CN115504980A - Pyrimidinic and nitrogen-containing six-membered aromatic heterocyclic compounds and uses thereof - Google Patents

Abstract

The invention provides a compound shown as a formula (I) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof. The compound has stronger MAT2A inhibition effect, and can be used for treating and/or preventing MAT2A mediated diseases, disorders and conditions, such as tumors and the like.

Description

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

technical field

The present application relates to the field of medical technology, in particular, to a class of novel compounds as MAT2A inhibitors and their use in the treatment and prevention of MAT2A-mediated diseases, disorders and conditions, such as tumors.

Background technique

The full name of MAT2A is Methionine adenosyltransferase 2A, also known as S-AdenosylmethionineSynthase Isoform Type.

MAT2A is expressed in all tissues including erythrocytes, brain, fetal liver, kidney, and pancreas, but less in adult liver tissues. Increased expression of MAT2A and MAT2B has been reported in human liver and colon cancers, 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 resulted in increased apoptosis and decreased cell growth, migration, and metastasis.

MTAP is a methionine transferase that catalyzes the transfer of adenylate and plays an important role in the salvage synthesis of ATP. MTAP deletions account for approximately 15% of all solid tumors. MTAP is missing to varying degrees in various types of tumors. Loss of MTAP leads to accumulation of the enzyme substrate methylthioadenosine (MTA). Increased MTA concentration partially inhibited the activity of PRMT5, while other methyltransferases were relatively unaffected. Inhibition of MAT2A will reduce the methyl donor S-adenosylmethionine (SAM), which is the substrate of PRMT5, thereby further inhibiting PRMT5, affecting tumor cell mRNA splicing and causing DNA damage. Therefore, MAT2A inhibitors can benefit MTAP-deficient tumors.

Several patent applications have disclosed MAT2A inhibitors, for example, WO2018039972, WO2019191470, WO2020139991, WO2020139992, WO2020243376, WO2020123395.

As the most important phase II metabolic enzymes in the body, UGTs are one of the important ways to clear exogenous drugs and endogenous substances in the body. UGT1A1 is an enzyme that catalyzes the glucuronidation of the toxic endogenous substance bilirubin. The glucuronidation reaction mediated by it is a necessary step for bilirubin to be excreted from the body, and is most closely related to human health. A large number of studies at home and abroad have confirmed that the gene mutation of UGT1A1 makes the ability of glucuronidation of bilirubin all or partly lost, which affects the metabolism of bilirubin, resulting in severe hyperbilirubinemia. In addition, some clinical drugs can inhibit UGT1A1, thereby reducing the body's ability to metabolize and remove bilirubin, causing an increase in bilirubin in the blood, leading to hyperbilirubinemia or exacerbating the patient's condition. Therefore, avoiding excessive UGT1A1 inhibitory ability is of great significance for safe drug use.

Contents of the invention

The present invention provides a class of novel structure MAT2A inhibitor compounds or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives or pharmaceutically acceptable salts, as well as the compounds or their Use of prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts to treat and prevent MAT2A mediated diseases, disorders and conditions.

Specifically, the present invention provides a compound represented by formula (I) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt:

in:

L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^a1 )C(O )-, -C(O)N(R ^a1 )- or -N(R ^a1 )-; each occurrence of R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^a is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by R ^a2 , wherein each occurrence of R ^a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^a3 , -OR ^a3 , -SR ^a3 , -S(O)R ^a3 , -SO ₂ (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 ), -SO ₂ NH(R ^a3 ), -SO ₂ N (R ^a3 )(R ^a4 ), -NHS(O)(R ^a3 ), -N(R ^a3 )S(O)(R ^a4 ), -NHSO ₂ (R ^a4 ), -N(R ^a3 )SO ₂ (R ^a4 ); wherein each occurrence of R ^a3 , R ^a4 is independently selected from hydrogen or is optionally selected from one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ;

L ₂ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^b1 )C(O )-, -C(O)N(R ^b1 )- or -N(R ^b1 )-; each occurrence of R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^b is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently replaced by R ^b2 , wherein each occurrence of R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -SO ₂ N (R ^b3 )(R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N(R ^b3 )SO ₂ (R ^b4 ); wherein each occurrence of R ^b3 , R ^b4 is independently selected from hydrogen or is optionally selected from one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ;

L ₃ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^c1 )C(O )-, -C(O)N(R ^c1 )- or -N(R ^c1 )-; each occurrence of R ^c1 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 ring Substituents of alkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by ^Rc2 , wherein each occurrence of ^Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, ^-Rc3 , ^-ORc3 , -SR ^c3 , -S(O)R ^c3 , -SO ₂ (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 ), -SO ₂ NH(R ^c3 ), -SO ₂ N (R ^c3 )(R ^c4 ), -NHS(O)(R ^c3 ), -N(R ^c3 )S(O)(R ^c4 ), -NHSO ₂ (R ^c4 ), -N(R ^c3 )SO ₂ (R ^c4 ); wherein R ^c3 , R ^c4 each occurrence are independently selected from hydrogen or optionally replaced by one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^c3 and R ^c4 are connected to the same nitrogen atom, R ^c3 and R ^c4 are connected to the Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ;

X ₁ is selected from N or CR ^d ;

R ^d 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 alkyl Amino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl, 5-12 membered heteroaryl; Optionally substituted means that the mentioned group is unsubstituted or independently substituted at one or more substitutable positions by ^Rd1 , wherein ^Rd1 is independently selected from each occurrence of deuterium, halogen, hydroxyl, amino, Nitro, mercapto, cyano, oxo, -R ^d2 , -OR ^d2 , -SR ^d2 , -S(O)R ^d2 , -SO ₂ (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 ); wherein R ^d2 , R ^d3 each occurrence are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy substituent substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

In a preferred embodiment of the present invention, L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -N(R ^a1 )C(O)-, -C (O)N(R ^a1 )- or -N(R ^a1 )-.

In a further preferred embodiment, L is selected from _a bond, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH-.

In a further preferred embodiment, L is selected from _a bond, -O-, -S-, -C(O)-.

In a further preferred embodiment, L is _a bond.

In a preferred embodiment of the present invention, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, and oxo.

In a further preferred embodiment, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 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 unsubstituted or in one or Multiple substitutable positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo.

In a further preferred embodiment, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or substitutable at one or more The positions are independently substituted by deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano.

In a further preferred embodiment R ^a1 is selected from hydrogen.

In a preferred embodiment of the present invention, R ^a is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-10 cycloalkyl, 3 -12-membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or independently at one or more substitutable positions Replaced by R ^a2 .

In ^a further preferred embodiment, R is selected from optionally substituted C _3-10 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl; Substitution means that the referenced group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In ^a further preferred embodiment, R is selected from optionally substituted 3-10 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl; The atoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted by R ^a2 .

In ^a further preferred embodiment, R is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-10 membered bicyclic heterocyclyl, C _6-8 aryl, 5-12 membered heteroaryl; The heteroatoms in the heterocycloalkyl, heterocyclyl and heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, R ^a is selected from optionally substituted 5-10 membered heteroaryl; the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2 One, three or four; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, R ^a is selected from optionally substituted 5-10 membered bicyclic heteroaryls; the heteroatoms in the heteroaryls are 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 independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, R ^a is selected from optionally substituted 9-10 membered bicyclic heteroaryl; the heteroatoms in the heteroaryl are selected from N, and the number of heteroatoms is 2; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a preferred embodiment of the present invention, R ^a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^a3 , -OR ^a3 , -SR ^a3 , -S( O)R ^a3 , -SO ₂ (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 ).

In a further preferred embodiment, R ^a2 is independently selected from halogen, hydroxy, amino, cyano, -R ^a3 .

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C ₃ -3-10-membered heterocycloalkyl or 5-12-membered heteroaryl substituted by substituents of _-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl .

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C _6-14 aryl, 5-12 membered heteroaryl; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are formed together with the nitrogen atom to which they are connected, optionally by one or A plurality of 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl substituted by substituents independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy.

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy Substituent C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _6-8 aryl, 5-6 heteroaryl base.

In a further preferred embodiment, R ^a3 , R ^a4 are independently selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino.

In a further preferred embodiment, R ^a3 , R ^a4 are independently selected from hydrogen or C _1-4 alkyl optionally substituted with one or more hydroxy substituents.

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen, C _1-4 alkyl.

In ^a preferred embodiment of the present invention, R is selected from 5-10 membered bicyclic heteroaryls optionally substituted by C _1-4 alkyls; the heteroatoms in the heteroaryls are selected from N, and the number of heteroatoms 1, 2, 3 or 4.

In a further preferred embodiment, R ^a is selected from

In a preferred embodiment of the present invention, L ₂ is selected from a bond, -CH ₂ -, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^b1 )C (O)-, -C(O)N(R ^b1 )-.

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

_In a further preferred embodiment, L2 is selected from a bond.

In a preferred embodiment of the present invention, R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl base replaced.

In a further preferred embodiment, R ^b1 is independently selected from hydrogen or C _1-6 alkyl, C _3-6 cycloalkane optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino Base, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b1 is independently selected from hydrogen or C _1-4 alkyl.

In a preferred embodiment of the present invention, R ^b is selected from optionally substituted C _3-10 cycloalkyl, 3-12 membered heterocyclyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^b2 at one or more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted C _3-10 cycloalkyl, 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^b2 at one or more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; said optionally substituted means the mentioned The group is unsubstituted or independently substituted by R at one or ^more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted C _6-8 aryl, 5-6 membered heteroaryl; said optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R ^b2 .

In a further preferred embodiment, R ^b is selected from optionally substituted phenyl; said optionally substituted means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable ^positions replace.

In a preferred embodiment of the present invention, R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S( O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -SO ₂ N(R ^b3 )( R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N(R ^b3 )SO ₂ (R ^b4 ).

In a further preferred embodiment, R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -NHS(O)(R ^b3 ), -NHSO ₂ (R ^b4 ).

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxyl, amino, -R ^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 ).

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxy, amino, -R ^b3 , -OR ^b3 .

In a preferred embodiment of the present invention, R ^b2 is independently selected from halogen, or -O(C _1-6 alkyl), C _1-6 alkyl optionally substituted by one or more halogens.

In a further preferred embodiment, R ^b2 is independently selected from halogen, or -O(C _1-4 alkyl) optionally substituted with one or more halogens.

In a further preferred embodiment, R ^b2 is independently selected from chlorine, -OCH ₃ , -OCH ₂ CH ₃ , -O(CH ₂ F), -O(CHF ₂ ), -O(CF ₃ ), -CH ₃ , -CH ₂ CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CHFCH ₃ , -CH ₂ CHF ₂ .

In a preferred embodiment of the present invention, R ^b3 and R ^b4 are independently selected from hydrogen or optionally selected from one or more 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C ₃ -3-10-membered heterocycloalkyl or 5-12-membered heteroaryl substituted by substituents of _-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl .

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-6 alkyl, C _1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino ₆ alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl .

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-6 alkyl, C _1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino ₆ alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-6 alkyl, C _1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino ₆ alkoxy, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 , R ^b4 are independently selected from C _1-6 alkyl optionally substituted by one or more halogens.

In a preferred embodiment of the present invention, L ₃ is selected from -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, - N(R ^c1 )C(O)-, -C(O)N(R ^c1 )- or -N(R ^c1 )-.

In a further preferred embodiment, L ₃ is selected from -O-, -C(O)-, -N(R ^c1 )C(O)-, -C(O)N(R ^c1 )- or -N(R ^c1 )-.

In a further preferred embodiment, L ₃ is selected from -O-, -N(R ^c1 )-, -C(O)-.

In a preferred embodiment of the present invention, L ₃ is selected from -CH ₂ -, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or - NH-.

_In a further preferred embodiment, L3 is selected from -O-, -NH-, -C(O)-.

_In a further preferred embodiment, L3 is selected from -O-, -NH-.

In a preferred embodiment of the present invention, R ^c1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkene Base, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The groups mentioned are unsubstituted or are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C ₁ at one or more substitutable positions _-6 alkoxy, C _1-6 alkylamino, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aromatic Base, 5-6 membered heteroaryl substituted.

In a further preferred embodiment, R ^c1 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 group, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution refers to the mentioned group The group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkane at one or more substitutable positions Oxygen, C _1-6 alkylamino is substituted.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen or optionally replaced by one or more independently selected from halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy Substituent substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 -6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen or optionally replaced by one or more independently selected from halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy Substituent substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen.

In a preferred embodiment of the present invention, R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional replacement refers to the mentioned groups Unsubstituted or independently substituted by R ^c2 at one or more substitutable positions.

In a further preferred embodiment, R is selected from optionally substituted ^C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkyne 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 unsubstituted Or independently substituted by R ^c2 at one or more substitutable positions.

In a further preferred embodiment, R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _3-6 cycloalkyl, 3-6 member Heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replaced by ^c2 .

In a further preferred embodiment, ^Rc is selected from optionally substituted C _1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions Replaced by R ^c2 .

In a preferred embodiment of the invention, ^Rc is selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl group, cyclobutyl, cyclopentyl, cyclohexyl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^c2 at one or more substitutable positions.

In a preferred embodiment of the present invention, R ^c2 is 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 ).

