CN115504980A

CN115504980A - Pyrimido nitrogen-containing six-membered aromatic heterocyclic compound and application thereof

Info

Publication number: CN115504980A
Application number: CN202210725757.1A
Authority: CN
Inventors: 王矿磊; 褚文浩; 郭见桥; 赵传武; 张晓琳; 秦亚楠; 宁帅; 郭书龙
Original assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Current assignee: CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
Priority date: 2021-06-23
Filing date: 2022-06-23
Publication date: 2022-12-23
Also published as: WO2022268180A1

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

Pyrimido nitrogen-containing six-membered aromatic heterocyclic compound and application thereof

Technical Field

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

Background

MAT2A is called Methionine adenosyltransferase 2A, S-Adenosylmethionine Synthase Type.

MAT2A is expressed in all tissues including red blood cells, brain, fetal liver, kidney, pancreas tissue, but is present in a lesser amount in adult liver tissue. The expression of MAT2A and MAT2B in human liver cancer and colon cancer is increased, and the expression of MAT2A is also reported to be increased 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, and can catalyze the transfer of adenylate, playing an important role in the salvage and synthesis process of ATP. MTAP deletion accounts for about 15% of all solid tumors. MTAP is deficient to varying degrees in various types of tumors. MTAP deletion results in accumulation of the enzyme substrate Methylthioadenosine (MTA). An increase in MTA concentration partially inhibited PRMT5 activity, while other methyltransferases were relatively unaffected. Inhibition of MAT2A decreased the methyl donor S-adenosylmethionine (SAM), which is a substrate for PRMT5, thereby further inhibiting PRMT5, affecting tumor cell mRNA splicing and causing DNA damage. Thus, MAT2A inhibitors could benefit MTAP-deficient tumors.

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

UGTs is one of the important ways for exogenous drugs and endogenous substances to be eliminated in vivo as the most important II-phase metabolic enzyme in vivo. UGT1A1 is an enzyme for catalyzing acidification of bilirubin and glucuronate which are toxic endogenous substances, and the mediated glucuronate reaction is an essential step for bilirubin to be discharged from the body and has the closest relationship with human health. A large number of researches at home and abroad prove that UGT1A1 gene mutation causes all or partial deletion of bilirubin glucuronidation capability to influence bilirubin metabolism, thereby causing severe hyperbilirubinemia. In addition, some clinical drugs inhibit UGT1A1, thereby reducing the metabolic clearance of the body for bilirubin, causing an increase in bilirubin in the blood, which in turn leads to hyperbilirubinemia or aggravates the condition of the patient. Therefore, avoiding too high UGT1A1 inhibitory capacity is of great importance for safe medication.

Disclosure of Invention

The invention provides MAT2A inhibitor compounds with a novel structure or prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof, and also provides applications of the compounds or the prodrugs, tautomers, stereoisomers, solvates, isotopic derivatives or pharmaceutically acceptable salts thereof in treating and preventing MAT 2A-mediated diseases, disorders and conditions.

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

wherein:

L ₁ is selected from the group consisting of 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 )-；R ^a1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^a selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 Is substituted wherein R is ^a2 Independently at each occurrence, selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^a3 、R ^a4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₂ is selected from the group consisting of 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 )-；R ^b1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^b selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 Is substituted in which R ^b2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^b3 、R ^b4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^b3 And R ^b4 When bound to the same nitrogen atom, R ^b3 And R ^b4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl, aryl, heteroaryl, and heteroaryl,C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₃ is selected from the group consisting of 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 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^c selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 Is substituted in which R ^c2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R ^c3 、-OR ^c3 、-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 ) (ii) a Wherein R is ^c3 、R ^c4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R ^c3 And R ^c4 When bound to the same nitrogen atom, R ^c3 And R ^c4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

X ₁ selected from N or CR ^d ；

R ^d Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^d1 Is substituted wherein R is ^d1 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^d2 、R ^d3 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

unless otherwise indicated, the heteroatoms in the above heterocycloalkyl, heteroaryl, heterocyclyl groups 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 invention, L ₁ Is selected from the group consisting of 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 <xnotran> , -O-, -S-, -C (O) -, -NHC (O) -, -C (O) NH-. </xnotran>

In a further preferred embodiment, L ₁ Selected from the group consisting of a bond, -O-,; -S-, -C (O) -.

In a further preferred embodiment, L ₁ Is a key.

In a preferred embodiment of the invention, R ^a1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or substituted independently at one or more substitutable positions by a substituent selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.

In a further preferred embodiment, R ^a1 Independently selected from hydrogen orOptionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or substituted independently at one or more substitutable positions by a substituent selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.

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

In a further preferred embodiment, R ^a1 Selected from hydrogen.

In a preferred embodiment of the invention, R ^a Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

In a further preferred embodiment, R ^a Selected from optionally substituted C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substitution.

In a further preferred embodiment, R ^a Selected from optionally substituted 3-10 membered heterocyclic group, C _6-12 Aryl, 5-12 membered heteroaryl; the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of the heteroatoms is 1,2,3,4 or 5; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

In a further preferred embodiment, R ^a 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; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substitution.

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

In a further preferred embodiment, R ^a Selected from optionally substituted 5-10 membered bicyclic heteroaryl; the heteroatoms in the heteroaryl group are selected from N, the number of heteroatoms is 1,2,3 or 4; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substitution.

In a further preferred embodiment, R ^a Selected from optionally substituted 9-10 membered bicyclic heteroaryl; the hetero atoms in the heteroaryl group are selected from N, and the number of the hetero atoms is 2; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substitution.

In a preferred embodiment of the invention, R ^a2 Independently selected from deuterium, halogen, hydroxy, 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 Independently of one anotherSelected from halogen, hydroxy, amino, cyano, -R ^a3 。

In a preferred embodiment of the invention, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-6 membered heteroaryl, or 5-12 membered heteroaryl.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form an optionally substituted alkyl group optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 A 3-10 membered heterocycloalkyl group or a 5-12 membered heteroaryl group substituted with a substituent of an alkoxy group.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or optionallyIs selected from one or more of halogen, hydroxyl, amino and C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 An alkyl group.

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

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen, C _1-4 An alkyl group.

In a preferred embodiment of the invention, R ^a Is selected from any of C _1-4 An alkyl-substituted 5-10 membered bicyclic heteroaryl; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1,2,3 or 4.

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

In a preferred embodiment of the invention, L ₂ Is selected from the group consisting of 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, L ₂ Is selected from the group consisting of a bond, -CH ₂ -、-C(O)-、-C(O)O-、-OC(O)-。

In a further preferred embodiment, L ₂ Selected from the group consisting of bonds.

In a preferred embodiment of the invention, R ^b1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkanesBase, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b1 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 Alkyl radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b1 Independently selected from hydrogen or C _1-4 An alkyl group.

In a preferred embodiment of the invention, R ^b Selected from optionally substituted C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted C _3-10 Cycloalkyl, 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclic group, C _6-10 Aryl, 5-10 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substitution.

In a further preferred embodiment, R ^b Selected from optionally substituted 5-12 membered bicyclic heterocyclic group, C _6-10 Aryl, 5-10 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted C _6-8 Aryl, 5-6 membered heteroaryl; said optionalSubstituted means that the mentioned groups are unsubstituted or independently at one or more substitutable sites by R ^b2 And (4) substitution.

In a further preferred embodiment, R ^b Selected from optionally substituted phenyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a preferred embodiment of the invention, R ^b2 Independently selected from deuterium, halogen, hydroxy, 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 Independently selected from deuterium, halogen, hydroxy, 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 Independently selected from halogen, hydroxy, 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 Independently selected from halogen, hydroxy, amino, -R ^b3 、-OR ^b3 。

In a preferred embodiment of the invention, R ^b2 Independently selected from halogen, or-O (C) optionally substituted with one or more halogen _1-6 Alkyl), C _1-6 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from halogen, or-O (C) optionally substituted with one or more halogen _1-4 Alkyl groups).

In a further preferred embodiment, R ^b2 Independently selected from chloro, -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 invention, R ^b3 、R ^b4 Independently selected from hydrogen or optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^b3 And R ^b4 When bound to the same nitrogen atom, R ^b3 And R ^b4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-6 membered heteroaryl, or 5-12 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from C optionally substituted with one or more halogens _1-6 An alkyl group.

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 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 Selected from-O-, -N (R) ^c1 )-、-C(O)-。

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

In a further preferred embodiment, L ₃ Selected from-O-, -NH-, -C (O) -.

In a further preferred embodiment, L ₃ Selected from-O-, -NH-.

In a preferred embodiment of the invention, R ^c1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-4 Alkenyl radical, 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 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino groups.

In a further preferred embodiment, R ^c1 Independently selected from hydrogen or optionally substituted by one or more independently selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkanesBase, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^c1 Independently selected from hydrogen or optionally substituted by one or more independently selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 An alkylamino group.

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

In a preferred embodiment of the invention, R ^c Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substitution.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substitution.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-6 An alkyl group; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a preferred embodiment of the invention, R ^c Selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a preferred embodiment of the invention, R ^c2 Independently selected from deuterium, halogen, hydroxy, 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 Independently selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R ^c3 。

In a further preferred embodiment, R ^c2 Independently selected from halogen, hydroxyl, amino.

In a further preferred embodiment, R ^c2 Independently selected from halogens.

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

In a preferred embodiment of the invention, R ^c3 、R ^c4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 、R ^c4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, oxo _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 、R ^c4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano, oxo _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a preferred embodiment of the invention, R ^c Selected from optionally substituted C _1-6 An alkyl group; by optionally substituted is meant that the group referred to is unsubstituted or independently substituted at one or more substitutable sites with halogen.

In a preferred embodiment of the present invention, X ₁ Is selected from N.

In a preferred embodiment of the present invention, X ₁ Selected from the group consisting of CR ^d 。

In a preferred embodiment of the invention, R ^d Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions by R ^d1 And (4) substitution.

In a further preferred embodiment, R ^d Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^d1 And (4) substitution.

In a further preferred embodiment, R ^d Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^d1 And (4) substituting.

In a further preferred embodiment, R ^d Selected from hydrogen.

In a preferred embodiment of the invention, R ^d1 Independently selected from deuterium, halogen, hydroxy, 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 Independently selected from halogen, hydroxy, amino, cyano, -R ^d2 。

In a preferred embodiment of the invention, R ^d2 、R ^d3 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl.

In a further preferred embodiment, R ^d2 、R ^d3 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, cyano _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

The invention provides a compound shown as a formula (II) or a prodrug, a tautomer, a stereoisomer, a solvate, an isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure:

wherein:

L ₁ is selected from the group consisting of 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 )-；R ^a1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^a selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 Is substituted wherein R is ^a2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^a3 、R ^a4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₂ selected from the group consisting of a bond, -C (R) ^b1 ) ₂ -、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R ^b1 )C(O)-、-C(O)N(R ^b1 ) -or-N (R) ^b1 )-；R ^b1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitroRadical, mercapto group, cyano group, oxo group, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^b selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 Is substituted in which R ^b2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^b3 、R ^b4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R ^b3 And R ^b4 When bound to the same nitrogen atom, R ^b3 And R ^b4 To the nitrogen atom to which they are attachedTogether form a cyclic or branched chain optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₃ is selected from the group consisting of 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 Selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^c selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 Is substituted in which R ^c2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R ^c3 、-OR ^c3 、-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 ) (ii) a Wherein R is ^c3 、R ^c4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^c3 And R ^c4 When bound to the same nitrogen atom, R ^c3 And R ^c4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

In a further preferred embodiment, L ₁ Is selected from the group consisting of a bond, -CH ₂ -, -O-, -S-or-N (R) ^a1 ) -, wherein R ^a1 Selected from hydrogen or C _1-6 An alkyl group.

