Pyrimido-nitrogen-containing six-membered aromatic heterocyclic compounds and uses thereof

Abstract

The present application provides a kind of compound shown in formula (I) or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt.The present application compound has strong MAT2A inhibitory effect, can be used for treating and / or preventing MAT2A mediated diseases, disorders and conditions, for example, tumor etc.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and more specifically, to a class of novel compounds as MAT2A inhibitors and their use in the treatment and prevention of MAT2A-mediated diseases, symptoms and conditions, such as tumors. Background Technology

[0002] MAT2A stands for Methionine adenosyltransferase 2A, also known as S-Adenosylmethionine Synthase Isoform Type.

[0003] MAT2A is expressed in all tissues, including erythrocytes, brain, fetal liver, kidney, and pancreatic tissue, but at a lower level in adult liver tissue. Increased expression of MAT2A and MAT2B is observed in human liver and colon cancer, and increased MAT2A expression has also been reported in human gastric cancer and tamoxifen-resistant breast cancer cells. Higher MAT2A and MAT2B expression leads to cancer cell growth, migration, and invasion. Overall, lower MAT2A and MAT2B expression results in increased apoptosis and reduced cell growth, migration, and metastasis.

[0004] MTAP is a methionine transferase that catalyzes the transfer of adenosine nucleotides, playing a crucial role in ATP salvage synthesis. MTAP deficiency occurs in approximately 15% of all solid tumors. MTAP deficiency is present to varying degrees in different tumor types. MTAP deficiency leads to the accumulation of the enzyme substrate methionine (MTA). Increased MTA concentration partially inhibits PRMT5 activity, while other methyltransferases are relatively unaffected. Inhibition of MAT2A reduces the methyl donor S-adenosylmethionine (SAM), a substrate of PRMT5, further inhibiting PRMT5, affecting tumor cell mRNA splicing, and causing DNA damage. Therefore, MAT2A inhibitors can benefit MTAP-deficient tumors.

[0005] Several patent applications have disclosed MAT2A inhibitors, such as WO2018039972, WO2019191470, WO2020139991, WO2020139992, WO2020243376, and WO2020123395.

[0006] UGTs, as the most important phase II metabolic enzymes in the body, are one of the key pathways for the clearance of exogenous drugs and endogenous substances. UGT1A1 is an enzyme that catalyzes the glucuronidation of the toxic endogenous substance bilirubin. The glucuronidation reaction it mediates is a necessary step for the elimination of bilirubin and is most closely related to human health. Numerous studies both domestically and internationally have confirmed that mutations in the UGT1A1 gene result in the complete or partial loss of the ability to glucuronize bilirubin, thus affecting bilirubin metabolism and leading to severe hyperbilirubinemia. Furthermore, some clinical drugs inhibit UGT1A1, thereby reducing the body's ability to metabolize and clear bilirubin, causing an increase in blood bilirubin levels, leading to hyperbilirubinemia or exacerbating the patient's condition. Therefore, avoiding excessive UGT1A1 inhibition is crucial for safe medication use. Summary of the Invention

[0007] This invention provides a class of novel MAT2A inhibitor compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts, and provides the use of such compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts for the treatment and prevention of MAT2A-mediated diseases, symptoms and conditions.

[0008] Specifically, the present invention provides a compound of formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] L1 is selected from the following: -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O-), -N(R a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-;R a1 Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0012] R a Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. a2 Replaced, of which R a2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. a3 -OR a3 -SR a3 -S(O)R a3 -SO2(R a3 -C(O)R a3 -C(O)OR a3 -OC(O)R a3 -NH(R) a3 ), -N(R a3 (R) a4 ), -C(O)NH(R a3 -C(O)N(R) a3 (R) a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O)(R a4 ), -S(O)NH(R a4 ), -S(O)N(R a3 (R) a4 ),-SO2NH(R a3 -SO2N(R) a3 (R) a4 ), -NHS(O)(R a3 ), -N(R a3 )S(O)(R a4 ),-NHSO2(R a4 ), -N(R a3 SO2(R) a4 ); where R a3 Ra4 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0013] L2 is selected from the following: -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O-), -N(R b1 )C(O)-、-C(O)N(R b1 - or -N(R) b1 )-;R b1 Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0014] R b Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 Replaced, of which R b2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R) b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b3 (R) b4 ),-SO2NH(R b3 -SO2N(R) b3 (R) b4 ), -NHS(O)(R b3 ), -N(R b3 )S(O)(R b4 ),-NHSO2(R b4 ), -N(R b3 SO2(R) b4 ); where R b3 R b4 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R b3 and R b4 When R is attached to the same nitrogen atom, b3 and R b4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0015] L3 is selected from the following groups: -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O-), -N(R c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-;R c1 Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0016] R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 Replaced, of which R c2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. c3 -OR c3 -SR c3 -S(O)R c3 -SO2(R c3 -C(O)R c3 -C(O)OR c3 -OC(O)R c3 -NH(R) c3 ), -N(R c3 (R) c4 ), -C(O)NH(R c3 -C(O)N(R) c3 (R) c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ), -S(O)NH(R c4 ), -S(O)N(R c3 (R) c4 ),-SO2NH(R c3 -SO2N(R) c3 (R) c4 ), -NHS(O)(R c3 ), -N(R c3 )S(O)(R c4 ),-NHSO2(R c4 ), -N(R c3 SO2(R) c4 ); where R c3 R c4 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R c3 and R c4 When R is attached to the same nitrogen atom, c3 and R c4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0017] X1 is selected from N or CR d ;

[0018] R d The C group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. d1 Replaced, of which R d1 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. d2 -OR d2 -SR d2 -S(O)R d2 -SO2(R d2 -C(O)R d2 -C(O)OR d2 -OC(O)R d2 -N(R) d2 (R) d3 -C(O)N(R) d2(R) d3 ), -N(R d2 )C(O)(R d3 ); where R d2 R d3 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl;

[0019] Unless otherwise stated, the heteroatoms in the above heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0020] In a preferred embodiment of the present invention, L1 is selected from bonds, -CH2-, -O-, -S-, -C(O)-, -N(R)- .... a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-.

[0021] In a further preferred embodiment, L1 is selected from bonds, -O-, -S-, -C(O)-, -NHC(O)-, and -C(O)NH-.

[0022] In a further preferred embodiment, L1 is selected from bond, -O-, -S-, -C(O)-.

[0023] In a further preferred embodiment, L1 is a key.

[0024] In a preferred embodiment of the present invention, R a1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a group selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or oxo.

[0025] In a further preferred embodiment, R a1C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a group selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or oxo.

[0026] In a further preferred embodiment, R a1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a group selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano.

[0027] In a further preferred embodiment, R a1 Selected from hydrogen.

[0028] In a preferred embodiment of the present invention, R a Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. a2 What it replaced.

[0029] In a further preferred embodiment, R a Selected from C (optional substitution) 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. a2 What it replaced.

[0030] In a further preferred embodiment, R a Selected from substituted 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl; the heteroatom in the heterocyclic group or heteroaryl group is independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0031] In a further preferred embodiment, R a Selected from optionally substituted 3-6 membered monocyclic heterocyclic alkyl groups, 5-10 membered bicyclic heterocyclic groups, C 6-8 Aryl, 5-12 membered heteroaryl; the heteroatoms in the heterocyclic alkyl, heterocyclic, and heteroaryl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0032] In a further preferred embodiment, R a Selected from optionally substituted 5-10-membered heteroaryl groups; the heteroatoms in the heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; the optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substitutable sites by R. a2 What it replaced.

[0033] In a further preferred embodiment, R a Selected from optionally substituted 5-10 membered bicyclic heteroaryl groups; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1, 2, 3, or 4; the optional substitution means that the mentioned group is not substituted or is independently substituted by R at one or more substituted sites. a2 What it replaced.

[0034] In a further preferred embodiment, R a Selected from optionally substituted 9-10 membered bicyclic heteroaryl groups; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 2; the optional substitution means that the mentioned group is not substituted or is independently substituted by R at one or more substituted sites. a2 What it replaced.

[0035] In a preferred embodiment of the present invention, R a2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R a3 -OR a3 -SR a3 -S(O)R a3 -SO2(R a3 -C(O)R a3 -C(O)OR a3 -OC(O)R a3 -NH(R) a3 ), -N(R a3 (R) a4 ), -C(O)NH(R a3 -C(O)N(R) a3 (R) a4), -NHC(O)(R a3 ), -N(R a3 )C(O)(R a4 ).

[0036] In a further preferred embodiment, R a2 Independently selected from halogen, hydroxyl, amino, cyano, -R a3 .

[0037] In a preferred embodiment of the present invention, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 A 3-10 heterocyclic alkyl group or a 5-12 heterocyclic alkyl group substituted with aryl, 5-6 heteroaryl groups.

[0038] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently of one or more halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 The alkoxy substituent is a 3-10 membered heterocyclic alkyl or a 5-12 membered heteroaryl.

[0039] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0040] In a further preferred embodiment, R a3 R a4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 alkyl.

[0041] In a further preferred embodiment, R a3 R a4 C10 independently selected from hydrogen or optionally substituted with one or more hydroxyl groups 1-4 alkyl.

[0042] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen, C 1-4 alkyl.

[0043] In a preferred embodiment of the present invention, R a Selected from C (optional) 1-4 Alkyl-substituted 5-10 membered bicyclic heteroaryl groups; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1, 2, 3 or 4.

[0044] In a further preferred embodiment, R a Selected from

[0045] In a preferred embodiment of the present invention, L2 is selected from the following: -CH2-, -C(O)-, -C(O)O-, -OC(O)-, -N(Rb1 )C(O)-、-C(O)N(R b1 )-.

[0046] In a further preferred embodiment, L2 is selected from bond, -CH2-, -C(O)-, -C(O)O-, -OC(O)-.

[0047] In a further preferred embodiment, L2 is selected from the key.

[0048] In a preferred embodiment of the present invention, R b1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 It is replaced by aryl and 5-6 heteroaryl groups.

[0049] In a further preferred embodiment, R b1 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0050] In a further preferred embodiment, R b1 Independently selected from hydrogen or C 1-4 alkyl.

[0051] In a preferred embodiment of the present invention, R b Selected from C (optional substitution) 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0052] In a further preferred embodiment, R bSelected from C (optional substitution) 3-10 Cycloalkyl, 3-6 member monocyclic heterocyclic alkyl, 5-12 member bicyclic heterocyclic, C 6-10 Aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0053] In a further preferred embodiment, R b Selected from optionally substituted 5-12 membered bicyclic heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0054] In a further preferred embodiment, R b Selected from C (optional substitution) 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0055] In a further preferred embodiment, R b Selected from optionally substituted phenyl groups; wherein optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0056] In a preferred embodiment of the present invention, R b2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R) b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b3 (R) b4),-SO2NH(R b3 -SO2N(R) b3 (R) b4 ), -NHS(O)(R b3 ), -N(R b3 )S(O)(R b4 ),-NHSO2(R b4 ), -N(R b3 SO2(R) b4 ).

[0057] In a further preferred embodiment, R b2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R) b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ),-SO2NH(R b3 ), -NHS(O)(R b3 ),-NHSO2(R b4 ).

[0058] In a further preferred embodiment, R b2 Independently selected from halogens, hydroxyl groups, amino groups, and -R groups. b3 -OR b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -C(O)NH(R b3 ), -NHC(O)(R b3 ).

[0059] In a further preferred embodiment, R b2 Independently selected from halogens, hydroxyl groups, amino groups, and -R groups.b3 -OR b3 .

[0060] In a preferred embodiment of the present invention, R b2 -O(C) is independently selected from halogens, or optionally substituted by one or more halogens. 1-6 Alkyl), C 1-6 alkyl.

[0061] In a further preferred embodiment, R b2 -O(C) is independently selected from halogens, or optionally substituted with one or more halogens. 1-4 alkyl).

[0062] In a further preferred embodiment, R b2 Independently selected from chlorine, -OCH3, -OCH2CH3, -O(CH2F), -O(CHF2), -O(CF3), -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CHFCH3, -CH2CHF2.

[0063] In a preferred embodiment of the present invention, R b3 R b4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R b3 and R b4 When R is attached to the same nitrogen atom, b3 and R b4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 A 3-10 heterocyclic alkyl group or a 5-12 heterocyclic alkyl group substituted with aryl, 5-6 heteroaryl groups.

[0064] In a further preferred embodiment, R b3 R b4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0065] In a further preferred embodiment, R b3 R b4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0066] In a further preferred embodiment, R b3 R b4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl, C 1-6 Alkoxy, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0067] In a further preferred embodiment, R b3 R b4 C is independently selected from those optionally substituted with one or more halogens. 1-6 alkyl.

[0068] In a preferred embodiment of the present invention, L3 is selected from -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-. c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-.

[0069] In a further preferred embodiment, L3 is selected from -O-, -C(O)-, and -N(R). c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-.

[0070] In a further preferred embodiment, L3 is selected from -O-, -N(R) c1)-、-C(O)-.

[0071] In a preferred embodiment of the present invention, L3 is selected from -CH2-, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or -NH-.

[0072] In a further preferred embodiment, L3 is selected from -O-, -NH-, and -C(O)-.

[0073] In a further preferred embodiment, L3 is selected from -O- and -NH-.

[0074] In a preferred embodiment of the present invention, R c1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 It is replaced by aryl and 5-6 heteroaryl groups.

[0075] In a further preferred embodiment, R c1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino groups are substituted.

[0076] In a further preferred embodiment, R c1Independently selected from hydrogen or optionally selected by one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0077] In a further preferred embodiment, R c1 Independently selected from hydrogen or optionally selected by one or more independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino.

[0078] In a further preferred embodiment, R c1 It is independently selected from hydrogen.

[0079] In a preferred embodiment of the present invention, R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0080] In a further preferred embodiment, R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0081] In a further preferred embodiment, Rc Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0082] In a further preferred embodiment, R c Selected from C (optional substitution) 1-6 Alkyl; the optional substitution refers to the mentioned group not being substituted or being independently replaced by R at one or more substituted sites. c2 What it replaced.

[0083] In a preferred embodiment of the present invention, R c Selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. c2 What it replaced.

[0084] In a preferred embodiment of the present invention, R c2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 -OR c3 -C(O)R c3 -C(O)OR c3 -OC(O)R c3 -NH(R) c3 ), -N(R c3 (R) c4 ), -C(O)NH(R c3 -C(O)N(R) c3 (R) c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ).

[0085] In a further preferred embodiment, R c2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 .