In a further preferred embodiment, R ^c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^c3 .

In a further preferred embodiment, R ^c2 is independently selected from halogen, hydroxy, amino.

In a further preferred embodiment, R ^c2 is independently selected from halogen.

In a further preferred embodiment, R ^c2 is F.

In a preferred embodiment of the present invention, R ^c3 , R ^c4 are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, oxo, C _1-6 alkane Base, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5- C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 Membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl.

In a further preferred embodiment, ^Rc3 , ^Rc4 are independently selected from hydrogen or _C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5 -12 membered heteroaryl.

In a further preferred embodiment, R ^c3 and R ^c4 are independently selected from hydrogen or C _3-10 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a preferred embodiment of the present invention, R ^c is selected from optionally substituted C _1-6 alkyl; said optional substitution means that the mentioned group is unsubstituted or at one or more substitutable positions Dots are independently replaced by halogen.

In _a preferred embodiment of the invention, X is selected from N.

In a preferred embodiment of the invention, X ₁ is selected from CR ^d .

In a preferred embodiment of the present invention, R ^d 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^d1 at one or more substitutable positions.

In a further preferred embodiment, R 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 Member heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^d1 at one or more substitutable positions.

In a further preferred embodiment, R 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 groups are unsubstituted or independently substituted by ^Rd1 at one or more substitutable positions.

In a further preferred embodiment, ^Rd is selected from hydrogen.

In a preferred embodiment of the present invention, R ^d1 is independently 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 ).

In a further preferred embodiment, R ^d1 is independently selected from halogen, hydroxy, amino, cyano, -R ^d2 .

In a preferred embodiment of the present invention, ^Rd2 , ^Rd3 are independently selected from hydrogen or C _1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano Alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5 -12 membered heteroaryl.

In a further preferred embodiment, ^Rd2 , ^Rd3 are independently selected from hydrogen or _C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

The present invention provides a compound represented by formula (II) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt, which has the following structure:

in:

L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^a1 )C(O )-, -C(O)N(R ^a1 )- or -N(R ^a1 )-; each occurrence of R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^a is selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl; said optional substitution means that the mentioned group is unsubstituted or in a or a plurality of substitutable positions are independently substituted by R ^a2 , wherein each occurrence of R ^a2 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 , -SO ₂ (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 ), -SO ₂ NH(R ^a3 ), -SO ₂ N(R ^a3 )(R ^a4 ), -NHS(O)(R ^a3 ), -N(R ^a3 )S (O)(R ^a4 ), -NHSO ₂ (R ^a4 ), -N(R ^a3 )SO ₂ (R ^a4 ); wherein each occurrence of R ^a3 , R ^a4 is independently selected from hydrogen or optionally replaced by one or more 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 C _{1-6 alkyl} , _{C 1-6} Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; Or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 form together with the nitrogen atom they are connected , cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered A 3-10 membered heterocycloalkyl group or a 5-12 membered heteroaryl group substituted by a substituent of a heteroaryl group;

L ₂ is selected from 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 )-; each occurrence of R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered Heteroaryl; said optionally substituted means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano at one or more substitutable positions , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3 - Substituents of 10-membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^b is selected from optionally substituted 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; said optional substitution means that the mentioned group is unsubstituted or in a or multiple substitutable positions are independently substituted by R ^b2 , wherein each occurrence of R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , - OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ) , -SO ₂ N(R ^b3 )(R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N( R ^b3 )SO ₂ (R ^b4 ); wherein each occurrence of R ^b3 , R ^b4 is independently selected from hydrogen or is optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano group, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C _6-14 aryl, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C 2-6 alkynyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 Together with the nitrogen atom they are attached to form optionally one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkane _3-10 membered _{heterocycloalkyl} or 5- 12-membered heteroaryl;

L ₃ is selected from a bond, -CH ₂ -, -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 is 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl The optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxygen at one or more substitutable positions Substitute, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 Substituents of membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl;

R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by ^Rc2 , wherein each occurrence of ^Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, ^-Rc3 , ^-ORc3 , -SR ^c3 , -S(O)R ^c3 , -SO ₂ (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 ), -SO ₂ NH(R ^c3 ), -SO ₂ N (R ^c3 )(R ^c4 ), -NHS(O)(R ^c3 ), -N(R ^c3 )S(O)(R ^c4 ), -NHSO ₂ (R ^c4 ), -N(R ^c3 )SO ₂ (R ^c4 ); wherein R ^c3 , R ^c4 each occurrence are independently selected from hydrogen or optionally replaced by one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^c3 and R ^c4 are connected to the same nitrogen atom, R ^c3 and R ^c4 are connected to the Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ;

Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

In a preferred embodiment of the present invention, L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -N(R ^a1 )C(O)-, -C (O)N(R ^a1 )- or -N(R ^a1 )-.

In a further preferred embodiment, L ₁ is selected from a bond, -CH ₂ -, -O-, -S- or -N(R ^a1 )-, wherein R ^a1 is selected from hydrogen or C _1-6 alkyl.

In a further preferred embodiment, L is selected from _a bond, -O-, -S-, -C(O)-, -NH-, -NHC(O)-, -C(O)NH-.

In a further preferred embodiment, L is selected from _a bond, -O-, -S-, -C(O)-, -NH-.

In a further preferred embodiment, L is selected from _a bond, -NH-, -O- or -S-.

In a further preferred embodiment, L is _a bond.

In a preferred embodiment of the present invention, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are independently substituted by substituents selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, and oxo.

In a further preferred embodiment, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 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 unsubstituted or in one or Multiple substitutable positions are independently substituted with substituents selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.

In a further preferred embodiment, R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or substitutable at one or more The sites are independently substituted with substituents selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano.

In a further preferred embodiment R ^a1 is selected from hydrogen.

In a preferred embodiment of the present invention, R ^a is selected from optionally substituted 3-12 membered heterocyclic groups, C _6-14 aryl groups, 5-14 membered heteroaryl groups, said heterocyclic group, heteroaryl group The heteroatoms in are independently selected from O, N or S, the number of heteroatoms is 1, 2, 3 or 4, and the optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R ^a2 .

R ^a is selected from optionally substituted 3-10 membered heterocyclic group, C _6-12 aryl group, 5-12 membered heteroaryl group; said optional substitution means that the mentioned group is unsubstituted or in a or multiple substitutable positions are independently substituted by R ^a2 .

In ^a further preferred embodiment, R is selected from optionally substituted 3-10 membered heterocyclyl, C _6-12 aryl, 5-12 membered heteroaryl; The atoms are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3, 4 or 5; the optional substitution means that the mentioned group is unsubstituted or in one or Multiple substitutable positions are independently substituted by R ^a2 .

In ^a further preferred embodiment, R is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-10 membered bicyclic heterocyclyl, C _6-8 aryl, 5-12 membered heteroaryl; The heteroatoms in the heterocycloalkyl, heterocyclyl and heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; the optional substitution is means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, R ^a is selected from optionally substituted 5-10 membered bicyclic heterocyclic groups, 5-10 membered heteroaryl groups; the heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O , N or S, the number of heteroatoms is 1, 2, 3 or 4; the optional substitution means that the mentioned group is unsubstituted or independently replaced at one or more substitutable positions R ^a2 replaced.

In a further preferred embodiment, R ^a is selected from optionally substituted 5-10 membered bicyclic heterocyclyl, 5-10 membered bicyclic heteroaryl, and the heteroatoms in the heterocyclic group and heteroaryl are independently selected from O or N, the number of heteroatoms is 1, 2 or 3, the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions .

In a further preferred embodiment, R ^a is selected from optionally substituted 5-10 membered heteroaryl; the heteroatoms in the heteroaryl are independently selected from O, N or S, and the number of heteroatoms is 1, 2 One, three or four; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, R ^a is selected from an optionally substituted 5-10 membered bicyclic heterocyclic group; the heteroatoms in the heterocyclic group are independently selected from O or N, and the number of heteroatoms is 1 or 2 , 3 or 4; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a further preferred embodiment, Ra is selected from optionally substituted 5-10 membered bicyclic heteroaryls; the heteroatoms in the heteroaryls are selected from N, and the number of heteroatoms is 1, 2, 3 or 4 The optional substitution means that the mentioned group is unsubstituted or independently substituted by Ra2 at one or more substitutable positions.

所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R^a2所取代。In a further preferred embodiment, R ^a is selected from optionally substituted

The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R^a2所取代。In a further preferred embodiment, R ^a is selected from optionally substituted

The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

所述任选取代是指所提及的基团未被取代或在一个或多个可取代位点独立地被R^a2所取代。In a further preferred embodiment, R ^a is selected from optionally substituted

The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions.

In a preferred embodiment of the present invention, R ^a2 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 , -SO ₂ (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 ).

In a further preferred embodiment, R ^a2 is 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 ).

In a preferred embodiment of the present invention, R ^a2 is independently selected from halogen, hydroxyl, amino, cyano, -C _1-6 alkylene-N(R ^a3 )(R ^a4 ), -R ^a3 .

In a preferred embodiment of the present invention, R ^a2 is 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 alkylhydroxy.

In a preferred embodiment of the present invention, R ^a2 is independently selected from halogen, -C(O)R ^a3 , hydroxyl, amino, -C _1-6 alkylene-N(R ^a3 )(R ^a4 ), any C _{1-6 alkyl} optionally substituted by one or more independently selected from halogen, hydroxy, amino, C _1-6 alkoxy.

In a preferred embodiment of the present invention, R ^a2 is independently selected from -C _1-6 alkylene-N(R ^a3 )(R ^a4 ), optionally selected from one or more independently selected from hydroxyl and C C _1-6 alkyl substituted by _1-6 alkoxy.

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituents of aryl, 5-6 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C ₃ -3-10-membered heterocycloalkyl or 5-12-membered heteroaryl substituted by substituents of _-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl .

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C _6-14 aryl, 5-12 membered heteroaryl; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are formed together with the nitrogen atom to which they are connected, optionally by one or A plurality of 3-10 membered heterocycloalkyl or 5-12 membered heteroaryl substituted by substituents independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy.

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy Substituent C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, C _6-8 aryl, 5-6 heteroaryl group; when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from halogen, hydroxyl, C _1-6 alkane A 3-10-membered heterocycloalkyl group substituted by a substituent of a C _1-6 alkoxy group, the heteroatoms in the heterocycloalkyl group are selected from N, S, O, and the number of heteroatoms is 1 or 2 or 3.

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino; when R ^a3 When R ^a4 is connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from F, Cl, Br, hydroxyl, methyl, methoxy A 3-10-membered heterocycloalkyl group substituted by a substituent, wherein the heteroatoms in the heterocycloalkyl group are selected from N and O, and the number of heteroatoms is 1 or 2.

In a further preferred embodiment, R ^a3 and R ^a4 are independently selected from hydrogen, C _1-4 alkyl, -C _1-4 alkyl hydroxyl; when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^together with the nitrogen atom to which they are attached form tetrahydropyrrolyl, piperidinyl or morpholinyl optionally substituted by one or more substituents independently selected from F, hydroxyl, methyl, methoxy .

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 Alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl Substituent substituted C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; or when R ^a3 and R ^a4 When connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom they are connected to form are optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 Alkoxy, C _3-6 cycloalkyl, 3-6 member heterocycloalkyl, C _6-8 aryl, 5-6 member heteroaryl substituent substituted 3-10 member heterocycloalkyl or 5 -12-membered heteroaryl, the heteroatoms in the heterocycloalkyl or heteroaryl are selected from N, S, O, and the number of heteroatoms is 1, 2 or 3.

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 C _1-6 alkyl substituted by substituents of alkoxy group; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom to which they are connected are optionally formed by one or more 3-10 membered heterocycloalkyl groups independently selected from halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy substituents, the heteroatoms in the heterocycloalkyl are selected from N , S, O, and the number of heteroatoms is 1, 2 or 3.

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino; Or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from halogen, hydroxyl, C _1-4 alkyl , a 3-10 membered heterocycloalkyl group substituted by a C _1-4 alkoxy substituent, the heteroatoms in the heterocycloalkyl group are selected from N and O, and the number of heteroatoms is 1 or 2.

In a preferred embodiment of the present invention, R ^a3 and R ^a4 are independently selected from C _1-4 alkyl; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are connected with the The nitrogen atoms together form tetrahydropyrrolyl, piperidinyl or morpholinyl optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxy.

In a further preferred embodiment, R ^a2 is independently selected from methyl, Br,

In a further preferred embodiment, R ^a2 is independently selected from

In a further preferred embodiment, R ^a is selected from

In a further preferred embodiment, R ^a is selected from

In a preferred embodiment of the present invention, L ₂ is selected from a bond, -CH ₂ -, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^b1 )C (O)-, -C(O)N(R ^b1 )-.

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

In a further preferred embodiment, L2 is selected from a bond, _-CH2- , _-C (O)-.

_In a further preferred embodiment, L2 is selected from a bond, _-CH2- .

_In a further preferred embodiment, L is a bond.

In a preferred embodiment of the present invention, R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl , C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned groups are unsubstituted or One or more substitutable positions are 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, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl base replaced.

In a further preferred embodiment, R ^b1 is independently selected from hydrogen or C _1-6 alkyl, C _3-6 cycloalkane optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino Base, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b1 is independently selected from hydrogen or C _1-4 alkyl.

