. Pre-incubate in a 37 °C water bath for 10 minutes. The final concentration of the control compound was 10 μM, and the final concentration of the test compound was 2.2 μM.

[0239] 2) Start the reaction by adding 20 μL of UDPGA solution at a final concentration of 2 mM, react at 37 °C for 5 minutes, and then stop the reaction by adding 400 μL of cold acetonitrile containing the internal standard. 3) Vortex the sample for 5 minutes at 4 °C and 3220 g, and then centrifuge for 40 minutes. Then, transfer 100 μL of the supernatant to a new 96-well plate and analyze it by LC-MS / MS for the formation of metabolites. The inhibition rate (%) is calculated by comparing the decrease in metabolite formation (quantification of peak area) between the test drug and the control group. UGT1A1 is involved in the metabolism of bilirubin in the body. When UGT1A1 is inhibited, the metabolism of bilirubin is inhibited, and ultimately, the bilirubin in the body increases. The IC 50 of the above compound of the present invention against UGT1A1 is greater than 50 μM, indicating that the compound of the present invention has a low risk of inhibiting UGT1A1.

[0240] Test Example 4 Study on Mouse In Vivo Pharmacokinetics Experimental animals: CD-1 mice (male, 22 - 25 g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Test steps: Intravenous injection / gastric administration of the test compound to CD-1 mice (male, 22 - 25 g). After 5 minutes, 15 minutes, 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours of administration, collect the plasma of the mice, detect the compound concentration by LC-MS / MS, and calculate its plasma clearance Cl, elimination half-life T 1 / 2 , peak time T max , peak concentration C maxThe area under the drug time curve AUC, apparent volume of distribution Vss, absolute bioavailability F, and other pharmacokinetic parameters were examined.

[0241] Measurement method: Acetonitrile / water (1:1) was used as the stock solution to dilute the analyte, and a series of working solution concentrations were obtained. 10 μL of the 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 calibration standards of 1 - 10000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng / mL) in a total volume of 20 μL. Five quality control (QC) samples (2 ng / mL, 5 ng / mL, 10 ng / mL, 800 ng / mL, 8000 ng / mL) were prepared in the same manner as the calibration standards on the day of analysis. 20 μL of the standard, 20 μL of the QC sample, and 20 μL of the unknown sample (10 μL of unknown sample plasma and 10 μL of blank solution) were added to 200 μL of the IS mixture containing acetonitrile to precipitate the protein. Then, the sample was vortexed for 3 minutes. After centrifugation at 4700 rpm for 15 minutes 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.

[0242] The pharmacokinetic results indicate that the oral absolute bioavailability of the compounds of the present invention is high (preferred compounds can reach 70% or more), the clearance rate is moderate, and the dose - exposure correlation is good.

[0243] Test Example 5 hERG test The potential inhibitory effect of the test article on the hERG channel was evaluated by an automated patch - clamp system. In this study, a CHO cell line stably expressing the hERG gene was used, and cisapride was used as the positive control. The CHO-hERG-DUO cell line that stably expresses the hERG channel was purchased from B’SYS GmbH. The cells were cultured in a medium containing F12 (HAM) medium, 10% FBS, 100 U / mL penicillin-streptomycin, 100 μg / mL hygromycin, and 100 μg / mL G418. The cells were passaged three times a week and maintained at approximately 80% confluence. The test compound was dissolved in DMSO to form a stock solution with a final concentration of 10 mM, and then the stock solution was serially diluted 1:3 (3.33, 1.11, and 0.37 mM) with DMSO. The final concentrations of the compound were 30, 10, 3.33, 1.11, and 0.37 μM.

[0244] A baseline was established for the blank solvent. After the hERG current had stabilized for at least 5 minutes, the compound working solution was perfused. The hERG current was recorded for more than 5 minutes until a steady state was reached, and then 5 scans were captured. If a steady state was not reached within 10 minutes, the average peak current of the last 5 scans was used instead of the steady state value. The test was performed twice (n = 2), and hERG current inhibition of the compound at 5 concentrations was detected, and IC 50 was measured.

[0245] The current inhibition rate was calculated using the following formula.

Number

[0246] The test results indicate that the above-preferred compounds of the present invention have no obvious inhibitory effect on the hERG channel within the detection concentration range of this test, and IC 50 is greater than 30 μM, which indicates that the risk of cardiotoxicity of the compounds of the present invention is low. 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 principle scope of the present invention shall be included in the protection scope of the present invention.