In a further preferred embodiment, L ₁ <xnotran> , -O-, -S-, -C (O) -, -NH-, -NHC (O) -, -C (O) NH-. </xnotran>

In a further preferred embodiment, L ₁ Selected from the group consisting of a bond, -O-, -S-,; -C (O) -, -NH-.

In a further preferred embodiment, L ₁ Selected from the group consisting of a bond, -NH-, -O-or-S-.

In a further preferred embodiment, L ₁ Is a bond.

In a preferred embodiment of the invention, R ^a1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or substituted independently at one or more substitutable positions by substituents selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.

In a further preferred embodiment, R ^a1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or substituted independently at one or more substitutable positions by a substituent selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo.

In a further preferred embodiment, R ^a1 Selected from hydrogen.

In a preferred embodiment of the invention, R ^a Selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, wherein the heteroatoms in said heterocyclyl or heteroaryl are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4, said optional substitution meaning that the group in question is unsubstituted or independently substituted at one or more substitutable sites by R ^a2 And (4) substitution.

R ^a Selected from optionally substituted 3-10 membered heterocyclyl, C _6-12 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

In a further preferred embodiment, R ^a Selected from optionally substituted 3-10 membered heterocyclyl, C _6-12 Aryl, 5-12 membered heteroaryl; the heteroatoms in the heterocyclic group and the heteroaryl group are independently selected from O, N or S, and the number of the heteroatoms is 1,2,3,4 or 5; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

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

In a further preferred embodiment, R ^a Selected from optionally substituted 5-10 membered bicyclic heterocyclic group, 5-10 membered bicyclic heteroaryl group, wherein the heteroatoms in the heterocyclic and heteroaryl groups are independently selected from O or N, and the heteroatoms are independently selected fromThe number is 1,2 or 3, said optional substitution means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

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

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

In a further preferred embodiment, ra is selected from optionally substituted 5-10 membered bicyclic heteroaryl; the heteroatom in the heteroaryl group is selected from N, and the number of heteroatoms is 1,2,3 or 4; by optionally substituted is meant that the group referred to is unsubstituted or independently substituted at one or more substitutable sites with Ra 2.

In a further preferred embodiment, R ^a Selected from optionally substituted

Said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substitution.

In a further preferred embodiment, R ^a Selected from optionally substituted

Said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 And (4) substituting.

In a further preferred embodiment, R ^a Selected from optionally substituted

In a preferred embodiment of the invention, R ^a2 Independently selected from deuterium, halogen, hydroxy, 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 Independently selected from halogen, hydroxy, 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 invention, R ^a2 Independently selected from halogen, hydroxy, amino, cyano, -C _1-6 alkylene-N (R) ^a3 )(R ^a4 )、-R ^a3 。

In a preferred embodiment of the invention, R ^a2 Independently selected from halogen, hydroxy, 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 An alkyl hydroxy group.

In a preferred embodiment of the invention, R ^a2 Independently selected from halogen, -C (O) R ^a3 Hydroxy, amino, -C _1-6 alkylene-N (R) ^a3 )(R ^a4 ) Optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkoxy-substituted C ₁ - ₆ An alkyl group.

In a preferred embodiment of the invention, R ^a2 Is independently selected from-C _1-6 alkylene-N (R) ^a3 )(R ^a4 ) Optionally substituted with one or more substituents independently selected from hydroxy and C _1-6 Alkoxy-substituted C _1-6 An alkyl group.

In a preferred embodiment of the invention, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-6 membered heteroaryl, or 5-12 membered heteroaryl.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 A 3-10 membered heterocycloalkyl group or a 5-12 membered heteroaryl group substituted with a substituent of an alkoxy group.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 A 3-10 membered heterocycloalkyl substituted with a substituent of alkoxy, wherein the heteroatom in the heterocycloalkyl is selected from N, S, O, and the number of heteroatoms is 1,2 or 3.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 An alkyl group; when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a 3-10 membered heterocycloalkyl group optionally substituted with one or more substituents independently selected from F, cl, br, hydroxy, methyl, methoxy, the heteroatoms in the heterocycloalkyl group being selected from N, O, the number of heteroatoms being 1 or 2.

In a further preferred embodiment, R ^a3 、R ^a4 Independently selected from hydrogen, C _1-4 Alkyl, -C _1-4 An alkyl hydroxy group; when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a tetrahydropyrrolyl, piperidinyl or morpholinyl group optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxy.

In a preferred embodiment of the invention, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl, or 5-12 membered heteroaryl, wherein 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 invention, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 An alkyl group; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more substituents independently selected from halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 A 3-10 membered heterocycloalkyl substituted with a substituent of alkoxy, wherein the heteroatom in the heterocycloalkyl is selected from N, S, O, and the number of heteroatoms is 1,2 or 3.

In a preferred embodiment of the invention, R ^a3 、R ^a4 Independently selected from hydrogen or optionally oneOr C substituted with a plurality of substituents independently selected from halogen, hydroxyl and amino _1-6 An alkyl group; or when R ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, C _1-4 Alkyl radical, C _1-4 3-10 membered heterocycloalkyl substituted with a substituent of alkoxy, wherein the heteroatom in the heterocycloalkyl is selected from N, O, and the number of heteroatoms is 1 or 2.

In a preferred embodiment of the invention, R ^a3 、R ^a4 Is independently selected from C _1-4 An alkyl group; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a tetrahydropyrrolyl, piperidinyl or morpholinyl group optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxy.

In a further preferred embodiment, R ^a2 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 further preferred embodiment, L ₂ Is selected from the group consisting of a bond, -CH ₂ -、-C(O)-。

In a further preferred embodiment, L ₂ Is selected from the group consisting of a bond, -CH ₂ -。

In a further preferred embodiment, L ₂ Is a key.

In a preferred embodiment of the invention, R ^b1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a preferred embodiment of the invention, R ^b Selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl radicals5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted 3-6 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted 5-10 membered bicyclic heterocyclic group, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted 5-12 membered bicyclic heterocyclic group, C _6-10 Aryl, 5-10 membered heteroaryl, said optionally substituted meaning that the mentioned groups are unsubstituted or independently at one or more substitutable sites by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted phenyl, pyridyl or benzotetrahydrofuranyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

In a further preferred embodiment, R ^b Selected from optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substitution.

In a further preferred embodiment, R ^b Selected from optionally substituted phenyl; said optionalSubstituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substitution.

In a further preferred embodiment, R ^b2 Independently selectFrom halogen, hydroxy, amino, -R ^b3 、-OR ^b3 。

In a preferred embodiment of the invention, R ^b2 Independently selected from halogen, hydroxy, or-O (C) optionally substituted with one or more halogens _1-6 Alkyl), -O (C) _1-6 Alkyl) phenyl, C _1-6 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from halogen, hydroxy, or-O (C) optionally substituted with one or more halogens _1-4 Alkyl), -O (C) _1-4 Alkyl) phenyl or C _1-4 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from chloro, -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 invention, R ^b2 Independently selected from halogen, hydroxy, amino, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Is selected from optionally substituted by one or more independently selected from halogen or C _6-10 Aryl substituent substituted C _1-6 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from halogen, hydroxy, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Selected from C optionally substituted with one or more substituents independently selected from halogen or phenyl _1-4 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from fluorine, chlorine, -OH, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Selected from C optionally substituted with one or more substituents independently selected from chloro or phenyl _1-4 An alkyl group.

In a further preferred embodiment, R ^b2 Independently selected from chloro, cyclopropyl or-O (C) optionally substituted with one or more halogens _1-4 Alkyl).

In a further preferred embodiment, R ^b2 Independently selected from chlorine or-O (C) optionally substituted by one or more fluorine _1-4 Alkyl).

In a further preferred embodiment, R ^b2 Independently selected from chloro, -OCH ₃ 、-O(CHF ₂ ) or-O (CF) ₃ )。

In a further preferred embodiment, R ^b2 Independently selected from-O (CHF) ₂ )。

In a preferred embodiment of the invention, R ^b3 、R ^b4 Independently selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C ₂ - ₆ Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C ₁ - ₆ Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^b3 And R ^b4 When bound to the same nitrogen atom, R ^b3 And R ^b4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-6 membered heteroaryl, or 5-12 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _6-8 Aryl substituent substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, phenyl _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, phenyl _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _3-4 Cycloalkyl radical, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, phenyl _1-4 Alkyl radical, C _1-4 Alkoxy or cyclopropyl.

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

In a further preferred embodiment, R ^b3 、R ^b4 Independently selected from methoxy optionally substituted with 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 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 Selected from hydrogen or C _1-6 An alkyl group.

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

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

In a further preferred embodiment, L ₃ Selected from-O-, -NH-, -C (O) -.

In a further preferred embodiment, L ₃ Selected from-O-, -NH-.

In a further preferred embodiment, L ₃ Is selected from-O-.

In a preferred embodiment of the invention, R ^c1 Independently selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-4 Alkenyl radical, 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 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-4 Alkenyl radical, 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 Independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, cyano, C _1-6 Alkyl radical, C _1-6 C substituted by substituents of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 An alkylamino group.

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

In a preferred embodiment of the invention, R ^c Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl(ii) a Said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substitution.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-4 Alkyl radical, C _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-4 Alkyl or C _3-6 A cycloalkyl group; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substitution.

In a further preferred embodiment, R ^c Selected from optionally substituted C _1-3 An alkyl group; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substituting.

In a preferred embodiment of the invention, R ^c Selected from optionally substituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 And (4) substitution.

In a preferred embodiment of the invention, R ^c2 Independently selected from deuterium, halogen, hydroxy, ammoniaRadical, 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 Independently selected from halogen, hydroxy, amino or-R ^c3 。

In a further preferred embodiment, R ^c2 Independently selected from halogen or-R ^c3 。

In a further preferred embodiment, R ^c3 、R ^c4 Independently selected from hydrogen or optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, cyano, oxygenSubstituted with substituted substituents C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl.

In a further preferred embodiment, R ^c3 、R ^c4 Independently selected from hydrogen or CF ₃ 。

In a preferred embodiment of the invention, R ^c Selected from C optionally substituted by one or more halogens _1-6 Alkyl or optionally substituted by one or more R ^c3 Substituted C _3-6 Cycloalkyl, wherein R ^c3 Selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen _1-6 An alkyl group.

In a further preferred embodiment, R ^c Selected from C optionally substituted by one or more halogen _1-4 Alkyl or optionally by CF ₃ Substituted C _3-6 A cycloalkyl group.

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

In a further preferred embodiment, R ^c Selected from ethyl,

In a further preferred embodiment, R ^c Selected from ethyl.

Representative compounds of the invention have the structural formula and numbering shown in the following table:

the invention also aims to provide a method for preparing the compound shown in the general formula (II) or tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein X in the general formula (I) is N.

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

Intermediate 1.6 is reacted with a boronic acid or boronic ester in the presence of a palladium catalyst to give the final product 1.7.

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

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

2, 4-dichloro-5-nitropyrimidine (1.1) is used as a starting material and reacts with different types of primary amine to obtain an intermediate 1.2, and the intermediate 1.2 reacts with corresponding R ^c -L ₃ Reacting H to obtain an intermediate 1.3, reducing the nitro of the intermediate 1.3 into amino by adopting a reducing agent to obtain an intermediate 1.4, reacting the intermediate 1.4 with oxalyl chloride monomethyl ester to obtain a cyclized compound 1..5, reacting the intermediate 1.5 with thionyl chloride to obtain an intermediate 1.6, and finally reacting with boric acid or boric acid ester in the presence of a palladium catalyst to obtain a final product 1.7. The definition of each substituent in the compound is as described in the specification.