In a preferred embodiment of the present invention, R ^b is selected from optionally substituted 3-12 membered heterocyclic group, C _6-14 aryl, 5-12 membered heteroaryl; The groups mentioned are unsubstituted or independently substituted by R ^b2 at one or more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^b2 at one or more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; said optionally substituted means the mentioned The group is unsubstituted or independently substituted by R at one or ^more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted 5-10 membered bicyclic heterocyclyl, C _6-8 aryl, 5-6 membered heteroaryl; The group is unsubstituted or independently substituted by R at one or ^more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, the optional substitution refers to the mentioned The group is unsubstituted or independently substituted by R at one or ^more substitutable positions.

In a further preferred embodiment, R ^b is selected from optionally substituted phenyl, pyridyl or benzotetrahydrofuranyl; said optionally substituted means that the mentioned groups are unsubstituted or may be substituted in one or more The positions are independently replaced by R ^b2 .

In a further preferred embodiment, R ^b is selected from optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or independently replaced at one or more substitutable positions R ^b2 replaced.

In a further preferred embodiment, R ^b is selected from optionally substituted phenyl; said optionally substituted means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable ^positions replace.

In a preferred embodiment of the present invention, R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S( O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -SO ₂ N(R ^b3 )( R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N(R ^b3 )SO ₂ (R ^b4 ).

In a further preferred embodiment, R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -NHS(O)(R ^b3 ), -NHSO ₂ (R ^b4 ).

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxyl, amino, -R ^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 ).

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxy, amino, -R ^b3 , -OR ^b3 .

In a preferred embodiment of the present invention, R ^b2 is independently selected from halogen, hydroxyl, or -O(C _1-6 alkyl) optionally substituted by one or more halogen, -O(C _1-6 Alkyl) phenyl, C _1-6 alkyl.

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxyl, or -O(C _1-4 alkyl), -O(C _1-4 alkyl) optionally substituted by one or more halogen Phenyl or C _1-4 alkyl.

In a further preferred embodiment, R ^b2 is independently selected from chlorine, -OCH ₃ , -OH, -O-benzyl, -OCH ₂ CH ₃ , -O(CH ₂ F), -O(CHF ₂ ), - O(CF ₃ ), -CH ₃ , -CH ₂ CH ₃ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CHFCH ₃ , -CH ₂ CHF ₂ or

In a preferred embodiment of the present invention, R ^b2 is independently selected from halogen, hydroxyl, amino, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is selected from optionally selected from one or more independently C _1-6 alkyl substituted by substituents from halogen or C _6-10 aryl.

In a further preferred embodiment, R ^b2 is independently selected from halogen, hydroxyl, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is selected from optionally selected from one or more independently selected from halogen or phenyl C _1-4 alkyl substituted by substituents.

In a further preferred embodiment, R ^b2 is independently selected from fluorine, chlorine, -OH, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is selected from optionally selected from one or more independently selected from chlorine Or C _1-4 alkyl substituted by a substituent of phenyl.

In a further preferred embodiment, R ^b2 is independently selected from chloro, cyclopropyl or -O(C _1-4 alkyl) optionally substituted with one or more halogen.

In a further preferred embodiment, R ^b2 is independently selected from chloro or -O(C _1-4 alkyl) optionally substituted with one or more fluoro.

In a further preferred embodiment, R ^b2 is independently selected from chlorine, -OCH ₃ , -O(CHF ₂ ) or -O(CF ₃ ).

In a further preferred embodiment, R ^b2 is independently selected from -O(CHF ₂ ).

In a preferred embodiment of the present invention, R ^b3 and R ^b4 are independently selected from hydrogen or optionally selected from one or more 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, C _3-6 cycloalkyl, _3-6 membered heterocycloalkyl, C _6-8 Aryl, C _1-6 alkyl substituted by substituents of _5-6 membered heteroaryl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C ₃ -3-10-membered heterocycloalkyl or 5-12-membered heteroaryl substituted by substituents of _-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl .

In a further preferred embodiment, R ^b3 , R ^b4 are independently selected from hydrogen or C _1- optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C _6-8 aryl ₆ alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C ₃ - ₁₀ cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl.

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, phenyl, C _1-6 alkoxy, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-4 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, phenyl, C _1-4 alkoxy, C _3-4 cycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 and R ^b4 are independently selected from hydrogen or C _1-4 alkyl, C _1-4 optionally substituted by one or more substituents independently selected from halogen and phenyl Alkoxy or cyclopropyl.

In a further preferred embodiment, R ^b3 , R ^b4 are independently selected from hydrogen or C _1-4 alkoxy optionally substituted by one or more substituents independently selected from halogen, phenyl.

In a further preferred embodiment, R ^b3 , R ^b4 are independently selected from methoxy optionally substituted by one or more substituents independently selected from F, Cl.

In a further preferred embodiment, R ^b is selected from

In a further preferred embodiment, R ^b is selected from

In a preferred embodiment of the present invention, L ₃ is selected from -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, - N(R ^c1 )C(O)-, -C(O)N(R ^c1 )- or -N(R ^c1 )-.

In a further preferred embodiment, L ₃ is selected from -CH ₂ -, -O-, -S- or -N(R ^c1 )-, wherein R ^c1 is selected from hydrogen or C _1-6 alkyl.

In a further preferred embodiment, L ₃ is selected from -O-, -S-, -C(O)-, -N(R ^c1 )C(O)-, -C(O)N(R ^c1 )- or -N(R ^c1 )-.

In a further preferred embodiment, L ₃ is selected from -O-, -N(R ^c1 )-, -C(O)-.

In a further preferred embodiment, L ₃ is selected from -O-, -N(R ^c1 )-, wherein R ^c1 is selected from hydrogen or C _1-6 alkyl.

In a preferred embodiment of the present invention, L ₃ is selected from -CH ₂ -, -O-, -S-, -C(O)-, -NHC(O)-, -C(O)NH- or - NH-.

_In a further preferred embodiment, L3 is selected from -O-, -NH-, -C(O)-.

_In a further preferred embodiment, L3 is selected from -O-, -NH-.

_In a further preferred embodiment, L3 is selected from -O-.

In a preferred embodiment of the present invention, R ^c1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkene Base, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The groups mentioned are unsubstituted or are independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C ₁ at one or more substitutable positions _-6 alkoxy, C _1-6 alkylamino, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aromatic Substituents of radicals, 5-6 membered heteroaryl groups.

In a further preferred embodiment, R ^c1 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 group, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution refers to the mentioned group The group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkane at one or more substitutable positions Oxygen, C _1-6 alkylamino is substituted.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino substituted by substituents.

In a further preferred embodiment, R ^c1 is independently selected from hydrogen.

In a preferred embodiment of the present invention, R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _{2 -6} alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional replacement refers to the mentioned group Unsubstituted or independently substituted by R ^c2 at one or more substitutable positions.

In a further preferred embodiment, R is selected from optionally substituted ^C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkyne 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 unsubstituted Or independently substituted by R ^c2 at one or more substitutable positions.

In a further preferred embodiment, R ^c is selected from optionally substituted C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino, C _3-6 cycloalkyl, 3-6 member Heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or independently replaced by R at one or more substitutable positions replaced by ^c2 .

In a further preferred embodiment, R ^c is selected from optionally substituted C _1-4 alkyl or C _3-6 cycloalkyl; said optional substitution means that the mentioned groups are unsubstituted or in one or Multiple substitutable positions are independently substituted by R ^c2 .

In a further preferred embodiment, R ^c is selected from optionally substituted C _1-3 alkyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions Replaced by R ^c2 .

In a preferred embodiment of the invention, ^Rc is selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl group, cyclobutyl, cyclopentyl, cyclohexyl; the optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^c2 at one or more substitutable positions.

In a preferred embodiment of the present invention, R ^c2 is 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 ).

In a further preferred embodiment, R ^c2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^c3 .

In a further preferred embodiment, R ^c2 is independently selected from halogen, hydroxy, amino or -R ^c3 .

In a further preferred embodiment, R ^c2 is independently selected from halogen or -R ^c3 .

In a preferred embodiment of the present invention, R ^c3 , R ^c4 are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, cyano, oxo, C _1-6 alkane Base, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, 5- C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 Membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl.

In a further preferred embodiment, ^Rc3 , ^Rc4 are independently selected from hydrogen or _C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5 -12 membered heteroaryl.

In a further preferred embodiment, ^Rc3 , ^Rc4 are independently selected from hydrogen or _C1-6 optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, cyano, oxo Alkyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-8 aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^c3 , R ^c4 are independently selected from hydrogen or CF ₃ .

In a preferred embodiment of the present invention, R is selected from ^C _1-6 alkyl optionally substituted by one or more ^halogens or C _3-6 cycloalkane optionally substituted by one or more R A group, wherein R ^c3 is selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen.

In a preferred embodiment of the present invention, R ^c is selected from optionally substituted C _1-6 alkyl; said optional substitution means that the mentioned group is unsubstituted or at one or more substitutable positions Dots are independently replaced by halogen.

In a further preferred embodiment, R ^c is selected from C _1-4 alkyl optionally substituted by one or more halogens or C _3-6 cycloalkyl optionally substituted by CF ₃ .

In a further preferred embodiment, R ^c is selected from methyl, ethyl,

In a further preferred embodiment, R ^c is selected from ethyl,

In a further preferred embodiment, ^Rc is selected from ethyl.

The structural formula and numbering of representative compounds of the present invention are shown in the following table:

The object of the present invention also includes providing a method for preparing the compound represented by the general formula (I) in which X is N, the general formula (II), or its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof.

The method can be prepared, for example, using the methods shown in the following schemes.

Intermediate 1.6 reacts with boronic acid or boronate in the presence of a palladium catalyst to give final product 1.7.

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

In a further preferred embodiment, the compound or its tautomer, stereoisomer, or pharmaceutically acceptable salt thereof can be prepared by the following steps:

Using 2,4-dichloro-5-nitropyrimidine (1.1) as the starting material, react with different kinds of primary amines to obtain intermediate 1.2, and react intermediate 1.2 with the corresponding R ^c -L ₃ H to obtain intermediate 1.3 , using a reducing agent to reduce the nitro group of 1.3 to amino to obtain intermediate 1.4, intermediate 1.4 reacts with monomethyl oxalyl chloride to obtain compound 1..5, and intermediate 1.5 obtains intermediate under the action of thionyl chloride 1.6, and finally in the presence of a palladium catalyst with boric acid or boric acid ester to obtain the final product 1.7. The definitions of the substituents in the compounds shown are as described above.

Note: The reaction steps of protection and deprotection involved in this step have been omitted.

Another aspect of the present invention also provides the following intermediate compounds:

Wherein L ² , L ³ , R ^b and R ^c are as described in the compound of formula (I) or formula (II);

^In a further preferred embodiment, L is ^a bond, R is optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or at one or more substitutable positions dots are independently replaced by R ^b2

Another aspect of the present invention also provides a pharmaceutical composition, which comprises the compound of the present invention or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable Salt.

Further, the pharmaceutical composition of the present invention also includes pharmaceutically acceptable excipients.

The compounds of the present invention or their prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts can be administered in pure form or in a suitable pharmaceutical composition by providing a similar Any acceptable mode of administration of the drug for 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 composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations. Generally, the above-mentioned pharmaceutical composition can be prepared by conventional preparation methods using conventional excipients in the formulation field.

Another aspect of the present invention also provides the compounds of the present invention or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof or the pharmaceutical composition of the present invention for the prevention and/or treatment of Use in medicine for diseases, disorders and conditions mediated by MAT2A.

Further, in the uses provided by the present invention, the diseases, disorders and conditions are MTAP-deficient tumors.

Further, in the use provided by the present invention, the tumor includes solid tumor and hematological tumor; preferably, the solid tumor includes colorectal cancer.

In certain contexts in the art, the cancer may also be referred to as a malignancy.

In yet another aspect, the present application provides methods for preventing and/or treating diseases, disorders and conditions mediated by MAT2A, comprising administering the compounds of the present invention or their prodrugs, tautovariants to individuals in need thereof conformation, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt or the pharmaceutical composition of the present invention; preferably, said disease, disorder and condition are MTAP-deficient cancer; more preferably, said Tumors include solid tumors and hematological tumors.

In yet another aspect, the present application provides the compounds described in the present invention or their prodrugs, tautomers, stereoisomers, solvates for preventing and/or treating diseases, disorders and conditions mediated by MAT2A , isotope derivatives or pharmaceutically acceptable salts or the pharmaceutical composition of the present invention; preferably, the diseases, disorders and conditions are MTAP-deficient cancers; more preferably, the tumors include solid tumors and hematological tumors.

Further, in the use or method provided by the present invention, the compound described in the present invention or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt or the present invention The inventive pharmaceutical composition is used in combination with another, two or more drugs having tumor suppressing activity.

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 One or more drugs with tumor suppressive activity.

definition

The terms "optional", "any", "optionally" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes the circumstances under which said event or circumstance occurs as well as The absence of the stated event or condition.