Claims

1. A compound represented by formula (I), or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, having the following structure. 【Chemical 1】 (In the formula, Ring A is C ５～１０ a carbocyclic group, C ６～１４ an aryl, a 5- to 12-membered heteroaryl, or a 5- to 12-membered heterocyclyl, and is selected from R １ is optionally substituted C ３～１２ carbocyclic group, C ６～１４ aryl, 5- to 14-membered heteroaryl, 5- to 14-membered heterocyclyl, each of the carbocyclic group, aryl, heteroaryl, and heterocyclyl being optionally substituted by one or more R ａ and is optionally substituted by L is selected from bonding, -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 ), and the alkylene is optionally substituted by one or more R ａ１ ; R ａ is, independently at each occurrence, deuterium, halogen, oxo, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ａ１ , -W-SR ａ１ , -W-C(O)R ａ４ , -W-C(O)OR ａ１ , -W-OC(O)R ａ１ , -W-OC(O)OR ａ１ , -W-C(O)NR ａ２ R ａ３ , -W-C(O)NRO ａ２ R ａ１ , -W-OC(O)NR ａ２ R ａ３ , -W-NRR ａ２ R ａ３ , -W-NRC(O)R ａ２ R ａ４ , -W-NRC(O)OR ａ２ R ａ１ , -W-NRC(O)NR ａ２ R ａ２ R ａ３ , -W-S(O)R ａ４ , -W-S(O) ２ R ａ４ , -W-SO ２ NR ａ２ R ａ３ , -W-NRS(O)R ａ２ R ２ R ａ４ , -W-OS(O)R ２ R ａ４ , -W-NRS(O)NR ａ２ R ２ NR ａ２ R ａ３ , -W-OS(O)NR ２ NR ａ２ R ａ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ cycloalkenyl, C ６～１４ Selected from aryl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom R ａ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl, or 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C ６～１４ aryl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted with one or more substituents selected therefrom, R ａ２ and R ａ３ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, or C １～６ alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxy, C １～６ alkyl, C １～６ alkoxy, C １～６ alkyl, C ３～８ cycloalkyl, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, or when R ａ２ and R ａ３ are attached to the same nitrogen atom, R ａ２ and R ａ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl, R ａ４ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～８ cycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl, or 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, heteroaryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, X is N or CR ６ and R ２ 、R ３ and R ６ are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-OC(O)OR ｂ１ , -W-C(O)NR ｂ２ R ｂ３ , -W-C(O)NRO ｂ２ R ｂ１ , -W-OC(O)NR ｂ２ R ｂ３ , -W-NRR ｂ２ R ｂ３ , -W-NRC(O)R ｂ２ ｂ４ ｂ４ , -W-NRC(O)OR ｂ２ ｂ１ ｂ１ , -W-NRC(O)NR ｂ２ R ｂ２ ｂ３ ｂ３ , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , -W-SOR ２ NR ｂ２ R ｂ３ , -W-NRS(O)R ｂ２ ２ ２ R ｂ４ , -W-OS(O)R ２ R ｂ４ , -W-NRS(O)NR ｂ２ ２ ２ NR ｂ２ R ｂ３ , -W-OS(O)NR ２ NR ｂ２ R ｂ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ cycloalkenyl, C ６～１４ Selected from aryl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom, R ｂ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, C ６～１４ aryl, or a 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C ６～１４ aryl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl; R ｂ２ and R ｂ３ are, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, or C １～６ alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxy, C １～６ alkyl, C １～６ alkoxy, C １～６ alkyl, C ３～８ cycloalkyl, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, or when R ｂ２ and R ｂ３ are attached to the same nitrogen atom, R ｂ２ and R ｂ３ together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl, R ｂ４ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～８ cycloalkyl, C ６～１４ aryl, or a 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C ６～１４ aryl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl R ４ and R ５ are each independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ ｃ４ , -W-NRC(O)OR ｃ２ ｃ１ , -W-NRC(O)NR ｃ２ R ｃ２ ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NRSO ｃ２ R ２ , -W-NRSO ｃ４ R ２ , -W-OS(O)R ｃ４ ｃ２ R ２ , -W-NRSO ｃ２ ｃ３ ２ NR ｃ２ R ｃ３ , -W-OS(O)NR １～６ ２～６ R ２～６ １～６ , C １～６ alkyl, C ３～１０ alkenyl, C ３～１０ alkynyl, C ６～１４ ​​​​​​​​Selected from aryl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl is optionally substituted by one or more R ｃ and alternatively R ４ and R ５ are linked on the same, adjacent, or one atom-separated ring atoms, and together with the carbon atom and / or nitrogen atom to which they are linked, optionally substituted C ３～１０ forms cycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, and the term "optionally substituted" means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by a substituent selected from R ｃ which means that it is substituted by a substituent selected from, R ｃ is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)OR ｃ２ R ｃ１ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NRS(O)R ｃ２ R ２ R ｃ４ , -W-OS(O)R ２ R ｃ４ , -W-NRS(O)NR ｃ２ R ２ NR ｃ２ R ｃ３ , -W-OS(O)NR ２ NR ｃ２ R ｃ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ Selected from cycloalkenyl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom, R ｃ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, C ６～１４ aryl, or a 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C ６～１４ aryl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl R ｃ２ and R ｃ３ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, or C １～６ alkoxy, where each of said alkyl and alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxy, C １～６ alkyl, C １～６ alkoxy, C １～６ alkyl, C ３～８ cycloalkyl, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, or R ｃ２ and R ｃ３ are linked to the same nitrogen atom, R ｃ２ and R ｃ３ together with the nitrogen atom to which they are linked, are optionally substituted by one or more of halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C １～６ alkyl, C １～６ alkoxy, C ３～１０ cycloalkyl, 3- to 10-membered heterocycloalkyl, C ６～１４ aryl, 5- to 12-membered heteroaryl to form a 3- to 10-membered heterocycloalkyl or 5- to 12-membered heteroaryl optionally substituted by one or more thereof, R ｃ４ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～８ cycloalkyl, C ６～１４ aryl, or a 3- to 20-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C ６～１４ aryl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl W is a bond, C １～３ alkylene, -OC １～３ alkylene, -SC １～３ selected from alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ and is optionally substituted by one or more substituents selected from, Unless otherwise specified, the heteroatoms in the heterocyclyl and heteroaryl are independently selected from O, N, or S, and the number of heteroatoms is one, two, or three.)