Remarking: the protection and deprotection steps involved in this step have been omitted.

In another aspect, the present invention provides the following intermediate compounds:

wherein L is ² 、L ³ 、R ^b And R ^c As described for compounds of formula (I) or formula (II);

in a further preferred embodiment, L ² Is a bond, R ^b Is optionally substituted phenyl or pyridyl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 Is substituted by

In another aspect, the present invention also provides a pharmaceutical composition comprising a compound described herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof.

Furthermore, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.

Administration of a compound of the invention, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, can be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable mode of administration which provides a drug of similar use. The pharmaceutical compositions of the present invention may be prepared by combining a compound of the present invention with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention may be formulated as solid, semi-solid, liquid or gaseous formulations. Generally, the above pharmaceutical composition can be prepared by a conventional preparation method using an excipient which is conventional in the formulation field.

In another aspect, the present invention also provides the use of a compound of the present invention, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention and/or treatment of diseases, disorders, and conditions mediated by MAT 2A.

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

Further, in the uses provided by the present invention, the tumor includes solid tumor and hematological tumor; preferably, the solid tumor comprises 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 a method for preventing and/or treating diseases, disorders, and conditions mediated by MAT2A, comprising administering to a subject in need thereof a compound described herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention; preferably, the diseases, disorders and conditions are MTAP-deficient cancers; more preferably, the tumor comprises a solid tumor and a hematological tumor.

In yet another aspect, the present application provides a compound described herein, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention, for use in the prevention and/or treatment of diseases, disorders, and conditions mediated by MAT 2A; preferably, the diseases, disorders and conditions are MTAP-deficient cancers; more preferably, the tumor comprises a solid tumor and a hematological tumor.

Further, in the uses or methods provided by the present invention, the compound of the present invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention is used in combination with another, two or more drugs having tumor-inhibiting activity.

The invention also provides a pharmaceutical composition comprising a compound of the invention or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, and another, two or more drugs having tumor-inhibiting activity.

Definition of

The terms "optional," "any," "optionally," or "optionally" refer to a subsequently described event or circumstance which may, but need not, occur, and include instances where said event or circumstance occurs and instances where it does not.

Unless otherwise specified, the term "optionally substituted" or "optionally substituted" means that the group referred to is unsubstituted or substituted with one or more groups independently selected from hydroxy, halogen, hydroxy, amino, nitro, mercapto, cyano, azido, oxo, carboxy, -C (O) C _1-6 Alkyl, -C (O) O-C _1-6 Alkyl, -OC (O) -C _1-6 Alkyl, -NH (C) _1-6 Alkyl), -N (C) _1-6 Alkyl) (C _1-6 Alkyl), -C (O) NH-C _1-6 Alkyl, -NHC (O) -C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; wherein said C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl radical, C _3-10 Cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl or 5-12 membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, hydroxy, ammoniaRadical, cyano radical, C _1-6 Alkyl or C _1-6 Substituted by a substituent of alkoxy.

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

Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight or branched chain group containing 1-20 carbon atoms, preferably 1-10 carbon atoms (i.e., C) _1-10 Alkyl group), further preferably containing 1 to 8 carbon atoms (C) _1-8 Alkyl), more preferably containing 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl) such as "C _1-6 By alkyl is meant that the group is alkyl 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like.

Unless otherwise specified, the term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one double bond. The alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C) _2-10 Alkenyl), further preferably containing 2 to 8 carbon atoms (C) _2-8 Alkenyl), more preferably containing 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl), 2-5 carbon atoms (i.e., C) _2-5 Alkenyl), 2-4 carbon atoms (i.e., C) _2-4 Alkenyl), 2-3 carbon atoms (i.e., C) _2-3 Alkenyl), 2 carbon atoms (i.e., C) ₂ Alkenyl) such as "C _2-6 By alkenyl "is meant that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 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 chain unsaturation having at least one triple bond, consisting of carbon and hydrogen atomsAn aliphatic hydrocarbon group. Alkynyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C) _2-10 Alkynyl) and further preferably contains 2 to 8 carbon atoms (C) _2-8 Alkynyl) and more preferably contains 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl), 2-5 carbon atoms (i.e., C) _2-5 Alkynyl), 2-4 carbon atoms (i.e., C) _2-4 Alkynyl), 2-3 carbon atoms (i.e., C) _2-3 Alkynyl), 2 carbon atoms (i.e., C) ₂ Alkynyl) such as "C _2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2,3,4, 5 or 6). Non-limiting examples of alkynyl groups 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 radical having the specified number of carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., C) _3-12 Cycloalkyl), more preferably containing 3 to 10 carbon atoms (C) _3-10 Cycloalkyl group), further preferably 3 to 7 carbon atoms (C) _3-7 Cycloalkyl), 4 to 6 carbon atoms (C) _4-6 Cycloalkyl), 5 to 6 carbon atoms (C) _5-6 Cycloalkyl groups). 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, i.e. containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.

Unless otherwise specified, the term "alkylamino" means-NR 'R ", R' and R", which are identical or different, and may be H or an alkyl radical as defined above, said alkyl radical being as defined above, i.e.containing from 1 to 20 carbon atoms, preferablyOptionally, 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (specifically 1,2,3,4, 5 or 6). Representative examples include, but are not limited to, -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 the like.

The term "halogen" or "halo" means, unless otherwise specified, F, cl, br, I. The term "haloalkyl" means an alkyl group as defined above wherein one, two or more hydrogen atoms or all hydrogen atoms are replaced by halogen. Representative examples of haloalkyl groups include CCl ₃ 、CF ₃ 、CHCl ₂ 、CH ₂ Cl、CH ₂ Br、CH ₂ I、CH ₂ CF ₃ 、CF ₂ CF ₃ And the like.

Unless otherwise specified, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic nonaromatic substituent having ring carbon atoms and 1 or more ring heteroatoms, comprising from 3 to 20 ring atoms of which 1,2,3 or more ring atoms are selected from N, O or S, the remaining ring atoms being C. Preferably 3 to 12 ring atoms (3-12 membered heterocyclyl), further preferably 3 to 10 ring atoms (3-10 membered heterocyclyl), or 3 to 8 ring atoms (3-8 membered heterocyclyl), 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). The heteroatoms are preferably 1-4, more preferably 1 to 3 (i.e. 1,2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl and the like. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. "heterocyclyl" may be monocyclic ("monocyclic heterocyclyl") or a fused ("fused heterocyclyl" or "heterofused ring group"), bridged ("heterobridged ring group" or "bridged heterocyclyl") or spiro-fused ("heterospirocyclic" or "spiroheterocyclyl") ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The heterocyclyl bicyclic ring system may be in oneOr one or more heteroatoms in both rings. "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more carbocyclyl groups, with the point of attachment being on the carbocyclyl or heterocyclyl ring, or "heterocyclyl" also includes ring systems in which the heterocyclyl ring as defined above is fused by one or more aryl or heteroaryl groups, or the cycloalkyl ring as defined above is fused by one or more heteroaryl groups, with the point of attachment being on the heterocyclyl ring or cycloalkyl ring, and in such cases the number of elements of the heterocyclyl ring system is the number of ring system atoms after fusion. In certain embodiments, each instance of a heterocyclyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, aziridinyl, oxacyclopropaneyl (oxalanyl), and thiacyclopropanyl (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-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, dioxolanyl, oxathiacyclopentane, dithiolane, and

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

Diazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiacyclohexyl (thianyl). Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazineOxazinyl, morpholinyl, dithiinyl and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexane, oxadiazinyl, thiadiazinyl, oxathiazinyl, and dioxazazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxepinyl, and thiacycloheptyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azacyclooctyl, oxocyclooctyl, and thietanyl. Condensed to a C ₆ Exemplary 5-membered heterocyclyl groups on an aryl ring (also referred to herein as a5, 6-bicyclic heterocycle) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzo

Oxazolinone groups, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a6, 6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, the ring atoms being as defined above, i.e. comprising from 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being from 1 to 4 (1, 2,3 or 4), preferably from 1 to 3 (1, 2 or 3), wherein the heteroatoms are each independently selected from N, O or S. Preferably 3 to 12 ring atoms ("3-12 membered heterocycloalkyl"), further preferably 3 to 10 ring atoms ("3-10 membered heterocycloalkyl"), still further preferably 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), still further preferably 4 to 7 ring atoms ("4-7 membered heterocycloalkyl"), still further preferably 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), still further preferably 5 to 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 (a ") with one or more substituents"Substituted heterocycloalkyl "). Some exemplary "heterocycloalkyl" groups have been given above for the "heterocyclyl" or "heterocyclic" moiety, and also include, but are not limited to, aziridinyl, oxetanyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, oxiranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxathia-nyl, oxa-thienyl, oxa-and/or oxa-thienyl,

Oxazolidinyl, di

Alkyl, dithiacyclohexyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidinyl and the like.

Unless otherwise specified, the term "aryl" or "aromatic ring group" means monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, pyrenyl, or the like.

Unless otherwise specified, the term "heteroaryl" or "heteroaryl ring group" denotes an aromatic monocyclic or polycyclic ring system containing a 5-14 membered structure, or preferably a 5-10 membered structure, or preferably a 5-8 membered structure, more preferably a 5-6 membered structure, 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 being preferably 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl,

Azolyl, thiazolyl, iso

Azolyl group,

Oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolyl, isoquinolyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrazinyl, benzimidazolyl, phthalizinyl, pyrrolo [2,3-b ] b]Pyridyl, imidazo [1,2-a ]]Pyridyl, pyrazolo [1,5-a ]]Pyridyl, pyrazolo [1,5-a ]]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, [1,2,4]]Triazolo [4,3-b ]]Pyridazinyl, [1,2,4]]Triazolo [1,5-a ]]Pyrimidinyl, [1,2,4]]Triazolo [1,5-a ]]Pyridyl, and the like.

Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refer to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, such as the medically acceptable salts of amines, carboxylic acids, and other types of compounds, are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base or free acid with a suitable reagent.

The compounds of the invention also include "isotopic derivatives" thereof. The term "isotopic derivative" means, unless otherwise specified, that the compounds of the present invention can exist in isotopically labeled or enriched forms, containing one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number of the largest quantity of atoms found in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes commonly used as isotopic labels are: an isotope of hydrogen, ² h and ³ h; carbon isotope: ¹³ c and ¹⁴ c; chlorine isotope: ³⁵ cl and ³⁷ cl; fluorine isotope: ¹⁸ f; iodine isotope: ¹²³ i and ¹²⁵ i; nitrogen isotope: ¹³ n and ¹⁵ n; oxygen isotope: ¹⁵ O、 ¹⁷ o and ¹⁸ o; and a sulfur isotope: ³⁵ and S. These isotopically labeled compounds can be used to study the distribution of pharmaceutically acceptable molecules in tissues. In particular ² H and ¹³ c, because they are easy to label and convenient to detect, the application is more extensive. Certain heavy isotopes, such as heavy hydrogen (c: (b)) ² H) The substitution can enhance the metabolic stability and prolong the half-life so as to achieve the aim of reducing the dosage and provide the curative effect advantage. Isotopically-labeled compounds are generally synthesized by known synthetic techniques as are non-isotopically-labeled compounds, starting from a starting material which has been labeled.