Unless otherwise specified, the "optionally substituted" or "optionally substituted" means that the mentioned groups are unsubstituted or replaced by one or more independently selected from hydroxyl, halogen, hydroxyl, amino, nitro, Mercapto, cyano, azido, 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, -NHC(O) -C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, C _3-10 ring Substituents of alkylsulfonyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; wherein the C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C _6-14 aryl or 5 -12-membered heteroaryl is optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, C _1-6 alkyl or C _1-6 alkoxy.

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

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight-chain or branched, containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e. C _1-10 Alkyl), further preferably containing 1-8 carbon atoms (C _1-8 alkyl), more preferably containing 1-6 carbon atoms (ie C _1-6 alkyl), for example "C _1-6 alkyl" It means that the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1 and 6 (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-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl , N-octyl, etc.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. Alkenyl can contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e. C _2-10 alkenyl), more preferably 2-8 carbon atoms (C _2-8 alkenyl), more preferably 2-6 carbon atoms (ie C _2-6 alkenyl), 2-5 carbon atoms (ie C _2-5 alkenyl), 2-4 carbon atoms (ie C _2-4 alkenyl), 2- 3 carbon atoms (i.e. C _2-3 alkenyl), 2 carbon atoms (i.e. C ₂ alkenyl), for example "C _2-6 alkenyl" means that the group is alkenyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.

Unless otherwise specified, the term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, having at least one triple bond. The alkynyl group can contain 2-20 carbon atoms, preferably contains 2-10 carbon atoms (i.e. C _2-10 alkynyl), further preferably contains 2-8 carbon atoms (C _2-8 alkynyl), more preferably contains 2-6 carbon atoms (ie C _2-6 alkynyl), 2-5 carbon atoms (ie C _2-5 alkynyl), 2-4 carbon atoms (ie C _2-4 alkynyl), 2- 3 carbon atoms (i.e. C _2-3 alkynyl), 2 carbon atoms (i.e. C ₂ alkynyl), for example "C _2-6 alkynyl" means that the group is alkynyl, and the carbon chain The number of carbon atoms is between 2-6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.

Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms, preferably containing 3-12 carbon atoms (i.e. C _3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C _3-10 cycloalkyl), more preferably 3-7 carbon atoms (C _3-7 cycloalkyl), 4-6 carbon atoms (C _4-6 cycloalkyl), 5-6 carbon atoms (C _5-6 cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.

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

Unless otherwise specified, the term "alkylamino" refers to -NR'R", R' and R" are the same or different, and can be H or an alkyl group as defined above, and the alkyl group is as defined above, that is, includes 1 - 20 carbon atoms, preferably comprising 1-10 carbon atoms, preferably 1-8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1, 2, 3, 4 , 5 or 6). Representative examples include, but are not limited to, -NH(CH ₃ ), -N(CH ₃ )(CH ₃ ), -N(CH ₂ CH ₃ )(CH ₃ ), -N(CH ₂ CH ₃ )[CH(CH ₃ ) ₂ ] and so on.

The terms "halogen" or "halo" refer to F, Cl, Br, I unless otherwise specified. The term "haloalkyl" refers to an alkyl group as defined above in which one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples _of haloalkyl include _CCl3 , _CF3 , _CHCl2 , _CH2Cl , _CH2Br , _CH2I , _CH2CF3 , _{CF2CF3 ,} and the like.

唑烷-2-酮。含有3个杂原子的示例性5元杂环基基团包括，但不限于三唑啉基、

二唑啉基和噻二唑啉基。含有1个杂原子的示例性6元杂环基基团包括，但不限于哌啶基、四氢吡喃基、二氢吡啶基以及硫杂环己烷基(thianyl)。含有2个杂原子的示例性6元杂环基基团包括，但不限于哌嗪基、吗啉基、二硫杂环己烷基以及二氧杂环己烷基。含有3个杂原子的示例性6元杂环基基团包括，但不限于三氮杂环己烷基、氧杂二嗪烷基、噻二嗪烷基、氧杂噻嗪烷基以及二氧杂氮杂环己烷基(dioxazinanyl)。含有1个杂原子的示例性7元杂环基基团包括，但不限于氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。含有1个杂原子的示例性8元杂环基基团包括，但不限于氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。稠合到一个C₆芳基环上的示例性5元杂环基基团(在此又称为一种5,6-双环杂环)包括，但不限于二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并

唑啉酮基等。稠合到一个芳基环上的示例性6元杂环基基团(在此又称为一种6,6-双环杂环)包括，但不限于四氢喹啉基、四氢异喹啉基等。Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic ring non-aromatic substituent having ring carbon atoms and 1 or more ring heteroatoms, Contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. It preferably contains 3 to 12 ring atoms (3-12 membered heterocyclic group), further preferably contains 3 to 10 ring atoms (3-10 membered heterocyclic group), or 3 to 8 ring atoms (3-8 membered heterocyclic group). ring), or 3 to 6 ring atoms (3-6 membered heterocyclyl), or 4 to 6 ring atoms (4-6 membered heterocyclyl), or 5 to 6 ring atoms (5-6 membered heterocyclyl) heterocyclyl). The number of heteroatoms is preferably 1-4, more preferably 1-3 (ie 1, 2 or 3). Examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. "Heterocyclyl" can be monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused cycloyl"), bridged ("heterobridged cycloyl" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclyl" or "spiroheterocyclyl") ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and can be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or "Heterocyclyl" also includes ring systems wherein the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or a cycloalkyl ring as defined above is fused by one or more A ring system fused to a heteroaryl group, wherein the point of attachment is on the heterocyclyl ring or cycloalkyl ring, and in such cases, the number of members of the heterocyclyl ring system is the post-fused ring system atomic number. In certain embodiments, each instance of heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents ( a "substituted heterocyclyl"). Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl- 2,5-diketones. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl, dithiolanyl, and

Oxazolidin-2-ones. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazolinyl,

oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxo Dioxazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacanyl, oxocanyl, and thiecanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as a 5,6-bicyclic heterocycle) fused to a _C6 aryl ring include, but are not limited to, indolinyl, isodihydro Indolyl, Dihydrobenzofuranyl, Dihydrobenzothienyl, Benzo

oxazolinone, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as a 6,6-bicyclic heterocycle) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl Base etc.

唑烷基、二

烷基、二硫杂环己基、噻唑烷基、吡咯烷基、吡唑烷基、咪唑啉啶等。Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, with ring atoms as defined above, i.e. containing 3 to 20 ring atoms ("3 -20-membered heterocycloalkyl"), the number of heteroatoms is 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein The atoms are each independently selected from N, O or S. Preferably comprising 3 to 12 ring atoms (“3-12 membered heterocycloalkyl”), more preferably comprising 3 to 10 ring atoms (“3-10 membered heterocycloalkyl”), still more preferably comprising 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), more preferably contain 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), still more preferably contain 5-10 ring atoms ("5-10 membered heterocycloalkyl"), more preferably comprising 5-6 ring atoms ("5-6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted by one or more Substituted (a "substituted heterocycloalkyl"). The above "heterocyclyl" or "heterocycle" part has given some exemplary "heterocycloalkyl", including, but not limited to, aziridine, oxirane, thiiridine Azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl , Oxathianyl,

Azolidinyl, two

Alkyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, etc.

Unless otherwise specified, the term "aryl" or "aromatic ring group" means a group containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms Monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems, 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, anthracenyl, phenanthrenyl, or pyrenyl, and the like.

唑基、噻唑基、异

唑基、

二唑基、噻二唑基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、硫代二唑基、三嗪基、酞嗪基、喹啉基、异喹啉基、喋啶基、嘌呤基、吲哚基、异吲哚基、吲唑基、苯并呋喃基、苯并噻吩基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、苯并咪唑基、苯并酞嗪基、吡咯并[2,3-b]吡啶基、咪唑并[1,2-a]吡啶基、吡唑并[1,5-a]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、[1,2,4]三唑并[4,3-b]哒嗪基、[1,2,4]三唑并[1,5-a]嘧啶基、[1,2,4]三唑并[1,5-a]吡啶基等。Unless otherwise specified, the term "heteroaryl" or "heteroaryl ring group" means a group containing 5-14 membered structure, or preferably 5-10 membered structure, or preferably 5-8 membered structure, more preferably 5-6 membered structure An aromatic monocyclic or polycyclic ring system, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N or S, the number of heteroatoms Preferably it is 1, 2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl,

Azolyl, thiazolyl, iso

Azolyl,

Diazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl , Phthalazinyl, quinolinyl, isoquinolyl, pteridyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzene Pyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1 ,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b ]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to any salt suitable for use within the scope of sound medical judgment without undue toxicity, irritation, allergic reaction, or in contact with the tissues of mammals, especially humans. Salts commensurate with a reasonable benefit/risk ratio, such as the pharmaceutically 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 isolation and purification of the compounds of the invention, or alone by reacting the free base or acid with a suitable reagent.

The compounds of the present invention also include "isotopic derivatives" thereof. Unless otherwise specified, the term "isotopically derivative" means that the compounds of the present invention may exist in isotopically labeled or enriched forms containing one or more atoms having an atomic mass or mass number different from that found in nature The atomic mass or mass number of the most abundant atom. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used for isotope 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 are more widely used because of their easy labeling and convenient detection. The substitution of certain heavy isotopes, such as deuterium ( ² H ), can enhance the stability of metabolism, prolong the half-life and thus achieve the purpose of reducing the dose and provide therapeutic advantages. Isotopically labeled compounds are generally synthesized starting from labeled starting materials and carried out in the same way as non-isotopically labeled compounds using known synthetic techniques.

The compounds of the present invention also include "solvates" and "solvates" thereof. Unless otherwise specified, the terms "solvate", "solvate" mean a physical association of a compound of the present invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be isolated. Solvent molecules in solvates may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, and the like. The resulting mixture of any stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereoisomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography method and/or fractional crystallization.

Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Bonded tautomers include interconversions by recombination of some of the bonding electrons.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

The compounds of the present invention also include "prodrugs" thereof. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. Prodrugs are often useful to ameliorate some identified, undesirable physical or biological property. Physical properties are usually related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too fast metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they are bioavailable orally, whereas the parent is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of, but not limited to, a prodrug may be any compound of the invention administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but once in Intracellular water solubility is beneficial, which is then metabolically hydrolyzed to carboxylic acids, the active entities. Another example of a prodrug could be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.

Abbreviations used in the Preparations, Examples and elsewhere herein are:

DMF: N,N-Dimethylformamide

DIPEA: N,N-Diisopropylethylamine

Beneficial effects of the present invention:

This application designs a class of compounds with novel structures, which provides a new direction for the treatment of diseases such as tumors. Tests show that the compound of the present invention has a strong inhibitory effect on MAT2A, shows strong cell proliferation activity on HCT116 MTAP knockout cells, shows weak cell proliferation activity on MTAP wild-type HCT116 cells, and shows relatively strong cell proliferation activity. good selectivity. Has good in vivo efficacy. Moreover, the enzyme activity test of human UGT1A1 shows that the risk of the compound of the present invention inhibiting UGT1A1 is small. Combined with the detection of serum total bilirubin in vivo, it shows that the compound of the present invention does not cause pathological increase of bilirubin, has low toxicity and good safety. In addition, the present invention studies a specific synthesis method, which has simple process, convenient operation, and is beneficial to large-scale industrial production and application.

detailed description

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials shown herein are for demonstration purposes only.

The following are preparation examples of exemplary compounds of the present application.

Preparation 1: 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (A1)

Step 1: 2-Chloro-N-(4-chlorophenyl)-5-nitropyrimidin-4-amine

To a 250 mL round bottom flask was added 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 ), and the reaction was stirred at room temperature. After the reaction, the reaction solution was poured into 500mL water, precipitated, filtered, and dried to obtain 2-chloro-N-(4-chlorophenyl)-5-nitropyrimidin-4-amine (8.80g, yield 79.3% ). ESI-MS (m/z): 285.0 [M+H] ⁺ .

Step 2: Synthesis of N-(4-chlorophenyl)-2-ethoxy-5-nitropyrimidin-4-amine

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

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

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

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

Take the previous product N ⁴ -(4-chlorophenyl)-2-ethoxypyrimidine-4,5-diamine (350mg, 1.30mmol), DIPEA (503mg, 3.90mmol), toluene (15mL) and dichloro Methane (3mL) was added to a 50mL round-bottomed flask, ice-bathed, a dichloromethane solution containing monomethyl oxalyl chloride (159mg, 1.30mmol) was added dropwise, raised to room temperature, stirred and reacted for 2 hours, cesium carbonate (1059mg , 3.25mmol), the temperature was raised to 50°C for reaction. After the reaction, add 20mL ethyl acetate and 15mL water, separate layers, wash the water phase twice with 20mL ethyl acetate, combine the organic phase, wash the organic phase with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography The target product 8-(4-chlorophenyl)-2-ethoxy-5,8-dihydropteridine-6,7-dione (203 mg, yield 55.3%) was obtained. ESI-MS (m/z): 319.1 [M+H] ⁺ .