2. Ring A is C ５～１０ Cycloalkyl, C ６～１０ Aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, preferably, Ring A is C ５～１０ Cycloalkyl, C ６ Aryl, 5- to 8-membered heteroaryl, 5- to 10-membered heterocyclyl, preferably, Ring A is C ５～１０ Cycloalkyl, 5- to 10-membered heterocyclyl, preferably, Ring A is selected from 5- to 10-membered heterocyclyls, preferably, Ring A is selected from 5- to 8-membered heterocyclyls, preferably, Ring A is selected from 5- to 7-membered heterocyclyls, the heteroatoms are independently selected from O or N, the number of heteroatoms is one or two, preferably, Ring A is [Chemical Formula 2] Selected from, preferably, ring A is 【Chemical 3】 Selected from, preferably, ring A is [Chemical Formula 4] Characterized by being selected from The compound according to claim 1, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

3. X is selected from N or CH, preferably, X is selected from N, preferably, X is characterized by being selected from CH The compound according to claim 1 or 2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

4. R １ is optionally substituted C ３～１０ cycloalkyl, C ５～１０ bridged cycloalkyl, C ５～１０ fused cycloalkyl, C ５～１０ spirocycloalkyl, C ６～１０ is selected from aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, 5- to 10-membered spiroheterocyclyl, and each of the cycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R ａ and is Preferably, R １ is optionally substituted C ３～６ cycloalkyl, C ５～１０ fused cycloalkyl, C ５～１０ spirocycloalkyl, C ６～１０ aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, 5- to 10-membered spiroheterocyclyl, and each of the cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R ａ and Preferably, R １ is optionally substituted C ６～１０ aryl, 5- to 10-membered heteroaryl, 5- to 10-membered monocyclic heterocyclyl, 5- to 10-membered bridged heterocyclyl, 5- to 10-membered fused heterocyclyl, 5- to 10-membered spiroheterocyclyl, wherein each of said aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R ａ and is optionally substituted by Preferably, R １ is optionally substituted C ６～１０ aryl, 5- to 8-membered heteroaryl, 5- to 8-membered monocyclic heterocyclyl, 5- to 8-membered bridged heterocyclyl, 5- to 8-membered fused heterocyclyl, 5- to 8-membered spiroheterocyclyl, each of the aryl, heteroaryl, monocyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, and spiroheterocyclyl is optionally substituted by one or more R ａ and is optionally substituted by Preferably, R １ is optionally substituted C ６ aryl, 5- to 8-membered heteroaryl, 5- to 8-membered monocyclic heterocyclyl, each of said aryl, heteroaryl, monocyclic heterocyclyl being optionally substituted by one or more R ａ and is optionally substituted by Preferably, R １ is optionally substituted C ６ aryl, 5- to 6-membered heteroaryl, 5- to 6-membered monocyclic heterocyclyl, wherein the aryl, heteroaryl, monocyclic heterocyclyl is optionally substituted by one or more R ａ and is optionally substituted by Preferably, R １ is optionally substituted C ６ aryl, 5- to 6-membered heteroaryl, each of said aryl, heteroaryl being optionally substituted by one or more R ａ and is optionally substituted by Preferably, R １ is phenyl, pyridyl, or imidazolyl optionally substituted by one or more R ａ and is selected from the group consisting of: Preferably, R １ is selected from pyridyl optionally substituted by one or more R ａ and is optionally substituted by one or more R Preferably, R １ is 【Chemical Formula 5】 selected from, preferably, R １ is 【Chemical Formula 6】 Characterized by being selected from The compound according to any one of claims 1 to 3, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

5. L is selected from a bond, -O-, -S-, -C １～４ alkylene - or -OC １～４ alkylene -, the alkylene being optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ and is optionally substituted by one or more substituents selected from: Preferably, L is a bond, -O-, -S-, -C １～２ alkylene-, or -OC １～２ alkylene-, and the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ and is optionally substituted by one or more substituents selected from the group consisting of Preferably, L is selected from a bond, -O-, -S-, methylene, or ethylene, and the methylene or ethylene is optionally substituted with one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ and is optionally substituted by one or more substituents selected from Preferably, L is selected from a bond, -O-, methylene, or ethylene, Preferably, L is selected from a bond or methylene, Preferably, L is characterized by being selected from a bond The compound according to any one of claims 1 to 4, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

