WO2022063128A1

WO2022063128A1 - Aromatic ring or arylheterocyclic pyridone compound, pharmaceutical compositions, and use thereof

Info

Publication number: WO2022063128A1
Application number: PCT/CN2021/119638
Authority: WO
Inventors: 万惠新; 王亚周; 查传涛; 马金贵
Original assignee: 上海凌达生物医药有限公司
Priority date: 2020-09-24
Filing date: 2021-09-22
Publication date: 2022-03-31
Also published as: CN115960099A

Abstract

An aromatic ring or arylheterocyclic pyridone compound, pharmaceutical compositions, and a use thereof, in particular an aromatic ring or arylheterocyclic pyridone compound represented by formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs thereof, preparation methods therefor and a pharmaceutical use thereof. The compound has good MAT2a enzyme activity inhibition, and significantly inhibits the growth of multiple types of tumor cells, particularly tumor cells that are MTAP null.

Description

A kind of aromatic ring or aryl heterocyclic pyridone compound, pharmaceutical composition and application thereof

This application claims the priority of the Chinese patent application 2020110183911 with the filing date of 2020/9/24, the priority of the Chinese patent application 2020115111271 with the filing date of 2020/12/19, and the Chinese patent with the filing date of 2021/1/10 The priority of the application 2021100275150, the priority of the Chinese patent application 2021101855079 with the filing date of 2021/2/10, and the priority of the Chinese patent application 2021103638917 with the filing date of 2021/4/2. This application cites the full text of the above Chinese patent application.

technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a class of aromatic ring or aryl heterocyclic pyridone compounds, which have the activity of inhibiting methionine adenosyltransferase (MAT2a) and can be used to prepare compounds with MAT2a or MTAP. Therapeutic and prophylactic drugs for diseases associated with activity or expression.

Background technique

Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthase) catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP cellular enzyme and is considered the rate-limiting step of the methionine cycle. SAM is the propylamino donor in polyamine biosynthesis and the major methyl donor for DNA methylation, and it is involved in gene transcription and cell proliferation and the production of secondary metabolites. Pharmacological methods have found that the proliferation and metastasis of tumor cells are abnormally dependent on methionine, and inhibiting the methionine cycle can significantly inhibit the proliferation and metastasis of tumor stem cells (Nature Medicine (2019), 25, 825-837).

Methylthioadenosine phosphorylase (MTAP) is involved in the salvage pathway of methionine, metabolizing methylthioadenosine (MTA) to adenine and methionine. MTAP is located on chromosome 9p21 and is similar to the tumor suppressor gene CDKN2A. MTAP deficiency exists in various tumors such as leukemia, glioma, melanoma, lung and ovarian cancer, endometrial cancer, and breast cancer. Among them, the deletion rate was 41% in glioma, 31% in mesothelioma, and 26% in pancreatic cancer. S-adenosyl-L-methionine (SAM) is an enzymatic cofactor involved in methyl transfer reactions and polyamine biosynthesis, which can be transferred from ATP and L-methionine to methionine adenosine Enzyme family (MAT) proteins catalyzed by the reaction generated. In mammalian tissues, there are mainly two different isoenzymes of the MAT gene, encoded by MAT1a and MAT2a, respectively. MAT1a is only expressed in adult liver tissue, is liver-specific, and its main function is to promote SAM synthesis. MAT2a is expressed in all non-liver tissues and its main function is to inhibit SAM synthesis. MAT2a is a key enzyme in the adenosylmethionine (SAM) synthesis pathway. Studies have shown that the expression of MAT2a is up-regulated in a variety of cancer cells, and knocking out the MAT2a gene can lead to cancer cell death. MTAP-deficient tumors are the most sensitive. Therefore, MAT2a is a potential therapeutic target for MTAP-deficient tumors. The discovery and search of MAT2a inhibitors with novel structures and excellent druggability has become a hot spot in the development of MTAP-deficient tumor therapy drugs.

SUMMARY OF THE INVENTION

One of the technical problems to be solved by the present invention is to provide a novel MAT2a inhibitor for the preparation of tumor therapeutic drugs. After long-term and in-depth research, the inventor has prepared a class of aromatic ring or aryl heterocyclic pyridone compounds with a novel structure shown in formula I, and found that it has better inhibition of MAT2a enzyme activity, and the described The compound has a specific inhibitory effect on MAT2a protein at very low concentration (as low as less than 100 nM), and has excellent inhibitory activity on cell proliferation related to MTAP deletion. Based on the above findings, the inventors have completed the present invention.