Step 5: 6-Chloro-8-(4-chlorophenyl)-2-ethoxypteridin-7(8H)-one

The previous step product 8-(4-chlorophenyl)-2-ethoxy-5,8-dihydropteridine-6,7-dione (150mg, 1.30mmol), DMF (0.2mL) and toluene ( 5 mL) into a 25 mL round bottom flask, then added thionyl chloride (350 mg, 1.30 mmol), followed by heating to 50°C and stirring the reaction. After the reaction, it was concentrated under reduced pressure to obtain the target compound 6-chloro-8-(4-chlorophenyl)-2-ethoxypteridin-7(8H)-one (103 mg, yield 64.9%). ESI-MS (m/z): 337.1 [M+H] ⁺ .

Step 6: 8-(4-Chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one

Take the previous step product 6-chloro-8-(4-chlorophenyl)-2-ethoxypteridin-7(8H)-one (30mg, 0.089mmol), 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) were added to a 25 mL round bottom The flask was replaced with nitrogen three times, and then heated to 100°C. After the reaction, add 100 mL of ethyl acetate and 5 mL of water to the reaction solution, extract the aqueous phase twice with ethyl acetate, combine the organic phase, wash the organic phase with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography The target compound 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (18mg, yield 46.8%), ESI-MS (m/z): 433.1[M+H] ⁺ ; ¹ H NMR (600MHz, CDCl ₃ ) 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).

Preparation examples 2 to 14:

Referring to the synthetic route and operation of Preparation Example 1, the corresponding intermediates were used as starting materials to prepare compounds A2-A14.

Preparation 15: 8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazole-5- Base) pteridin-7(8H)-one (A15)

According to the method of synthesis A1, 8-(4-methoxyphenyl)-2-((2,2,2 -trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (50mg, yield 57%), ESI-MS (m /z): 482.1[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 16: 8-(3-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazole-5- Base) pteridin-7(8H)-one (A16)

According to the method of synthesis A1, 8-(3-methoxyphenyl)-2-((2,2,2 -trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (135mg, yield 42%), ESI-MS (m /z): 482.1[M+H] ⁺ .

Preparation 17: 8-(3-Hydroxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl) Pteridin-7(8H)-one (A17)

Take compound A16 (100mg, 0.208mmol) and 20mL of anhydrous dichloromethane into a 50mL round bottom flask, put it in an ethanol bath, cool to -20°C, and add boron tribromide (1.0M solution in dichloromethane) dropwise (1.4 mL, 1.4 mmol). After the reaction, slowly add water to quench the reaction, wash the organic phase with water and saturated sodium chloride solution successively, concentrate, and purify 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).

Preparation 18: 2-Ethoxy-8-(6-methoxypyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)pteridine-7(8H)- Ketones (A18)

Synthesize 6-chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypteridin-7(8H)-one according to the method of Preparation Example 1, take the intermediate (50mg, 0.150mmol ), 2-methyl-5-amino-2H-indazole (33mg, 0.225mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (20mg, 0.030mmol), potassium carbonate (63mg, 0.450mmol) and dioxane (2mL) were added into a 25mL round bottom flask, replaced with nitrogen three times, and heated to 100°C for 3h. After the reaction, add 100mL ethyl acetate and 50mL water to the reaction solution, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography Obtain the target compound 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (30mg, yield 45%), ESI-MS (m/z): 433.1[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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, 1.6 Hz,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 = 7.0 Hz, 3H).

Preparation 19: 2-Ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7 (8H)-Kone (A19)

Step 1: 2-Methyl-2H-indazol-5-ol

Take 2-methyl-2H-indazole-5-boronic acid (600mg, 3.409mmol), ammonium bicarbonate (270mg, 3.409mmol), hydrogen peroxide (660μL) and acetonitrile (8mL) into a 50mL round bottom flask and react at room temperature 2h. . After the reaction, add 100mL ethyl acetate and 50mL water to the reaction solution, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated sodium chloride solution successively, concentrate, and perform column chromatography The target compound 2-methyl-2H-indazol-5 alcohol (350 mg, yield 69%) was purified, ESI-MS (m/z): 149.1 [M+H] ⁺ ;

Step 2: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7( 8H)-ketone

Take 6-chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypteridin-7(8H)-one (55 mg, 0.165 mmol), 2-methyl-2H-indazole -5 Alcohol (24mg, 0.164mmol), potassium carbonate (63mg, 0.450mmol) and N,N-dimethylformamide (1mL) were added into a 5mL round bottom flask, heated to 100°C for 3h. After the reaction, add 25 mL of ethyl acetate and 10 mL of water to the reaction solution, extract the water phase twice with ethyl acetate, combine the organic phase, wash the organic phase with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography Obtain target compound 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)oxy)pteridine-7( 8H)-ketone (40mg, yield 54%), ESI-MS (m/z): 446.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 20: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(2,3,3a,7a-tetrahydrobenzofuran-6-yl)pteridine-7( 8H)-ketone (A20)

According to the method of synthesis A1, 2-ethoxypyridine was synthesized from 6-methoxypyridin-3-amine, (2,3,3a,7a-tetrahydrobenzofuran-6-yl)boronic acid and ethanol as starting materials -8-(6-methoxypyridin-3-yl)-6-(2,3,3a,7a-tetrahydrobenzofuran-6-yl)pteridin-7(8H)-one (16mg, yield 25%), ESI-MS (m/z): 420.2[M+H] ⁺ ; ¹ H NMR (600MHz, CDCl ₃ ) 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).

Preparation 21: 2-ethoxy-8-(6-methoxypyridin-3-yl)-6-(7-bromo-3,4-dihydroisoquinolin-2(1H)yl)pteridine -7(8H)-one (A21)

According to the method of synthesizing A18, 2-ethoxy-8-(6 -Methoxypyridin-3-yl)-6-(7-bromo-3,4-dihydroisoquinolin-2(1H)yl)pteridin-7(8H)-one (8mg, yield 35% ), ESI-MS (m/z): 509.2 [M+H] ⁺ .

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

According to the method of synthesis A1, 8 was synthesized with p-methoxyaniline, 2,2,2-trifluoroethanol and [1,2,4]triazol[4,3a]pyridin-6-ylboronic acid as starting materials. -(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)oxy)-6-([1,2,4]triazol[4,3a]pyridine-6 -yl)pteridin-7(8H)-one (5 mg, yield 7%), ESI-MS (m/z): 470.1 [M+H] ⁺ .

Preparation 23: 8-(4-Chlorophenyl)-2-ethoxy-6-(2,3-dihydrobenzofuran-5-yl)pteridin-7(8H)-one (A23)

According to the method of synthesis A1, 8-(4-chlorophenyl)-2-ethoxy-6-(2,3- Dihydrobenzofuran-5-yl)pteridin-7(8H)-one (1.2mg, yield 5%), ESI-MS (m/z): 421.1[M+H] ⁺ ; ¹ H NMR ( 600MHz,DMSO-d ₆ )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).

Preparation 24: 2-Ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7 (8H)-Kone (A24)

Step 1: Methyl 3-((2-methyl-2H-indazol-5-yl)thio)propanoate

Take 5-bromo-2-methyl-2H-indazole (1000mg, 4.730mmol), methyl 3-mercaptopropionate (850mg, 7.110mmol), tris[dibenzylideneacetone]dipalladium (260mg, 0.280mmol ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (274mg, 0.473mmol), N,N-diisopropylethylamine (2.34mL, 1.420mmol) and dioxane A ring (40 mL) was added into a 100 mL round-bottomed flask, replaced with nitrogen three times, and heated to 100° C. for 4 h. After the reaction, 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 phase was combined, and the organic phase was washed with water and saturated sodium chloride solution successively, concentrated, and subjected to column chromatography The target compound was purified to obtain methyl 3-((2-methyl-2H-indazol-5-yl)thio)propionate (500 mg, yield 42%), ESI-MS (m/z): 251.1 [M +H] ⁺ ;

Step 2: 2-Methyl-2H-indazole-5-thiol

Take methyl 3-((2-methyl-2H-indazol-5-yl)thio)propanoate (500mg, 1.997mmol), sodium hydroxide (80mg, 2.000mmol) and methanol (5mL) into 25mL The round bottom flask was replaced with nitrogen three times, and heated to 50° C. for 3 h. After the reaction, add 25 mL of ethyl acetate and 10 mL of water to the reaction solution, adjust the pH to 4 with acetic acid, extract the aqueous phase twice with ethyl acetate, combine the organic phases, and wash the organic phases with water and saturated sodium chloride solution successively. 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] ⁺ ;

Step 3: 2-Ethoxy-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7( 8H)-ketone

Take 6-chloro-8-(6-methoxypyridin-3-yl)-2-ethoxypteridin-7(8H)-one (100mg, 0.300mmol), 2-methyl-2H-indazole -5 mercaptan (98mg, 0.599mmol), tris[dibenzylideneacetone]dipalladium (33mg, 0.036mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (35mg , 0.060mmol), potassium carbonate (208mg, 1.498mmol) and dioxane (5mL) were added into a 25mL round bottom flask, replaced with nitrogen three times, and heated to 100°C for 3h. After the reaction, add 25 mL of ethyl acetate and 10 mL of water to the reaction solution, extract the water phase twice with ethyl acetate, combine the organic phase, wash the organic phase with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography Obtain target compound 2-ethoxy group-8-(6-methoxypyridin-3-yl)-6-((2-methyl-2H-indazol-5-yl)thio)pteridine-7( 8H)-ketone (18 mg, yield 13%), ESI-MS (m/z): 462.1[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 25: 8-(2-Hydroxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl) Pteridin-7(8H)-one (A25)

According to the method of synthesis A17, 8-(2-hydroxyphenyl)-2-((2,2,2-tri Fluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (50mg, yield 57%), ESI-MS (m/z ): 468.1 [M+H] ⁺ .

Preparation 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)

Step 1: 2-(6-Bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethan-1-ol

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

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

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

硼戊环-2-基)-1H-苯并[d]咪唑-2-基)乙基)吗啉Step 3: 4-(2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-di

Borolane-2-yl)-1H-benzo[d]imidazol-2-yl)ethyl)morpholine

Take 4-(2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)morpholine (67mg, 0.207mmol), double pinacol borate ( 79mg, 0.310mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (23mg, 0.031mmol), potassium acetate (61mg, 0.621mmol) and dioxane (2mL) were added to In a 10mL round-bottomed flask, after replacing with nitrogen three times, heat to 110°C for 3 hours. After the reaction, cool down to room temperature and use it directly in the next step. ESI-MS (m/z): 372.2[M+H] ⁺ .

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

Compound 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholine ethyl)-1H-benzo[d]imidazol-6-yl was synthesized according to the method of synthesis A1 )-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (20mg, yield 16%), ESI-MS(m/z): 595.2[M+ H] ⁺ ; ¹ H NMR (600MHz,DMSO-d ₆ )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 ).

Preparation 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)

According to the method of 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 (20mg, yield 21%), ESI-MS (m/z): 526.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO -d ₆ )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, 2H), 3.85(s, 3H), 3.84-3.82(m, 1H), 3.80(s, 3H), 3.08(t, J=6.7Hz, 2H).

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

According to the synthesis of 8-(4-methoxyphenyl)-6-(1-methyl-2-(2-morpholine ethyl)-1H-benzo[d]imidazol-6-yl)-2-( (2,2,2-Trifluoroethyl)amino)pterin-7(8H)-one (A26) by the method of 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methyl Synthesis of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl) -1-Methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (240mg, yield 38%), ESI-MS(m/z): 509.2[M+ H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) δ9.10(s, 1H), 8.47(s, 1H), 8.12(d, J=8.4Hz, 1H), 7.66(d, J=8.5 Hz, 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=7.0 Hz, 3H).

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

According to the method for synthesizing A26, 8-(4-(di Fluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7 (8H)-ketone (48 mg, yield 35%), ESI-MS (m/z): 509.2[M+H] ⁺ ; ¹ HNMR (600MHz, DMSO-d ₆ ) 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=8.7 Hz,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).

Preparation 30: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1- Methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A30)

Take 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole- 6-yl)pterin-7(8H)-one (A26) (40 mg, 0.079 mmol) was dissolved in dichloromethane (5 ml) in a 25 mL round bottom flask, triethylamine (109 μL, 0.786 mmol), methyl Sulfonyl chloride (50 μL, 0.629 mmol) was reacted at room temperature for 1 h, 3-methoxypyrrolidine hydrochloride (162 mg, 1.179 mmol) and triethylamine (220 μL, 1.572 mmol) were added and reacted at room temperature for 48 h. After the reaction, add 100mL ethyl acetate and 50mL water to the reaction solution, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography The target compound 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1-meth Base-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (18 mg, yield 39%), ESI-MS (m/z): 592.2[M+H] ⁺ ; ¹ H NMR (600MHz,DMSO-d ₆ )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).

Preparation 31: 8-(2,3-Dihydrobenzofuran-4-yl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pterin-7( 8H)-Kone (A31)

According to the method of synthesis A1, 8-(2,3-dihydrobenzofuran-4-yl)-2-ethoxy- 6-(2-Methyl-2H-indazol-5-yl)pterin-7(8H)-one (15mg, yield 53%), ESI-MS(m/z): 441.2[M+H] ⁺ .