The compounds of the present invention also include "solvates", "solvates" thereof. Unless otherwise specified, the terms "solvate," "solvate," and "solvate" mean a physical association of a compound of the invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In certain instances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular and/or disordered arrangement. Solvates may comprise 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 "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

Unless otherwise specified, the term "tautomer" refers to structural isomers having different energies that can interconvert through low energy barriers. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons.

Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): for example, the R, S configuration containing asymmetric centers, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.

The compounds of the present invention also include "prodrugs" thereof, where the term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful, which may improve some determined, undesirable physical or biological property. Physical properties are often associated solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may itself be associated with physicochemical properties. For example, they can be bioavailable by oral administration, whereas the parent cannot. The prodrugs also have improved solubility in pharmaceutical compositions as compared to the parent drug. An example, without limitation, of a prodrug would be any compound of the invention administered as an ester ("prodrug") to facilitate transport across a cell membrane, where water solubility is detrimental to mobility, but once intracellular water solubility is beneficial, it is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to show an active moiety.

The abbreviations used in the preparation examples, examples and elsewhere herein are:

DMF: n, N-dimethylformamide

DIPEA: n, N-diisopropylethylamine

The invention has the beneficial effects that:

the application designs a compound with a novel structure, and provides a new direction for treating diseases such as tumor and the like. Experiments show that the compound has stronger inhibiting effect on MAT2A, shows stronger cell proliferation activity on HCT116 MTAP knocked-out cells, shows weaker cell proliferation activity on MTAP wild-type HCT116 cells, and shows better selectivity. Has good in vivo drug effect. Also, human UGT1A1 enzyme activity tests indicate that the compounds of the invention are less at risk of inhibiting UGT1 A1. The compound does not cause the pathological increase of bilirubin, and has small toxicity and good safety by combining the detection of serum total bilirubin in vivo. In addition, the invention researches a specific synthesis method, and the synthesis method has the advantages of simple process and convenient operation, and is beneficial to large-scale industrial production and application.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or under conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials are described herein for illustrative purposes only.

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

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

And 2, step: synthesis of N- (4-chlorophenyl) -2-ethoxy-5-nitropyrimidine-4-amine

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

And 3, step 3: n is a radical of hydrogen ⁴ Synthesis of- (4-chlorophenyl) -2-ethoxypyrimidine-4, 5-diamine

Adding the product N- (4-chlorphenyl) -2-ethoxy-5-nitropyrimidine-4-amine (730mg, 2.477mmol), zinc powder (1296mg, 19.817mmol), ammonium chloride (2114mg, 39.6mmol) and methanol (20 mL) into a50 mL round-bottom flask, stirring at room temperature, finishing the reaction after two hours, filtering, concentrating the filtrate, and directly purifying by column chromatography to obtain N- (4-chlorphenyl) -2-ethoxy-5-nitropyrimidine-4-amine ⁴ - (4-chlorophenyl) -2-ethoxypyrimidine-4, 5-diamine (560 mg, yield 85.4%). ESI-MS (m/z): 265.1[ 2 ] M + H] ⁺ 。

And 4, step 4: synthesis of 8- (4-chlorophenyl) -2-ethoxy-5, 8-dihydropteridine-6, 7-dione

Taking the product N in the last step ⁴ - (4-chlorophenyl) -2-ethoxypyrimidine-4, 5-diamine (350mg, 1.30mmol), DIPEA (503mg, 3.90mmol), toluene (15 mL) and methylene chloride (3 mL) were charged into a50 mL round-bottomed flask, and a solution of oxalyl chloride monomethyl ester (159mg, 1.30mmol) in methylene chloride was added dropwise with ice bath, allowed to warm to room temperature, stirred for 2 hours, added cesium carbonate (1059mg, 3.25mmol), and warmed to 50 ℃ for reaction. After the reaction, 20mL of ethyl acetate and 15mL of water were added, the layers were separated, the aqueous layer was washed twice with 20mL of ethyl acetate, and the organic layers were combined to obtain the organic layerThe organic phase is washed with water and saturated sodium chloride solution in turn, concentrated and purified by column chromatography to obtain the target product 8- (4-chlorophenyl) -2-ethoxy-5, 8-dihydropteridine-6, 7-dione (203 mg, yield 55.3%). ESI-MS (m/z): 319.1[ 2 ] M + H] ⁺ 。

And 5: 6-chloro-8- (4-chlorophenyl) -2-ethoxypteridine-7 (8H) -one

The product of the previous step, 8- (4-chlorophenyl) -2-ethoxy-5, 8-dihydropteridine-6, 7-dione (150mg, 1.30mmol), DMF (0.2 mL) and toluene (5 mL) were added to a25 mL round bottom flask, followed by addition of thionyl chloride (350mg, 1.30mmol), followed by heating to 50 ℃ and stirring of the reaction. After the reaction, the reaction mixture was concentrated under reduced pressure to give the desired compound, 6-chloro-8- (4-chlorophenyl) -2-ethoxypteridine-7 (8H) -one (103 mg, yield 64.9%). ESI-MS (m/z): 337.1[ alpha ] M + H] ⁺ 。

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

The product of the previous step, 6-chloro-8- (4-chlorophenyl) -2-ethoxypteridine-7 (8H) -one (30mg, 0.089mmol), 2-methyl-2H-indazole-5-boronic acid (26mg, 0.1486mmol), tetrakis (triphenylphosphine) palladium (3mg, 0.01335mmol), potassium carbonate (25mg, 0.178mmol), dioxane (10 mL) and water (1 mL) were charged into a25 mL round-bottomed flask, replaced three times with nitrogen, and then heated to 100 ℃. After the reaction is finished, 100mL of ethyl acetate and 5mL of water are added into the reaction solution, the water phase is extracted with ethyl acetate for 2 times, organic phases are combined, the organic phase is washed with water and a saturated sodium chloride solution in sequence, concentrated and purified by column chromatography to obtain a target compound 8- (4-chlorophenyl) -2-ethoxy-6- (2-methyl-2H-indazol-5-yl) pteridine-7 (8H) -one (18 mg, yield 46.8%), ESI-MS (m/z): 433.1[ 2 ] 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:

compounds A2 to a14 were prepared by following the synthetic route and procedure of preparation example 1, using the corresponding intermediates as starting materials.

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

According to the method for synthesizing A1, 8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (50 mg, yield 57%) was synthesized using p-anisidine, 2-trifluoroethylamine, and the like as starting materials, ESI-MS (m/z): 482.1[ 2 ] 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 example 16:8- (3-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (A16)

Synthesis of 8- (3-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amine from m-methoxyaniline and 2, 2-trifluoroethylamine etc. as starting materials according to the method for synthesizing A1) Amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (135 mg, 42% yield), ESI-MS (m/z): 482.1[ 2 ] M + H] ⁺ 。

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

Compound A16 (100mg, 0.208mmol) and 20mL of anhydrous dichloromethane were added to a50 mL round-bottomed flask, placed in an ethanol bath, cooled to-20 ℃, and boron tribromide (1.0M in dichloromethane) (1.4mL, 1.4mmol) was added dropwise. After the reaction, water was slowly added to quench the reaction, the organic phase was washed with water and saturated sodium chloride solution in order, concentrated, and purified by column chromatography to obtain the target compound (45 mg, yield 46%), ESI-MS (m/z): 468.2[ M ] +H] ⁺ ； ¹ H NMR(600MHz,DMSO)δ9.79–9.63(m,1H),8.92–8.77(m,2H),8.49(s,1H),8.40–8.13(m,1H),8.08(d,J＝9.2Hz,1H),7.65(d,J＝9.2Hz,1H),7.33(s,1H),6.89(d,J＝8.0Hz,1H),6.81(s,2H),4.18(s,3H),4.15(s,1H),3.80(s,1H)。

Preparation example 18: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (A18)

6-chloro-8- (6-methoxypyridin-3-yl) -2-ethoxypteridin-7 (8H) -one was synthesized according to the procedure of preparation example 1, and this intermediate (50mg, 0.150mmol), 2-methyl-5-amino-2H-indazole (33mg, 0.225mmol), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (20mg, 0.030mmol), potassium carbonate (63mg, 0.450mmol) and dioxane (2 mL) were charged into a25 mL round-bottomed flask, replaced three times with nitrogen, and then heated to 100 ℃ for 3 hours. After the reaction, adding 100mL ethyl acetate and 50mL water into the reaction solution, extracting the water phase with ethyl acetate for 2 times, combining the organic phases, washing the organic phase with water and saturated sodium chloride solution in turn, concentrating, and purifying by column chromatographyTo obtain the target compound 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (30 mg, 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＝9.2,1.6Hz,1H),7.58(d,J＝9.2Hz,1H),7.06(d,J＝8.7Hz,1H),4.20(d,J＝7.0Hz,2H),4.13(s,3H),3.96(s,3H),1.24(t,J＝7.0Hz,3H)。

Preparation example 19: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- ((2-methyl-2H-indazol-5-yl) oxy) pteridin-7 (8H) -one (A19)

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

2-methyl-2H-indazole-5-boronic acid (600mg, 3.409mmol), ammonium bicarbonate (270mg, 3.409mmo1), hydrogen peroxide (660. Mu.L) and acetonitrile (8 mL) were added to a50 mL round-bottom flask and reacted at room temperature for 2 hours. . After the reaction, 100mL of ethyl acetate and 50mL of water were added to the reaction mixture, the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, the organic phase was washed successively with water and a saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound 2-methyl-2H-indazol-5 alcohol (350 mg, yield 69%), ESI-MS (m/z): 149.1[ 2 ], [ M ] +H] ⁺ ；

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

6-chloro-8- (6-methoxypyridin-3-yl) -2-ethoxypteridin-7 (8H) -one (55mg, 0.165mmol), 2-methyl-2H-indazol-5-ol (24mg, 0.164mmo 1), potassium carbonate (63mg, 0.450mmol), and N, N-dimethylformamide (1 mL) were charged into a 5mL round-bottomed flask and heated to 100 ℃ for 3H. After the reaction is finished, adding 25mL of ethyl acetate and 10mL of water into the reaction solution, extracting the water phase for 2 times by using ethyl acetate, combining the organic phases, washing the organic phases by using water and saturated sodium chloride solution in turn, concentrating, and purifying by column chromatography to obtain the target compound 2-ethoxy-8- (6-methoxypyridine-3-yl) -6- ((2-methyl-2H-indazole-5-yl) oxy) pteridin-7 (8H) -one (40 mg, 54% yield), ESI-MS (m/z): 446.2[ 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 example 20: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- (2, 3,3a, 7a-Tetrahydrophenylfuran-6-yl) pteridin-7 (8H) -one (A20)

2-ethoxy-8- (6-methoxypyridin-3-yl) -6- (2, 3,3a, 7a-tetrahydrobenzofuran-6-yl) pteridin-7 (8H) -one (16 mg,25% yield), ESI-MS (m/z) was synthesized according to the method for synthesizing A1 starting from 6-methoxypyridin-3-amine, (2, 3,3a, 7a-tetrahydrobenzofuran-6-yl) boronic acid, ethanol and the like: 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 example 21: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- (7-bromo-3, 4-dihydroisoquinolin-2 (1H) -yl) pteridin-7 (8H) -one (A21)

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

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

According to the method for synthesizing A1, p-methoxyaniline, 2-trifluoroethanol and [1,2,4]]Triazole [4,3a]Synthesis of 8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) oxy) -6- ([ 1,2, 4) using pyridin-6-ylboronic acid or the like as a starting Material]Triazole [4,3a]Pyridin-6-yl) pteridin-7 (8H) -one (5 mg, 7% yield), ESI-MS (m/z): 470.1[ 2 ] M + H] ⁺ 。