The present invention solves the above technical problems through the following technical solutions.

The present invention provides an aromatic ring or aryl heterocyclic pyridone compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof , tautomer, torsion isomer, solvate, polymorph or prodrug,

where:

Ar is selected from 5-12-membered monocyclic or cycloaryl, monocyclic or cycloaryl substituted by 1-3 Rn, "heteroatom is selected from one or more of N, O, P and S" , 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms" and "heteroatoms substituted by 1-3 Rn" selected from one or more of N, O, P and S Species, 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms";

The Rn is independently selected from deuterium, halogen, cyano, amide, sulfonamide, hydroxyl, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ -C ₁₂ alkyl, C ₁ - C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy, -NRz ₁ Rz ₂ , alkenyl, alkynyl, 3-12 membered monocyclic, spirocyclic or bridged cycloalkanes base, "heteroatoms selected from one or more of N, O, P and S, and 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl groups with 1-3 heteroatoms", C ₁ -C ₁₂ alkyl-S-, C ₁ -C ₁₂ alkyl-SO-, C ₁ -C ₁₂ alkyl-SO ₂ -, 3-12-membered cycloalkyl ether, 3-12-membered heterocycloalkane base ether, 5-10-membered monocyclic or cyclic aryl and "heteroatoms selected from one or more of N, O, P and S, and 3-12-membered monocyclic rings with 1-3 heteroatoms Or cycloheteroaryl"; or any two of the above Rn can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through a carbon chain or a heteroatom; Rz ₁ and Rz ₂ are independently selected from H and C ₁ -C ₁₂ alkyl;

R ₁ is selected from halogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy, C ₁ -C ₁₂ monoalkylamino, C ₁ -C ₁₂ dialkylamino, C ₁ -C ₁₂ haloalkylamino, 3-12-membered monocyclic, spiro or bridged cycloalkyl, "heteroatom selected from N, O, P and S One or more of 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms, C ₁ -C ₁₂ alkyl-S-, C ₁ -C ₁₂ alkyl-SO-, C ₁ -C ₁₂ alkyl-SO ₂ -, 3-12-membered cycloalkyl ether, 3-12-membered heterocycloalkyl ether, 5-10-membered monocyclic or cyclic aryl and "The heteroatom is selected from one or more of N, O, P and S, and the 3-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms";

R ₂ is selected from halogen, cyano, amide, sulfonamide, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ -C ₁₂ haloalkyl and C ₁ -C ₁₂ haloalkoxy;

R _3a is selected from hydrogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl substituted by one or more Rm ₁ , C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ monoalkylaminoalkyl, C ₁ -C ₁₂ dialkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 membered monocyclic, spirocyclic or bridged ring Cycloalkyl, 3-12-membered monocyclic, spirocyclic or bridged cycloalkyl substituted by one or more Rm ₂ , "heteroatom selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm ₃ selected from N, O, P and S One or more of 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl groups with 1-3 heteroatoms";

R _3b is selected from C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl substituted by one or more Rm ₁ , C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C 12Monoalkylaminoalkyl, _C1 - _{C12dialkylaminoalkyl} , cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, _3-12 -membered monocyclic, spirocyclic or bridged cycloalkane base, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm ₂ , "heteroatom selected from one or more of N, O, P and S, heteroatom A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1 to 3 "heterocycloalkyl groups" and "heteroatoms substituted by one or more Rm ₃ are selected from one of N, O, P and S. One or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";

Alternatively, the above-mentioned R _3a and R _3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl", "heteroatoms substituted by one or more Rm ₄ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms are selected from one or more of N, O, P and S, and 3-heteroatoms with 1-3 heteroatoms 12-membered monocyclic or heterocyclic heteroaryl" or "heteroatoms substituted by one or more Rm ₅ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic or heterocyclic heteroaryl";

The Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ and Rm ₅ are independently selected from deuterium, oxo (=O), halogen, cyano, amide, sulfonamide, hydroxyl, urea, phosphoryl, alkyl Phosphoroxy, alkylsilyl, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl substituted by one or more Ry ₁ , C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl , C ₁ -C ₁₂ haloalkoxy, alkenyl, alkynyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl, 3-12-membered monocyclic, spiro substituted by one or more Ry ₂ Ring or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged rings with 1-3 heteroatoms "Heterocycloalkyl", "heteroatoms substituted by one or more Ry ₃ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3 3-12-membered units Ring, spirocyclic or bridged heterocycloalkyl", C ₁ -C ₁₂ alkyl-S-, C ₁ -C ₁₂ alkyl-SO-, C ₁ -C ₁₂ alkyl-SO ₂ -, -NRz ₁ Rz ₂ and

Or the above-mentioned two Rm ₁ , two Rm ₂ , two Rm ₃ , two Rm ₄ or two Rm ₅ can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through carbon chains or heteroatoms;

Rx is selected from C ₁ -C ₁₂ alkyl and C ₁ -C ₁₂ alkoxy;

Ry ₁ is independently hydroxyl;

Ry ₂ is independently selected from C ₁ -C ₁₂ alkyl and hydroxy-substituted C ₁ -C ₁₂ alkyl;

Ry ₃ is independently selected from C ₁ -C ₁₂ alkyl and C ₁ -C ₁₂ haloalkyl;

W, Z, Y are independently selected from O, S, CR ₄ and N; wherein R ₄ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amido, sulfonamido, C ₁ -C ₁₂ Alkyl, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ alkyl-S-, C ₁ -C ₁₂ alkyl -SO-, C ₁ -C ₁₂ alkyl -SO ₂ -, C ₁ -C ₁₂ Alkyl-O-, C ₁ -C ₁₂ haloalkyl-O-, -NRz ₁ Rz ₂ , 3-12-membered cycloalkylamino, 3-12-membered heterocycloalkylamino, 3-12-membered monocyclic, spiro Ring or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged rings with 1-3 heteroatoms "Heterocycloalkyl", 3-12-membered halogenated cycloalkyl or halogenated heterocycloalkyl, 3-12-membered cycloalkyl-O-, 3-12-membered halogenated cycloalkyl-O-, 3- 12-membered heterocycloalkyl-O-, 5-12-membered monocyclic or cycloaryl and 5-12-membered monocyclic or cycloheteroaryl;

Or -Y=Z- can form =CH-, =N-, -O-, -S- or -NR ₅ ; R ₅ is selected from hydrogen, C ₁ -C ₁₂ alkyl, 3-12 membered monocyclic, spiro Ring or bridged cycloalkyl and "hetero atoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spiro or bridged rings with 1-3 heteroatoms. Heterocycloalkyl";

The above-mentioned aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) does not include the following compounds:

In certain preferred embodiments of the present invention, the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof , certain groups in diastereomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs are defined below, and unmentioned groups are the same as any of the embodiments of the present invention Said (referred to as "in a certain aspect of the present invention"),

Ar is independently selected from a 5-12-membered monocyclic or bicyclic aromatic ring or heteroaromatic ring, which may be substituted by 1-3 different substituents Rn, and the Rn Selected from hydrogen, deuterium, halogen, cyano, amide, sulfonamide, hydroxyl, amino, ureido, phosphoryl, alkylphosphooxy, alkylsilyl, _C1 - _C10 alkyl, _C1 - _C10 Alkoxy, haloalkyl, haloalkoxy, C ₁ -C ₁₀ monoalkylamino, C ₁ -C ₁₀ dialkylamino, alkenyl, alkynyl, 3-10 membered cycloalkyl or heterocycloalkyl, C ₁ -C ₁₀ alkyl-S-, C ₁ -C ₁₀ alkyl-SO-, C ₁ -C ₁₀ alkyl-SO ₂ -, 3-10 membered cycloalkyl ether or heterocycloalkyl ether, 5 -10-membered aryl or heteroaryl, etc.; or any two of the above Rn can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through carbon chains or heteroatoms;

R ₁ is independently selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ haloalkoxy, C ₁ -C ₁₀ monoalkylamino , C ₁ -C ₁₀ dialkylamino, C ₁ -C ₁₀ haloalkylamino, 3-10 membered cycloalkyl or heterocycloalkyl, C ₁ -C ₁₀ alkyl-S-, C ₁ -C ₁₀ Alkyl-SO-, C ₁ -C ₁₀ alkyl-SO ₂ -, 3-10 membered cycloalkyl ether or heterocycloalkyl ether, 5-10 membered aryl or heteroaryl;