6. R ａ is, independently at each occurrence, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ａ１ , -W-SR ａ１ , -W-C(O)R ａ４ , -W-C(O)OR ａ１ , -W-OC(O)R ａ１ , -W-C(O)NR ａ２ R ａ３ , -W-OC(O)NR ａ２ R ａ３ , -W-NR ａ２ R ａ３ , -W-NR ａ２ C(O)R ａ４ , -W-S(O)R ａ４ , -W-S(O) ２ R ａ４ , -W-SO ２ NR ａ２ R ａ３ , -W-NR ａ２ S(O) ２ R ａ４ , -W-OS(O) ２ R ａ４ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 16-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, phenyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom Preferably, R ａ is, in each occurrence independently, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ａ１ , -W-SR ａ１ , -W-C(O)R ａ４ , -W-C(O)OR ａ１ , -W-OC(O)R ａ１ , -W-C(O)NR ａ２ R ａ３ , -W-NR ａ２ R ａ３ , -W-NR ａ２ C(O)R ａ４ , -W-S(O)R ａ４ , -W-S(O) ２ R ａ４ , -W-SO ２ NR ａ２ R ａ３ , -W-NR ａ２ S(O) ２ R ａ４ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, and is optionally substituted by one or more substituents selected therefrom Preferably, R ａ is, in each occurrence independently, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ａ１ , -W-SR ａ１ , -W-C(O)R ａ４ , -W-C(O)OR ａ１ , -W-OC(O)R ａ１ , -W-C(O)NR ａ２ R ａ３ , -W-NR ａ２ R ａ３ , -W-NR ａ２ C(O)R ａ４ , -W-S(O) ２ R ａ４ , -W-SO ２ NR ａ２ R ａ３ , -W-NR ａ２ S(O) ２ R ａ４ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkoxy, each of said alkyl, alkenyl, alkynyl, and alkoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, and is optionally substituted by one or more substituents selected therefrom, Preferably, R ａ is, independently at each occurrence, deuterium, halogen, -CN, -OH, -NH ２ , -W-OR ａ１ , -W-SR ａ１ , -W-C(O)R ａ４ , -W-C(O)OR ａ１ , -W-OC(O)R ａ１ , -W-NR ａ２ C(O)R ａ４ , -C １～４ alkyl, C １～４ alkoxy, and the alkyl and alkoxy are optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C １～４ alkoxy, Preferably, R ａ is, independently at each occurrence, deuterium, halogen, -OH, -NH ２ , -W-NR ａ２ C(O)R ａ４ , C １～４ alkyl, C １～４ alkoxy, and the alkyl and alkoxy are optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -OH, -NH ２ , C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, Preferably, R ａ is, independently at each occurrence, deuterium, halogen, C １～４ alkyl, -W-NR ａ２ C(O)R ａ４ , C １～４ haloalkyl, wherein said alkyl or haloalkyl is optionally substituted by one or more deuteriums, Preferably, R ａ is, independently at each occurrence, deuterium, halogen, C １～４ alkyl, C １～４ alkoxy, -W-NR ａ２ C(O)R ａ４ is selected from, and the alkyl or haloalkyl is optionally substituted with one or more deuteriums, Preferably, R ａ is, independently at each occurrence, deuterium, halogen, C １～４ alkyl, C １～４ alkoxy, -NHC(O)R ａ４ selected from, said alkyl being optionally substituted by one or more deuteriums, Preferably, R ａ is, independently at each occurrence, halogen, C １～４ alkyl, C １～４ alkoxy, and is selected from Preferably, R ａ is, independently at each occurrence, selected from deuterium, F, Cl, Br, methyl, ethyl, propyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, or -NHC(O)-phenyl, Preferably, R ａ is independently selected from Cl, methyl, methoxy, or -NHC(O)-phenyl at each occurrence, characterized in that The compound according to any one of claims 1 to 5, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

7. R ａ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, and the heteroatom is independently selected from O, N, or S, and the number of heteroatoms is one, two, or three, Preferably, R ａ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C Preferably, R ａ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, or a 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, Preferably, R ａ１ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where the methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and Preferably, R ａ１ is, independently at each occurrence, hydrogen, methyl, ethyl, propyl, where the methyl, ethyl, propyl are optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and is characterized in that it is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 6, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

8. R ａ２ and R ａ３ each independently at each occurrence is hydrogen, deuterium, C １～４ alkyl, or C １～４ alkoxy, where the alkyl or alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, Preferably, R ａ２ and R ａ３ are, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, or C １～４ alkoxy, where the alkyl or alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C Preferably, R ａ２ and R ａ３ are, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where the methyl, ethyl, propyl, methoxy, ethoxy, propoxy are optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C １～４ alkyl, C １～４ alkoxy, Preferably, R ａ２ and R ａ３ are, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where said methyl, ethyl, propyl are optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and are characterized in that they are optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 7, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

9. R ａ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～８ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and the heteroatoms are independently selected from O, N or S and the number of heteroatoms is 1, 2 or 3, Preferably, R ａ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, or a 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C Preferably, R ａ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, or C ６ aryl, where each of said alkyl, alkoxy, cycloalkyl, aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C Preferably, R ａ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, where the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C Preferably, R ａ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl, where the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, or phenyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is characterized in that it is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 8, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