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

According to the method for synthesizing A1, 8- (4-chlorophenyl) -2-ethoxy-6- (2, 3-dihydrobenzofuran-5-yl) pteridin-7 (8H) -one (1.2 mg, yield 5%), ESI-MS (m/z): 421.1[ mu ] 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 example 24: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- ((2-methyl-2H-indazol-5-yl) thio) pteridin-7 (8H) -one (A24)

Step 1:3- ((2-methyl-2H-indazol-5-yl) thio) propionic acid methyl ester

5-bromo-2-methyl-2H-indazole (1000mg, 4.730mmol), methyl 3-mercaptopropionate (850mg, 7.110mmo1), and tris [ dibenzylideneacetone ] were taken]Dipalladium (260mg, 0.280mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (274mg, 0.473mmol), N-diisopropylethylAmine (2.34mL, 1.420mmol) and dioxane (40 mL) were charged into a 100mL round-bottomed flask, replaced three times with nitrogen, and then heated to 100 ℃ for reaction for 4 hours. After the reaction was completed, 25mL of ethyl acetate and 10mL of water were added to the reaction solution, the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, the organic phase was washed successively with water and a saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound methyl 3- ((2-methyl-2H-indazol-5-yl) thio) propionate (500 mg, yield 42%), ESI-MS (m/z): 251.1[ M ] +H] ⁺ ；

And 2, step: 2-methyl-2H-indazole-5-thiol

Methyl 3- ((2-methyl-2H-indazol-5-yl) thio) propionate (500mg, 1.997mmol), sodium hydroxide (80mg, 2.000mmo 1) and methanol (5 mL) were charged into a25 mL round bottom flask, replaced with nitrogen three times, and heated to 50 ℃ for reaction for 3 hours. After the reaction was completed, 25mL of ethyl acetate and 10mL of water were added to the reaction solution, pH =4 was adjusted with acetic acid, the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, the organic phase was washed successively with water and a saturated sodium chloride solution, 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] ⁺ ；

And 3, step 3: 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- ((2-methyl-2H-indazol-5-yl) thio) pteridin-7 (8H) -one

Taking 6-chloro-8- (6-methoxypyridin-3-yl) -2-ethoxypteridine-7 (8H) -ketone (100mg, 0.300mmol), 2-methyl-2H-indazole-5 thiol (98mg, 0.599mmo 1) and tris [ dibenzylideneacetone]Dipalladium (33mg, 0.036mmol), 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (35mg, 0.060mmol), potassium carbonate (208mg, 1.498mmol) and dioxane (5 mL) were charged into a25 mL round-bottomed flask, replaced with nitrogen three times, and then heated to 100 ℃ for 3 hours. After the reaction, 25mL of ethyl acetate and 10mL of water were added to the reaction solution, the aqueous phase was extracted 2 times with ethyl acetate, the organic phases were combined, the organic phase was washed successively with water and a saturated sodium chloride solution, concentrated, and purified by column chromatography to obtain the target compound 2-ethoxy-8- (6-methoxypyridin-3-yl) -6- ((2-methyl-2H-indazol-5-yl) thio) pteridin-7 (8H) -one (18 mg, yield 13%), ESI-MS (m/z): 462.1[ 2 ] 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 example 25:8- (2-hydroxyphenyl) -2- ((2, 2-trifluoroethyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (A25)

According to the method for synthesizing A17, 8- (2-hydroxyphenyl) -2- ((2, 2-trifluoroethyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (50 mg, yield 57%) was synthesized using o-anisidine, 2-trifluoroethylamine and the like as starting materials, ESI-MS (m/z): 468.1[ 2 ] M + H] ⁺ 。

Preparation example 26:8- (4-methoxyphenyl) -6- (1-methyl-2- (2-morpholinoethyl) -1H-benzo [ d ] imidazol-6-yl) -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 (15g, 0.181mmol), 3-hydroxypropionic acid (28% aqueous solution) (33.6mL, 111.90mmol), hydrochloric acid (150 mL), and water (120 mL) were charged into a 500mL round-bottomed flask, and heated to 105 ℃ for reaction for 48 hours. After the reaction is finished, adjusting the pH value to 8-9 by using sodium hydroxide, extracting the water phase for 3 times by using ethyl acetate, combining the organic phases, washing the organic phase by using water and saturated sodium chloride solution in turn, concentrating, and purifying by using column chromatography to obtain the target compound 2- (6-bromo-1-methyl-1H-benzo [ d ] d]Imidazol-2-yl) ethan-1-ol (3.5 g, 18% yield), ESI-MS (m/z): 255.1[ m ] +H] ⁺ ；

And 2, step: 4- (2- (6-bromo-1-methyl-1H-benzo [ d ] imidazol-2-yl) ethyl) morpholine

Taking 25mL round-bottom flask 2- (6-bromo-1-methyl-1H-Benzo [ d ] carbonyl]Imidazol-2-yl) ethan-1-ol (200mg, 0.789 mmol) was dissolved in methylene chloride (5 mL), and triethylamine (238mg, 2.352mmol) and methanesulfonyl chloride (135mg, 1.176mmol) were added to react at room temperature for 1 hour. Morpholine (341mg, 3.920 mmol) was added and reacted at room temperature for 48 hours. After the reaction is finished, 100mL of ethyl acetate and 50mL of water are added into the reaction solution, the water phase is extracted for 2 times by ethyl acetate, the organic phases are combined, the organic phase is washed by water and saturated sodium chloride solution in sequence, and the target compound 4- (2- (6-bromo-1-methyl-1H-benzo [ d ] is obtained by concentration and purification by column chromatography]Imidazol-2-yl) ethyl) morpholine (179 mg, 70% yield), ESI-MS (m/z): 324.1[ m ] +H] ⁺ ；

And 3, step 3:4- (2- (1-methyl-6- (4, 5-tetramethyl-1, 3, 2-di-methyl-)

Borolan-2-yl) -1H-benzo [ d]Imidazol-2-yl) ethyl) morpholine

Taking 4- (2- (6-bromo-1-methyl-1H-benzo [ d)]Imidazol-2-yl) ethyl) morpholine (67mg, 0.207mmol), bis pinacol borate (79mg, 0.310mmol), 1' -bis (diphenylphosphino) ferrocene dichloropalladium (23mg, 0.031mmol), potassium acetate (61mg, 0.621mmol) and dioxane (2 mL) were added to a 10mL round bottom flask, replaced three times with nitrogen, heated to 110 ℃ for reaction for 3h, after completion of the reaction, cooled to room temperature and used directly in the next step, ESI-MS (m/z): 372.2[ M ] +H] ⁺ 。

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

Synthesis of 8- (4-methoxyphenyl) -6- (1-methyl-2- (2-morpholinoethyl) -1H-benzo [ d ] according to the procedure for the Synthesis of A1]Imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pterin-7 (8H) -one (20 mg, 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 example 27:6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pterin-7 (8H) -one (A27)

According to the method for synthesizing A26, 6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] is synthesized by using 4-methoxyaniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and the like as starting materials]Imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pterin-7 (8H) -one (20 mg, yield 21%), ESI-MS (m/z): 526.2[ 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 example 28:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pterin-7 (8H) -one (A28)

According to the synthesis 8- (4-methoxyphenyl) -6- (1-methyl-2- (2-morpholinoethyl) -1H-benzo [ d ]]Method for synthesizing 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] b-enzo [ d ] from 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropanoic acid alkane, and the like as starting materials, and imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pterin (8H) -one (A26)]Imidazol-6-yl) pterin-7 (8H) -one (240 mg, 38% yield), ESI-MS (m/z): 509.2[ 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＝8.5Hz,1H),7.54(d,J＝8.7Hz,2H),7.41(d,J＝8.6Hz,2H),7.39(t,J＝73.9Hz,1H),4.91(t,J＝5.3Hz,1H),4.26(q,J＝6.9Hz,2H),3.90-3.87(m,2H),3.81(s,3H),3.08(t,J＝6.6Hz,2H),1.26(t,J＝7.0Hz,3H)。

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

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (methoxymethyl) -1-methyl-1H-benzo [ d ] using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 2-methoxyacetic acid, etc., as starting materials according to the method for synthesizing A26]Imidazol-6-yl) pterin-7 (8H) -one (48 mg, 35% yield), ESI-MS (m/z): 509.2[ M ] +H] ⁺ ； ¹ H NMR(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＝8.7Hz,2H),7.39(t,J＝73.9Hz,1H),4.75(s,2H),4.27(q,J＝7.0Hz,2H),3.86(s,3H),3.37(s,3H),1.26(t,J＝7.0Hz,3H)。

Preparation example 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)

Taking 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d)]Imidazol-6-yl) pterin-7 (8H) -one (A26) (40mg, 0.079 mmol) was dissolved in dichloromethane (5 mL) in a25 mL round-bottomed flask, and triethylamine (109. Mu.L, 0.786 mmol) and methanesulfonyl chloride (50. Mu.L, 0.629 mmol) were added and reacted at room temperature for 1H, and 3-methoxypyrrolidine hydrochloride (162mg, 1.179 mmol) and triethylamine (220. Mu.L, 1.572 mmol) were added and reacted at room temperature for 48H. After the reaction is finished, 100mL of ethyl acetate and 50mL of water are added into the reaction solution, the water phase is extracted for 2 times by ethyl acetate, the organic phases are combined, the organic phase is washed by water and saturated sodium chloride solution in sequence, and the target compound 8- (4- (difluoromethoxy) phenyl is obtained by concentration and purification by column chromatography) -2-ethoxy-6- (2- (3-methoxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d]Imidazol-6-yl) pterin-7 (8H) -one (18 mg, 39% yield), ESI-MS (m/z): 592.2[ 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 example 31:8- (2, 3-Dihydrobenzofuran-4-yl) -2-ethoxy-6- (2-methyl-2H-indazol-5-yl) pterin-7 (8H) -one (A31)

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

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

Synthesis of 6- (2- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzimidazol-6-yl) -8- (4-methoxyphenyl) -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 example 33:6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (3- (benzyloxy) phenyl) pterin-7 (8H) -one (A33)

Synthesis of 6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] according to the method for synthesizing A1, starting with 3-benzyloxyaniline, 2-trifluoroethylamine and the like]Imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (3- (benzyloxy) phenyl) pterin-7 (8H) -one (9 mg, yield 42%), ESI-MS (m/z): 558.2[ 2 ] M + H] ⁺ 。

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

Synthesis of 6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d ] using 3-phenylethylaniline, 2-trifluoroethylamine, and the like as starting materials according to the method for synthesizing A1]Imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (3- (phenylethoxy) phenyl) pterin-7 (8H) -one (13 mg, 58% yield), ESI-MS (m/z): 572.2[ M ] +H] ⁺ 。

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

According to the method for synthesizing A26, 4- (trifluoromethoxy) aniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and the like are used as starting materials to synthesize 6- (2- (2-hydroxyethyl)) -1-methyl-1H-benzo [ d]Imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (33 mg, yield 15%), ESI-MS (m/z): 580.2[ 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 example 36:6- (2- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (A36)

Synthesis of 6- (2- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] is carried out according to the method for synthesizing A26 using 4- (trifluoromethoxy) aniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, pyrrolidinol and the like as starting materials]Imidazol-6-yl) -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 example 37:6- (2, 4-Difluoropiperidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (A37)