R ₂ is independently selected from halogen, cyano, amide, sulfonamide, phosphoryl, alkylphosphooxy, alkylsilyl, haloalkyl, haloalkoxy;

R _3a is selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ monoalkylaminoalkyl, C ₁ -C ₁₀ dioxane alkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 membered cycloalkyl or heterocycloalkyl; R _3b is independently selected from C ₁ -C ₁₀ alkyl, C ₁ - C ₁₀ alkoxy, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₀ monoalkylaminoalkyl, C ₁ -C ₁₀ dialkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylamino Alkyl, 3-12-membered cycloalkyl or heterocycloalkyl; the above R _3a and R _3b can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through carbon chains or heteroatoms; the alkane (monoalkyl, dialkyl, haloalkyl), cycloalkyl or heterocycloalkyl may be substituted by 1-2 different substituents Rm selected from hydrogen, deuterium, halogen, cyano , amide, sulfonamide, hydroxyl, amino, urea, phosphoryl, alkyl phosphoroxy, alkylsilyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, haloalkyl, haloalkoxy , C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C ₁ -C ₆ alkyl-S- , C ₁ -C ₆ alkyl-SO-, C ₁ -C ₆ alkyl-SO ₂ -, etc; the ring system;

W, Z, Y are independently selected from CR ₄ or N; wherein R ₄ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, amido, sulfonamido, C ₁ -C ₁₂ alkyl , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-S-, C ₁ -C ₆ alkyl -SO-, C ₁ -C ₆ alkyl -SO ₂ -, C ₁ -C ₆ alkyl -O-, C ₁ -C ₆ haloalkyl-O-, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, 3-12 membered cycloalkylamino or heterocycloalkylamino, 3-12-membered cycloalkyl or heterocycloalkyl, 3-12-membered halocycloalkyl or haloheterocycloalkyl, 3-12-membered cycloalkyl-O-, 3-12-membered halocycloalkyl -O-, 3-12-membered heterocycloalkyl-O-, 5-12-membered aryl or 5-12-membered heteroaryl;

Or -Z=Y- can be independently selected from -O- or -S- or -NR ₅ ; R ₅ is selected from hydrogen, C ₁ -C ₁₂ alkyl, 3-12-membered cycloalkyl, 3-12-membered heteroalkyl cycloalkyl;

One or more hydrogen atoms on any of the above-mentioned groups can be substituted by a substituent selected from the following group: including but not limited to deuterium, halogen, C ₁ -C ₈ alkyl; wherein, the heteroaryl group includes 1-3 heteroatoms selected from the group consisting of N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, the The ring system includes spiro rings, bridged rings, fused rings, and rings and other saturated or partially unsaturated ring systems.

In a certain scheme of the present invention, the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is a compound represented by any of the following general formulas:

wherein the ranges of R ₁ , R ₂ , R _3a , R _3b , R ₄ , R ₅ , Ar are as defined above.

Wherein: M ₆ is selected from C or N; M ₁ , M ₂ , M ₃ , M ₄ , M ₅ are independently selected from CR ₆ or N; R ₆ is preferably selected from hydrogen, deuterium, halogen, cyano, C ₁ - C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; other groups such as any of the rest.

In a certain embodiment of the present invention, said Rn is independently selected from halogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy and 3- to 10-membered monocyclic cycloalkyl groups.

In a certain embodiment of the present invention, R ₁ is selected from halogen, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy and 3-10 membered monocyclic cycloalkyl.

In a certain embodiment of the present invention, R ₂ is cyano.

In a certain embodiment of the present invention, R _3a is selected from hydrogen and C ₁ -C ₁₂ alkyl;

R _3b is selected from C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkyl substituted by one or more Rm ₁ , C ₁ -C ₁₂ dialkylaminoalkyl, 3-12 membered monocyclic ring, spirocyclic ring or bridged cycloalkyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm ₂ , "heteroatom selected from one of N, O, P and S or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm ₃ are selected from N, O, One or more of P and S, a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";

Alternatively, the above-mentioned R _3a and R _3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm ₄ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12 membered monocyclic, spirocyclic or bridged heterocycloalkyl".