10. R ２ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-OC(O)OR ｂ１ , -W-C(O)NR ｂ２ R ｂ３ , -W-C(O)N(R) ｂ２ OR ｂ１ , -W-NR ｂ２ R ｂ３ , -W-NR ｂ２ C(O)R ｂ４ , -W-NR ｂ２ C(O)NR ｂ２ R ｂ３ , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , -W-SO ２ NR ｂ２ R ｂ３ , -W-NR ｂ２ S(O) ２ R ｂ４ , -W-OS(O) ２ R ｂ４ C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～６ cycloalkyl, C ６～１２ is selected from aryl, 3- to 6-membered heterocyclyl, 5- to 12-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ Haloalkyl, C １～６ Optionally substituted by one or more substituents selected from haloalkoxy, Preferably, R ２ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-OC(O)OR ｂ１ , -W-C(O)NR ｂ２ R ｂ３ , -W-C(O)NRO ｂ２ R ｂ１ , -W-NRR ｂ２ R ｂ３ , -W-NRCO ｂ２ R ｂ４ , -W-NRCO ｂ２ NR ｂ２ R ｂ３ , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , -W-SO ２ NR ｂ２ R ｂ３ , -W-NR ｂ２ S(O) ２ R ｂ４ , -W-OS(O) ２ R ｂ４ , C １～６ alkyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～６ cycloalkyl, C ６～１２ aryl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ Optionally substituted by one or more substituents selected from haloalkoxy, Preferably, R ２ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SO ２ NR ｂ２ R ｂ３ , -W-NR ｂ２ S(O) ２ R ｂ４ , C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, and each of the alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted Preferably, R ２ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, -W-SO ２ NR ｂ２ R ｂ３ , -W-NR ｂ２ S(O) ２ R ｂ４ selected from, and the methyl, ethyl, isopropyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy Preferably, R ２ is hydrogen, deuterium, halogen, -CN, -OH, -NH ２ , methyl, ethyl, isopropyl, -SO ２ NH ２ , -NHSO ２ H, and is selected from Preferably, R ２ is selected from hydrogen, characterized by The compound according to any one of claims 1 to 9, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

11. R ３ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-OC(O)OR ｂ１ , -W-C(O)NR ｂ２ R ｂ３ , -W-C(O)NRO ｂ２ R ｂ１ , -W-NRR ｂ２ R ｂ３ , -W-NRR ｂ２ C(O)R ｂ４ , -W-NRR ｂ２ C(O)NR ｂ２ R ｂ３ , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , -W-SO ２ NR ｂ２ R ｂ３ , -W-NRR ｂ２ S(O) ２ R ｂ４ , -W-OS(O) ２ R ｂ４ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～６ cycloalkyl, C ６～１２ aryl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ Haloalkyl, C １～６ optionally substituted by one or more substituents selected from haloalkoxy, Preferably, R ３ is hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-OC(O)OR ｂ１ , -W-C(O)NR ｂ２ R ｂ３ , -W-C(O)NRO ｂ２ R ｂ１ , -W-NRR ｂ２ R ｂ３ , -W-NR ｂ２ C(O)R ｂ４ , -W-NR ｂ２ C(O)NR ｂ２ R ｂ３ , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , -W-SO ２ NR ｂ２ R ｂ３ , -W-NR ｂ２ S(O) ２ R ｂ４ , -W-OS(O) ２ R ｂ４ , C １～４ alkyl, C ２～４ alkenyl, C ２～４ alkynyl, C １～４ alkoxy, C １～４ alkylthio, C ３～６ cycloalkyl, C ６～ aryl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, aryl, heterocyclyl, and heteroaryl is deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ Optionally substituted by one or more substituents selected from haloalkoxy, Preferably, R ３ is hydrogen, deuterium, halogen, -CN, -OH, -NH ２ , -W-OR ｂ１ , -W-SR ｂ１ , -W-C(O)R ｂ４ , -W-C(O)OR ｂ１ , -W-OC(O)R ｂ１ , -W-C(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 , -W-S(O)R ｂ４ , -W-S(O) ２ R ｂ４ , C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６～ aryl, 3- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, and is optionally substituted Preferably, R ３ is hydrogen, deuterium, halogen, -OH, -NH ２ , C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, 5- to 6-membered heterocyclyl, and each of said alkyl, alkoxy, cycloalkyl, and heterocyclyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted Preferably, R ３ is selected from F, Cl, Br, -CF ３ , -CHF ２ , -CH ２ , -CH ２ FCH ３ , -OCF ３ or cyclopropyl, Preferably, R ３ is Cl or -CF ３ selected from, Preferably, R ３ is selected from halogen, C １～４ alkyl optionally substituted by one or more halogens, Preferably, R ３ is selected from halogen, Preferably, R ３ is selected from Cl, characterized in that, The compound according to any one of claims 1 to 10, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof.