According to the method for synthesizing A26, 4- (trifluoromethoxy) aniline, 2-trifluoroethylamine and 4-bromo-2-methylamino are adoptedSynthesis of 6- (2, 4-difluoropiperidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] using aniline, 3-hydroxypropionic acid, 4-difluoropiperidine and the like as starting materials]Imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (25 mg, yield 11%), ESI-MS (m/z): 683.2[ 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 example 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 for synthesizing A1, 8- (4- (trifluoromethoxy) phenyl) -2- ((1- (trifluoromethyl) cyclopropyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (30 mg, yield 20%), ESI-MS (m/z): 562.1[ 2 ] 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 example 39:6- (2- (2- (3-Methoxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- (2, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (A39)

Synthesis of 6- (2- (2- (3-methoxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] p-henyl [ d ] according to the method for synthesizing A26, starting from 4- (trifluoromethoxy) aniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid and 3-methoxypyrrolidine]Imidazol-6-yl) -2- (22, 2-trifluoroethyl) amino) -8- (4- (trifluoromethoxy) phenyl) pterin-7 (8H) -one (9 mg, 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 example 40:8- (4- (Difluoromethoxy) phenyl) -6- (2- (2- (3-methoxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pterin-7 (8H) -one (A40)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -6- (2- (2- (3-methoxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] b-enz [ d ] according to the method for synthesizing A26, starting from 4- (difluoromethoxy) aniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, 3-methoxypyrrolidine and the like]Imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pterin-7 (8H) -one (13 mg, yield 9%), ESI-MS (m/z): 645.2[ 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 example 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 synthesis of A26, toSynthesis of 8- (4- (difluoromethoxy) phenyl) -6- (2- (2- (2, 6-dimethylmorpholinyl) ethyl) -1-methyl-1H-benzo [ d ] using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, and 2, 6-dimethylmorpholine as starting materials]Imidazol-6-yl) -2-ethoxypterin-7 (8H) -one (51 mg, 27% yield), ESI-MS (m/z): 606.2[ 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 example 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)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2- (3-hydroxypyrrolidin-1-yl) ethyl) -1-methyl-1H-benzo [ d ] according to the method for synthesizing A26, starting from 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, pyrrolidinol and the like]Imidazol-6-yl) pterin-7 (8H) -one (32 mg, 16% yield) (25 mg, 11% yield), ESI-MS (m/z): 578.2[ 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 example 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)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (1-methyl-2- (2- (piperidin-1-yl) ethyl) -1H-benzo [ d ] using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, piperidine, and the like as starting materials according to the method for synthesizing A26]Imidazol-6-yl) pterin-7 (8H) -one (32 mg, 16% yield), ESI-MS (m/z): 576.2 2[ 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 example 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)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (1-methyl-2- (2- (pyrrolidin-1-yl) ethyl) -1H-benzo [ d ] g starting with 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, tetrahydropyrrolidine and the like according to the procedure for the synthesis of A26]Imidazol-6-yl) pterin-7 (8H) -one (17 mg, 9% yield), 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 example 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)

Taking 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1-methyl-1H-benzo [ d)]Imidazol-6-yl) pterin-7 (8H) -one (A28) (40mg, 0.079 mmol) was dissolved in dichloromethane (5 mL) in a25 mL round-bottomed flask, and triethylamine (109. Mu.L, 0.786 mmol) and methanesulfonyl chloride (50. Mu.L, 0.629 mmol) were added and reacted at room temperature for 1 hour, and 3-fluorotetrahydropyrrole hydrochloride (99mg, 0.786 mmol) and triethylamine (164. Mu.L, 1.179 mmol) were added and reacted at room temperature for 48 hours. After the reaction is finished, 100mL of ethyl acetate and 50mL of water are added into the reaction liquid, the water phase is extracted for 2 times by the ethyl acetate, the organic phases are combined, the organic phase is washed by water and saturated sodium chloride solution in turn, concentrated and purified by column chromatography to obtain 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 (21 mg, 47% yield), ESI-MS (m/z): 580.2[ 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 example 46:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pterin-7 (8H) -one (A46)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] c starting with 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid and the like according to the method for synthesizing A26]Imidazol-6-yl) pterin-7 (8H) -one (150 mg, 21% yield), ESI-MS (m/z): :495.2[ M ] +H] ⁺ ； ¹ H NMR(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＝7.1Hz,3H)。

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

Synthesis of 8- (4- (difluoromethoxy) phenyl) -6- (2- (2- (dimethylamino) ethyl) -1-methyl-1H-benzo [ d ] is carried out according to the method for synthesizing A45, starting from 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, dimethylamine hydrochloride, and the like]Imidazol-6-yl) -2-ethoxypteridin-7 (8H) -one (16 mg, 38% yield), ESI-MS (m/z): 536.2 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 example 48:6- (2- (2- (diethylamino) ethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (A48)

Synthesis of 6- (2- (2- (diethylamino) ethyl) -1-methyl-1H-benzo [ d ] using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 3-hydroxypropionic acid, diethylamine hydrochloride and the like as starting materials according to the method for synthesizing A45]Imidazol-6-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (15 mg, 37% yield), ESI-MS (m/z): 564.2 2[ 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 example 49:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pteridin-7 (8H) -one (A49)

Synthesis of 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d ] is carried out according to the method for synthesizing A26, starting from 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid, diethylamine hydrochloride, and the like]Imidazol-6-yl) pteridin-7 (8H) -one (35 mg, 35% yield), 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 example 50:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1H-indol-5-yl) pteridin-7 (8H) -one (A50)

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

A100 mL flask was charged with 5-bromoindole (1.96g, 10mmol), (2-bromoethoxy) -tert-butyldimethylsilane (4.78g, 20mmol), norbornene (1.88g, 20mmol), bis (acetonitrile) dichloropalladium (260 mg,1 mmol), potassium carbonate (2.76g, 20mmol), and DMF (20 mL), and after displacement with nitrogen, the reaction was stirred at 70 ℃. After the reaction, the temperature was reduced and 150mL of water was added, extracted twice with 200mL of ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated. By column chromatographyPurifying to obtain 5-bromo-2- (2- ((tert-butyl dimethyl silicon) oxy) ethyl) -1H-indole (1.0 g, yield 28%), ESI-MS (m/z): 354.1,356.1, M +H] ⁺ ；

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

Taking the product of the last step, namely 5-bromo-2- (2- ((tert-butyl dimethyl silicon base) oxy) ethyl) -1H-indole (200mg, 0.56mmol), bis (pinacolato) diboron (0.28g, 1.14mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (82mg, 0.11mmol), potassium acetate (165mg, 1.6 mmol) and dioxane (5 mL) were charged into a 100mL round-bottomed flask, and after replacement with nitrogen, the reaction was stirred at 105 ℃. After the reaction is finished, directly cooling without further treatment to carry out the next reaction, ESI-MS (m/z): 402.3[ 2 ] M + H] ⁺ ；

And 3, step 3:6- (2- ((tert-butyldimethylsilyl) oxy) -1H-indol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one

Water (1 mL), 6-chloro-8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (100mg, 0.28mmol), and [1,1' -bis (diphenylphosphino) ferrocene were added to the above reaction solution]Palladium dichloride (82mg, 0..11 mmol) and potassium acetate (165mg, 1.6 mmol) were purged with nitrogen, and then the reaction was stirred at 100 ℃. After the reaction is finished, the temperature is reduced, 100mL of water is added, 200mL of ethyl acetate is added for extraction twice, organic phases are combined and dried by anhydrous sodium sulfate, concentrated after filtration and purified by column chromatography to obtain 6- (2- ((tert-butyldimethylsilyl) oxy) -1H-indol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (50 mg, yield 29%), ESI-MS (m/z): 608.2[ M ] +H] ⁺ ；

And 4, step 4:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1H-indol-5-yl) pteridin-7 (8H) -one

The product of the previous step, 6- (2- ((tert-butyldimethylsilyl) oxy) -1H-indol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (20mg, 0..033 mmol), tetrahydrofuran (5 mL) and tetrabutylammonium fluoride (1M, 0.1ml) were charged in a 100mL round-bottomed flask and the reaction was stirred at room temperature. After the reaction is finished, the reaction solution is concentrated and purified by thin plate chromatographyTo give 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1H-indol-5-yl) pteridin-7 (8H) -one (4 mg, 25%), ESI-MS (m/z): 494.2[ 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 example 51:8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (2-hydroxyethyl) -1-methyl-1H-indol-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

6- (2- ((tert-butyldimethylsilyl) oxy) -1H-indol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (30mg, 0.049 mmol) and DMF (5 mL) were charged into a 100mL round-bottomed flask, 60% sodium hydride (4mg, 0.1mmol) was added under ice bath, stirred at room temperature for 10 minutes, iodomethane (14.2mg, 0.1mmol) was added, and the reaction was stirred at room temperature. After the reaction, 100mL of water and 200mL of ethyl acetate were added and extracted twice, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by thin plate chromatography gave 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 2[ M ] +H] ⁺

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

The product of the previous step, 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 (5 mL) and tetrabutylammonium fluoride (1M, 0.1mL), was taken and addedThe reaction mixture was charged into a 100mL round-bottomed flask, and the reaction was stirred at room temperature. After the reaction, the reaction mixture was concentrated and purified by thin plate chromatography to give 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[ 2 ] M + H] ⁺ ； ¹ H NMR(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 example 52: 2-ethoxy-8- (4-fluorophenyl) -6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pteridin-7 (8H) -one (A52)

According to the method for synthesizing A26, the 2-ethoxy-8- (4-fluorophenyl) -6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] is synthesized by taking para-fluoroaniline, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid and the like as starting materials]Imidazol-6-yl) pteridin-7 (8H) -one (19 mg, 15% yield), 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 example 53:8- (4-chlorophenyl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pteridin-7 (8H) -one (A53)

According to the method for synthesizing A26, the 8- (4-chlorphenyl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] is synthesized by taking parachloroaniline, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid and the like as starting materials]Imidazol-6-yl) pteridin-7 (8H) -one (12 mg, 13% yield), ESI-MS (m/z): 463.1[ 2 ] 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 example 54:8- (6-Cyclopropylpyridin-3-yl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) pterin-7 (8H) -one (A54)

According to the method for synthesizing A26, the 8- (6-cyclopropylpyridin-3-yl) -2-ethoxy-6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] is synthesized by using p-6-cyclopropylpyridin-3-amine, ethanol, 4-bromo-2-methylaminoaniline, glycolic acid and the like as starting materials]Imidazol-6-yl) pterin-7 (8H) -one (10 mg, 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＝7.1Hz,3H),1.24–1.22(m,2H),1.03-1.00(m,2H)。

Preparation example 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 for synthesizing A26, 6- (2- (tert-butyl) -1-methyl-1H-benzo [ d ] is synthesized by using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, pivalic acid and the like as starting materials]Imidazol-6-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (50 mg, 35% yield), 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 example 56:6- (2-acetyl-2H-indazol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (A56)

According to the method for synthesizing a26, 6- (2-acetyl-2H-indazol-5-yl) -8- (4- (difluoromethoxy) phenyl) -2-ethoxypteridin-7 (8H) -one (35 mg, yield 18%), ESI-MS (m/z): 493.1[ M ] C + 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 example 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 for synthesizing A26, the 8- (4- (difluoromethoxy) phenyl) -2-ethoxy-6- (2- (1-hydroxyethyl) -1-methyl-1H-benzo [ d ] is synthesized by using 4- (difluoromethoxy) aniline, ethanol, 4-bromo-2-methylaminoaniline, lactic acid and the like as starting materials]Imidazol-6-yl) pteridin-7 (8H) -one (25 mg, 18% yield), 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 example 58:6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (A58)

According to the method for synthesizing A26, 4-methoxyaniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid and the like are used as starting materials to synthesize 6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d]Imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (20 mg, yield 14%), ESI-MS (m/z): 540.2[ 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 example 59:6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (A59)

According to the method for synthesizing A26, 4-methoxyaniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, glycolic acid and the like are used as starting materials to synthesize 6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d]Imidazol-6-yl) -8- (4-methoxyphenyl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (25 mg, 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 example 60:8- ((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 (A60)

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 was synthesized according to the procedure for the synthesis of A26 starting from (1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) methylamine, ethanol, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid and the like.