[0086] In a further preferred embodiment, R c2 It is independently selected from halogens, hydroxyl groups, and amino groups.

[0087] In a further preferred embodiment, R c2 It is independently selected from halogens.

[0088] In a further preferred embodiment, R c2 It is F.

[0089] In a preferred embodiment of the present invention, R c3 R c4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0090] In a further preferred embodiment, R c3 R c4 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, and oxo groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0091] In a further preferred embodiment, R c3 R c4 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, and oxo groups. 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0092] In a preferred embodiment of the present invention, R c Selected from C (optional substitution) 1-6 Alkyl; optional substitution means that the mentioned group is not substituted or is independently substituted by a halogen at one or more substituted sites.

[0093] In a preferred embodiment of the present invention, X1 is selected from N.

[0094] In a preferred embodiment of the present invention, X1 is selected from CR. d .

[0095] In a preferred embodiment of the present invention, R d The C group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. d1 What it replaced.

[0096] In a further preferred embodiment, R d The C group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. d1 What it replaced.

[0097] In a further preferred embodiment, R d The C group is independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. d1 What it replaced.

[0098] In a further preferred embodiment, R d Selected from hydrogen.

[0099] In a preferred embodiment of the present invention, R d1Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R d2 -OR d2 -N(R) d2 (R) d3 -C(O)N(R) d2 (R) d3 ), -N(R d2 )C(O)(R d3 ).

[0100] In a further preferred embodiment, R d1 Independently selected from halogen, hydroxyl, amino, cyano, -R d2 .

[0101] In a preferred embodiment of the present invention, R d2 R d3 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, or cyano groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0102] In a further preferred embodiment, R d2 R d3 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, or cyano groups. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0103] The present invention provides a compound of formula (II) or a prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof, having the following structure:

[0104]

[0105] in:

[0106] L1 is selected from the following: -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O-), -N(R a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-;R a1Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0107] R a Selected from substituted 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-14 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. a2 Replaced, of which R a2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -C. 1-6 Alkylene-N(R) a3 (R) a4 -R a3 -OR a3 -SR a3 -S(O)R a3 -SO2(R a3 -C(O)R a3 -C(O)OR a3 -OC(O)R a3 -NH(R) a3 ), -N(R a3 (R) a4 ), -C(O)NH(R a3 -C(O)N(R) a3 (R) a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O)(R a4 ), -S(O)NH(R a4 ), -S(O)N(R a3 (R) a4 ),-SO2NH(R a3-SO2N(R) a3 (R) a4 ), -NHS(O)(R a3 ), -N(R a3 )S(O)(R a4 ),-NHSO2(R a4 ), -N(R a3 SO2(R) a4 ); where R a3 R a4 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0108] L2 is selected from the bond, -C(R) b1 )2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C(O)-、-C(O)N(R b1 - or -N(R) b1 )-;R b1 Each time it appears, it is independently selected from hydrogen or optionally substituted C. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0109] R b Selected from substituted 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 Replaced, of which R b2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R) b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b3 (R) b4 ),-SO2NH(R b3 -SO2N(R) b3 (R) b4 ), -NHS(O)(R b3 ), -N(R b3 )S(O)(R b4 ),-NHSO2(R b4 ), -N(R b3 SO2(R)b4 ); where R b3 R b4 Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R b3 and R b4 When R is attached to the same nitrogen atom, b3 and R b4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0110] L3 is selected from the following groups: -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O-), -N(R c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-;R c1 C selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Substituents of aryl and 5-12 heteroaryl groups;

[0111] R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 Replaced, of which R c2 Each time it appears, it is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R. c3 -OR c3 -SR c3 -S(O)R c3 -SO2(R c3 -C(O)R c3 -C(O)OR c3 -OC(O)R c3 -NH(R) c3 ), -N(R c3 (R) c4 ), -C(O)NH(R c3 -C(O)N(R) c3 (R) c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ), -S(O)NH(R c4 ), -S(O)N(R c3 (R) c4 ),-SO2NH(R c3 -SO2N(R) c3 (R) c4 ), -NHS(O)(R c3 ), -N(R c3 )S(O)(R c4 ),-NHSO2(R c4 ), -N(R c3 SO2(R) c4 ); where R c3 R c4Each time it appears, it is independently selected from hydrogen or optionally selected independently from one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 C-substituents of aryl and 5-12 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R c3 and R c4 When R is attached to the same nitrogen atom, c3 and R c4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 3-10-membered heterocyclic alkyl groups or 5-12-membered heteroaryl groups substituted with aryl or 5-12-membered heteroaryl groups;

[0112] Unless otherwise stated, the heteroatoms in the above heterocyclic alkyl, heteroaryl, and heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4.

[0113] In a preferred embodiment of the present invention, L1 is selected from bonds, -CH2-, -O-, -S-, -C(O)-, -N(R)- .... a1 )C(O)-、-C(O)N(R a1 - or -N(R) a1 )-.

[0114] In a further preferred embodiment, L1 is selected from the following: -CH2-, -O-, -S-, or -N(R). a1 )-, where R a1 Selected from hydrogen or C 1-6 alkyl.

[0115] In a further preferred embodiment, L1 is selected from bonds, -O-, -S-, -C(O)-, -NH-, -NHC(O)-, and -C(O)NH-.

[0116] In a further preferred embodiment, L1 is selected from bonds, -O-, -S-, -C(O)-, and -NH-.

[0117] In a further preferred embodiment, L1 is selected from bond, -NH-, -O-, or -S-.

[0118] In a further preferred embodiment, L1 is a key.

[0119] In a preferred embodiment of the present invention, R a1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a substituent selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo.

[0120] In a further preferred embodiment, R a1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a substituent selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo.

[0121] In a further preferred embodiment, R a1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substituted sites by a substituent selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano.

[0122] In a further preferred embodiment, R a1 Selected from hydrogen.

[0123] In a preferred embodiment of the present invention, R a Selected from substituted 3-12 membered heterocyclic groups, C 6-14Aryl, 5-14 membered heteroaryl, wherein the heteroatom in the heterocyclic group or heteroaryl group is independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4. The optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substitutable sites by R. a2 What it replaced.

[0124] R a Selected from substituted 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. a2 What it replaced.

[0125] In a further preferred embodiment, R a Selected from substituted 3-10 membered heterocyclic groups, C 6-12 Aryl, 5-12 membered heteroaryl; the heteroatom in the heterocyclic group or heteroaryl group is independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0126] In a further preferred embodiment, R a Selected from optionally substituted 3-6 membered monocyclic heterocyclic alkyl groups, 5-10 membered bicyclic heterocyclic groups, C 6-8 Aryl, 5-12 membered heteroaryl; the heteroatoms in the heterocyclic alkyl, heterocyclic, and heteroaryl groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0127] In a further preferred embodiment, R a Selected from optionally substituted 5-10 membered bicyclic heterocyclic groups and 5-10 membered heteroaryl groups; the heteroatoms in the heterocyclic group or heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; the optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0128] In a further preferred embodiment, R a The heterocyclic group is selected from optionally substituted 5-10 membered bicyclic heterocyclic groups and 5-10 membered bicyclic heteroaryl groups, wherein the heteroatom in the heterocyclic group or heteroaryl group is independently selected from O or N, and the number of heteroatoms is 1, 2 or 3. Optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substitutable sites by R. a2 What it replaced.

[0129] In a further preferred embodiment, R a Selected from optionally substituted 5-10-membered heteroaryl groups; the heteroatoms in the heteroaryl group are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, 3, or 4; the optional substitution means that the mentioned group is not substituted or is independently substituted at one or more substitutable sites by R. a2 What it replaced.

[0130] In a further preferred embodiment, R a Selected from 5-10 membered bicyclic heterocyclic groups with optional substitution; the heteroatoms in the heterocyclic group are independently selected from O or N, and the number of heteroatoms is 1, 2, 3, or 4; optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. a2 What it replaced.

[0131] In a further preferred embodiment, Ra is selected from optionally substituted 5-10 membered bicyclic heteroaryl groups; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution means that the mentioned group is not substituted or is independently substituted by Ra2 at one or more substituted sites.

[0132] In a further preferred embodiment, R a Selected from optional replacements The optional substitution refers to the mentioned group not being substituted or being independently replaced by R at one or more substituted sites. a2 What it replaced.

[0133] In a further preferred embodiment, R a Selected from optional replacements The optional substitution refers to the mentioned group not being substituted or being independently replaced by R at one or more substituted sites. a2 What it replaced.

[0134] In a further preferred embodiment, R a Selected from optional replacements The optional substitution refers to the mentioned group not being substituted or being independently replaced by R at one or more substituted sites. a2 What it replaced.

[0135] In a preferred embodiment of the present invention, R a2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -C 1-6 Alkylene-N(R) a3 (R) a4 -R a3 -OR a3-SR a3 -S(O)R a3 -SO2(R a3 -C(O)R a3 -C(O)OR a3 -OC(O)R a3 -NH(R) a3 ), -N(R a3 (R) a4 ), -C(O)NH(R a3 -C(O)N(R) a3 (R) a4 ), -NHC(O)(R a3 ), -N(R a3 )C(O)(R a4 ).

[0136] In a further preferred embodiment, R a2 Independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 Alkylene-N(R) a3 (R) a4 -R a3 -OR a3 -N(R) a3 (R) a4 -C(O)N(R) a3 (R) a4 ), -N(R a3 )C(O)(R a4 ).

[0137] In a preferred embodiment of the present invention, R a2 Independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 Alkylene-N(R) a3 (R) a4 -R a3 .

[0138] In a preferred embodiment of the present invention, R a2 Independently selected from halogen, hydroxyl, amino, cyano, -C 1-6 Alkylene-N(R) a3 (R) a4 C 1-4 Alkyl, -C 1-4 Alkyl-C 1-4 alkoxy or -C 1-4 Alkyl hydroxyl.

[0139] In a preferred embodiment of the present invention, R a2 Independently selected from halogens, -C(O)R a3 hydroxyl, amino, -C1-6 Alkylene-N(R) a3 (R) a4 ), optionally selected independently by one or more halogens, hydroxyl groups, amino groups, C 1-6 Alkoxy-substituted C1-6 alkyl groups.

[0140] In a preferred embodiment of the present invention, R a2 Independently selected from -C 1-6 Alkylene-N(R) a3 (R) a4 ), optionally selected by one or more independently chosen from hydroxyl and C 1-6 alkoxy-substituted C 1-6 alkyl.

[0141] In a preferred embodiment of the present invention, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 A 3-10 heterocyclic alkyl group or a 5-12 heterocyclic alkyl group substituted with aryl, 5-6 heteroaryl groups.

[0142] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 alkoxy substituents of C1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently of one or more halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 The alkoxy substituent is a 3-10 membered heterocyclic alkyl or a 5-12 membered heteroaryl.

[0143] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently from one or more halogens, hydroxyl groups, C, and N atoms. 1-6 Alkyl, C 1-6 The alkoxy-substituted 3-10 membered heterocyclic alkyl group, wherein the heteroatom in the heterocyclic alkyl group is selected from N, S, O, and the number of heteroatoms is 1, 2 or 3.

[0144] In a further preferred embodiment, R a3 R a4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl; when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form 3-10 membered heterocyclic alkyl groups optionally substituted by one or more substituents independently selected from F, Cl, Br, hydroxyl, methyl, methoxy, wherein the heteroatom in the heterocyclic alkyl group is selected from N, O, and the number of heteroatoms is one or two.

[0145] In a further preferred embodiment, R a3 R a4 Independently selected from hydrogen, C 1-4 Alkyl, -C 1-4 alkyl hydroxyl; when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form tetrahydropyrrole, piperidinyl, or morpholino groups, which are optionally substituted by one or more substituents independently selected from F, hydroxy, methyl, or methoxy.

[0146] In a preferred embodiment of the present invention, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently of one or more halogens, hydroxyl groups, amino groups, and C atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 The heterocyclic alkyl group is a 3-10-membered heterocyclic alkyl group or a 5-12-membered heterocyclic alkyl group substituted with an aryl or 5-6-membered heteroaryl group, wherein the heteroatom in the heterocyclic alkyl or heteroaryl group is selected from N, S, or O, and the number of heteroatoms is 1, 2, or 3.

[0147] In a preferred embodiment of the present invention, R a3 R a4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and Ra4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently from one or more halogens, hydroxyl groups, C, and N atoms. 1-6 Alkyl, C 1-6 The alkoxy-substituted 3-10 membered heterocyclic alkyl group, wherein the heteroatom in the heterocyclic alkyl group is selected from N, S, O, and the number of heteroatoms is 1, 2 or 3.

[0148] In a preferred embodiment of the present invention, R a3 R a4 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form elements optionally selected independently from one or more halogens, hydroxyl groups, C, and N atoms. 1-4 Alkyl, C 1-4 The alkoxy-substituted 3-10 membered heterocyclic alkyl group, wherein the heteroatom in the heterocyclic alkyl group is selected from N or O, and the number of heteroatoms is one or two.

[0149] In a preferred embodiment of the present invention, R a3 R a4 Selected independently from C 1-4 Alkyl; or when R a3 and R a4 When R is attached to the same nitrogen atom, a3 and R a4 Together with the nitrogen atoms to which they are attached, they form tetrahydropyrrole, piperidinyl, or morpholino groups, which are optionally substituted by one or more substituents independently selected from F, hydroxy, methyl, or methoxy.

[0150] In a further preferred embodiment, R a2 Independently selected from methyl, Br,

[0151] In a further preferred embodiment, R a2 Selected independently

[0152] In a further preferred embodiment, R a Selected from

[0153] In a further preferred embodiment, R a Selected from

[0154] In a preferred embodiment of the present invention, L2 is selected from the following: -CH2-, -C(O)-, -C(O)O-, -OC(O)-, -N(R b1 )C(O)-、-C(O)N(R b1 )-.

[0155] In a further preferred embodiment, L2 is selected from bond, -CH2-, -C(O)-, -C(O)O-, -OC(O)-.

[0156] In a further preferred embodiment, L2 is selected from bond, -CH2-, and -C(O)-.

[0157] In a further preferred embodiment, L2 is selected from the bond, -CH2-.

[0158] In a further preferred embodiment, L2 is the key.

[0159] In a preferred embodiment of the present invention, R b1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 It is replaced by aryl and 5-6 heteroaryl groups.