12. R ｂ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy; Preferably, R ｂ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, Preferably, R ｂ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted Preferably, R ｂ１ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where the methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, Preferably, R ｂ１ is, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where the methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and is characterized in that it is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 11, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

13. R ｂ２ and R ｂ３ each independently at each occurrence is hydrogen, deuterium, C １～４ alkyl, or C １～４ alkoxy, where the alkyl or alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted by one or more substituents selected therefrom, Preferably, R ｂ２ and R ｂ３ are, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, or C １～４ alkoxy, where the alkyl or alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C Preferably, R ｂ２ and R ｂ３ are, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where the methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected therefrom, Preferably, R ｂ２ and R ｂ３ are, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where the methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and is characterized by being optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 12, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

14. R ｂ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～８ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom, Preferably, R ｂ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, or 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted. Preferably, R ｂ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, or C ６ aryl, where each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C Preferably, R ｂ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, where the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C Preferably, R ｂ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where the methyl, ethyl, propyl, methoxy, ethoxy, propoxy is halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ optionally substituted by one or more substituents selected from alkoxy, characterized in that, The compound according to any one of claims 1 to 13, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. R ４ and R ５ are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NRSO ｃ２ R ２ R ｃ４ , -W-OS(O) ２ R 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- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and each of the alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R ｃ or R ４ and R ５ are linked on the same, adjacent, or one atom-separated ring atoms, and together with the carbon and / or nitrogen atoms to which they are linked, optionally substituted C ３～１０ forms cycloalkyl, C ６～１２ aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, and the term "optionally substituted" means that the hydrogen in the group to be substituted is unsubstituted or that one or more substitutable sites of the group to be substituted are independently substituted by substituents selected from R ｃ which means that, Preferably, R ４ and R ５ are each independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NRS(O) ｃ２ R ２ R ｃ４ , -W-OS(O) ２ R 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- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, and each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R ｃ or R ４ and R ５ are linked on the same, adjacent, or separated by one atom ring atoms, and, together with the carbon atoms and / or nitrogen atoms to which they are linked, optionally substituted C ３～１０ cycloalkyl, C ６～１２ aryl, 5- to 12-membered heteroaryl, 5- to 12-membered heterocyclyl, and the term "optionally substituted" means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by a substituent selected from R ｃ which means that it is substituted by a substituent selected from, Preferably, R ４ and R ５ are each independently hydrogen, deuterium, halogen, -CN, -OH, -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-NR ｃ２ C(O)R ｃ４ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NR ｃ２ S(O) ２ R ｃ４ , -W-OS(O) ２ R ｃ４ , C １～４ alkyl, C １～４ alkoxy, C １～４ alkylthio, C ３～６ cycloalkyl, C ４～６ cycloalkenyl, C ６ aryl, 4- to 10-membered heterocyclyl, 5- to 12-membered heteroaryl, and each of said alkyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, and heteroaryl is optionally substituted by one or more R ｃ , and the heteroatoms are each independently selected from O, N, or S, and the number of heteroatoms is one, two, or three, Preferably, R ４ and R ５ are each independently hydrogen, deuterium, halogen, -OH, -W-C(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-SO ２ NR ｃ２ R ｃ３ , -W-C(O)R ｃ４ , -W-S(O) ２ R ｃ４ , C １～４ alkyl, C ３～６ cycloalkyl, 4- to 10-membered heterocyclyl, C ６～１２ aryl, or 5- to 10-membered heteroaryl, and each of said alkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl is optionally substituted by one or more R ｃ ; or R ４ and R ５ together with the carbon and / or nitrogen atoms to which they are attached form an optionally substituted C ３～１０ cycloalkyl, 5- to 12-membered heterocyclyl, where said optionally substituted means that the hydrogen in the group to be substituted is unsubstituted or one or more substitutable sites of the group to be substituted are independently substituted by substituents selected from R ｃ which means being substituted by a substituent selected from, Preferably, R ４ is hydrogen, deuterium, halogen, -OH, C １～４ alkyl, C １～４ alkoxy, 4- to 6-membered heterocycloalkyl, and the alkyl, alkoxy, azetidinyl, or pyrrolidinyl is optionally substituted by one or more R ｃ ; R ５ is hydrogen, deuterium, halogen, -OH, -W-C(O)NR ｃ２ R ｃ３ ; -W-NR ｃ２ R ｃ３ ; -W-SO ２ NR ｃ２ R ｃ３ ; -W-C(O)R ｃ４ ; -W-S(O) ２ R ｃ４ ; C １～４ alkyl, C ３～６ cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, or 9- to 10-membered heteroaryl, and each of the alkyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl is optionally substituted by one or more R ｃ ; Preferably, R ４ is hydrogen, deuterium, halogen, -OH, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, or pyrrolidinyl, and the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, azetidinyl, or pyrrolidinyl is optionally substituted by one or more R ｃ ; R ５ is hydrogen, deuterium, halogen, -OH, -W-C(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-SO ２ NR ｃ２ R ｃ３ , -W-C(O)R ｃ４ , -W-S(O) ２ R ｃ４ , methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, benzopyrazolyl, and the methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, benzopyrazolyl are optionally substituted by one or more R ｃ ; and Preferably, R ４ is hydrogen, halogen, —OH, methyl, ethyl, propyl, methoxy, ethoxy, azetidinyl, or pyrrolidinyl, and the methyl, ethyl, propyl, methoxy, ethoxy, azetidinyl, or pyrrolidinyl is optionally substituted by one or more R ｃ ; R ５ is hydrogen, halogen, —OH, —C １～３ alkylene-C(O)NR ｃ２ R ｃ３ , —C １～３ alkylene-NR ｃ２ R ｃ３ , —C １～３ alkylene-SO ２ NR ｃ２ R ｃ３ , —C(O)R ｃ４ , —S(O) ２ R ｃ４ , methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, benzopyrazolyl, and each of the methyl, ethyl, phenyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, and benzopyrazolyl is optionally substituted by one or more R ｃ ; Preferably, R ４ is hydrogen, deuterium, halogen, -OH, methyl, 【Chemical Formula 7】 and R ５ is hydrogen, methyl, phenyl, benzoyl, -SO ２ CH ３ , 【Chemical Formula 8】 selected from Preferably, R ４ is hydrogen, halogen, -OH, or methyl, and R ５ is hydrogen, methyl, phenyl, benzoyl, -SO ２ CH ３ , 【Chemical Formula 9】 selected from Preferably, R ４ is hydrogen, and R ５ is selected from hydrogen, C １～６ alkyl, phenyl, and 9- to 10-membered bicyclic heteroaryl, where the phenyl and the heteroaryl are optionally substituted by one or more R ｃ ; Preferably, R ４ is hydrogen, and R ５ is selected from hydrogen, C １～４ alkyl, phenyl, and 9- to 10-membered bicyclic heteroaryl, where the phenyl and the heteroaryl are optionally substituted by one or more halogens, -OH, C １～４ alkyl, Preferably, R ４ is hydrogen, and R ５ is selected from hydrogen, C １～４ alkyl, phenyl, 9- to 10-membered bicyclic heteroaryl, where the phenyl and the heteroaryl are optionally substituted by one or more of -F, -Cl, -Br, -OH, methyl, ethyl, n-propyl, isopropyl, and the heteroatom in the heteroaryl is selected from N, and the number of heteroatoms is one, two, or three, characterized in that The compound according to any one of claims 1 to 14, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