Taking 2-ethoxy-6- (2- (2-hydroxypropane-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 (50mg, 0.084 mmol) was dissolved in dichloromethane (5 mL) in a25 mL round bottom flask, 2.5mL trifluoroacetic acid was added and reacted at room temperature for 3H. After the reaction is finished, removing the solvent under reduced pressure, adding 50mL of water, adjusting the pH value to about 7 by sodium bicarbonate, extracting the water phase with ethyl acetate for 2 times, combining the organic phases, washing the organic phases with water and saturated sodium chloride solution in turn, concentrating, and purifying by column chromatography to obtain the target compound 8- ((1H-imidazole-2-yl) methyl) -2-ethoxy-6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d ] n]Imidazol-6-yl) pteridin-7 (8H) -one (12 mg, 31% yield), 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 example 61:8- (4-chlorophenyl) -6- (2- (hydroxymethyl) -1-methyl-1H-benzo [ d ] imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (A61)

According to the method for synthesizing A26, the 8- (4-chlorphenyl) -6- (2- (hydroxymethyl) methyl) -aniline is synthesized by using 4-chloroaniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, glycolic acid and the like as starting materials) -1-methyl-1H-benzo [ d]Imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (15 mg, yield 11%), ESI-MS (m/z): 516.1[ m ] +H] ⁺ ； ¹ H NMR(600MHz,DMSO)δ8.91(d,J＝16.5Hz,1H),8.46(s,1H),8.45-8.20(m,1H),8.10(d,J＝8.4Hz,1H),7.70–7.60(m,3H),7.50(s,2H),5.63(t,J＝5.8Hz,1H),4.75(d,J＝5.8Hz,2H),4.16(s,1H),3.86(s,3H),3.78(s,1H)。

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

According to the method for synthesizing A26, 4-chloroaniline, 2-trifluoroethylamine, 4-bromo-2-methylaminoaniline, 2-methyl-2-hydroxypropionic acid and the like are used as starting materials to synthesize 8- (4-chlorophenyl) -6- (2- (2-hydroxypropan-2-yl) -1-methyl-1H-benzo [ d]Imidazol-6-yl) -2- ((2, 2-trifluoroethyl) amino) pteridin-7 (8H) -one (20 mg, yield 14%), ESI-MS (m/z): 544.2[ 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 example 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 for synthesizing A1, 8- (4-methoxyphenyl) -2- ((2, 2-difluoroethyl) amino) -6- (2-methyl-2H-indazol-5-yl) pteridin-7 (8H) -one (30 mg, yield 43%) was synthesized using p-methoxyaniline, 2-difluoroethylamine, and the like as starting materials, and 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 efficacy tests and data for the compounds of the present invention.

Test example 1: MAT2A enzymatic Activity assay

The inhibitory effect of the test compound on the enzymatic activity of MAT2A was determined using the MAT2A inhibitor enzymatic screening kit (BPS Bioscience, catalog: 71402). The specific operation procedure is as follows:

1) The test compound was dissolved in DMSO and mixed well until the test compound was completely dissolved. All compounds were diluted with DMSO to an initial concentration of 2mM and 3-fold dilutions were made in a total of 10 concentration gradients, duplicate wells, 1:100 was added to the reaction system (final concentration up to 20. Mu.M). 100X positive control (1 mM AGI-2452) and 100X negative control (100% DMSO) were prepared.

2) To the reaction plate (784075, greiner) was transferred 200nL of the diluted compound per well using an Echo 550 pipetting system, the reaction plate was sealed with a sealing plate film, and centrifuged at 1000g for 1 minute. The final concentration of DMSO is 1%.

3) Preparation of 1 × MAT2A enzyme reaction buffer: 1 times the volume of 5 x MAT2A enzyme reaction buffer and 4 times the volume of water fully mixed.

4) 2 XMAT 2A enzyme solution was prepared using 1 Xenzyme reaction buffer.

5) mu.L of 2 XMAT 2A enzyme solution per well was added to 384-reaction plates (Corning 3702), and the plates were sealed with a sealing plate membrane.

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

7) A mixture of 2 XL-methionine and ATP was prepared using 1 XMAT 2A enzyme reaction buffer.

8) To 384-reaction plate (Corning 3702), 10. Mu.L of a2 XL-methionine and ATP mixture was added per well, and the plate was sealed with a sealing plate. The total reaction system was 20. Mu.L.

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

10 Preparation of a Colorimetric Detection Reagent (Colorimetric Detection Reagent) for Detection buffer.

11 20. Mu.L of assay buffer was added to each well, centrifuged at 1000g for 30 seconds, and reacted at room temperature for 15 minutes.

12 630nm fluorescence signal was measured with a multifunctional microplate reader (PerkinElmer, nivo).

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

A represents IC ₅₀ 50nM or less, B represents 50nM<IC ₅₀ ≤100nM。

The data show that the compound has stronger MAT2A inhibition effect.

Test example 2 inhibition of cell proliferation test

The specific operation procedure is as follows: tumor cells are treated with the compounds for 5 days and the effect of the test compound on tumor cell proliferation is assessed. HCT116-MTAP ^-/- And wild type control HCT116-WT cells were plated at a density of 600/well in 384 well plates, treated with different concentrations of test compound (20. Mu.M start, 10 concentration gradients). The cells were assayed at 37 ℃ and 5% CO ₂ And incubating for 5 days under saturated humidity conditions.

Cell proliferation was detected using an ATP-based Cell proliferation assay kit (Cell Titer Glo, promega Corporation). Cells were equilibrated at room temperature for 30 min before treatment with Cell Titer Glo reagent. The dishes were then covered with aluminum foil and shaken for 15 minutes to allow for thorough mixing and lysis. Chemiluminescence detection was performed using a multifunctional microplate reader (Envision 2105, perkinelmer). Blank wells (blank, no cells) and DMSO control wells were set.

The Inhibition Rate (IR) of the test compound was calculated by the following formula:

IR (%) = [1- (RLU Compound-RLU blank)/(RLU vehicle control-RLU blank) ]. Times.100%

Mapping, data analysis and IC Using GraphPad Prism ₅₀ And (4) calculating.

The compounds of the invention were tested in the above assay and their IC's for inhibiting cell proliferation were determined ₅₀ The following table shows.

The result shows that the compound to be tested shows stronger cell proliferation activity on HCT116 MTAP knocked-out cells and weaker cell proliferation activity on MTAP wild-type HCT116 cells, namely, better selectivity is shown.

Test example 3 human UGT1A1 enzyme Activity test

The enzyme inhibitory activity of the compounds on UGT1A1 was determined by the following specific procedure:

1) mu.L of 2mM control compound (atazanavir), 1. Mu.L of 440. Mu.M test compound or 1. Mu.L of dimethyl sulfoxide (solvent control) was added to the plate, and the main reaction solution containing UGT1A1 (Corning, 456411), 0.5. Mu.M substrate Bilirubin (Bilirubin) and Tris buffer at a final concentration of 0.01mg/mL was added, and preincubated in a water bath at 37 ℃ for 10min, with a final concentration of 10. Mu.M control compound and 2.2. Mu.M test compound.

2) The reaction was started by adding 20. Mu.L of UDPGA solution at a final concentration of 2mM, reacted at 37 ℃ for 5min, and stopped by adding 400. Mu.L of cold acetonitrile containing an internal standard.

3) The sample was vortexed for 5 minutes at 4 ℃ and 3220g, and centrifuged for 40min. Then 100. Mu.L of the supernatant was transferred to a new 96-well plate and analyzed for metabolite formation by LC-MS/MS. The% inhibition was calculated by comparing the amount of metabolite formation reduction (peak area quantification) of the test drug to the control group.

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

% inhibition =100-% residual activity

The above results indicate that the compound a49 has less risk of inhibiting UGT1A1, while the compounds 45 and 91 of WO2021139775 have higher inhibition rate on UGT1A1, with risk of bilirubin increase in vivo.

Test example 4 in vivo pharmacokinetic study in mice

Experimental animals: CD-1 mice (male, 22-25 g) were purchased from Experimental animals technology, inc. of Viton, beijing.

The test steps are as follows: injecting test compound (2 mg/kg) into CD-1 mice (male, 22-25 g) intravenously, administering test compound (5 mg/kg) by intragastric administration, collecting mouse plasma at administration time of 5min, 15min, 0.5h, 1h, 2h, 4h, 8h, and 24h, detecting compound concentration by LC-MS/MS, and examining plasma clearance rate Cl and elimination half-life T _1/2 Peak time T _max Peak concentration C _max Pharmacokinetic parameters such as area under curve AUC, apparent distribution volume Vss and absolute bioavailability F.

The determination method comprises the following steps: the stock solution of analyte was diluted with 50% acetonitrile to obtain the desired working solution concentration series. To 10 μ L of blank CD1 mouse plasma, 10 μ L of working solution (1, 2,5, 10, 50, 100, 500, 1000, 5000, 10000 ng/mL) was added to reach a total volume of 20 μ L of 1-10000ng/mL (1, 2,5, 10, 50, 100, 500, 1000, 5000, 10000 ng/mL) calibration standard. 5 Quality Control (QC) samples (2 ng/mL, 5ng/mL, 10ng/mL,800ng/mL,8000 ng/mL) were prepared in the same manner as the calibration standard on the day of analysis. mu.L of the standard, 20. Mu.L of the QC sample, 20. Mu.L of the unknown sample (10. Mu.L of the unknown sample plasma and 10. Mu.L of the blank solution) were added to 200. Mu.L of the IS mixture containing acetonitrile, respectively, to precipitate proteins. The sample was then vortexed for 3min with shaking. After centrifugation at 4700rpm for 15min at 4 ℃, the supernatant was diluted with ultrapure water at a ratio of 1 (V/V) and then 10 μ L of the diluted supernatant was injected into an LC/MS system for quantitative analysis.

The pharmacokinetic parameters for compound a49 are given in the following table:

I.V.: intravenous injection; P.O.: orally taking; cl: apparent clearance rate; t is _1/2 : a half-life; AUC _last : area under the time-of-drug curve from the start of dosing to the last point (24 hours); AUC _inf : area under the drug time curve from the start of dosing to the theoretical extrapolated infinite time; MRT _Inf : average residence time from zero time to infinite time; vss: apparent volume of distribution; t is a unit of _max : time to peak; c _max : peak concentration; f: relative bioavailability.

Test example 5 examination of antitumor Effect of Compound in vivo

Compound A49 of the present invention was tested against HCT116-MTAP ^-/- Inhibition of growth of transplanted tumors in mice.

Experimental animals: female BALB/c nude mice were purchased from Jiangsu Jiejiaokang Biotechnology GmbH, with a weight range of 18-22g, and were housed in SPF-level, constant temperature and humidity, laminar flow clean rooms, using independent ventilated cages IVC, one cage per 5 mice.