In a certain aspect of the present invention, the Rm ₁ , Rm ₂ , Rm ₃ and Rm ₄ are independently selected from oxo (=O), halogen, cyano, hydroxyl, C ₁ -C ₁₂ alkyl, a or more Ry ₁ -substituted C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, 3-8 membered monocyclic, spiro or bridged cycloalkyl, One or more Ry ₂ -substituted 3-8-membered monocyclic, spirocyclic or bridged cycloalkyl, "heteroatoms are selected from one or more of N, O, P and S, and the number of heteroatoms is 1 -3 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms substituted by one or more _Ry3 " selected from one or more of N, O, P and S Species, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms", -NRz ₁ Rz ₂ and

In one embodiment of the present invention, Rz ₁ and Rz ₂ are independently selected from C ₁ -C ₁₂ alkyl groups.

In one embodiment of the present invention, Y is CH or N.

In one embodiment of the present invention, Z is CH.

In a certain aspect of the present invention, W is CH or N.

In a certain scheme of the present invention, Ar is selected from 5-12-membered monocyclic or non-cyclic aryl, monocyclic or non-cyclic aryl substituted by 13 Rn, "heteroatom is selected from N, O, P and S One or more of 5-12-membered monocyclic or heterocyclic heteroaryl groups with 1-3 heteroatoms” and “heteroatoms substituted by 1-3 Rn are selected from N, O, P and S One or more of the 5-12-membered monocyclic or heterocyclic heteroaryl groups with 1-3 heteroatoms";

Said Rn is independently selected from halogen, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy and 3-10 membered monocyclic ring cycloalkyl;

for

R ₁ is selected from halogen, C ₁ -C ₁₂ haloalkyl, C ₁ -C ₁₂ haloalkoxy and 3-10-membered monocyclic cycloalkyl;

R ₂ is cyano;

R _3a is selected from hydrogen and C ₁ -C ₁₂ alkyl;

Alternatively, the above-mentioned R _3a and R _3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm ₄ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl";

Said Rm ₁ , Rm ₂ , Rm ₃ and Rm ₄ are independently selected from oxo (=O), halogen, cyano, hydroxyl, C ₁ -C ₁₂ alkyl, C substituted by one or more Ry ₁ ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, C ₁ -C ₁₂ haloalkyl, 3-8 membered monocyclic, spiro or bridged cycloalkyl, substituted by one or more Ry ₂ 3-8 membered monocyclic, spirocyclic or bridged cycloalkyl, "heteroatom selected from one or more of N, O, P and S, 3-12 membered with 1-3 heteroatoms Monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms substituted by one or more Ry ₃ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1- 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", -NRz ₁ Rz ₂ and

Rx is C ₁ -C ₁₂ alkyl or C ₁ -C ₁₂ alkoxy;

Ry ₁ is independently hydroxyl;

Ry ₂ is independently C ₁ -C ₁₂ alkyl or hydroxy-substituted C ₁ -C ₁₂ alkyl;

Ry ₃ is independently C ₁ -C ₁₂ alkyl or C ₁ -C ₁₂ haloalkyl;

Rz ₁ and Rz ₂ are independently selected from C ₁ -C ₁₂ alkyl.

In a certain aspect of the present invention,

for

In a certain embodiment of the present invention, R ₁ is selected from Cl, CF ₃ , OCF ₃ and cyclopropyl.

In a certain scheme of the present invention, Ar is selected from phenyl,

In a certain aspect of the present invention,

selected from

In a certain embodiment of the present invention, in Ar, Rn, R ₁ and R ₄ , the aryl group is independently a 6-10-membered monocyclic or bicyclic aryl group, such as phenyl or naphthyl.

In a certain scheme of the present invention, in Ar, Rn, R ₁ , R _3a , R _3b and R ₄ , the heteroaryl group is independently "the heteroatom is selected from one or more of N, O and S. , a 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms".

In a certain aspect of the present invention, in Ar, the "heteroatom is selected from one or more of N, O, P and S, and a 5-12-membered monocyclic ring with 1-3 heteroatoms or a Cyclic heteroaryl" and "heteroatoms substituted by 1-3 Rn" are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 5-12-membered monocyclic or "Heteroatoms are selected from one or more of N, O, P and S, and a 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms" in "heteroaryl group" independently pyridyl (e.g.