16. R ｃ is independently deuterium, halogen, oxime, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)OR ｃ２ R ｃ１ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NRSO ｃ２ R ２ R ｃ４ , -W-OS(O)R ２ R ｃ４ , -W-NRSO ｃ２ R ２ NR ｃ２ R ｃ３ , -W-OS(O)NR ２ NR ｃ２ R ｃ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ cycloalkenyl, C ６～１２ Selected from aryl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted by one or more substituents selected therefrom Preferably, R ｃ is, independently, deuterium, halogen, oxime, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)OR ｃ２ R ｃ１ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NR ｃ２ S(O) ２ R ｃ４ , -W-OS(O) ２ R ｃ４ , -W-NR ｃ２ S(O) ２ NR ｃ２ R ｃ３ , -W-OS(O) ２ NR ｃ２ R ｃ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ cycloalkenyl, C ６～１２ Selected from aryl, 3- to 12-membered heterocyclyl, and 5- to 16-membered heteroaryl, each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is optionally substituted with one or more substituents selected therefrom Preferably, R ｃ is, independently, deuterium, halogen, oxime, -CN, -OH, -SH, -NO ２ , -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-OC(O)OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-C(O)NRO ｃ２ R ｃ１ , -W-OC(O)NR ｃ２ R ｃ３ , -W-NRR ｃ２ R ｃ３ , -W-NRC(O)R ｃ２ R ｃ４ , -W-NRC(O)OR ｃ２ R ｃ１ , -W-NRC(O)NR ｃ２ R ｃ２ R ｃ３ , -W-S(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NR ｃ２ S(O) ２ R ｃ４ , -W-OS(O) ２ R ｃ４ , -W-NR ｃ２ S(O) ２ NR ｃ２ R ｃ３ , -W-OS(O) ２ NR ｃ２ R ｃ３ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ haloalkyl, C １～６ haloalkoxy, C １～６ alkoxy, C １～６ alkylthio, C ３～１０ cycloalkyl, C ３～１０ Cycloalkenyl, 3- to 12-membered heterocyclyl, C ６～１２ selected from aryl, 5- to 12-membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～６ alkyl, C ６～１４ aryl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ optionally substituted by one or more substituents selected from haloalkoxy, halophenyl, Preferably, R ｃ is independently deuterium, halogen, -CN, -OH, -SH, -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-NR ｃ２ C(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NR ｃ２ S(O) ２ R ｃ４ , C １～４ alkyl, C １～４ alkoxy, C ３～８ cycloalkyl, a 4- to 8-membered heterocyclyl, C ６～１２ aryl, a 5- to 8-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C ６～１２ aryl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted. Preferably, R ｃ is independently deuterium, halogen, -CN, -OH, -SH, -NH ２ , -W-OR ｃ１ , -W-SR ｃ１ , -W-C(O)R ｃ４ , -W-C(O)OR ｃ１ , -W-OC(O)R ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-NR ｃ２ C(O)R ｃ４ , -W-S(O) ２ R ｃ４ , -W-SO ２ NR ｃ２ R ｃ３ , -W-NR ｃ２ S(O) ２ R ｃ４ , C １～４ alkyl, C １～４ alkoxy, C ３～８ cycloalkyl, 4- to 8-membered heterocyclyl, C ６ aryl, 5- to 6-membered heteroaryl, and each of said alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl is optionally substituted with one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO ２ , -NH ２ , C １～４ alkyl, C ６～１２ aryl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted Preferably, R ｃ is, independently, deuterium, halogen, -CN, -OH, -W-OR ｃ１ , -W-C(O)NR ｃ２ R ｃ３ , -W-NR ｃ２ R ｃ３ , -W-SO ２ NR ｃ２ R ｃ３ , C １～４ alkyl, 4- to 8-membered heterocyclyl, wherein the heterocyclyl is optionally substituted by one or more substituents selected from deuterium, halogen, -OH, C １～４ alkyl C １～４ haloalkyl, C １～４ haloalkoxy, and is optionally substituted by one or more substituents selected therefrom Preferably, R ｃ is independently selected from -F, -Cl, -Br, -CH ２ -OH, -OH, -C(O)NH-CH ３ , -N(CH ３ ), ２ , -SO ２ CH ３ , -SO ２ N(CH ３ ), ２ morpholinyl, methyl, ethyl, n-propyl, isopropyl, characterized in that it is selected from The compound according to any one of claims 1 to 15, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