Preparation 32: 6-(2-(2-(3-Hydroxypyrrolidin-1-yl)ethyl)-1-methyl-1H-benzimidazol-6-yl)-8-(4-methoxy phenylphenyl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A32)

According to the method of synthesizing A26, 4-methoxyaniline and 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, pyrrolidinol, etc. are used as starting materials Synthesis of 6-(2-(2-(3-hydroxypyrrolidin-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%), ESI-MS (m/z): 595.2 [M +H] ⁺ ; ¹ H NMR (600MHz, CDCl ₃ ) 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), 2.67-2.64(m, 2H), 2.50-2.40(m, 1H), 2.28-2.22(m, 2H), 1.87-1.78(m, 2H) .

Preparation 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)

According to the method of synthesis 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)- Ketone (9 mg, yield 42%), ESI-MS (m/z): 558.2 [M+H] ⁺ .

Preparation 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)

According to the method of synthesis A1, 6-(2-(2-hydroxyethyl)-1-methyl-1H was synthesized using 3-phenylethylaniline and 2,2,2-trifluoroethylamine as starting materials -Benzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethyl)amino)-8-(3-(phenylethoxy)phenyl)pterin-7( 8H)-ketone (13 mg, yield 58%), ESI-MS (m/z): 572.2 [M+H] ⁺ .

Preparation 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)

According to the method for the synthesis of A26, 4-(trifluoromethoxy)aniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, etc. were used as starting materials Synthesis of 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%), ESI-MS (m/z): 580.2[M+H] ⁺ ; ¹ H NMR (600MHz,DMSO-d ₆ )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).

Preparation 36: 6-(2-(2-(3-Hydroxypyrrolidin-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)

According to the method of synthesizing A26, with 4-(trifluoromethoxy)aniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and pyrrolidinol, etc. Synthesis of 6-(2-(2-(3-hydroxypyrrolidin-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%), ESI-MS (m/z): 649.2[M+H] ⁺ ; ¹ H NMR (600MHz,DMSO-d ₆ )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).

Preparation 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)

According to the synthesis method of A26, with 4-(trifluoromethoxy)aniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and 4,4- Synthesis of 6-(2-(2,4-difluoropiperidin-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl from difluoropiperidine etc. )-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (25mg, yield 11 %), ESI-MS (m/z): 683.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 38: 8-(4-(Trifluoromethoxy)phenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)-6-(2-methyl-2H- Indazol-5-yl)pteridin-7(8H)-one (A38)

According to the method of synthesis A1, 8-(4-(trifluoromethoxy) Phenyl)-2-((1-(trifluoromethyl)cyclopropyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (30mg, yield 20%), ESI-MS (m/z): 562.1[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 39: 6-(2-(2-(3-Methoxypyrrolidin-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)

According to the method of synthesis A26, with 4-(trifluoromethoxy)aniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and 3-methoxy Synthesis of 6-(2-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1-methyl-1H-benzo[d]imidazole-6- Base)-2-(2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)pterin-7(8H)-one (9mg, yield 6 %), ESI-MS (m/z): 663.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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),3.80(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).

Preparation 40: 8-(4-(Difluoromethoxy)phenyl)-6-(2-(2-(3-methoxypyrrolidin-1-yl)ethyl)-1-methyl- 1H-Benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (A40)

According to the method of synthesis A26, with 4-(difluoromethoxy)aniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and 3-methoxy Synthesis of 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(3-methoxypyrrolidin-1-yl)ethyl)- 1-Methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterin-7(8H)-one (13mg, yield 9%), ESI-MS (m/z): 645.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) δ8.93-8.90 (m, 1H), 8.43 (s, 1H), 8.18(s, 1H), 8.08(d, J=8.5Hz, 1H), 7.63(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).

Preparation 41: 8-(4-(Difluoromethoxy)phenyl)-6-(2-(2-(2,6-Dimethylmorpholinyl)ethyl)-1-methyl-1H -Benzo[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (A41)

According to the method of synthesizing A26, start with 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and 2,6-dimethylmorpholine, etc. Synthesis of 8-(4-(difluoromethoxy)phenyl)-6-(2-(2-(2,6-dimethylmorpholinyl)ethyl)-1-methyl-1H-benzene from starting materials And[d]imidazol-6-yl)-2-ethoxypterin-7(8H)-one (51 mg, yield 27%), ESI-MS (m/z): 606.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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).

Preparation 42: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1 -Methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A42)

According to the method for synthesizing A26, 8-(4 -(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1-methyl-1H-benzo [d] imidazol-6-yl)pterin-7(8H)-one (32 mg, yield 16%) (25 mg, yield 11%), ESI-MS (m/z): 578.2 [M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ )δ9.10(s,1H),8.49(s,1H),8.13(d,J=8.5Hz,1H),7.67(d,J=8.5Hz, 1H), 7.54(d, J=8.7Hz, 2H), 7.41(d, J=8.7Hz, 2H), 7.39(t, J=74Hz, 1H), 5.10(brs, 1H), 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).

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

According to the method of synthesizing A26, 8-(4- (Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(piperidin-1-yl)ethyl)-1Hbenzo[d]imidazole- 6-yl)pterin-7(8H)-one (32mg, yield 16%), ESI-MS (m/z): 576.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ ) 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 ).

Preparation 44: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(pyrrolidin-1-yl)ethyl) -1H-Benzo[d]imidazol-6-yl)pterin-7(8H)-one (A44)

According to the method for synthesizing A26, 8-( 4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-1H-benzo[d ]imidazol-6-yl)pterin-7(8H)-one (17mg, yield 9%), ESI-MS (m/z): 562.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO- d ₆ )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).

Preparation 45: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1 -Methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (A45)

Take 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d]imidazole- 6-yl)pterin-7(8H)-one (A28) (40 mg, 0.079 mmol) was dissolved in dichloromethane (5 ml) in a 25 mL round bottom flask, triethylamine (109 μL, 0.786 mmol), methyl Sulfonyl chloride (50 μL, 0.629 mmol) was reacted at room temperature for 1 h, 3-fluorotetrahydropyrrole hydrochloride (99 mg, 0.786 mmol) and triethylamine (164 μL, 1.179 mmol) were added and reacted at room temperature for 48 h. After the reaction, add 100mL ethyl acetate and 50mL water to the reaction solution, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated sodium chloride solution successively, concentrate, and purify by column chromatography The target compound 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1- Methyl-1H-benzo[d]]imidazol-6-yl)pterin-7(8H)-one (21mg, yield 47%), ESI-MS(m/z): 580.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO-d ₆ )δ9.10(s,1H),8.47(s,1H),8.12(d,J=7.8Hz,1H),7.66(d,J=8.1Hz, 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=6.5Hz, 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).

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

According to the method of synthesizing A26, 8-(4-(difluoromethoxy) Base)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one (150mg, yield 21%), ESI-MS (m/z): 495.2[M+H] ⁺ ; ¹ HNMR (600MHz, DMSO-d ₆ ) 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=8.7Hz, 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 = 7.1 Hz, 3H).

Preparation 47: 8-(4-(Difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d] Imidazol-6-yl)-2-ethoxypteridin-7(8H)-one (A47)

According to the method of synthesizing A45, using 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and dimethylamine hydrochloride as starting materials to synthesize 8 -(4-(Difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl )-2-ethoxypteridin-7(8H)-one (16mg, yield 38%), 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).

Preparation 48: 6-(2-(2-(Diethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethane Oxy)phenyl)-2-ethoxypteridin-7(8H)-one (A48)

According to the method of synthesizing A45, using 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and diethylamine amine hydrochloride as starting materials to synthesize 6-(2-(2-(Diethylamino)ethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)benzene base)-2-ethoxypteridin-7(8H)-one (15mg, yield 37%), 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).

Preparation 49: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzene And[d]imidazol-6-yl)pteridin-7(8H)-one (A49)

According to the method of synthesizing A26, with 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid and diethylamine amine hydrochloride, etc. Synthesis of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H- Benzo[d]imidazol-6-yl)pteridin-7(8H)-one (35mg, yield 35%), ESI-MS (m/z): 523.2[M+H] ⁺ ; ¹ H 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).

Preparation 50: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine -7(8H)-Kone (A50)

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

Add 5-bromoindole (1.96g, 10mmol), (2-bromoethoxy)-tert-butyldimethylsilane (4.78g, 20mmol), norbornene (1.88g, 20mmol) into a 100mL flask, Bis(acetonitrile)palladium dichloride (260mg, 1mmol), potassium carbonate (2.76g, 20mmol) and DMF (20mL) were replaced with nitrogen and stirred at 70°C. After the reaction, cool down and add 150 mL of water, extract twice with 200 mL of ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, filter and concentrate. Purified by column chromatography to obtain 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (1.0g, yield 28%), ESI- MS (m/z): 354.1, 356.1 [M+H] ⁺ ;

Step 2: 2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa Borane-2-yl)-1H-indole

Take the previous step product 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole (200mg, 0.56mmol), bis(pinacol) di Boron (0.28g, 1.14mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (82mg, 0.11mmol), potassium acetate (165mg, 1.6mmol) and dioxane (5 mL) was added into a 100 mL round bottom flask, and after nitrogen replacement, the reaction was stirred at 105°C. After the reaction was completed, the temperature was directly lowered for the next reaction without further treatment, ESI-MS (m/z): 402.3[M+H] ⁺ ;

Step 3: 6-(2-((tert-Butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2 -Ethoxypteridin-7(8H)-one

Add water (1mL), 6-chloro-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (100mg, 0.28mmol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (82mg, 0..11mmol) and potassium acetate (165mg, 1.6mmol), after nitrogen replacement, stirred at 100°C for reaction. Cool down after the reaction, add 100mL of water, extract twice with 200mL of ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, concentrate after filtration, obtain 6-(2-((tert-butyldimethylsilyl) by column chromatography Base)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (50mg, yield rate of 29%), ESI-MS (m/z): 608.2[M+H] ⁺ ;

Step 4: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1H-indol-5-yl)pteridine- 7(8H)-keto

Take the previous step product 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)- 2-Ethoxypteridin-7(8H)-one (20mg, 0..033mmol), tetrahydrofuran (5mL) and tetrabutylammonium fluoride (1M, 0.1ml) were added into a 100mL round bottom flask, stirred at room temperature reaction. After the reaction, 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)pteridin-7(8H)-one (4mg, 25%), ESI-MS (m/z): 494.2[M+H] ⁺ ; ¹ H NMR (600MHz, DMSO- d ₆ )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).

Preparation 51: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indole-5 -yl)pteridin-7-(8H)-one (A51)

Step 1: 6-(2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4-( Difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one

Take 6-(2-((tert-butyldimethylsilyl)oxy)-1H-indol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethane Oxypteridine-7(8H)-one (30mg, 0.049mmol) and DMF (5mL) were added in a 100mL round bottom flask, 60% sodium hydride (4mg, 0.1mmol) was added under ice-cooling, stirred at room temperature for 10 Minutes, iodomethane (14.2 mg, 0.1 mmol) was added, and the reaction was stirred at room temperature. After the reaction, 100 mL of water was added, extracted twice with 200 mL of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by thin plate chromatography afforded 6-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-( 4-(Difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (20mg, 65%), ESI-MS(m/z): 622.3[M+H] ⁺

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-indole-5- Base) pteridin-7-(8H)-one

Get the previous step product 6-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1-methyl-1H-indol-5-yl)-8-(4- (Difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (20mg, 0.032mmol), tetrahydrofuran (5mL) and tetrabutylammonium fluoride (1M, 0.1mL) were added In a 100mL round bottom flask, stir the reaction at room temperature. After the reaction, 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)pteridin-7-(8H)-one (5 mg, yield 31%), ESI-MS (m/z): 508.2[M+H] ⁺ ; ¹ HNMR(600MHz,DMSO-d ₆ )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).

Preparation 52: 2-Ethoxy-8-(4-fluorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterene Pyridine-7(8H)-one (A52)

According to the method for synthesizing A26, 2-ethoxy-8-(4-fluorophenyl)-6- (2-(Hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridin-7(8H)-one (19mg, yield 15%), 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).

Preparation 53: 8-(4-Chlorophenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterene Pyridine-7(8H)-one (A53)

According to the method of synthesizing A26, 8-(4-chlorophenyl)-2-ethoxy-6- (2-(Hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridin-7(8H)-one (12mg, yield 13%), 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).

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

According to the method for synthesizing A26, 8-(6-cyclopropylpyridine-3-amine, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid, etc. 3-yl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pterin-7(8H)-one ( 10mg, yield 11%), 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, 3H), 2.26–2.21 (m, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.24–1.22 (m, 2H), 1.03–1.00 (m, 2H).

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

According to the method of synthesizing A26, 6-(2-(tert-butyl)) was synthesized with 4-(difluoromethoxy)aniline, ethanol, 4-bromo-2-methylaminoaniline, pivalic acid, etc. as starting materials -1-Methyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (50mg, yield 35%), ESI-MS (m/z): 521.2[M+H] ⁺ ; ¹ H 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).

Preparation 56: 6-(2-Acetyl-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridine-7(8H) - Ketone (A56)

According to the method of synthesizing A26, 6-(6- (2-Acetyl-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypteridin-7(8H)-one (35 mg, 18%), 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),7.52(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) .

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

According to the method of synthesis A26, 8-(4-(difluoromethoxy) Phenyl)-2-ethoxy-6-(2-(1-hydroxyethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)pteridin-7(8H)-one (25mg, 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).