) or imidazo[1,2-a]pyridine (e.g.

).

_In a certain embodiment of the present invention, in Rn, R1, R2, _Rm1 , _Rm2 , _Rm3 , _Rm4 , _Rm5 and _R4 , the halogen is independently F, _Cl , Br or I, such as F or Cl.

In a certain aspect of the present invention, Rn, Rz ₁ , Rz ₂ , R ₁ , R _3a , R _3b , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ , Rm ₅ , Rx, Ry ₂ , Ry ₃ , R ₄ In and R ₅ , the alkyl group is independently a C ₁ -C ₁₀ alkyl group, for example, the alkyl group is independently a C ₁ -C ₆ alkyl group, such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl or tert-butyl.

In a certain embodiment of the present invention, in Rn, R ₁ , R _3a , R _3b , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ , Rm ₅ and Rx, the alkoxy group is independently C ₁ -C ₁₀ alkoxy, for example, the alkoxy is independently a C ₁ -C ₆ alkoxy, another example is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, eg methoxy.

In a certain embodiment of the present invention, in Rn, R ₁ , R ₂ , R _3a , R _3b , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ , Rm ₅ , Ry ₃ and R ₄ , the haloalkyl groups are independently is a C ₁ -C ₁₀ haloalkyl, eg, the haloalkyl is independently a C ₁ -C ₆ haloalkyl, another example is CF ₃ or CH ₂ CF ₃ .

In a certain embodiment of the present invention, in Rn, R ₁ , R ₂ , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ and Rm ₅ , the haloalkoxy is independently a C ₁ -C ₁₀ haloalkoxy, For example the haloalkoxy is independently a _C1 _- _C6 haloalkoxy, another example is OCF3.

In a certain embodiment of the present invention, in Rn, R ₁ , R _3a , R _3b , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ , Rm ₅ , R ₄ and R ₅ , the cycloalkyl group is 3-10 A membered cycloalkyl group, for example, the cycloalkyl group is a 3-6 membered monocyclic, spirocyclic or bridged cycloalkyl group, and another example is a 3-6 membered monocyclic cycloalkyl group, and also such as cyclopropyl or cyclobutyl base.

In a certain embodiment of the present invention, in Rn, R ₁ , R _3a , R _3b , Rm ₁ , Rm ₂ , Rm ₃ , Rm ₄ , Rm ₅ , R ₄ and R ₅ , the heterocycloalkyl group is "heterocycloalkyl" Atoms are selected from one or more of N, O and S, 3-10-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms", for example "heteroatoms are selected from One or more of N and O, a 4-10-membered monocyclic or spirocyclic heterocycloalkyl group with 1-2 heteroatoms, also for example azetidinyl (for example

), oxetanyl (e.g.

), pyrrolidinyl (e.g.

), piperidinyl (such as

)or

In a certain scheme of the present invention, in R _3a and R _3b , when R _3b is "one or more heteroatoms selected from N, O, P and S, the number of heteroatoms is 1-3 3- 12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. -12-membered monocyclic, spirocyclic or bridged heterocycloalkyl" is

When R _3b is substituted by one or more Rm ₃ "heteroatoms are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro ring or bridged ring heterocycloalkyl", the "heteroatoms substituted by one or more Rm ₃ are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl" is

When R _3a and R _3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic rings with 1-3 heteroatoms or bridged ring heterocycloalkyl", the "heteroatom is selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro cyclic or bridged heterocycloalkyl" is

When R _3a and R _3b together with the atoms to which they are attached, form a "heteroatom selected from one or more of N, O, P and S, which is substituted by one or more Rm ₄ , and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", the "heteroatom substituted by one or more Rm ₄ is selected from one or more of N, O, P and S , a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" is

In a certain scheme of the present invention, in Rm ₁ , Rm ₂ , Rm ₃ and Rm ₄ , the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl" is

The "heteroatom substituted by one or more Ry ₃ is selected from one or more of N, O, P and S, and the 3-12-membered monocyclic, spirocyclic or Bridged ring heterocycloalkyl" is

In a certain aspect of the present invention,

for

E.g

In a certain scheme of the present invention, Ar is selected from phenyl,

Rn is independently selected from halogen (eg Cl, F), C ₁ -C ₆ haloalkyl (eg CF ₃ ), C ₁ -C ₆ haloalkoxy (eg OCF ₃ ) and 3-6 membered cycloalkyl (eg cyclo propyl).