[0160] In a further preferred embodiment, R b1 C10 groups are independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogens, hydroxyl groups, and amino groups. 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0161] In a further preferred embodiment, R b1 Independently selected from hydrogen or C 1-4 alkyl.

[0162] In a preferred embodiment of the present invention, R bSelected from substituted 3-12 membered heterocyclic groups, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0163] In a further preferred embodiment, R b Selected from optionally substituted 3-6 membered monocyclic heterocyclic alkyl groups, 5-12 membered bicyclic heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0164] In a further preferred embodiment, R b Selected from optionally substituted 5-12 membered bicyclic heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0165] In a further preferred embodiment, R b Selected from optionally substituted 5-10 member bicyclic heterocyclic groups, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0166] In a further preferred embodiment, R b Selected from optionally substituted 5-12 membered bicyclic heterocyclic groups, C 6-10 Aryl, 5-10 membered heteroaryl, wherein optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0167] In a further preferred embodiment, R b Selected from optionally substituted phenyl, pyridyl, or benzotetrahydrofuranyl; wherein optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0168] In a further preferred embodiment, R b Selected from optionally substituted phenyl or pyridyl groups; wherein optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0169] In a further preferred embodiment, R bSelected from optionally substituted phenyl groups; wherein optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 What it replaced.

[0170] In a preferred embodiment of the present invention, R b2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R) b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ), -S(O)N(R b3 (R) b4 ),-SO2NH(R b3 -SO2N(R) b3 (R) b4 ), -NHS(O)(R b3 ), -N(R b3 )S(O)(R b4 ),-NHSO2(R b4 ), -N(R b3 SO2(R) b4 ).

[0171] In a further preferred embodiment, R b2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R b3 -OR b3 -SR b3 -S(O)R b3 -SO2(R b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -N(R b3 (R)b4 ), -C(O)NH(R b3 -C(O)N(R) b3 (R) b4 ), -NHC(O)(R b3 ), -N(R b3 )C(O)(R b4 ), -S(O)NH(R b4 ),-SO2NH(R b3 ), -NHS(O)(R b3 ),-NHSO2(R b4 ).

[0172] In a further preferred embodiment, R b2 Independently selected from halogens, hydroxyl groups, amino groups, and -R groups. b3 -OR b3 -C(O)R b3 -C(O)OR b3 -OC(O)R b3 -NH(R) b3 ), -C(O)NH(R b3 ), -NHC(O)(R b3 ).

[0173] In a further preferred embodiment, R b2 Independently selected from halogens, hydroxyl groups, amino groups, and -R groups. b3 -OR b3 .

[0174] In a preferred embodiment of the present invention, R b2 -O(C) is independently selected from halogens, hydroxyl groups, or optionally substituted with one or more halogens. 1-6 alkyl), -O(C) 1-6 Alkyl)phenyl, C 1-6 alkyl.

[0175] In a further preferred embodiment, R b2 -O(C) is independently selected from halogens, hydroxyl groups, or optionally substituted with one or more halogens. 1-4 alkyl), -O(C) 1-4 alkyl)phenyl or C 1-4 alkyl.

[0176] In a further preferred embodiment, R b2 Independently selected from chlorine, -OCH3, -OH, -O-benzyl, -OCH2CH3, -O(CH2F), -O(CHF2), -O(CF3), -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CHFCH3, -CH2CHF2 or

[0177] In a preferred embodiment of the present invention, R b2 Independently selected from halogens, hydroxyl groups, amino groups, and C 3-6 cycloalkyl, -OR b3 , where R b3 Selected from one or more independently selected from halogens or C 6-10 Aryl substituents substituted C 1-6 alkyl.

[0178] In a further preferred embodiment, R b2 Independently selected from halogens, hydroxyl groups, and C 3-6 cycloalkyl, -OR b3 , where R b3 Selected from C groups optionally substituted with one or more substituents independently selected from halogens or phenyl groups. 1-4 alkyl.

[0179] In a further preferred embodiment, R b2 Independently selected from fluorine, chlorine, -OH, C 3-6 cycloalkyl, -OR b3 , where R b3 Selected from C groups optionally substituted with one or more substituents independently selected from chlorine or phenyl. 1-4 alkyl.

[0180] In a further preferred embodiment, R b2 -O(C) groups independently selected from chlorine, cyclopropyl, or optionally substituted with one or more halogens. 1-4 alkyl).

[0181] In a further preferred embodiment, R b2 -O(C) is independently selected from chlorine or optionally substituted with one or more fluorine molecules. 1-4 alkyl).

[0182] In a further preferred embodiment, R b2 It is independently selected from chlorine, -OCH3, -O(CHF2) or -O(CF3).

[0183] In a further preferred embodiment, R b2 It is independently selected from -O(CHF2).

[0184] In a preferred embodiment of the present invention, R b3 R b4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 alkenyl, C2-6 ynyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 aryl, 5-12 heteroaryl; or when R b3 and R b4 When R is attached to the same nitrogen atom, b3 and R b4 Together with the nitrogen atoms to which they are attached, they form groups optionally selected independently of one or more halogens, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 A 3-10 heterocyclic alkyl group or a 5-12 heterocyclic alkyl group substituted with aryl, 5-6 heteroaryl groups.

[0185] In a further preferred embodiment, R b3 R b4 Independently selected from hydrogen or optionally selected by one or more elements independently selected from halogen, hydroxyl, amino, C 6-8 Aryl substituents substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C3- 10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0186] In a further preferred embodiment, R b3 R b4 C is independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, or phenyl. 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0187] In a further preferred embodiment, R b3 R b4 C is independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, or phenyl. 1-4 Alkyl, C 1-4Alkoxy, C 3-4 cycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0188] In a further preferred embodiment, R b3 R b4 C10 groups are independently selected from hydrogen or optionally substituted with one or more substituents independently selected from halogens or phenyl groups. 1-4 Alkyl, C 1-4 Alkoxy or cyclopropyl.

[0189] In a further preferred embodiment, R b3 R b4 C10 groups are independently selected from hydrogen or optionally substituted with one or more substituents independently selected from halogens or phenyl groups. 1-4 Alkyl group.

[0190] In a further preferred embodiment, R b3 R b4 The methoxy group is independently selected from those optionally substituted by one or more substituents independently selected from F and Cl.

[0191] In a further preferred embodiment, R b Selected from

[0192] In a further preferred embodiment, R b Selected from

[0193] In a preferred embodiment of the present invention, L3 is selected from -CH2-, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-. c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-.

[0194] In a further preferred embodiment, L3 is selected from -CH2-, -O-, -S-, or -N(R) c1 )-, where R c1 Selected from hydrogen or C 1-6 alkyl.

[0195] In a further preferred embodiment, L3 is selected from -O-, -S-, -C(O)-, and -N(R). c1 )C(O)-、-C(O)N(R c1 - or -N(R) c1 )-.

[0196] In a further preferred embodiment, L3 is selected from -O-, -N(R) c1)-、-C(O)-.

[0197] In a further preferred embodiment, L3 is selected from -O-, -N(R) c1 )-, where R c1 Selected from hydrogen or C 1-6 alkyl.

[0198] In a preferred embodiment of the present invention, L3 is selected from -CH2-, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or -NH-.

[0199] In a further preferred embodiment, L3 is selected from -O-, -NH-, and -C(O)-.

[0200] In a further preferred embodiment, L3 is selected from -O- and -NH-.

[0201] In a further preferred embodiment, L3 is selected from -O-.

[0202] In a preferred embodiment of the present invention, R c1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Substituents of aryl and 5-6 heteroaryl groups.

[0203] In a further preferred embodiment, R c1 C is independently selected from hydrogen or optionally substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino groups are substituted.

[0204] In a further preferred embodiment, R c1 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0205] In a further preferred embodiment, R c1 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl, C 1-6 alkoxy substituents of C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino.

[0206] In a further preferred embodiment, R c1 It is independently selected from hydrogen.

[0207] In a preferred embodiment of the present invention, R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0208] In a further preferred embodiment, R c Selected from C (optional substitution) 1-6 Alkyl, C 1-6 Alkoxy, C 1-6Alkylamino, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0209] In a further preferred embodiment, R c Selected from C (optional substitution) 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0210] In a further preferred embodiment, R c Selected from C (optional substitution) 1-4 Alkyl or C 3-6 Cycloalkyl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. c2 What it replaced.

[0211] In a further preferred embodiment, R c Selected from C (optional substitution) 1-3 Alkyl; the optional substitution refers to the mentioned group not being substituted or being independently replaced by R at one or more substituted sites. c2 What it replaced.

[0212] In a preferred embodiment of the present invention, R c Selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; wherein optional substitution means that the mentioned group is not substituted or is independently substituted at one or more sites by R. c2 What it replaced.

[0213] In a preferred embodiment of the present invention, R c2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 -OR c3 -C(O)R c3 -C(O)OR c3 -OC(O)R c3 -NH(R) c3 ), -N(Rc3 (R) c4 ), -C(O)NH(R c3 -C(O)N(R) c3 (R) c4 ), -NHC(O)(R c3 ), -N(R c3 )C(O)(R c4 ).

[0214] In a further preferred embodiment, R c2 Independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R c3 .

[0215] In a further preferred embodiment, R c2 Independently selected from halogen, hydroxyl, amino or -R c3 .

[0216] In a further preferred embodiment, R c2 Independently selected from halogens or -R c3 .

[0217] In a preferred embodiment of the present invention, R c3 R c4 Independently selected from hydrogen or optionally selected by one or more groups independently selected from halogen, hydroxyl, amino, cyano, oxo, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 C-substituents of aryl and 5-6 heteroaryl groups 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0218] In a further preferred embodiment, R c3 R c4 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, and oxo groups. 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 heteroaryl.

[0219] In a further preferred embodiment, R c3 R c4 C groups independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, and oxo groups. 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic alkyl, C 6-8 Aryl, 5-6 aryl heteroaryl.

[0220] In a further preferred embodiment, R c3 R c4 It is independently selected from hydrogen or CF3.

[0221] In a preferred embodiment of the present invention, R c Selected from C that is optionally substituted with one or more halogens 1-6 Alkyl groups or optionally one or more R c3 Replacement C 3-6 cycloalkyl, wherein R c3 C selected from hydrogen or optionally substituted with one or more substituents independently selected from halogens. 1-6 alkyl.

[0222] In a preferred embodiment of the present invention, R c Selected from C (optional substitution) 1-6 Alkyl; optional substitution means that the mentioned group is not substituted or is independently substituted by a halogen at one or more substituted sites.

[0223] In a further preferred embodiment, R c Selected from C that is optionally substituted with one or more halogens 1-4 Alkyl groups or C groups optionally substituted with CF3 3-6 Cycloalkyl.

[0224] In a further preferred embodiment, R c Selected from methyl, ethyl,

[0225] In a further preferred embodiment, R c Selected from ethyl,

[0226] In a further preferred embodiment, R c Selected from ethyl.

[0227] The structural formulas and numbering of representative compounds of this invention are shown in the table below:

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234] The object of the present invention also includes providing a method for preparing a compound of general formula (I) in which X is N, a compound of general formula (II) or a tautomer, stereoisomer or a pharmaceutically acceptable salt thereof.

[0235] The method described below can be used, for example, to prepare the sample.

[0236]

[0237] Intermediate 1.6 reacts with boric acid or borate ester in the presence of a palladium catalyst to give final product 1.7.

[0238] In one embodiment, intermediate 1.6 can be prepared by the following steps:

[0239]

[0240] In a further preferred embodiment, the compound or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof can be prepared by the following steps:

[0241]

[0242] Starting with 2,4-dichloro-5-nitropyrimidine (1.1), it was reacted with different types of primary amines to give intermediate 1.2. Intermediate 1.2 was then reacted with the corresponding R... c -L3H reaction yields intermediate 1.3. The nitro group of 1.3 is reduced to an amino group using a reducing agent to give intermediate 1.4. Intermediate 1.4 reacts with monomethyl oxalyl chloride to give cyclic compound 1.5. Intermediate 1.5 reacts with thionyl chloride to give intermediate 1.6. Finally, in the presence of a palladium catalyst, it reacts with boric acid or a borate ester to give the final product 1.7. The substituents in the compounds shown are defined as previously described.

[0243] Note: The protection and deprotection reaction steps involved in this process have been omitted.

[0244] In another aspect, the present invention also provides the following intermediate compounds:

[0245]

[0246] Where L 2 L 3 R b and R c As described in compounds of formula (I) or (II);

[0247] In a further preferred embodiment, L 2 As the key, R b The optional substitution is phenyl or pyridyl; the optional substitution means that the mentioned group is not substituted or is independently replaced by R at one or more substituted sites. b2 Replaced

[0248] In another aspect, the present invention provides a pharmaceutical composition comprising the compound described herein or its prodrug, tautomer, stereoisomer, solvate, isotope derivative, or pharmaceutically acceptable salt.

[0249] Furthermore, the pharmaceutical composition of the present invention also comprises pharmaceutically acceptable excipients.

[0250] The administration of the compounds of the present invention, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts, can be carried out in pure form or as suitable pharmaceutical compositions by any acceptable route of administration providing a drug for similar use. The pharmaceutical compositions of the present invention can be prepared by combining the compounds of the present invention with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention can be formulated into solid, semi-solid, liquid, or gaseous formulations. Generally, the above-described pharmaceutical compositions can be prepared using excipients conventional in the field of pharmaceutical formulations by conventional preparation methods.

[0251] In another aspect, the present invention provides the use of the compounds described herein or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions of the present invention, in the preparation of medicaments for the prevention and / or treatment of diseases, symptoms, and conditions mediated by MAT2A.

[0252] Furthermore, in the uses provided by this invention, the disease, symptom, and condition are MTAP-deficient tumors.

[0253] Furthermore, in the uses provided by the present invention, the tumor includes solid tumors and hematomas; preferably, the solid tumor includes colorectal cancer.

[0254] In certain contexts within this field, the cancer may also be referred to as a malignant tumor.

[0255] In another aspect, this application provides methods for preventing and / or treating diseases, symptoms, and conditions mediated by MAT2A, comprising administering to an individual in need a compound of the present invention or a prodrug thereof, a tautomer, a stereoisomer, a solvate, an isotope derivative, or a pharmaceutically acceptable salt or a pharmaceutical composition of the present invention; preferably, the disease, symptom, or condition is MTAP-deficient cancer; more preferably, the tumor includes solid tumors and hematologic malignancies.