HCT116-MTAP ^-/- Cells were cultured in McCoy's 5a medium (GIBCO) containing 10% FBS. The cells were cultured at 5X 10 ⁶ A number of mice were inoculated subcutaneously in the back of 42 BALB/c nude mice, and on day 6 after inoculation, 30 tumors were selected with a volume of about 150mm ³ Mice of size, evenly grouped by tumor volume. The preparation is administered orally once a day for 14 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 indices.

Note: TV (television) _Xn : the nth balance of the administration group has the same tumor volume

TV _X1 : dose group 1 balance mean tumor volume

TV _Mn : model group nth balance mean tumor volume

TV _M1 : model group 1 day balance mean tumor volume

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

The results show that the compound of the invention does not cause the increase of bilirubin while showing better in vivo efficacy.

Test example 6 in vivo serum Total bilirubin assay

Female Nu/Nu mice, 18-22g, purchased from Experimental animals technology, inc. of Wei Tongli, beijing. The test compound was administered orally once a day for 14 consecutive days. After the animal is anesthetized, the heart collects whole blood, after the animal is kept stand for 0.5 hour at room temperature, the whole blood is centrifuged for 10min at 3500rpm, serum is separated, and the total bilirubin level of the blood is detected by a full-automatic biochemical analyzer. The results are shown in the table below, and the test compounds did not cause a significant increase in total bilirubin in the blood.

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

Claims

1. A compound of formula (I) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof:

wherein:

L ₁ is selected from the group consisting of 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 )-；R ^a1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^a selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 Is substituted wherein R is ^a2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^a3 、R ^a4 Independently at each occurrence selected from hydrogen or optionally one or more independently selected fromHalogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₂ is selected from the group consisting of 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 )-；R ^b1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^b selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 Is substituted in which R ^b2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^b3 、R ^b4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 When bound to the same nitrogen atom, R ^b3 And R ^b4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

L ₃ is selected from the group consisting of 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 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^c selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 Is substituted wherein R is ^c2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R ^c3 、-OR ^c3 、-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 ) (ii) a Wherein R is ^c3 、R ^c4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^c3 And R ^c4 When bound to the same nitrogen atom, R ^c3 And R ^c4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

X ₁ selected from N or CR ^d ；

R ^d Independently selected from hydrogen, deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^d1 Is substituted in which R ^d1 Independently at each occurrence, selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^d2 、R ^d3 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

2. A compound of formula (II) or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof:

wherein:

R ^a selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^a2 Is substituted wherein R is ^a2 Independently at each occurrence, is selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^a3 、R ^a4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 3-10 membered heterocycloalkyl substituted with aryl, 5-12 membered heteroaryl or 5-12 membered heteroarylA membered heteroaryl group;

L ₂ selected from the group consisting of a bond, -C (R) ^b1 ) ₂ -、-O-、-S-、-C(O)-、-C(O)O-、-OC(O)-、-N(R ^b1 )C(O)-、-C(O)N(R ^b1 ) -or-N (R) ^b1 )-；R ^b1 Independently at each occurrence, is selected from hydrogen or optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, 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 groups are unsubstituted or independently at one or more substitutable positions selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl;

R ^b selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 Is substituted wherein R is ^b2 Independently at each occurrence, selected from deuterium, halogen, hydroxy, 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 ) (ii) a Wherein R is ^b3 、R ^b4 Each occurrence is independently selected from hydrogen or optionally substituted with oneOne or more are independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^b3 And R ^b4 When bound to the same nitrogen atom, R ^b3 And R ^b4 Together with the nitrogen atom to which they are attached form a ring optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

R ^c selected from optionally substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-12-membered heterocyclic group, C _6-14 Aryl, 5-12 membered heteroaryl; said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^c2 Is substituted in which R ^c2 Independently at each occurrence, selected from deuterium, halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, -R ^c3 、-OR ^c3 、-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 ) (ii) a Wherein R is ^c3 、R ^c4 Independently at each occurrence selected from hydrogen or optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-to 10-membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl substituted C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R ^c3 And R ^c4 When bound to the same nitrogen atom, R ^c3 And R ^c4 Together with the nitrogen atom to which they are attached form an optionally substituted alkyl group optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, nitro, mercapto, cyano, oxo, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 3-10 membered heterocycloalkyl substituted with a substituent of 5-12 membered heteroaryl, or 5-12 membered heteroaryl;

3. The compound according to claim 1 or 2, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, wherein:

L ₁ is selected from the group consisting of a bond, -CH ₂ -, -O-, -S-or-N (R) ^a1 ) -, wherein R ^a1 Selected from hydrogen or C _1-6 An alkyl group;

preferably, L ₁ Selected from the group consisting of a bond, -O-, -S-, -NH-;

preferably, L ₁ Is a key.

4. A compound according to any one of claims 1 to 3, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that:

R ^a selected from optionally substituted 3-12 membered heterocyclyl, C _6-14 Aryl, 5-14 membered heteroaryl, wherein the heteroatoms in the heterocyclyl, heteroaryl are independently selected from O, N or S, the number of heteroatoms being 1,2,3 or 4;

preferably, R ^a Selected from optionally substituted 5-10 membered bicyclic heterocyclyl, 5-10 membered bicyclic heteroaryl, wherein the heteroatoms in said heterocyclyl, heteroaryl are independently selected from O or N, the number of heteroatoms being 1,2 or 3;

preferably, R ^a Selected from optionally substituted

Preferably, R ^a Selected from optionally substituted

Preferably, R ^a Selected from optionally substituted

5. The compound according to any one of claims 1 to 4, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, characterized in that:

R ^a2 independently selected from halogen, -C (O) R ^a3 Hydroxy, amino, -C _1-6 alkylene-N (R) ^a3 )(R ^a4 ) Optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkoxy-substituted C _1-6 An alkyl group;

preferably, R ^a2 Is independently selected from-C _1-6 alkylene-N (R) ^a3 )(R ^a4 ) Optionally substituted with one or more substituents independently selected from hydroxy and C _1-6 Alkoxy-substituted C _1-6 An alkyl group.

6. The compound according to any one of claims 1 to 5, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, characterized in that:

R ^a3 、R ^a4 independently selected from hydrogen or optionally substituted by one or more substituents independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, 5-6 membered heteroaryl substituted C _1-6 Alkyl radical, C _3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C _6-14 Aryl, 5-12 membered heteroaryl; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form an optionally substituted alkyl group optionally substituted by one or more groups independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C _6-8 Aryl, a 3-10 membered heterocycloalkyl substituted with a substituent of a 5-6 membered heteroaryl, or a 5-12 membered heteroaryl, wherein the heteroatoms in the heterocycloalkyl or heteroaryl are selected from N, S, O, and the number of heteroatoms is 1,2, or 3;

preferably, R ^a3 、R ^a4 Independently selected from hydrogen or optionally substituted by one or more independently selected from halogen, hydroxy, amino, C _1-6 Alkyl radical, C _1-6 Substituent-substituted C of alkoxy _1-6 An alkyl group; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 A 3-10 membered heterocycloalkyl substituted with a substituent of alkoxy, wherein the heteroatom in the heterocycloalkyl is selected from N, S, O, and the number of heteroatoms is 1,2 or 3;

preferably, R ^a3 、R ^a4 Independently selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen, hydroxy, amino _1-6 An alkyl group; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a ring optionally substituted by one or more groups independently selected from halogen, hydroxy, C _1-4 Alkyl radical, C _1-4 3-10 membered heterocycloalkyl substituted with a substituent of alkoxy, wherein the heteroatom in the heterocycloalkyl is selected from N, O, and the number of heteroatoms is 1 or 2;

preferably, R ^a3 、R ^a4 Independently selected from C _1-4 An alkyl group; or when R is ^a3 And R ^a4 When bound to the same nitrogen atom, R ^a3 And R ^a4 Together with the nitrogen atom to which they are attached form a substituted or unsubstituted alkyl or alkenyl group optionally substituted with one or more substituents independently selected from F, hydroxy, methyl, methoxyTetrahydropyrrolyl, piperidinyl or morpholinyl.

7. The compound according to any one of claims 1 to 6, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, characterized in that:

L ₂ is selected from the group consisting of a bond, -CH ₂ -；

Preferably, L ₂ Is a bond.

8. The compound according to any one of claims 1 to 7, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein:

R ^b selected from optionally substituted 5-12 membered bicyclic heterocyclic group, C _6-10 Aryl, 5-10 membered heteroaryl;

preferably, R ^b Selected from optionally substituted 5-10 membered bicyclic heterocyclic group, C _6-10 Aryl, 5-6 membered heteroaryl;

preferably, R ^b Selected from optionally substituted phenyl, pyridyl or benzotetrahydrofuranyl;

preferably, R ^b Selected from optionally substituted phenyl or pyridyl;

preferably, R ^b Selected from the group consisting of optionally substituted phenyl groups,

said optionally substituted means that the mentioned groups are unsubstituted or independently at one or more substitutable positions by R ^b2 And (4) substituting.

9. The compound according to any one of claims 1 to 8, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, characterized in that:

R ^b2 independently selected from halogen, hydroxy, amino, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Is selected from optionally substituted by one or more independently selected from halogen or C _6-10 Aryl substituted by substituents C _1-6 An alkyl group;

preferably, R ^b2 Independently selected from halogen, hydroxy, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Selected from C optionally substituted with one or more substituents independently selected from halogen or phenyl _1-4 An alkyl group;

preferably, R ^b2 Independently selected from fluorine, chlorine, -OH, C _3-6 Cycloalkyl, -OR ^b3 Wherein R is ^b3 Selected from C optionally substituted with one or more substituents independently selected from chloro or phenyl _1-4 An alkyl group;

preferably, R ^b2 Independently selected from chloro, cyclopropyl or-O (C) optionally substituted with one or more halogen _1-4 Alkyl groups);

preferably, R ^b2 Independently selected from chlorine or-O (C) optionally substituted by one or more fluorine _1-4 Alkyl);

preferably, R ^b2 Independently selected from chloro, -OCH ₃ 、-O(CHF ₂ ) or-O (CF) ₃ )。

10. The compound according to any one of claims 1 to 9, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative, or pharmaceutically acceptable salt thereof, characterized in that:

L ₃ is selected from-CH ₂ -, -O-, -S-or-N (R) ^c1 ) -, wherein R ^c1 Selected from hydrogen or C _1-6 An alkyl group;

preferably, L ₃ Selected from-O-, -N (R) ^c1 )-；

Preferably, L ₃ Selected from-O-, -NH-.

11. The compound according to any one of claims 1 to 10, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or pharmaceutically acceptable salt thereof, wherein:

R ^c selected from C optionally substituted by one or more halogens _1-6 Alkyl or optionally substituted by one or more R ^c3 Substituted C _3-6 Cycloalkyl, wherein R ^c3 Selected from hydrogen or C optionally substituted with one or more substituents independently selected from halogen _1-6 An alkyl group;

preferably, R ^c Selected from C optionally substituted by one or more halogen _1-4 Alkyl or optionally by CF ₃ Substituted C _3-6 A cycloalkyl group;

preferably, R ^c Selected from methyl, ethyl,

Preferably, R ^c Selected from ethyl,

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

13. a pharmaceutical composition characterized by: comprising a compound of any one of claims 1 to 12, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative thereof, or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 12, or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for the treatment of a disease, disorder or condition mediated by MAT 2A; preferably, the diseases, disorders and conditions are MTAP-deficient tumors; preferably, the tumor includes solid tumors and hematological tumors.

15. A pharmaceutical composition characterized by: comprising a compound of any one of claims 1 to 12 or a prodrug, tautomer, stereoisomer, solvate, isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 13 and another, two or more drugs having tumor-inhibiting activity.