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

According to the synthesis method of A26, start with 4-methoxyaniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid, etc. Synthesis of 6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2 -((2,2,2-trifluoroethyl)amino)pteridin-7(8H)-one (20 mg, yield 14%), ESI-MS (m/z): 540.2[M+H] ⁺ ; ¹ H 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).

Preparation 59: 6-(2-(Hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-(( 2,2,2-Trifluoroethyl)amino)pteridin-7(8H)-one (A59)

According to the method of synthesizing A26, 6-(2-( Hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl )amino)pteridin-7(8H)-one (25mg, yield 19%), 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).

Preparation 60: 8-((1H-Imidazol-2-yl)methyl)-2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzene And[d]imidazol-6-yl)pteridin-7(8H)-one (A60)

According to the method of synthesizing A26, with (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)methanamine, ethanol, 4-bromo-2-methyl 2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzene And[d]imidazol-6-yl)-8-((1-((2-(trimethylsilyl))ethoxy)methyl)-1H-imidazol-2-yl)methyl)pterene Pyridine-7(8H)-one.

Take 2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-8-((1-(( 2-(Trimethylsilyl))ethoxy)methyl)-1H-imidazol-2-yl)methyl)pteridin-7(8H)-one (50 mg, 0.084 mmol) dissolved in 25 mL round bottom Dichloromethane (5ml) in the flask was added with 2.5mL trifluoroacetic acid and reacted at room temperature for 3h. After the reaction, remove the solvent under reduced pressure, add 50mL of water, adjust the pH to about 7 with sodium bicarbonate, extract the aqueous phase twice with ethyl acetate, combine the organic phases, wash the organic phases with water and saturated sodium chloride solution successively, concentrate, Purified by column chromatography to obtain the target compound 8-((1H-imidazol-2-yl)methyl)-2-ethoxy-6-(2-(2-hydroxypropan-2-yl)-1-methyl -1H-benzo[d]imidazol-6-yl)pteridin-7(8H)-one (12mg, 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).

Preparation 61: 8-(4-Chlorophenyl)-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2, 2,2-Trifluoroethyl)amino)pteridin-7(8H)-one (A61)

According to the method of synthesizing A26, 8-(4-chlorophenyl )-6-(2-(Hydroxymethyl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)pterene Pyridine-7(8H)-one (15 mg, yield 11%), ESI-MS (m/z): 516.1[M+H] ⁺ ; ¹ HNMR (600MHz, DMSO) δ8.91 (d, J=16.5 Hz,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).

Preparation 62: 8-(4-Chlorophenyl)-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2 -((2,2,2-trifluoroethyl)amino)pteridin-7(8H)-one (A62)

According to the synthesis method of A26, synthesized from 4-chloroaniline, 2,2,2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid, etc. as starting materials 8-(4-chlorophenyl)-6-(2-(2-hydroxypropan-2-yl)-1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2 ,2,2-trifluoroethyl)amino)pteridin-7(8H)-one (20mg, yield 14%), 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),7.66(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).

Preparation 63: 8-(4-Methoxyphenyl)-2-((2,2-difluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl) Pteridin-7(8H)-one (A63)

According to the method of synthesis A1, 8-(4-methoxyphenyl)-2-((2,2-di Fluoroethyl)amino)-6-(2-methyl-2H-indazol-5-yl)pteridin-7(8H)-one (30mg, yield 43%), 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).

The following are the effect tests and data of the compounds of the present invention.

Test Example 1: MAT2A enzymatic activity test

MAT2A Inhibitor Enzyme Screening Kit (BPS Bioscience, Catalog: 71402) was used to determine the inhibitory effect of test compounds on MAT2A enzymatic activity. The specific operation procedure is as follows:

1) Dissolve the test compound in DMSO and mix thoroughly until the test compound is completely dissolved. All compounds were diluted with DMSO to an initial concentration of 2 mM, and three-fold serially diluted to a total of 10 concentration gradients, repeated wells, and added to the reaction system at a ratio of 1:100 during detection (the maximum final concentration was 20 μM). A 100x positive control (1 mM AGI-24512) and a 100x negative control (100% DMSO) were prepared.

2) Transfer 200 nL of the diluted compound to each well of the reaction plate (784075, Greiner) with the Echo 550 pipetting system, seal the reaction plate with a sealing film, and centrifuge at 1000 g for 1 minute. The final concentration of DMSO was 1%.

3) Prepare 1×MAT2A enzyme reaction buffer: 1 volume of 5×MAT2A enzyme reaction buffer plus 4 volumes of water and mix thoroughly.

4) Prepare 2×MAT2A enzyme solution with 1× enzyme reaction buffer.

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

6) Centrifuge at 1000g for 60 seconds and incubate at room temperature for 30 minutes.

7) Prepare 2×L-methionine and ATP mixture with 1×MAT2A enzyme reaction buffer.

8) Add 10 μL of 2×L-methionine and ATP mixture to each well of the 384-reaction plate (Corning3702), and seal the plate with a sealing film. The total reaction volume is 20 μL.

9) Centrifuge at 1000g for 60 seconds and incubate at room temperature for 60 minutes.

10) Prepare detection buffer colorimetric detection reagent (Colorimetric Detection Reagent).

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

12) Measure the fluorescence signal at 630 nm with a multifunctional microplate reader (PerkinElmer, Nivo).

The enzymatic activities of representative compounds of the present invention are shown in the table below.

A represents IC ₅₀ ≤50nM, B represents 50nM<IC ₅₀ ≤100nM.

The above data show that the compound of the present invention has strong MAT2A inhibitory effect.

Test Example 2. Test for Inhibition of Cell Proliferation

The specific operating procedure is as follows: the tumor cells are treated with the compound for 5 days, and the effect of the compound to be tested on the proliferation of the tumor cells is evaluated. HCT116-MTAP ^-/- and wild-type control HCT116-WT cells were seeded in a 384-well culture plate at a density of 600/well, and treated with different concentrations of test compounds (starting at 20 μM, 10 concentration gradients). Cells were incubated at 37°C, 5% CO ₂ , saturated humidity for 5 days.

Cell proliferation was detected using an ATP-based cell proliferation detection kit (Cell Titer Glo, Promega Corporation). Cells were treated with Cell Titer Glo reagent after equilibrating at room temperature for 30 minutes. The dish was then covered with aluminum foil and shaken for 15 minutes to allow for thorough mixing and lysis. Chemiluminescent detection was performed using a multi-functional microplate reader (Envision 2105, PerkinElmer). Set blank wells (blank, no cells) and DMSO control wells.

Use the following formula to calculate the inhibition rate (Inhibition rate, IR) of the test compound:

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

GraphPad Prism was used for graphing, data analysis and _IC50 calculation.

Compounds of the invention were tested in the assays described above and their _IC50 for inhibiting cell proliferation were determined as shown in the table below.

The results show that the compound to be tested exhibits strong cell proliferation activity on HCT116 MTAP knockout cells, and weak cell proliferation activity on MTAP wild-type HCT116 cells, that is, shows better selectivity.

Test example 3. Human UGT1A1 enzyme activity test

To measure the enzyme inhibitory activity of the compound on UGT1A1, the specific operation procedure is as follows:

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

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 was stopped by adding 400 μL of cold acetonitrile containing an internal standard.

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

% remaining activity = (average ratio of test compound or inhibitor)/(average ratio of vehicle control)*100

% inhibition = 100-% remaining activity

The above results show that compound A49 has a small risk of inhibiting UGT1A1, while compounds 45 and 91 of WO2021139775 have a high inhibitory rate on UGT1A1, and there is a risk of increased bilirubin in vivo.

Test Example 4. In vivo pharmacokinetic study in mice

Experimental animals: CD-1 mice (male, 22-25 g) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.

Test procedure: CD-1 mice (male, 22-25g) were intravenously injected with the test compound (2mg/kg), orally administered with the test compound (5mg/kg), after administration for 5min, 15min, 0.5h, 1h , 2h, 4h, 8h, and 24h to collect mouse plasma, LC-MS/MS to detect the concentration of the compound, and investigate its plasma clearance Cl, elimination half-life T _1/2 , peak time T _max , peak concentration C _max , and drug-time curve Pharmacokinetic parameters such as area AUC, apparent volume of distribution Vss, absolute bioavailability F, etc.

Determination method: Dilute the stock solution of the analyte with 50% acetonitrile to obtain the required concentration of the working solution series. 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 of 1-10000 ng/mL (1, 2, 5, 10, 50, 100, 500, 1000, 5000, 10000 ng/mL) calibration standards. Five quality control (QC) samples (2 ng/mL, 5 ng/mL, 10 ng/mL, 800 ng/mL, 8000 ng/ml) were prepared in the same manner as the calibration standards on the day of analysis. Add 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) to 200 μL of IS mixture containing acetonitrile to precipitate protein. The samples were then vortexed for 3 min. After centrifugation at 4 °C and 4700 rpm for 15 min, the supernatant was diluted with ultrapure water at a ratio of 1:2 (V/V), and then 10 μL of the diluted supernatant was injected into the LC/MS/MS system for quantitative analysis.

The pharmacokinetic parameters of compound A49 are as follows:

IV: intravenous injection; PO: oral administration; Cl: apparent clearance rate; T _1/2 : half-life; AUC _last : the area under the drug-time curve from the beginning of administration to the last point (24 hours); AUC _inf : from The area under the drug-time curve from the beginning of administration to the theoretically extrapolated infinity time; MRT _Inf : the average residence time from zero time to infinity time; _Vss : apparent volume of distribution; T _max : peak time; Peak concentration; F: relative bioavailability.

Test Example 5. Investigation of Antitumor Drug Efficacy of Compounds in Vivo

The inhibitory effect of the compound A49 of the present invention on the growth of HCT116-MTAP ^-/- cell transplanted tumor in mice was tested.

Experimental animals: female BALB/c nude mice were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., with a weight range of 18-22 g, and were kept in an SPF-level laminar flow clean room with constant temperature and humidity, using IVC cages with independent ventilation. One cage per 5 mice.

HCT116-MTAP ^-/- cells were cultured in McCoy's 5a medium (GIBCO) containing 10% FBS. The cells were inoculated subcutaneously on the back of 42 BALB/c nude mice at a quantity of 5×10 ⁶ /mouse. On the 6th day after inoculation, 30 mice with a tumor volume of about 150 mm ³ were selected and grouped evenly according to the tumor volume. Oral administration once a day for 14 consecutive days. The difference in tumor growth rate between the administration group and the solvent group was compared, and the tumor growth inhibition rate TGI (%) and the tumor weight inhibition rate TWI (%) were used as evaluation indexes.

Note: TV _Xn : average tumor volume on day n of the administration group

TV _X1 : Average tumor volume of the administration group on day 1

TV _Mn : mean tumor volume of the model group on day n

TV _M1 : the average tumor volume of the model group on day 1

Tumor weight inhibition rate=(1-Tumor weight of administration group/Tumor weight of solvent group)×100%

The above results show that the compound of the present invention exhibits good drug efficacy in vivo and does not cause the increase of bilirubin.

Test example 6. In vivo serum total bilirubin detection

Female Nu/Nu mice, 18-22 g, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. The test compound was orally administered once a day for 14 consecutive days. Whole blood was collected from the heart of the animal after anesthesia, and after standing at room temperature for 0.5 hour, it was centrifuged at 3500 rpm for 10 minutes to separate the serum, and the blood total bilirubin level was detected by an automatic biochemical analyzer. The results are shown in the table below, the test compound did not cause a significant increase in total blood bilirubin.

The above results indicate that the compound of the present invention does not cause pathological increase of bilirubin, has low toxicity and good safety.