[0256] In another aspect, this application provides compounds of the present invention or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts or pharmaceutical compositions of the present invention for the prevention and / or treatment of diseases, symptoms and conditions mediated by MAT2A; preferably, the diseases, symptoms and conditions are MTAP-deficient cancers; more preferably, the tumors include solid tumors and hematologic malignancies.

[0257] Furthermore, in the uses or methods provided by the present invention, the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition of the present invention, is used in combination with another, two or more drugs having antitumor activity.

[0258] The present invention also provides a pharmaceutical composition comprising the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt, and another, two or more drugs having antitumor activity.

[0259] definition

[0260] The terms “optional,” “arbitrary,” “optionally,” or “arbitrarily” refer to events or conditions that are subsequently described but are not required to occur, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0261] Unless otherwise specified, "optional substitution" or "arbitrary substitution" means that the mentioned group is not substituted or is replaced by one or more groups independently selected from hydroxyl, halogen, amino, nitro, mercapto, cyano, azide, oxo, carboxyl, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)-C 1-6 Alkyl, -NH(C) 1-6 alkyl), -N(C) 1-6 Alkyl)(C 1-6 Alkyl), -C(O)NH-C 1-6 Alkyl group, -NHC(O)-C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl, 5-12 membered heteroaryl substituents; wherein the C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-12 heteroaryl group is optionally composed of one or more groups independently selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 The alkoxy group is replaced by a substituent.

[0262] The term "oxo" refers to the substitution of two hydrogen atoms at the same substitution site by the same oxygen atom to form a double bond.

[0263] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0264] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C) 2-4alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0265] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0266] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-7 carbon atoms (C 3-7 cycloalkyl groups), 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0267] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0268] Unless otherwise specified, the term "alkylamino" refers to -NR′R″, where R′ and R″ may be the same or different, and may be H or an alkyl group as defined above. The alkyl group is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, -NH(CH3), -N(CH3)(CH3), -N(CH2CH3)(CH3), -N(CH2CH3)[CH(CH3)2], etc.

[0269] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0270] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and one or more ring heteroatoms, comprising 3 to 20 ring atoms, wherein one, two, three or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. Preferably, it comprises 3 to 12 ring atoms (3-12 membered heterocyclic group), more preferably 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused-ring group"), bridged ("heterobridged ring group" or "bridged ring heterocyclic group") or spiro-fused ("heterospirocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A bicyclic heterocyclic system can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclobutane, oxacyclobutane, and thioheterocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxopentyl, oxathiocyclopentyl, dithiocyclopentyl, and... 2-oxazolidinone. Exemplary 5-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazolinyl groups. Diazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiocyclohexyl, and dioxazinanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiaazinyl, oxathiaazinyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazinyl, and thiocycloheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxadiazinyl, and thiocycloheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, and benzo[…]. Azolinone groups, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0271] Unless otherwise specified, "heterocyclic alkyl" refers to a monocyclic, saturated "heterocyclic group" or "heterocycle" as defined above, with the same definition of ring atoms, i.e., containing 3 to 20 ring atoms ("3-20-membered heterocyclic alkyl"), and the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 12 ring atoms ("3-12-membered heterocyclic alkyl"), more preferably containing 3 to 10 ring atoms ("3-10-membered heterocyclic alkyl"), even more preferably containing 3 to 8 ring atoms ("3-8-membered heterocyclic alkyl"), even more preferably containing 4 to 7 ring atoms ("4-7-membered heterocyclic alkyl"), even more preferably containing 5 to 10 ring atoms ("5-10-membered heterocyclic alkyl"), and even more preferably containing 5 to 6 ring atoms ("5-6-membered heterocyclic alkyl"). In some embodiments, each example of a heterocyclic alkyl group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic alkyl group") or substituted with one or more substituents (a "substituted heterocyclic alkyl group"). The "heterocyclic" or "heterocyclic" section above has given some exemplary examples of "heterocyclic alkyl groups," and also includes, but is not limited to, azirropropyl, oxacyclopropyl, thiocyclopropyl, azirrobutyl, oxacyclobutyl, thiocyclobutyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiohexyl, etc. azolealkyl, di Alkyl, dithiohexyl, thiazolyl, pyrrolithic, pyrazolyl, imidazoline, etc.

[0272] Unless otherwise specified, the term "aryl" or "aromatic ring group" refers to a monocyclic, bicyclic, or tricyclic aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyrene.

[0273] Unless otherwise specified, the terms "heteroaryl" or "heteroaryl cycloyl" refer to an aromatic monocyclic or polycyclic system containing a 5-14 member structure, or preferably a 5-10 member structure, or preferably a 5-8 member structure, more preferably a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups include, but are not limited to, furanyl, thiophene, etc. azole group, thiazolyl group, iso- azole group, Diazolyl, thiadiazolyl, pyrroleyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purineyl, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophenyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyridazinyl Pyrido[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.

[0274] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within the bounds of reasonable medical judgment, is suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final separation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0275] The compounds of this invention also include their "isotope derivatives". Unless otherwise specified, the term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O、 17 O and 18 O; and sulfur isotopes: 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 2 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (…2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0276] The compounds of this invention also include their terms "solvate" or "solvent". Unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. Solvent molecules in a solvate may be present in a regular and / or disordered arrangement. Solvates may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0277] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0278] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0279] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0280] The compounds of this invention also include their “prodrugs,” the term “prodrug” meaning, unless otherwise specified, a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester (“prodrug”) to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0281] Preparation Examples, Examples, and other abbreviations used herein are:

[0282] DMF: N,N-Dimethylformamide

[0283] DIPEA: N,N-Diisopropylethylamine

[0284] The beneficial effects of this invention are:

[0285] This application designs a class of novel compounds, providing a new direction for the treatment of diseases such as tumors. Experiments show that the compounds of this invention have a strong inhibitory effect on MAT2A, exhibit strong cell proliferation activity against HCT116 MTAP knockout cells, and weak cell proliferation activity against MTAP wild-type HCT116 cells, demonstrating good selectivity. They also exhibit good in vivo efficacy. Furthermore, human UGT1A1 enzyme activity testing indicates that the compounds of this invention have a low risk of inhibiting UGT1A1. Combined with in vivo serum total bilirubin detection, this demonstrates that the compounds of this invention did not cause a pathological increase in bilirubin, indicating low toxicity and good safety. In addition, this invention studies a specific synthetic method, which is simple, convenient to operate, and conducive to large-scale industrial production and application. Detailed Implementation

[0286] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0287] The following are examples of the preparation of exemplary compounds of this application.

[0288] Preparation Example 1: 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (A1)

[0289]

[0290] Step 1: 2-Chloro-N-(4-Chlorophenyl)-5-nitropyrimidine-4-amine

[0291] 2,4-Dichloro-5-nitropyrimidine (7.55 g, 38.92 mmol), p-chloroaniline (4.965 g, 38.92 mmol), DIPEA (5.03 g, 38.92 mmol), and DMF (85 mL) were added to a 250 mL round-bottom flask and stirred at room temperature. After the reaction was complete, the reaction solution was poured into 500 mL of water, a precipitate formed, which was filtered and dried to give 2-chloro-N-(4-chlorophenyl)-5-nitropyrimidine-4-amine (8.80 g, yield 79.3%). ESI-MS (m / z): 285.0 [M+H] + .

[0292] Step 2: Synthesis of N-(4-chlorophenyl)-2-ethoxy-5-nitropyrimidine-4-amine

[0293] The product from the previous step, 2-chloro-N-(4-chlorophenyl)-5-nitropyrimidine-4-amine (1.50 g, 5.2817 mmol), potassium carbonate (1.0955 g, 7.922 mmol), and ethanol (50 mL) were added to a 100 mL round-bottom flask and stirred overnight. After the reaction was complete, the reaction solution was concentrated and purified directly by column chromatography to obtain the product N-(4-chlorophenyl)-2-ethoxy-5-nitropyrimidine-4-amine (750 mg, yield 48.4%). ESI-MS (m / z): 295.1 [M+H] + .

[0294] Step 3: N 4 Synthesis of 4-(4-chlorophenyl)-2-ethoxypyrimidine-4,5-diamine

[0295] The product from the previous step, N-(4-chlorophenyl)-2-ethoxy-5-nitropyrimidine-4-amine (730 mg, 2.477 mmol), zinc powder (1296 mg, 19.817 mmol), ammonium chloride (2114 mg, 39.6 mmol), and methanol (20 mL) were added to a 50 mL round-bottom flask. The mixture was stirred at room temperature, and the reaction was completed after two hours. The mixture was filtered, and the filtrate was concentrated and directly purified by column chromatography to obtain N. 4 4-(4-Chlorophenyl)-2-ethoxypyrimidine-4,5-diamine (560 mg, yield 85.4%). ESI-MS (m / z): 265.1 [M+H] + .

[0296] Step 4: Synthesis of 8-(4-chlorophenyl)-2-ethoxy-5,8-dihydropteridine-6,7-dione

[0297] Take the product N from the previous step 4 350 mg (1.30 mmol) of 4-chlorophenyl)-2-ethoxypyrimidine-4,5-diamine, 503 mg (3.90 mmol) of DIPEA, 15 mL of toluene, and 3 mL of dichloromethane were added to a 50 mL round-bottom flask. The flask was placed in an ice bath, and a solution of dichloromethane containing 159 mg (1.30 mmol) of oxaloyl chloride was added dropwise. The mixture was brought to room temperature and stirred for 2 hours. Then, 1059 mg (3.25 mmol) of cesium carbonate was added, and the mixture was heated to 50 °C. After the reaction was complete, 20 mL of ethyl acetate and 15 mL of water were added, and the mixture was allowed to separate into two phases. The aqueous phase was washed twice with 20 mL of ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The mixture was concentrated and purified by column chromatography to obtain the target product 8-(4-chlorophenyl)-2-ethoxy-5,8-dihydropteridine-6,7-dione (203 mg, yield 55.3%). ESI-MS (m / z): 319.1 [M+H] + .

[0298] Step 5: 6-Chloro-8-(4-Chlorophenyl)-2-ethoxypterin-7(8H)-one

[0299] The product from the previous step, 8-(4-chlorophenyl)-2-ethoxy-5,8-dihydropteridine-6,7-dione (150 mg, 1.30 mmol), DMF (0.2 mL), and toluene (5 mL) were added to a 25 mL round-bottom flask. Then, thionyl chloride (350 mg, 1.30 mmol) was added, and the mixture was heated to 50 °C with stirring. After the reaction was complete, the mixture was concentrated under reduced pressure to give the target compound, 6-chloro-8-(4-chlorophenyl)-2-ethoxypteridine-7(8H)-one (103 mg, yield 64.9%). ESI-MS (m / z): 337.1 [M+H]+ .

[0300] Step 6: 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one

[0301] Take the product from the previous step, 6-chloro-8-(4-chlorophenyl)-2-ethoxypterin-7(8H)-one (30 mg, 0.089 mmol), 2-methyl-2H-indazole-5-boronic acid (26 mg, 0.1486 mmol), tetrakis(triphenylphosphine)palladium (3 mg, 0.01335 mmol), potassium carbonate (25 mg, 0.178 mmol), dioxane (10 mL), and water (1 mL), add them to a 25 mL round-bottom flask, purge with nitrogen three times, and heat to 100 °C. After the reaction was complete, 100 mL of ethyl acetate and 5 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (18 mg, yield 46.8%), ESI-MS (m / z): 433.1 [M+H]. + ; 1 H NMR (600MHz, CDCl3) δ9.043(s,1H),9.036(s,1H),8.28(d,J=9.2Hz,1H),8.01(s,1H),7.78(d,J=9 .2Hz,1H),7.57(d,J=8.5Hz,2H),7.28(d,J=8.5Hz,2H),4.30–4.25(m,4H),1.34(t,J=7.1Hz,3H).

[0302] Preparation Examples 2 to 14:

[0303] Following the synthetic route and procedures of Preparation Example 1, compounds A2-A14 were prepared using the corresponding intermediates as starting materials.

[0304]

[0305]

[0306]

[0307]

[0308] Preparation Example 15: 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (A15)

[0309]

[0310] Following the method for synthesizing A1, 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (50 mg, yield 57%) was synthesized from p-methoxyaniline and 2,2,2-trifluoroethylamine as starting materials. ESI-MS (m / z): 482.1 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.89(d,J=16.8Hz,1H),8.83(s,1H),8.50(s,1H),8.09(d,J=9.0Hz,1H),7.67(d,J=9.0Hz, 1H),7.33(br,2H),7.11(d,J=6.0Hz,2H),6.82-6.81(m,1H),4.19(s,3H),4.15(br,1H),3.84(s,3H),3.80(br,1H).

[0311] Preparation Example 16: 8-(3-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (A16)

[0312]

[0313] Following the method for synthesizing A1, 8-(3-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (135 mg, yield 42%) was synthesized from m-methoxyaniline and 2,2,2-trifluoroethylamine as starting materials. ESI-MS (m / z): 482.1 [M+H] + .

[0314] Preparation Example 17: 8-(3-hydroxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (A17)

[0315]

[0316] Compound A16 (100 mg, 0.208 mmol) and 20 mL of anhydrous dichloromethane were added to a 50 mL round-bottom flask, placed in an ethanol bath, and cooled to -20 °C. Boron tribromide (1.0 M dichloromethane solution) (1.4 mL, 1.4 mmol) was added dropwise. After the reaction was complete, water was slowly added to quench the reaction. The organic phase was washed successively with water and saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound (45 mg, yield 46%), ESI-MS (m / z): 468.2 [M+H]. + ; 1 H NMR (600MHz, DMSO) δ9.79–9.63(m,1H),8.92–8.77(m,2H),8.49(s,1H),8.40–8.13(m,1H),8.08(d,J=9.2Hz,1H) ,7.65(d,J=9.2Hz,1H),7.33(s,1H),6.89(d,J=8.0Hz,1H),6.81(s,2H),4.18(s,3H),4.15(s,1H),3.80(s,1H).