17. R ｃ１ is, independently at each occurrence, hydrogen, deuterium, C １～６ alkyl, C １～６ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, C １～６ haloalkyl, C １～６ haloalkoxy, and is preferably, R ｃ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６～１０ aryl, or a 3- to 8-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is preferably, R ｃ１ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, or a 5- to 6-membered heterocyclyl, where each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is preferably, R ｃ１ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where said methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, and preferably, R ｃ１ is, independently at each occurrence, hydrogen, methyl, ethyl, or propyl, where said methyl, ethyl, or propyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, characterized in that it is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C The compound according to any one of claims 1 to 16, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

18. R ｃ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～８ cycloalkyl, C ６～１０ aryl, or a 3- to 10-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～６ alkyl, C １～６ alkoxy, phenyl, C １～６ haloalkyl, C １～６ haloalkoxy, halophenyl, and is preferably R ｃ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, C ６ aryl, or a 3- to 8-membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl, aryl, and heterocyclyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, C １～４ haloalkyl, C １～４ haloalkoxy, and is preferably R ｃ４ is, independently at each occurrence, hydrogen, deuterium, C １～４ alkyl, C １～４ alkoxy, C ３～６ cycloalkyl, or C ６ aryl, wherein each of said alkyl, alkoxy, cycloalkyl, and aryl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is preferably R ｃ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl, where said methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or phenyl is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, and is preferably R ｃ４ is, independently at each occurrence, hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, or propoxy, where said methyl, ethyl, propyl, methoxy, ethoxy, or propoxy is optionally substituted by one or more substituents selected from halogen, deuterium, hydroxy, amino, C １～４ alkyl, C １～４ alkoxy, characterized in that it is optionally substituted by one or more such substituents The compound according to any one of claims 1 to 17, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

19. W is a bond, C １～３ selected from alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ selected from alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH １～３ selected from alkylene, wherein the alkylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ selected from alkylene, preferably, W is selected from a bond, methylene, or ethylene, and the methylene or ethylene is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NH ２ selected from, characterized in that it is optionally substituted by one or more substituents The compound according to any one of claims 1 to 18, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

20. An atropisomer of a compound represented by formula (III-a), (III-b), (III-c), (III-d) or (III-e), or a pharmaceutically acceptable salt of the atropisomer. 【Chemical Formula 10】 (wherein R １ , R ２ , R ３ , R ４ , R ５ , R ６ and X are as described in the compounds represented by formula (I) of claims 1 to 18, wherein L is a bond, and R １ is substituted by at least one R ａ . )

21. Preferably, R １ is selected from pyridyl optionally substituted by one or more R ａ and preferably, R ａ is independently selected from Cl, methyl, methoxy at each occurrence, and more preferably, R １ is 【Chemical Formula 11】 selected from, an atropisomer of a compound represented by formula (III-a), (III-b), (III-c), (III-d) or (III-e) according to claim 20, or a pharmaceutically acceptable salt of the atropisomer.

22. selected from the following, the compound, or a tautomer, stereoisomer, atropisomer thereof or a pharmaceutically acceptable salt thereof. 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 【Table 7】 【Table 8】 【Table 9】 【Table 10】

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, or a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and an optional pharmaceutically acceptable adjuvant.

24. Use in the manufacture of a drug for preventing and / or treating a disease, disorder, and condition mediated by MAT2A, which is a compound according to any one of claims 1 to 22 or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, wherein preferably, the disease, disorder, and condition is an MTAP-deficient tumor, and more preferably, the tumor includes solid tumors and hematological tumors, and the solid tumors include colorectal cancer, the use.

25. Use in the manufacture of a drug for preventing and / or treating a tumor, which is a compound according to any one of claims 1 to 22 or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

26. A pharmaceutical composition, characterized by comprising a compound according to any one of claims 1 to 22 or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, and another one, two or more drugs having tumor inhibitory activity.

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