Claims (15)

1. A compound as shown in formula (I) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt:

in: L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^a1 )C(O )-, -C(O)N(R ^a1 )- or -N(R ^a1 )-; each occurrence of R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^a is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-14 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by R ^a2 , wherein each occurrence of R ^a2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^a3 , -OR ^a3 , -SR ^a3 , -S(O)R ^a3 , -SO ₂ (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 ), -SO ₂ NH(R ^a3 ), -SO ₂ N (R ^a3 )(R ^a4 ), -NHS(O)(R ^a3 ), -N(R ^a3 )S(O)(R ^a4 ), -NHSO ₂ (R ^a4 ), -N(R ^a3 )SO ₂ (R ^a4 ); wherein each occurrence of R ^a3 , R ^a4 is independently selected from hydrogen or is optionally selected from one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ; L ₂ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^b1 )C(O )-, -C(O)N(R ^b1 )- or -N(R ^b1 )-; each occurrence of R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^b is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently replaced by R ^b2 , wherein each occurrence of R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , -OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ), -SO ₂ N (R ^b3 )(R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N(R ^b3 )SO ₂ (R ^b4 ); wherein each occurrence of R ^b3 , R ^b4 is independently selected from hydrogen or is optionally selected from one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 are connected with their Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ; L ₃ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^c1 )C(O )-, -C(O)N(R ^c1 )- or -N(R ^c1 )-; each occurrence of R ^c1 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; the optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 ring Substituents of alkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by ^Rc2 , wherein each occurrence of ^Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, ^-Rc3 , ^-ORc3 , -SR ^c3 , -S(O)R ^c3 , -SO ₂ (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 ), -SO ₂ NH(R ^c3 ), -SO ₂ N (R ^c3 )(R ^c4 ), -NHS(O)(R ^c3 ), -N(R ^c3 )S(O)(R ^c4 ), -NHSO ₂ (R ^c4 ), -N(R ^c3 )SO ₂ (R ^c4 ); wherein R ^c3 , R ^c4 each occurrence are independently selected from hydrogen or optionally replaced by one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^c3 and R ^c4 are connected to the same nitrogen atom, R ^c3 and R ^c4 are connected to the Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ; X ₁ is selected from N or CR ^d ; R ^d 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 alkyl Amino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-12 membered heterocyclic group, C _6-14 aryl, 5-12 membered heteroaryl; Optionally substituted means that the mentioned group is unsubstituted or independently substituted at one or more substitutable positions by ^Rd1 , wherein ^Rd1 is independently selected from each occurrence of deuterium, halogen, hydroxyl, amino, Nitro, mercapto, cyano, oxo, -R ^d2 , -OR ^d2 , -SR ^d2 , -S(O)R ^d2 , -SO ₂ (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 ); wherein R ^d2 , R ^d3 each occurrence are independently selected from hydrogen or are optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy substituent substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _{3- 10} cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4. 2. A compound as shown in formula (II) or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt:

in: L ₁ is selected from a bond, -CH ₂ -, -O-, -S-, -C(O)-, -C(O)O-, -OC(O)-, -N(R ^a1 )C(O )-, -C(O)N(R ^a1 )- or -N(R ^a1 )-; each occurrence of R ^a1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; The optional substitution means that the mentioned group is unsubstituted or 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, C _3-10 cycloalkyl, 3-10 membered hetero Substituents of cycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^a is selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl; said optional substitution means that the mentioned group is unsubstituted or in a or a plurality of substitutable positions are independently substituted by R ^a2 , wherein each occurrence of R ^a2 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 , -SO ₂ (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 ), -SO ₂ NH(R ^a3 ), -SO ₂ N(R ^a3 )(R ^a4 ), -NHS(O)(R ^a3 ), -N(R ^a3 )S (O)(R ^a4 ), -NHSO ₂ (R ^a4 ), -N(R ^a3 )SO ₂ (R ^a4 ); wherein each occurrence of R ^a3 , R ^a4 is independently selected from hydrogen or optionally replaced by one or more 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 C _{1-6 alkyl} , _{C 1-6} Alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; Or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 form together with the nitrogen atom they are connected , cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered A 3-10 membered heterocycloalkyl group or a 5-12 membered heteroaryl group substituted by a substituent of a heteroaryl group; L ₂ is selected from 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 )-; each occurrence of R ^b1 is independently selected from hydrogen or optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered Heteroaryl; said optionally substituted means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano at one or more substitutable positions , oxo, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3 - Substituents of 10-membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^b is selected from optionally substituted 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; said optional substitution means that the mentioned group is unsubstituted or in a or multiple substitutable positions are independently substituted by R ^b2 , wherein each occurrence of R ^b2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, -R ^b3 , - OR ^b3 , -SR ^b3 , -S(O)R ^b3 , -SO ₂ (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 ), -SO ₂ NH(R ^b3 ) , -SO ₂ N(R ^b3 )(R ^b4 ), -NHS(O)(R ^b3 ), -N(R ^b3 )S(O)(R ^b4 ), -NHSO ₂ (R ^b4 ), -N( R ^b3 )SO ₂ (R ^b4 ); wherein each occurrence of R ^b3 , R ^b4 is independently selected from hydrogen or is optionally selected from one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano group, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl , C _6-14 aryl, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C 2-6 alkynyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; or when R ^b3 and R ^b4 are connected to the same nitrogen atom, R ^b3 and R ^b4 Together with the nitrogen atom they are attached to form optionally one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkane _3-10 membered _{heterocycloalkyl} or 5- 12-membered heteroaryl; L ₃ is selected from a bond, -CH ₂ -, -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 is 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl The optional substitution means that the mentioned group is unsubstituted or independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxygen at one or more substitutable positions Substitute, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkyl, 3-10 Substituents of membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; R ^c is selected from optionally substituted C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylamino, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 ring Alkyl, 3-12 membered heterocyclic group, C _6-14 aryl group, 5-12 membered heteroaryl group; the optional substitution means that the mentioned group is unsubstituted or can be substituted in one or more The position is independently substituted by ^Rc2 , wherein each occurrence of ^Rc2 is independently selected from deuterium, halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, ^-Rc3 , ^-ORc3 , -SR ^c3 , -S(O)R ^c3 , -SO ₂ (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 ), -SO ₂ NH(R ^c3 ), -SO ₂ N (R ^c3 )(R ^c4 ), -NHS(O)(R ^c3 ), -N(R ^c3 )S(O)(R ^c4 ), -NHSO ₂ (R ^c4 ), -N(R ^c3 )SO ₂ (R ^c4 ); wherein R ^c3 , R ^c4 each occurrence are independently selected from hydrogen or optionally replaced by one or more 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, C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-10 cycloalkane substituted by substituent of aryl, 5-12 membered heteroaryl base, 3-10 membered heterocycloalkyl group, C _6-14 aryl group, 5-12 membered heteroaryl group; or when R ^c3 and R ^c4 are connected to the same nitrogen atom, R ^c3 and R ^c4 are connected to the Nitrogen atoms together are optionally replaced by one or more independently selected from halogen, hydroxyl, amino, nitro, mercapto, cyano, oxo, C _1-6 alkyl, C _1-6 alkoxy, C _{3 -10} -membered heterocycloalkyl, 3-10-membered heterocycloalkyl, C _6-14 -membered aryl, 5-12-membered heteroaryl substituent substituted 3-10-membered heterocycloalkyl or 5-12-membered heteroaryl ; Unless otherwise specified, the heteroatoms in the above-mentioned heterocycloalkyl, heteroaryl and heterocyclyl are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4. 3. The compound or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt according to claim 1 or 2, characterized in that: L ₁ is selected from a bond, -CH ₂ -, -O-, -S- or -N(R ^a1 )-, wherein R ^a1 is selected from hydrogen or C _1-6 alkyl; Preferably, L is selected from bond, -O-, -S-, -NH- _; Preferably, L ₁ is a bond. 4. The compound or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt according to any one of claims 1 to 3, characterized in that: R is selected from optionally substituted ^3-12 membered heterocyclic groups, C _6-14 aryl groups, and 5-14 membered heteroaryl groups, and the heteroatoms in the heterocyclic group and heteroaryl groups are independently selected from O, N or S, the number of heteroatoms is 1, 2, 3 or 4; Preferably, R ^a is selected from optionally substituted 5-10 membered bicyclic heterocyclic groups and 5-10 membered bicyclic heteroaryl groups, and the heteroatoms in the heterocyclic group and heteroaryl group are independently selected from O or N, The number of heteroatoms is 1, 2 or 3; Preferably, R ^a is selected from optionally substituted

Preferably, R ^a is selected from optionally substituted

Preferably, R ^a is selected from optionally substituted

The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^a2 at one or more substitutable positions. 5. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 4, characterized in that: R ^a2 is independently selected from halogen, -C(O)R ^a3 , hydroxyl, amino, -C _1-6 alkylene-N(R ^a3 )(R ^a4 ), optionally selected from one or more independently selected C _1-6 alkyl substituted from halogen, hydroxyl, amino, C _1-6 alkoxy; Preferably, R ^a2 is independently selected from -C _1-6 alkylene-N(R ^a3 )(R ^a4 ), optionally substituted by one or more independently selected from hydroxyl and C _1-6 alkoxy C _1-6 alkyl. 6. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 5, characterized in that: R ^a3 and R ^a4 are independently selected from hydrogen or optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, C _2-4 alkenyl , C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 aryl, C _1-6 alkyl substituted by substituents of 5-6 membered heteroaryl , C _3-10 cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 aryl, 5-12 membered heteroaryl; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 is formed together with the nitrogen atom to which they are attached, and is optionally selected from one or more independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkane 3-10-membered heterocycloalkyl group or 5-12-membered heteroaryl group substituted by a substituent of C _6-8 aryl group, 5-6 membered heteroaryl group, or 5-12 membered heteroaryl group, said hetero The heteroatoms in the cycloalkyl or heteroaryl are selected from N, S, O, and the number of heteroatoms is 1, 2 or 3; Preferably, R ^a3 and R ^a4 are independently selected from hydrogen or are optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom to which they are connected are optionally selected from one or more independently selected from halogen, Hydroxy, C _1-6 alkyl, C _1-6 alkoxy substituent substituted 3-10 membered heterocycloalkyl, the heteroatom in the heterocycloalkyl is selected from N, S, O, heteroatom 1, 2 or 3 in number; Preferably, R ^a3 and R ^a4 are independently selected from hydrogen or C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen, hydroxyl, amino; or when R ^a3 and R ^a4 When connected to the same nitrogen atom, R ^a3 and R ^a4 form together with the nitrogen atom they are connected to, and are optionally selected from one or more independently selected from halogen, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy A 3-10 membered heterocycloalkyl group substituted by a substituent of the group, the heteroatoms in the heterocycloalkyl group are selected from N, O, and the number of heteroatoms is 1 or 2; Preferably, R ^a3 and R ^a4 are independently selected from C _1-4 alkyl groups; or when R ^a3 and R ^a4 are connected to the same nitrogen atom, R ^a3 and R ^a4 together with the nitrogen atom they are connected to form optionally Tetrahydropyrrolyl, piperidinyl or morpholinyl substituted by one or more substituents independently selected from F, hydroxy, methyl, methoxy. 7. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 6, characterized in that: L ₂ is selected from a bond, -CH ₂ -; Preferably, _L2 is a bond. 8. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 7, characterized in that: R ^b is selected from optionally substituted 5-12 membered bicyclic heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl; Preferably, R ^b is selected from optionally substituted 5-10 membered bicyclic heterocyclyl, C _6-10 aryl, 5-6 membered heteroaryl; Preferably, R ^b is selected from optionally substituted phenyl, pyridyl or benzotetrahydrofuryl; Preferably, R ^b is selected from optionally substituted phenyl or pyridyl; Preferably, R ^b is selected from optionally substituted phenyl, The optional substitution means that the mentioned group is unsubstituted or independently substituted by R ^b2 at one or more substitutable positions. 9. The compound or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt according to any one of claims 1 to 8, characterized in that: R ^b2 is independently selected from halogen, hydroxyl, amino, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is selected from optionally selected from one or more independently selected from halogen or C _6-10 aryl Substituent substituted C _1-6 alkyl; Preferably, R ^b2 is independently selected from halogen, hydroxyl, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is optionally substituted by one or more substituents independently selected from halogen or phenyl C _1-4 alkyl; Preferably, R ^b2 is independently selected from fluorine, chlorine, -OH, C _3-6 cycloalkyl, -OR ^b3 , wherein R ^b3 is selected from optionally selected from one or more independently selected from chlorine or phenyl Substituent substituted C _1-4 alkyl; Preferably, R ^b2 is independently selected from chlorine, cyclopropyl or -O(C _1-4 alkyl) optionally substituted by one or more halogens; Preferably, R ^b2 is independently selected from chlorine or -O(C _1-4 alkyl) optionally substituted by one or more fluorines; Preferably, R ^b2 is independently selected from chlorine, -OCH ₃ , -O(CHF ₂ ) or -O(CF ₃ ). 10. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 9, characterized in that: L ₃ is selected from -CH ₂ -, -O-, -S- or -N(R ^c1 )-, wherein R ^c1 is selected from hydrogen or C _1-6 alkyl; Preferably, L ₃ is selected from -O-, -N(R ^c1 )-; Preferably, L ₃ is selected from -O-, -NH-. 11. The compound or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt according to any one of claims 1 to 10, characterized in that: R ^c is selected from C _1-6 alkyl optionally substituted by one or more halogens or C _3-6 cycloalkyl optionally substituted by one or more R ^c3 , wherein R ^c3 is selected from hydrogen or any C _1-6 alkyl optionally substituted by one or more substituents independently selected from halogen; Preferably, R ^c is selected from C _1-4 alkyl optionally substituted by one or more halogens or C _3-6 cycloalkyl optionally substituted by CF ₃ ; Preferably, R ^c is selected from methyl, ethyl,

Preferably, R ^c is selected from ethyl,

12. The compound according to any one of claims 1 to 11 or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that : the compound is selected from:

13. A pharmaceutical composition, characterized in that: comprising the compound according to any one of claims 1 to 12 or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or its Pharmaceutically acceptable salts. 14. The compound according to any one of claims 1 to 12 or its prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof or claim 13 The use of the pharmaceutical composition in the preparation of medicines for the prevention and/or treatment of diseases, disorders and conditions mediated by MAT2A; preferably, the diseases, disorders and conditions are MTAP-deficient tumors; preferably Yes, the tumors include solid tumors and hematological tumors. 15. A pharmaceutical composition, characterized in that: comprising the compound according to any one of claims 1 to 12 or its prodrug, tautomer, stereoisomer, solvate, isotope derivative or its A pharmaceutically acceptable salt or the pharmaceutical composition according to claim 13 and another, two or more drugs having tumor suppressing activity.