[0317] Preparation Example 18: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (A18)

[0318]

[0319] 6-Chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypterin-7(8H)-one was synthesized according to the method of Preparation Example 1. The intermediate (50 mg, 0.150 mmol), 2-methyl-5-amino-2H-indazole (33 mg, 0.225 mmol), 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (20 mg, 0.030 mmol), potassium carbonate (63 mg, 0.450 mmol) and dioxane (2 mL) were added to a 25 mL round-bottom flask, purged with nitrogen three times, and then heated to 100 °C for 3 h. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (30 mg, yield 45%), ESI-MS (m / z): 433.1 [M+H]. + ; 1H NMR (600MHz, DMSO-d6) δ9.62(s,1H),8.72(d,J=8.6Hz,2H),8.32(s,1H),8.27(d,J=2.3Hz,1H),7.84(dd,J=8.7,2.5Hz,1H),7.71(dd,J =9.2, 1.6Hz, 1H), 7.58 (d, J = 9.2Hz, 1H), 7.06 (d, J = 8.7Hz, 1H), 4.20 (d, J = 7.0Hz, 2H), 4.13 (s, 3H), 3.96 (s, 3H), 1.24 (t, J = 7.0Hz, 3H).

[0320] Preparation Example 19: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7(8H)-one (A19)

[0321]

[0322] Step 1: 2-Methyl-2H-indazole-5-ol

[0323] 2-Methyl-2H-indazole-5-boric acid (600 mg, 3.409 mmol), ammonium bicarbonate (270 mg, 3.409 mmol), hydrogen peroxide (660 μL), and acetonitrile (8 mL) were added to a 50 mL round-bottom flask and reacted at room temperature for 2 h. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 2-methyl-2H-indazole-5-ol (350 mg, yield 69%), ESI-MS (m / z): 149.1 [M+H]. + ;

[0324] Step 2: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7(8H)-one

[0325] Take 55 mg of 6-chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypterin-7(8H)-one (0.165 mmol), 2-methyl-2H-indazole-5 alcohol (24 mg, 0.164 mmol), potassium carbonate (63 mg, 0.450 mmol), and N,N-dimethylformamide (1 mL) into a 5 mL round-bottom flask and heat to 100 °C for 3 h. After the reaction was complete, 25 mL of ethyl acetate and 10 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7(8H)-one (40 mg, yield 54%), ESI-MS (m / z): 446.2 [M+H]. + ; 1 H NMR (600MHz, DMSO-d6) δ8.59(s,1H),8.39(s,1H),8.25(d,J=2.5Hz,1H),7.81(dd,J=8.7,2.6Hz,1H),7.72(d,J=9.2Hz,1H),7.59(d,J= 2.0Hz, 1H), 7.20 (dd, J = 9.2, 2.2Hz, 1H), 7.08 (d, J = 8.7Hz, 1H), 4.21 (s, 3H), 4.19 (q, J = 7.0Hz, 2H), 3.96 (s, 3H), 1.23 (t, J = 7.0Hz, 3H).

[0326] Preparation Example 20: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2,3,3a,7a-tetrahydrophenylfuran-6-yl)pteridine-7(8H)-one (A20)

[0327]

[0328] Following the method for synthesizing A1, 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2,3,3a,7a-tetrahydrophenylfuran-6-yl)pteridine-7(8H)-one (16 mg, yield 25%) was synthesized from 6-methoxypyridin-3-amine, (2,3,3a,7a-tetrahydrophenylfuran-6-yl)pteridine-7(8H)-one. ESI-MS (m / z): 420.2 [M+H] + ; 1H NMR (600MHz, CDCl3) δ9.03(s,1H),8.17(s,1H),7.89(d,J=7.1Hz,1H),7.73(s,1H),7.56(d,J=7.7Hz,1H),7.31(d,J=8.6Hz,1H) ,6.96(d,J=8.3Hz,1H),4.65(t,J=8.1Hz,2H),4.32(q,J=6.5Hz,2H),4.05(s,3H),3.29(t,J=7.9Hz,2H),1.38(t,J=5.9Hz,3H).

[0329] Preparation Example 21: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(7-bromo-3,4-dihydroisoquinoline-2(1H)yl)pterin-7(8H)-one (A21)

[0330]

[0331] Following the method for synthesizing A18, 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(7-bromo-3,4-dihydroisoquinoline-2(1H)yl)pterin-7(8H)-one (8 mg, yield 35%) was synthesized from 6-methoxy-3-aminopyridine and 6-bromo-1,2,3,4-tetrahydroisoquinoline as starting materials. ESI-MS (m / z): 509.2 [M+H] + .

[0332] Preparation Example 22: 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)oxy)-6-([1,2,4]triazol[4,3a]pyridin-6-yl)pteridine-7(8H)-one (A22)

[0333]

[0334] Following the method for synthesizing A1, 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)oxy)-6-([1,2,4]triazol[4,3a]pyridin-6-ylboronic acid were synthesized from p-methoxyaniline, 2,2,2-trifluoroethanol, and [1,2,4]triazol[4,3a]pyridin-6-yl)pteridine-7(8H)-one (5 mg, yield 7%), ESI-MS (m / z): 470.1 [M+H] + .

[0335] Preparation Example 23: 8-(4-chlorophenyl)-2-ethoxy-6-(2,3-dihydrobenzofuran-5-yl)pteridine-7(8H)-one (A23)

[0336]

[0337] Following the method for synthesizing A1, 8-(4-chlorophenyl)-2-ethoxy-6-(2,3-dihydrobenzofuran-5-yl)pteridine-7(8H)-one (1.2 mg, yield 5%) was synthesized from 2,3-dihydrobenzofuran-5-ylboronic acid and other starting materials. ESI-MS (m / z): 421.1 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ9.04(s,1H),8.17(s,1H),8.13(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,2H),7.49(d,J=8.4Hz ,2H),6.90(d,J=8.4Hz,1H),4.64(t,J=9.0Hz,2H),4.25-4.21(m,2H),3.27-3.26(m,2H),1.24(t,J=7.2Hz,3H).

[0338] Preparation Example 24: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7(8H)-one (A24)

[0339]

[0340] Step 1: Methyl 3-((2-methyl-2H-indazol-5-yl)thio)propionate

[0341] 5-Bromo-2-methyl-2H-indazole (1000 mg, 4.730 mmol), methyl 3-mercaptopropionate (850 mg, 7.110 mmol), tris[dibenzylideneacetone]palladium (260 mg, 0.280 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (274 mg, 0.473 mmol), N,N-diisopropylethylamine (2.34 mL, 1.420 mmol), and dioxane (40 mL) were added to a 100 mL round-bottom flask. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 4 h. After the reaction was complete, 25 mL of ethyl acetate and 10 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound methyl 3-((2-methyl-2H-indazole-5-yl)thio)propionate (500 mg, yield 42%), ESI-MS (m / z): 251.1 [M+H]. + ;

[0342] Step 2: 2-Methyl-2H-indazole-5-thiol

[0343] 500 mg (1.997 mmol) of methyl 3-((2-methyl-2H-indazole-5-yl)thio)propionate, 80 mg (2.000 mmol) of sodium hydroxide, and 5 mL of methanol were added to a 25 mL round-bottom flask. The mixture was purged three times with nitrogen and then heated to 50 °C for 3 h. After the reaction was complete, 25 mL of ethyl acetate and 10 mL of water were added to the reaction solution. The pH was adjusted to 4 with acetic acid. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 2-methyl-2H-indazole-5-thiol (98 mg, yield 30%), ESI-MS (m / z): 165.1 [M+H]. + ;

[0344] Step 3: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7(8H)-one

[0345] 6-chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypterin-7(8H)-one (100 mg, 0.300 mmol), 2-methyl-2H-indazole-5-thiol (98 mg, 0.599 mmol), tris[dibenzylideneacetone]palladium (33 mg, 0.036 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (35 mg, 0.060 mmol), potassium carbonate (208 mg, 1.498 mmol), and dioxane (5 mL) were added to a 25 mL round-bottom flask. After purging with nitrogen three times, the mixture was heated to 100 °C and reacted for 3 h. After the reaction was complete, 25 mL of ethyl acetate and 10 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7(8H)-one (18 mg, yield 13%), ESI-MS (m / z): 462.1 [M+H]. + ; 1 H NMR (600MHz, DMSO-d6) δ8.58(s,1H),8.47(s,1H),8.25(d,J=2.2Hz,1H),8.06(s,1H),7.81(dd,J=8.7,1.9Hz,1H),7.74(d,J=8 .9Hz,1H),7.35(d,J=8.9Hz,1H),7.06(d,J=8.7Hz,1H),4.23(s,3H),4.19(q,J=7.0Hz,2H),3.95(s,3H),1.22(t,J=7.0Hz,3H).

[0346] Preparation Example 25: 8-(2-hydroxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (A25)

[0347]

[0348] Following the method for synthesizing A17, 8-(2-hydroxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (50 mg, yield 57%) was synthesized from o-methoxyaniline and 2,2,2-trifluoroethylamine as starting materials. ESI-MS (m / z): 468.1 [M+H] + .

[0349] Preparation Example 26: 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A26)

[0350]

[0351] Step 1: 2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethane-1-ol

[0352] 15 g (0.181 mmol) of 4-bromo-2-methylaminoaniline, 33.6 mL (111.90 mmol) of 3-hydroxypropionic acid (28% aqueous solution), 150 mL of hydrochloric acid, and 120 mL of water were added to a 500 mL round-bottom flask and heated to 105 °C for 48 h. After the reaction, the pH was adjusted to 8-9 with sodium hydroxide. The aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, washed successively with water and saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound 2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethane-1-ol (3.5 g, yield 18%), ESI-MS (m / z): 255.1 [M+H]. + ;

[0353] Step 2: 4-(2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)morpholine

[0354] Dissolve 2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethane-1-ol (200 mg, 0.789 mmol) in dichloromethane (5 mL) in a 25 mL round-bottom flask. Add triethylamine (238 mg, 2.352 mmol) and methanesulfonyl chloride (135 mg, 1.176 mmol), and react at room temperature for 1 h. Then add morpholine (341 mg, 3.920 mmol), and react at room temperature for 48 h. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. The solution was concentrated and purified by column chromatography to obtain the target compound 4-(2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)morpholine (179 mg, yield 70%), ESI-MS (m / z): 324.1 [M+H]. + ;

[0355] Step 3: 4-(2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-di) Boropentan-2-yl)-1H-benzo[d]imidazol-2-yl)ethyl)morpholine

[0356] 4-(2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)morpholine (67 mg, 0.207 mmol), bis(pinacol)boronic acid ester (79 mg, 0.310 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (23 mg, 0.031 mmol), potassium acetate (61 mg, 0.621 mmol), and dioxane (2 mL) were added to a 10 mL round-bottom flask. After purging with nitrogen three times, the mixture was heated to 110 °C and reacted for 3 h. After the reaction was completed, the mixture was cooled to room temperature and used directly in the next step. ESI-MS (m / z): 372.2 [M+H] + .

[0357] Step 4: 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one

[0358] The compound 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (20 mg, yield 16%) was synthesized according to the method for synthesizing A1. ESI-MS (m / z): 595.2 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ8.91(s,1H),8.43(s,1H),8.17(s,1H),8.08(d,J=7.5Hz,1H),7.62(d,J=8.5Hz,1H),7.34(s,2H),7.11(d,J=6.1Hz,2H) ,4.21-4.14(m,1H),3.85(s,3H),3.84-3.83(m,1H),3.80(s,3H),3.61- 3.59(m,4H),3.1(t,J=7.2Hz,2H),2.86-2.81(m,2H),2.50-2.46(m,4H).

[0359] Preparation Example 27: 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A27)

[0360]

[0361] Following the method for synthesizing A26, 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (20 mg, yield 21%) was synthesized from 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pterin-7(8H)-one, using 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pterin-7(8H)-one as starting materials. ESI-MS (m / z): 526.2 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ8.90(d,J=15.7Hz,1H),8.44(s,1H),8.17(s,1H),8.09(d,J=8.5Hz,1H),7.63(d,J=8.5Hz,1H),7.35(s,2H),7.11(d,J =6.9Hz,2H),4.89(t,J=5.3Hz,1H),4.21-4.13(m,1H),3.90-3.87(m,2 H), 3.85 (s, 3H), 3.84-3.82 (m, 1H), 3.80 (s, 3H), 3.08 (t, J = 6.7Hz, 2H).

[0362] Preparation Example 28: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A28)

[0363]

[0364] Following the method for synthesizing 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A26), 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (240 mg, yield 38%) was synthesized from 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, and 3-hydroxypropanoic acid as starting materials. ESI-MS (m / z): 509.2 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ9.10(s,1H),8.47(s,1H),8.12(d,J=8.4Hz,1H),7.66(d,J=8.5Hz,1H),7.54(d,J=8.7Hz,2H),7.41(d,J=8.6Hz,2H),7. 39(t,J=73.9Hz,1H),4.91(t,J=5.3Hz,1H),4.26(q,J=6.9Hz,2H),3.90 -3.87(m,2H),3.81(s,3H),3.08(t,J=6.6Hz,2H),1.26(t,J=7.0Hz,3H).

[0365] Preparation Example 29: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A29)

[0366]

[0367] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, and 2-methoxyacetic acid were synthesized as starting materials to produce 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (48 mg, yield 35%). ESI-MS (m / z): 509.2 [M+H]. + ; 1H NMR (600MHz, DMSO-d6) δ9.12(s,1H),8.53(s,1H),8.16(d,J=8.5Hz,1H),7.74(d,J=8.6Hz,1H),7.54(t,J=8.8Hz,2H),7.41( d,J=8.7Hz,2H),7.39(t,J=73.9Hz,1H),4.75(s,2H),4.27(q,J=7.0Hz,2H),3.86(s,3H),3.37(s,3H),1.26(t,J=7.0Hz,3H).

[0368] Preparation Example 30: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(3-methoxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A30)

[0369]

[0370] Dissolve 40 mg (0.079 mmol) of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A26) in 5 mL of dichloromethane in a 25 mL round-bottom flask. Add triethylamine (109 μL, 0.786 mmol) and methanesulfonyl chloride (50 μL, 0.629 mmol), and react at room temperature for 1 h. Then add 3-methoxypyrrolidine hydrochloride (162 mg, 1.179 mmol) and triethylamine (220 μL, 1.572 mmol), and react at room temperature for 48 h. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the organic phase was purified by column chromatography to obtain the target compound 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(3-methoxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (18 mg, yield 39%), ESI-MS (m / z): 592.2 [M+H]. + ; 1H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 8.47 (s, 1H), 8.13 (d, J = 8.4Hz, 1H), 7.66 (d, J=8.5Hz,1H),7.54(d,J=8.8Hz,2H),7.41(d,J=8.7Hz,2H),7.40(t,J=74Hz,1H), 4.26(q,J=7.0Hz,2H),3.90(s,1H),3.81(s,3H),3.19(s,3H),3.10(s,2H),2.94( s,2H),2.78(s,1H),2.70(s,1H),2.00(s,1H),1.68(s,1H),1.26(t,J=7.0Hz,3H).

[0371] Preparation Example 31: 8-(2,3-dihydrobenzofuran-4-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (A31)

[0372]

[0373] Following the method for synthesizing A1, 8-(2,3-dihydrobenzofuran-4-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (15 mg, yield 53%) was synthesized from 2,3-dihydro-4-aminobenzofuran and other starting materials. ESI-MS (m / z): 441.2 [M+H] + .

[0374] Preparation Example 32: 6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzimidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A32)

[0375]

[0376] Following the method for synthesizing A26, 6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzimidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (15 mg, yield 17%) was synthesized from 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pterin-7(8H)-one using pyrrolidone as starting materials. ESI-MS (m / z): 595.2 [M+H] + ; 1H NMR (600MHz, CDCl3) δ8.90(s,1H),8.60(s,1H),8.28(d,J=8.6Hz,1H),7.78(d,J=8.6Hz,1H),7.28–7.22(m,3H),7.12(d,J=8.7Hz,2H),5.91(brs ,1H),3.92(s,3H),3.86(s,1H),3.80(s,3H),2.89(t,J=10.2Hz,2H),2.6 7-2.64(m,2H),2.50-2.40(m,1H),2.28-2.22(m,2H),1.87-1.78(m,2H).

[0377] Preparation Example 33: 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(benzyloxy)phenyl)pterin-7(8H)-one (A33)

[0378]

[0379] Following the method for synthesizing A1, 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(benzyloxy)phenyl)pterin-7(8H)-one (9 mg, yield 42%) was synthesized from 3-benzyloxyaniline and 2,2,2-trifluoroethylamine as starting materials. ESI-MS (m / z): 558.2 [M+H] + .

[0380] Preparation Example 34: 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(phenylethoxy)phenyl)pterin-7(8H)-one (A34)

[0381]

[0382] Following the method for synthesizing A1, 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(phenylethoxy)phenyl)pterin-7(8H)-one (13 mg, yield 58%) was synthesized from 3-phenylethylaniline and 2,2,2-trifluoroethylamine as starting materials. ESI-MS (m / z): 572.2 [M+H] + .

[0383] Preparation Example 35: 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (A35)

[0384]

[0385] Following the method for synthesizing A26, 6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (33 mg, yield 15%) was synthesized from 4-(trifluoromethoxy)phenyl)aniline, 2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one. ESI-MS (m / z): 580.2 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ8.93-8.89(m,1H),8.44(s,1H),8.16(s,1H),8.08(s,1H),7.65–7.55(m,5H),4.87(t ,J=5.4Hz,1H),4.19-4.12(m,1H),3.89-3.86(m,2H),3.79(s,3H),3.77–3.70(m,1H),3.06(t,J=6.7Hz,2H).

[0386] Preparation Example 36: 6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (A36)

[0387]

[0388] Following the method for synthesizing A26, 6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (20 mg, yield 9%) was synthesized from 4-(trifluoromethoxy)phenyl)phenyl)pterin-7(8H)-one using 4-(trifluoromethoxy)aniline, 2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one as starting materials. ESI-MS (m / z): 649.2 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ8.94-8.91(m,1H),8.45(s,1H),8.18(s,1H),8.09(s,1H),7 .68–7.56(m,5H),4.71(brs,1H),4.23-4.16(m,2H),3.80(s,3H),3.78-3.73(m,1H), 3.07(t,J=7.5Hz,2H),2.94-2.86(m,2H),2.79(dd,J=9.2,6.3Hz,1H),2.71–2.63(m, 1H),2.54-2.52(m,1H),2.41(d,J=6.3Hz,1H),2.02-1.96(m,1H),1.59–1.52(m,1H).

[0389] Preparation Example 37: 6-(2-(2,4-difluoropiperidin-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (A37)

[0390]

[0391] Following the method for synthesizing A26, 6-(2-(2,4-difluoropiperidin-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (25 mg, yield 11%) was synthesized from 4-(trifluoromethoxy)phenyl)aniline, 2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one. ESI-MS (m / z): 683.2 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ8.94-8.90(m,1H),8.45(s,1H),8.18(s,1H),8.09(s,1H),7.67–7.56(m,5H),4.22-4.14(m,1H),3 .80(s,3H),3.78-3.74(m,1H),3.11(t,J=7.0Hz,2H),2.98-2.90(m,2H),2.70-2.62(m,4H),2.02-1.94(d,J=12.4Hz,4H).

[0392] Preparation Example 38: 8-(4-(trifluoromethoxy)phenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (A38)

[0393]

[0394] Following the method for synthesizing A1, 8-(4-(trifluoromethoxy)phenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)-one (30 mg, yield 20%) was synthesized from (1-(trifluoromethyl)cyclopropyl)amine and 4-(trifluoromethoxy)aniline as starting materials. ESI-MS (m / z): 562.1 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ8.94(br,1H),8.86(s,1H),8.63(s,1H),8.51(s,1H),8.10 (d,J=9.0Hz,1H),7.67-7.60(m,5H),4.20(s,3H),1.33-1.12(m,2H),0.90(br,2H).

[0395] Preparation Example 39: 6-(2-(2-(3-methoxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (A39)

[0396]

[0397] Following the method for synthesizing A26, 6-(2-(2-(3-methoxypyrrolidine-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (9 mg, yield 6%) was synthesized from 4-(trifluoromethoxy)phenyl)aniline, 2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one. ESI-MS (m / z): 663.2 [M+H] + ; 1H NMR(600MHz,DMSO-d6)δ8.94-8.92(m,1H),8.45(s,1H),8.18(s,1H),8.09(d ,J=4.5Hz,1H),7.66–7.57(m,5H),4.21-4.14(m,1H),3.92-3.88(m,2H),3.8 0(s,3H),3.76(s,3H),3.10(t,J=6.9Hz,2H),3.05(t,J=7.0Hz,2H),2.78(s, 1H),2.69(s,1H),2.63(s,1H),2.53(s,1H),2.01–1.98(m,1H),1.68(s,1H).

[0398] Preparation Example 40: 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(3-methoxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A40)

[0399]

[0400] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(3-methoxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (13 mg, yield 9%) was synthesized from 4-(difluoromethoxy)aniline, 2,2,2-trifluoroethyl)amino)pterin-7(8H)-one using 4-(difluoromethoxy)aniline, 2,2,2-trifluoroethyl)amino)pterin-7(8H)-one as starting materials. ESI-MS (m / z): 645.2 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ8.93-8.90(m,1H),8.43(s,1H),8.18(s,1H),8.08(d,J=8.5Hz,1H),7.6 3(d,J=8.5Hz,1H),7.56–7.48(m,2H),7.39(d,J=7.1Hz,2H),7.23(d,J=8.5Hz,1H),4.20-4.16(m ,1H),3.90-3.87(s,2H),3.79(s,3H),3.18(s,3H),3.10-3.03(m,2H),2.95-2.86(s,2H),2.76( s,1H),2.68(s,1H),2.63-2.60(m,1H),2.01-1.98(m,1H),1.69-1.64(m,1H),1.50-1.45(m,1H).

[0401] Preparation Example 41: 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(2,6-dimethylmorpholino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (A41)

[0402]

[0403] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(2-(2,6-dimethylmorpholino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (51 mg, yield 27%) was synthesized from 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and 2,6-dimethylmorpholino as starting materials. ESI-MS (m / z): 606.2 [M+H] + ; 1 H NMR(600MHz,DMSO-d6)δ9.10(d,J=6.8Hz,1H),8.46(s,1H),8.11(dd,J=8.6,1.4Hz,1H),7.65( d,J=8.5Hz,1H),7.54(d,J=8.8Hz,2H),7.41(d,J=8.7Hz,2H),7.39(t,J=73.8Hz,1H),4.26(q, J=7.0Hz,2H),3.80(s,3H),3.60–3.54(m,2H),3.10(t,J=7.5Hz,2H),2.88(d,J=10.6Hz,2H),2 .80(t,J=7.6Hz,2H),1.73(t,J=10.6Hz,2H),1.26(t,J=7.0Hz,3H),1.08(s,3H),1.07(s,3H).

[0404] Preparation Example 42: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A42)

[0405]

[0406] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one was synthesized from 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and pyrrolidol as starting materials. The yields were 32 mg (16%) and 25 mg (11%). ESI-MS (m / z): 578.2 [M+H]. + ; 1 H NMR(600MHz,DMSO-d6)δ9.10(s,1H),8.49(s,1H),8.13(d,J=8.5Hz,1H),7.67(d,J=8.5 Hz,1H),7.54(d,J=8.7Hz,2H),7.41(d,J=8.7Hz,2H),7.39(t,J=74Hz,1H),5.10(brs,1 H),4.35-4.31(m,1H),4.26(q,J=7.0Hz,2H),3.82(s,3H),3.25-3.21(m,3H),3.14-3.0 (m,3H),2.99–2.84(m,2H),2.12-2.06(m,1H),1.75-1.69(m,1H),1.26(t,J=7.0Hz,3H).

[0407] Preparation Example 43: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(piperidin-1-yl)ethyl)-1Hbenzi[d]imidazol-6-yl)pterin-7(8H)-one (A43)

[0408]

[0409] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and piperidine were synthesized as starting materials: 4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(piperidin-1-yl)ethyl)-1Hbenzi[d]imidazol-6-yl)pterin-7(8H)-one (32 mg, yield 16%). ESI-MS (m / z): 576.2 [M+H] + ; 1H NMR (600MHz, DMSO-d6) δ9.10 (s, 1H), 8.47 (s, 1H), 8.12 (d, J = 8.3Hz, 1H), 7.66 ( d,J=8.1Hz,1H),7.54(d,J=8.7Hz,2H),7.41(d,J=8.6Hz,2H),7.39(t,J=73.9Hz ,1H),4.26(q,J=7.0Hz,2H),3.81(s,3H),3.16-3.09(m,2H),2.95-2.82(m,2H) ,2.63-2.5(s,4H),1.59-1.52(m,4H),1.46-1.40(m,2H),1.26(t,J=7.0Hz,3H).

[0410] Preparation Example 44: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(pyrrolidone-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A44)

[0411]

[0412] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and tetrahydropyrrolidine were synthesized from starting materials as 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(pyrrolidone-1-yl)ethyl)-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (17 mg, yield 9%), ESI-MS (m / z): 562.2 [M+H] + ; 1 H NMR (600MHz, DMSO-d6) δ9.11(s,1H),8.49(s,1H),8.14(s,1H),7.69(s,1H),7.54(d,J=8.1Hz,2H),7.41(d,J=8.3Hz,2H),7.39(t, J=74.1Hz,1H),4.27(q,J=6.8Hz,2H),3.83(s,3H),3.27–3.20(m,4H),3.02-2.88(m,4H),1.89-1.81(m,4H),1.26(t,J=6.7Hz,3H).

[0413] Preparation Example 45: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-fluoropyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A45)

[0414]

[0415] Dissolve 40 mg (0.079 mmol) of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A28) in 5 mL of dichloromethane in a 25 mL round-bottom flask. Add triethylamine (109 μL, 0.786 mmol) and methanesulfonyl chloride (50 μL, 0.629 mmol), and react at room temperature for 1 h. Then add 3-fluorotetrahydropyrrole hydrochloride (99 mg, 0.786 mmol) and triethylamine (164 μL, 1.179 mmol), and react at room temperature for 48 h. After the reaction was complete, 100 mL of ethyl acetate and 50 mL of water were added to the reaction solution. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the organic phase was purified by column chromatography to obtain the target compound 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-fluoropyrrolidone-1-yl)ethyl)-1-methyl-1H-benzo[d]]imidazol-6-yl)pterin-7(8H)-one (21 mg, yield 47%), ESI-MS (m / z): 580.2 [M+H]. + ; 1 H NMR(600MHz,DMSO-d6)δ9.10(s,1H),8.47(s,1H),8.12(d,J=7.8Hz,1H),7.66(d,J=8.1H z,1H),7.54(d,J=7.4Hz,2H),7.52-7.27(m,3H),5.22(d,J=55..7Hz,1H),4.26(q,J=6.5 Hz,2H),3.81(s,3H),3.12(t,J=6.0Hz,2H),2.97(t,J=6.0Hz,2H),2.92(s,2H),2.72-2. 67(m,1H),2.42(s,1H),2.16(s,1H),1.92-1.87(m,J=24.9Hz,1H),1.26(t,J=6.5Hz,3H).

[0416] Preparation Example 46: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A46)

[0417]

[0418] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid, and other starting materials were used to synthesize 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (150 mg, yield 21%). ESI-MS (m / z): 495.2 [M+H] + ; 1 HNMR (600MHz, DMSO-d6) δ9.11(s,1H),8.52(s,1H),8.15(d,J=8.5Hz,1H),7.71(d,J=8.6Hz,1H),7.54(d,J=8.8Hz,2H),7.41(d,J=8.7H z, 2H), 7.39 (t, J = 73.9Hz, 1H), 5.67 (t, J = 6.0Hz, 1H), 4.78 (d, J = 6.0Hz, 2H), 4.27 (q, J = 7.0Hz, 2H), 3.88 (s, 3H), 1.26 (t, J = 7.1Hz, 3H).

[0419] Preparation Example 47: 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (A47)

[0420]

[0421] Following the method for synthesizing A45, 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (16 mg, yield 38%) was synthesized from 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and dimethylamine hydrochloride as starting materials. ESI-MS (m / z): 536.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.09(s,1H),8.46(s,1H),8.11(d,J=8.4Hz,1H),7.65(d,J=8.4Hz,1H),7.53(d,J=8.4Hz,2H),7.51– 7.25(m,3H),4.25(q,J=,6.8Hz,2H),3.80(s,3H),3.10(t,J=6.7Hz,2H),2.89(s,2H),2.34(s,6H),1.25(t,J=6.9Hz,3H).

[0422] Preparation Example 48: 6-(2-(2-(diethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (A48)

[0423]

[0424] Following the method for synthesizing A45, 6-(2-(2-(diethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (15 mg, yield 37%) was synthesized from 4-(difluoromethoxy)phenyl)-4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and diethylaminoamine hydrochloride as starting materials. ESI-MS (m / z): 564.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.09(s,1H),8.46(s,1H),8.11(d,J=8.5Hz,1H),7.65(d,J=8.4Hz,1H),7.53(d,J=8.7Hz,2H),7.40(d,J=8.7Hz,2H ),7.38(t,J=73.7Hz,1H),4.25(q,J=7.0Hz,2H),3.80(s,3H),3.10–2.90(m,4H),2.70–2.55(s,4H),1.25(t,J=7.0Hz,3H),1.01(s,6H).

[0425] Preparation Example 49: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridine-7(8H)-one (A49)

[0426]

[0427] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (35 mg, yield 35%) was synthesized from 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid, and diethylamine hydrochloride as starting materials. ESI-MS (m / z): 523.2 [M+H] + ; 1H NMR (600MHz, DMSO) δ9.10(s,1H),8.47(s,1H),8.12(d,J=8.5Hz,1H),7.69(d,J=8.5Hz,1H),7.53(d,J=8.7Hz,2H),7.40(d, J=8.7Hz,2H),7.38(t,J=73.7Hz,1H),5.69(s,1H),4.25(q,J=7.0Hz,2H),4.05(s,3H),1.65(s,6H),1.25(t,J=7.0Hz,3H).

[0428] Preparation Example 50: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine-7(8H)-one (A50)

[0429]

[0430] Step 1: 5-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole

[0431] 5-Bromoindole (1.96 g, 10 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (4.78 g, 20 mmol), norbornene (1.88 g, 20 mmol), bis(acetonitrile)palladium dichloride (260 mg, 1 mmol), potassium carbonate (2.76 g, 20 mmol), and DMF (20 mL) were added to a 100 mL flask. After purging with nitrogen, the mixture was stirred at 70 °C. After the reaction was complete, the mixture was cooled and 150 mL of water was added. The mixture was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by column chromatography to give 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (1.0 g, yield 28%), ESI-MS (m / z): 354.1, 356.1 [M+H]. + ;

[0432] Step 2: 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-indole

[0433] The product from the previous step, 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (200 mg, 0.56 mmol), bis(pinacolyl)diboron (0.28 g, 1.14 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (82 mg, 0.11 mmol), potassium acetate (165 mg, 1.6 mmol), and dioxane (5 mL) were added to a 100 mL round-bottom flask. After purging with nitrogen, the mixture was stirred at 105 °C. After the reaction was complete, no further treatment was performed; the temperature was directly lowered to proceed to the next step. ESI-MS (m / z): 402.3 [M+H] + ;

[0434] Step 3: 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one

[0435] Water (1 mL), 6-chloro-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (100 mg, 0.28 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (82 mg, 0.11 mmol), and potassium acetate (165 mg, 1.6 mmol) were added to the above reaction solution. After nitrogen purging, the mixture was stirred at 100 °C. After the reaction was completed, the mixture was cooled, and 100 mL of water and 200 mL of ethyl acetate were added for extraction twice. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (50 mg, yield 29%), ESI-MS (m / z): 608.2 [M+H]. + ;

[0436] Step 4: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine-7(8H)-one

[0437] The product from the previous step, 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridine-7(8H)-one (20 mg, 0.033 mmol), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1 M, 0.1 mL) were added to a 100 mL round-bottom flask and stirred at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by thin-plate chromatography to obtain 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine-7(8H)-one (4 mg, 25%), ESI-MS (m / z): 494.2 [M+H]. + ; 1 H NMR (600MHz, DMSO-d6) δ11.14(s,1H),9.04(s,1H),8.50(s,1H),7.98(dd,J=8.4,1.2Hz,1H),7.52(d,J=9.0Hz,2H),7.39-7.36(m,3H),7 .38(t,J=73.8Hz,1H),6.29(s,1H),4.25-4.22(m,2H),3.74(t,J=7.2Hz,2H),2.44(br,1H)2.88(t,J=6.6Hz,2H),1.24(t,J=6.6Hz,3H).

[0438] Preparation Example 51: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)pteridine-7-(8H)-one (A51)

[0439]

[0440] Step 1: 6-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one

[0441] 30 mg (0.049 mmol) of 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one and 5 mL of DMF were added to a 100 mL round-bottom flask. 60% sodium hydride (4 mg, 0.1 mmol) was added under ice bath conditions, and the mixture was stirred at room temperature for 10 minutes. Iodomethane (14.2 mg, 0.1 mmol) was then added, and the mixture was stirred at room temperature. After the reaction was complete, 100 mL of water and 200 mL of ethyl acetate were added, and the mixture was extracted twice. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The product was purified by thin-layer chromatography to obtain 6-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (20 mg, 65%), ESI-MS (m / z): 622.3 [M+H]. +

[0442] Step 2: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)pteridine-7-(8H)-one

[0443] The product from the previous step, 6-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (20 mg, 0.032 mmol), tetrahydrofuran (5 mL), and tetrabutylammonium fluoride (1 M, 0.1 mL) were added to a 100 mL round-bottom flask and stirred at room temperature. After the reaction was complete, the reaction solution was concentrated and purified by thin-plate chromatography to obtain 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indol-5-yl)pterin-7-(8H)-one (5 mg, yield 31%), ESI-MS (m / z): 508.2 [M+H]. + ; 1 HNMR(600MHz,DMSO-d6)δ9.04(s,1H),8.52(s,1H),7.52-7.50(m,4H),,7.39-7.37(m,3H) ,6.38(s,1H),4.25-4.22(m,2H),3.77-3.73(m,5H),2.95-2.92(m,2H),1.25-1.23(m,3H).

[0444] Preparation Example 52: 2-ethoxy-8-(4-fluorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A52)

[0445]

[0446] Following the method for synthesizing A26, 2-ethoxy-8-(4-fluorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (19 mg, yield 15%) was synthesized from p-fluoroaniline, ethanol, 4-bromo-2-methylaminoaniline, and glycolic acid as starting materials. ESI-MS (m / z): 447.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.10(s,1H),8.51(s,1H),8.14(dd,J=8.6,1.5Hz,1H),7.70(d,J=8.6Hz,1H),7..53(dd,J=8.8,5.1Hz,2H) ,7.44(t,J=8.8Hz,2H),5.64(t,J=5.8Hz,1H),4.76(d,J=5.8Hz,2H),4.23(q,J=7.0Hz,2H),3.87(s,3H),1.24(t,J=7.0Hz,3H).

[0447] Preparation Example 53: 8-(4-chlorophenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A53)

[0448]

[0449] Following the method for synthesizing A26, 8-(4-chlorophenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (12 mg, yield 13%) was synthesized from p-chloroaniline, ethanol, 4-bromo-2-methylaminoaniline, and glycolic acid as starting materials. ESI-MS (m / z): 463.1 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.10(s,1H),8.50(s,1H),8.14(d,J=8.5Hz,1H),7.71(d,J=8.5Hz,1H),7.67(d,J=8.6Hz,2H),7.51( d,J=8.6Hz,2H),5.64(t,J=5.8Hz,1H),4.76(d,J=5.8Hz,2H),4.24(q,J=7.0Hz,2H),3.87(s,3H),1.25(t,J=7.1Hz,3H).

[0450] Preparation Example 54: 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A54)

[0451]

[0452] Following the method for synthesizing A26, 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (10 mg, yield 11%) was synthesized from p-6-cyclopropylpyridin-3-amine, ethanol, 4-bromo-2-methylaminoaniline, and glycolic acid as starting materials. ESI-MS (m / z): 470.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.11 (s, 1H), 8.49 (s, 1H), 8.46 (d, J = 2.3Hz, 1H), 8.13 (dd, J = 8 .6,1.6Hz,1H),7.77(dd,J=8.3,2.5Hz,1H),7.70(d,J=8.5Hz,1H),7.48(d,J=8.5Hz ,1H),5.64(t,J=5.8Hz,1H),4.76(d,J=5.8Hz,2H),4.26(q,J=7.0Hz,2H),3.76(s,3 H),2.26–2.21(m,2H),1.26(t,J=7.1Hz,3H),1.24–1.22(m,2H),1.03-1.00(m,2H).

[0453] Preparation Example 55: 6-(2-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (A55)

[0454]

[0455] Following the method for synthesizing A26, 6-(2-(tert-butyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridine-7(8H)-one (50 mg, yield 35%) was synthesized from 4-(difluoromethoxy)phenyl)-2-ethoxypteridine-7(8H)-one as starting materials. ESI-MS (m / z): 521.2 [M+H] + ; 1H NMR (600MHz, DMSO) δ9.09(s,1H),8.45(s,1H),8.10(d,J=8.5Hz,1H),7.66(d,J=8.5Hz,1H),7.53(d,J=8.7Hz,2H),7 .39(d,J=8.7Hz,2H),7.38(t,J=73.7Hz,1H),4.25(q,J=7.0Hz,2H),3.95(s,3H),1.51(s,9H),1.25(t,J=7.0Hz,3H).

[0456] Preparation Example 56: 6-(2-acetyl-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (A56)

[0457]

[0458] Following the method for synthesizing A26, 6-(2-acetyl-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypterin-7(8H)-one (35 mg, yield 18%) was synthesized from 4-(difluoromethoxy)aniline, ethanol, and 1-(5-bromo-2H-indazol-2-yl)ethane-1-one as starting materials. ESI-MS (m / z): 493.1 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.11(s,1H),8.84(d,J=0.7Hz,1H),8.62(s,1H),8.45(dd,J=8.8,1.6Hz,1H),8.41(d,J=8.8Hz,1H),7.5 2(d,J=8.8Hz,2H),7.40(d,J=8.8Hz,2H),7.39(t,J=73.7Hz,1H),4.25(q,J=7.0Hz,2H),2.75(s,3H),1.25(t,J=7.0Hz,3H).

[0459] Preparation Example 57: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(1-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridine-7(8H)-one (A57)

[0460]

[0461] Following the method for synthesizing A26, 8-(4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, lactic acid, etc., were synthesized as starting materials to produce 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(1-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (25 mg, yield 18%). ESI-MS (m / z): 509.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ9.10(s,1H),8.49(s,1H),8.13(d,J=8.5Hz,1H),7.70(d,J=8.5Hz,1H),7.53(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H),7.38 (t,J=73.7Hz,1H),5.66(d,J=6.1Hz,1H),5.11–5.06(m,1H),4.25(q,J=6.9Hz,2H),3.90(s,3H),1.60(d,J=6.5Hz,3H),1.25(t,J=7.0Hz,3H).

[0462] Preparation Example 58: 6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (A58)

[0463]

[0464] Following the method for synthesizing A26, 6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (20 mg, yield 14%) was synthesized from 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one using 2-methyl-2-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one as starting materials. ESI-MS (m / z): 540.2 [M+H] + ; 1H NMR (600MHz, DMSO) δ8.89(d,J=15..8Hz,1H),8.44(s,1H),8.40-8.16(m,1H),8.08(d,J=8.3Hz,1H),7.65(d,J=8.5Hz,1H),7 .34(s,2H),7.10(d,J=6.1Hz,2H),5.67(s,1H),4.20–4.12(m,1H),4.04(s,3H),3.84(s,3H),3.82–3.77(m,1H),1.65(s,6H).

[0465] Preparation Example 59: 6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (A59)

[0466]

[0467] Following the method for synthesizing A26, 6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (25 mg, yield 19%) was synthesized from 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one using 4-methoxyaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one as starting materials. ESI-MS (m / z): 512.2 [M+H] + ; 1 H NMR (600MHz, DMSO) δ8.90(d,J=15.9Hz,1H),8.47(s,1H),8.40-8.17(m,1H),8.10(d,J=8.6Hz,1H),7.67(d,J=8.6Hz,1H),7.34(s,2H) ,7.10(d,J=6.8Hz,2H),5.64(t,J=5.4Hz,1H),4.75(d,J=5.4Hz,2H),4.19–4.12(m,1H),3.86(s,3H),3.84(s,3H),3.81–3.76(m,1H).

[0468] Preparation Example 60: 8-((1H-imidazol-2-yl)methyl)-2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridine-7(8H)-one (A60)

[0469]

[0470] Following the method for synthesizing A26, 2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1H-benzo[d]imidazol-6-yl)-8-((1-((2-(trimethylsilyl))ethoxy)methyl)-1H-imidazol-2-yl)methyl)pteridine-7(8H)-one was synthesized from (1-((2-(trimethylsilyl))ethoxy)methyl)-1H-imidazol-2-yl)methyl)pteridine-7(8H)-one.

[0471] Dissolve 50 mg (0.084 mmol) of 2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-((1-((2-(trimethylsilyl))ethoxy)methyl)-1H-imidazol-2-yl)methyl)pteridine-7(8H)-one in 5 mL of dichloromethane in a 25 mL round-bottom flask, add 2.5 mL of trifluoroacetic acid, and react at room temperature for 3 h. After the reaction was complete, the solvent was removed under reduced pressure, 50 mL of water was added, and the pH was adjusted to approximately 7 with sodium bicarbonate. The aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed successively with water and saturated sodium chloride solution. After concentration, the organic phase was purified by column chromatography to obtain the target compound 8-((1H-imidazol-2-yl)methyl)-2-ethoxy-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (12 mg, yield 31%), ESI-MS (m / z): 461.2 [M+H]. + ; 1 H NMR (600MHz, DMSO) δ12.03(brs,1H),9.06(s,1H),8.48(s,1H),8.11(d,J=8.5Hz,1H),7.67(d,J=8.5Hz,1H),7..55(s ,1H),7.04(s,1H),5.70(s,1H),5.45(s,2H),4.48(q,J=7.0Hz,2H),4.07(s,3H),1.65(s,6H),1.37(t,J=7.0Hz,3H).

[0472] Preparation Example 61: 8-(4-chlorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (A61)

[0473]

[0474] Following the method for synthesizing A26, 8-(4-chlorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (15 mg, yield 11%) was synthesized from 4-chloroaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one using 4-chloroaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one as starting materials. ESI-MS (m / z): 516.1 [M+H] + ; 1 HNMR(600MHz,DMSO)δ8.91(d,J=16.5Hz,1H),8.46(s,1H),8.45-8.20(m,1H),8.10(d,J=8.4Hz,1H),7.70–7. 60(m,3H),7.50(s,2H),5.63(t,J=5.8Hz,1H),4.75(d,J=5.8Hz,2H),4.16(s,1H),3.86(s,3H),3.78(s,1H).

[0475] Preparation Example 62: 8-(4-chlorophenyl)-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (A62)

[0476]

[0477] Following the method for synthesizing A26, 8-(4-chlorophenyl)-6-(2-(2-hydroxypropyl-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one (20 mg, yield 14%) was synthesized from 4-chloroaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one using 4-chloroaniline, 2,2,2-trifluoroethyl)amino)pteridine-7(8H)-one as starting materials. ESI-MS (m / z): 544.2 [M+H] + ; 1 H NMR(600MHz,DMSO)δ8.91(d,J=16.8Hz,1H),8.44(s,2H),8.20(s,1H),8.09(d,J=8.5Hz,1H),7.6 6(m,J=8.5Hz,3H),7.50(s,2H),5.67(s,1H),4.16(s,1H),4.04(s,3H),3.78(s,1H),1.65(s,6H).

[0478] Preparation Example 63: 8-(4-methoxyphenyl)-2-((2,2-difluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (A63)

[0479]

[0480] Following the method for synthesizing A1, 8-(4-methoxyphenyl)-2-((2,2-difluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pterin-7(8H)-one (30 mg, yield 43%) was synthesized from p-methoxyaniline and 2,2,2-difluoroethylamine as starting materials. ESI-MS (m / z): 464.1 [M+H] + ; 1 H NMR (600MHz, DMSO) δ8.89-8.79(m,2H),8.49(s,1H),8.08(d,J=9.1Hz,1H),8.05(d,J=169Hz,1H),7.91(s,1H),7.65(d,J=9.2Hz, 1H),7.38–7.25(d,J=7.5Hz,2H),7.10(d,J=8.9Hz,2H),5.94(td,J=168,56Hz,2H),4.18(s,3H),3.83(s,3H),3.77–3.62(s,1H).

[0481] The following are the experimental results and data on the effects of the compounds of this invention.

[0482] Experimental Example 1: MAT2A Enzymatic Activity Assay

[0483] The inhibitory effect of the test compounds on MAT2A enzyme activity was determined using a MAT2A inhibitor enzyme screening kit (BPS Bioscience, Catalog: 71402). The specific operating procedure is as follows:

[0484] 1) Dissolve the test compound in DMSO, mixing thoroughly until completely dissolved. Dilute all compounds to an initial concentration of 2 mM with DMSO, and then serially dilute 3-fold to create 10 concentration gradients. Perform replicates on each well, adding the compound 1:100 to the reaction system during detection (final concentration maximum 20 μM). Prepare a 100× positive control (1 mM AGI-24512) and a 100× negative control (100% DMSO).

[0485] 2) Using an Echo 550 pipette system, transfer 200 nL of the diluted compound to each well of the reaction plate (784075, Greiner). Seal the reaction plate with sealing film and centrifuge at 1000 g for 1 minute. The final concentration of DMSO is 1%.

[0486] 3) Prepare 1×MAT2A enzyme reaction buffer: Add 1 volume of 5×MAT2A enzyme reaction buffer to 4 volumes of water and mix thoroughly.

[0487] 4) Prepare 2×MAT2A enzyme solution using 1× enzyme reaction buffer.

[0488] 5) Add 10 μL of 2×MAT2A enzyme solution to each well of the 384-reaction plate (Corning3702) and seal the plate with sealing film.

[0489] 6) Centrifuge at 1000g for 60 seconds, then incubate at room temperature for 30 minutes.

[0490] 7) Prepare a mixture of 2×L-methionine and ATP using 1×MAT2A enzyme reaction buffer.

[0491] 8) Add 10 μL of a mixture of 2×L-methionine and ATP to each well of a 384-reaction plate (Corning 3702), and seal the plate with sealing film. The total reaction volume is 20 μL.

[0492] 9) Centrifuge at 1000g for 60 seconds, then incubate at room temperature for 60 minutes.

[0493] 10) Prepare the detection buffer and colorimetric detection reagent.

[0494] 11) Add 20 μL of detection buffer to each well, centrifuge at 1000g for 30 seconds, and react at room temperature for 15 minutes.

[0495] 12) The fluorescence signal at 630 nm was measured using a multi-functional microplate reader (PerkinElmer, Nivo).

[0496] The enzyme activities of representative compounds of this invention are shown in the table below.

[0497]

[0498]

[0499] A represents IC 50 ≤50nM, where B represents 50nM <IC 50 ≤100nM.

[0500] The above data indicate that the compound of the present invention has a strong MAT2A inhibitory effect.

[0501] Experimental Example 2. Test for Inhibition of Cell Proliferation

[0502] The specific operating procedure is as follows: Tumor cells were treated with the compound for 5 days, and the effect of the test compound on tumor cell proliferation was evaluated. HCT116-MTAP was then... - / - Wild-type control HCT116-WT cells were seeded at a density of 600 cells / well in 384-well culture plates, and different concentrations of the test compound were added simultaneously (20 μM starting, 10 concentration gradients). The cells were incubated at 37°C, 5% CO2, and saturated humidity for 5 days.

[0503] Cell proliferation was assessed using an ATP-based cell proliferation assay kit (Cell Titer Glo, Promega Corporation). Cells were equilibrated at room temperature for 30 minutes and then treated with Cell Titer Glo reagent. The culture dishes were then covered with aluminum foil and agitated for 15 minutes to ensure thorough mixing and lysis. Chemiluminescence detection was performed using a multi-functional microplate reader (Envision 2105, PerkinElmer). Blank wells and DMSO control wells were prepared.

[0504] The inhibition rate (IR) of the detected compound is calculated using the following formula:

[0505] IR (%) = [1 - (RLU compound - RLU blank control) / (RLU solvent control - RLU blank control)] × 100%

[0506] Using GraphPad Prism for plotting, data analysis, and IC (Integrated Circuits) 50 calculate.

[0507] The compounds of the present invention were tested in the above assays, and their IC50 inhibitory activity against cell proliferation was determined. 50 As shown in the table below.

[0508]

[0509] The results showed that the test compound exhibited strong cell proliferation activity against HCT116 MTAP knockout cells and weak cell proliferation activity against MTAP wild-type HCT116 cells, indicating good selectivity.

[0510] Experimental Example 3. Human UGT1A1 Enzyme Activity Assay

[0511] The specific procedure for determining the inhibitory activity of the compound against UGT1A1 is as follows:

[0512] 1) Add 1 μL of 2 mM control compound (atazanavir), 1 μL of 440 μM test compound or 1 μL of dimethyl sulfoxide (solvent control) to the culture plate, add the master reaction solution containing 0.01 mg / mL UGT1A1 (Corning, 456411), 0.5 μM substrate bilirubin, and Tris buffer, and pre-incubate in a 37°C water bath for 10 min. The final concentration of the control compound is 10 μM, and the final concentration of the test compound is 2.2 μM.

[0513] 2) The reaction was started by adding 20 μL of UDPGA solution with a final concentration of 2 mM, reacted at 37 °C for 5 min, and then stopped by adding 400 μL of cold acetonitrile containing the internal standard.

[0514] 3) Vortex the sample for 5 minutes, centrifuge at 3220g for 40 minutes at 4°C. Then transfer 100 μL of the supernatant to a new 96-well plate for LC-MS / MS analysis of metabolite formation. The % inhibition rate is calculated by comparing the reduction in metabolite formation (peak area quantification) between the test drug and the control group.

[0515] % Remaining activity = (Average ratio of tested compound or inhibitor) / (Average ratio of vector control) * 100

[0516] % Inhibition = 100 - % Residual Activity

[0517]

[0518] The above results indicate that compound A49 has a low risk of inhibiting UGT1A1, while compounds 45 and 91 of WO2021139775 have a high inhibition rate of UGT1A1 and pose a risk of elevated bilirubin levels in vivo.

[0519] Example 4. Pharmacokinetic Study in Mice

[0520] Laboratory animals: CD-1 mice (male, 22-25g) were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0521] Experimental procedure: Male CD-1 mice (22-25g) were intravenously injected with the test compound (2 mg / kg) and administered the test compound (5 mg / kg) by gavage. Plasma samples were collected at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The compound concentration was detected by LC-MS / MS to investigate its plasma clearance (Cl) and elimination half-life (T). 1 / 2 Peak time T max Peak concentration C max Pharmacokinetic parameters such as area under the curve (AUC), apparent volume of distribution (Vss), and absolute bioavailability (F) are used.

[0522] Assay Method: Dilute the stock solution of the analyte with 50% acetonitrile to obtain the required series of working solution concentrations. Add 10 μL of working solution (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng / mL) to 10 μL of blank CD1 mouse plasma to achieve a total volume of 20 μL for calibration standards ranging from 1 to 10000 ng / mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng / mL). Five quality control (QC) samples (2 ng / mL, 5 ng / mL, 10 ng / mL, 800 ng / mL, 8000 ng / mL) are prepared on the day of analysis in the same manner as the calibration standards. 20 μL of standard, 20 μL of QC sample, and 20 μL of unknown sample (10 μL of unknown sample plasma and 10 μL of blank solution) were added to 200 μL of IS mixture containing acetonitrile to precipitate proteins. The samples were then vortexed for 3 min. After centrifugation at 4700 rpm for 15 min at 4 °C, the supernatant was diluted with ultrapure water at a ratio of 1:2 (v / v), and 10 μL of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0523] The pharmacokinetic parameters of compound A49 are shown in the table below:

[0524]

[0525]

[0526] IV: Intravenous injection; PO: Oral administration; Cl: Apparent clearance; T 1 / 2 Half-life; AUC last Area under the curve (AUC) from the start of administration to the last point (24 hours). inf The area under the drug-time curve (MRT) is the time from the start of drug administration to the theoretical extrapolation infinity. Inf : Average residence time from zero to infinity; Vss: Apparent volume of distribution; T max Peak time; C max Peak concentration; F: relative bioavailability.

[0527] Experimental Example 5. In vivo antitumor efficacy study of the compound

[0528] The effect of compound A49 of the present invention on HCT116-MTAP was tested. - / - Inhibitory effect of cell-mediated tumor growth in mouse xenografts.

[0529] Experimental animals: Female BALB / c nude mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., with a weight range of 18-22g. They were housed in an SPF-grade constant temperature and humidity laminar flow clean room using independently ventilated IVC cages, with 5 mice per cage.

[0530] HCT116-MTAP - / - Cells were cultured in McCoy's 5a medium (GIBCO) containing 10% FBS. Cells were cultured at 5 × 10⁶ cells / day. 6 / 42 BALB / c nude mice were subcutaneously injected into their backs. On day 6 post-inoculation, 30 mice with tumors approximately 150 mm in size were selected. 3 Mice of different sizes were evenly grouped according to tumor volume. The drugs were administered orally once daily for 14 consecutive days. Tumor growth rate differences between the drug-treated group and the solvent-treated group were compared, using tumor growth inhibition rate (TGI) and tumor weight inhibition rate (TWI) as evaluation indicators.

[0531]

[0532] Note: TV Xn Mean tumor volume on day n in the treatment group

[0533] TV X1 Mean tumor volume on day 1 in the treatment group

[0534] TV Mn : Average tumor volume on day n in the model group

[0535] TV M1 Average tumor volume on day 1 in the model group

[0536] Tumor weight inhibition rate = (1 - tumor weight in the drug-treated group / tumor weight in the solvent-treated group) × 100%

[0537]

[0538] The above results indicate that the compound of the present invention exhibits good in vivo efficacy without causing an increase in bilirubin.

[0539] Experimental Example 6. Detection of total serum bilirubin in vivo

[0540] Female Nu / Nu mice, weighing 18-22g, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. The test compound was administered orally once daily for 14 consecutive days. Whole blood was collected from the heart after anesthesia and allowed to stand at room temperature for 0.5 hours before centrifugation at 3500 rpm for 10 min. Serum was separated, and total bilirubin levels were measured using an automated biochemical analyzer. The results are shown in the table below; the test compound did not cause a significant increase in total bilirubin.

[0541]

[0542] The above results demonstrate that the compounds of this invention do not cause pathological increases in bilirubin, have low toxicity, and are safe.

Claims

1. A compound of Formula (II) or a pharmaceutically acceptable salt thereof: wherein: L2 is a bond; L1is a bond; and R a is selected from optionally substituted The optional substitution means that the mentioned group is unsubstituted or independently substituted at one or more substitutable positions with R a2 , wherein R a2 is independently selected from -C 1-6 alkylene-N(R a3 )(R a4 ) and optionally substituted C 1-6 alkyl with one or more substituents independently selected from hydroxy and C 1-6 alkoxy; wherein R a3 , R a4 is independently selected from C 1-6 alkyl; or R a3 and R a4 together with the nitrogen atom to which they are attached form a 3-8 membered heterocycloalkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy; the heteroatom in said heterocycloalkyl being selected from N, O, the number of heteroatoms being 1 or 2. L3 is selected from -O- or -NH-; R b is selected from optionally substituted phenyl or optionally substituted pyridyl; said optionally substituted phenyl means that the phenyl group is unsubstituted or independently substituted at one or more available positions with R b2 , wherein R b2 is independently selected from halogen, -OR b3 ; wherein R b3 is selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen; said optionally substituted pyridyl means that the pyridyl group is unsubstituted or independently substituted at one or more available positions with C 3-6 cycloalkyl; 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R c selected from C 1-6 alkyl; and the compound of formula (II) is not 3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R a selected from optionally substituted 4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R a is optionally substituted 5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R a2 independently selected from -C 1-6 alkylene-N(R a3 )(R a4 ) and optionally substituted C 1-4 alkyl with one or more independently selected from hydroxy and C 1-4 alkoxy.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R a3 , R a4 are independently selected from C 1-4 alkyl; or R a3 and R a4 form, together with the nitrogen atom to which they are attached, a tetrahydropyrrolyl, piperidinyl or morpholinyl group optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxy.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R b selected from optionally substituted phenyl.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R b2 independently selected from chloro, cyclopropyl, or -0(C 1-4 alkyl).

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R b2 independently selected from chloro or -0(C 1-4 alkyl).

10. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R b2 is independently selected from the group consisting of chloro, -OCH3, -O(CHF2), or -O(CF3).

11. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R c selected from C 1-4 alkyl optionally substituted with one or more halogen.

12. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R c selected from methyl, ethyl, the compound is selected from: R c selected from ethyl, 13. A compound, or a pharmaceutically acceptable salt thereof, characterized in that: a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. 。 14. A pharmaceutical composition, characterized by:

15. Use of a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14, for the manufacture of a medicament for the treatment, prevention and / or treatment of a disease, disorder and condition mediated by MAT2A. the disease, disorder and condition is a MTAP-deficient tumor.

16. Use according to claim 15, characterized in that, the tumor comprises a solid tumor and a hematological tumor.

17. Use according to claim 16, characterized in that, a compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 14, and another, two or more drugs having inhibitory activity on tumors.

18. A pharmaceutical composition, characterized by: ​

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