In a certain scheme of the present invention, R ₁ is Cl or CF ₃ ;

R _3a is hydrogen;

R _3b is independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted with 1-3 Rm ₁ , C ₁ -C ₆ dialkylaminoalkyl, 3-6 membered monocyclic Cycloalkyl, 3-6-membered monocyclic cycloalkyl substituted by 1-3 Rm ₂ , "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2 The 3-6-membered monocyclic or spirocyclic heterocycloalkyl" and the "heteroatoms substituted by 1-3 Rm ₃ are selected from one or more of N, O and S, and the number of heteroatoms is 1- 2 3-6 membered monocyclic or spirocyclic heterocycloalkyl";

Alternatively, the above R _3a and R _3b together with the atoms to which they are attached form "the heteroatom is selected from N, a 3-5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms" or is surrounded by 1-3 Rm ₄ Substituted "heteroatoms are selected from N, 3-5-membered monocyclic heterocycloalkyl with 1-2 heteroatoms", wherein, when the above R _3a and R _3b together with the atoms to which they are attached, form "hetero atoms selected from From N, a 5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms "or a 5-membered heteroatom substituted with 1-3 Rm ₄ " from N, with 1-2 heteroatoms "monocyclic heterocycloalkyl", Ar is phenyl or

In a certain scheme of the present invention, the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is selected from any of the following compounds:

The present invention also provides a method for preparing an aromatic ring or an aryl heterocyclic pyridone compound shown in formula (I), which mainly includes the following preparation methods one and two:

The first method for preparing an aromatic ring or an aryl heterocyclic pyridone compound shown in formula (I) is mainly characterized in that the method mainly comprises the following steps a-d:

A, with general formula (A) compound and R The acetyl arylamine (B) that replaces generates general formula (C) compound by base-catalyzed substitution reaction, wherein R is formyl halide or formate group;

b. The compound of general formula (C) is generated by dehydration and ring closure reaction under alkali catalysis to generate the compound of general formula (D);

c. React the compound of general formula (D) with a halogenating reagent, or phosphoryl halide or acid anhydride, or sulfonic acid halide or acid anhydride, etc., to generate a compound of general formula (E), wherein LG is a leaving group such as halogen, sulfonate, etc. group;

d. Substituting the general formula (E) with R _3a R _3b NH under base catalysis generates an aromatic ring or an aryl heterocyclic pyridone compound represented by the formula (I).

The second method for preparing the aromatic ring or aryl heterocyclic pyridone compound shown in formula (I) is mainly characterized in that the method mainly comprises the following steps e-f:

e. The compound of general formula (F) is generated by dehydration and ring closure reaction under alkali catalysis to generate the compound of general formula (G); Rc is an ester group or a cyano group;

f. When the compound G of the general formula is a hydroxy compound, adopt the same method as steps c and d of the above method 1 to prepare the aromatic ring or aryl heterocyclic pyridone compound shown in formula (I); when the general formula When the compound of formula G is an amino compound, the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) can be obtained by various methods of amino functional group transformation.

Preferably, the step is performed in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, diethyl ether Methyl sulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or its composition.

Preferably, the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium bicarbonate, or a combination thereof; the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.

Preferably, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, formic acid, acetic acid, trifluoromethanesulfonic acid or combinations thereof;

Preferably, the halogenating agent is selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride or a combination thereof.

The present invention also provides a pharmaceutical composition comprising:

(1) An aromatic ring or aryl heterocyclic pyridone compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof Isomers, torsion isomers, solvates, polymorphs or prodrugs; and

(2) A pharmaceutically acceptable carrier.

In a certain aspect of the present invention, the pharmaceutical composition comprises:

(i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof ;and

(ii) A pharmaceutically acceptable carrier.

The present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof. A drug (or pharmaceutical composition) of a isomer, solvate, polymorph, or prodrug.

The present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof. Conforms, solvates, polymorphs or prodrugs for the treatment of diseases (or pharmaceutical compositions) associated with MAT2a or MTAP protein activity or expression.

The disease related to the activity or expression of MAT2a or MTAP protein is especially a preventive or therapeutic drug for tumor or autoimmune disease.

The present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof The application of the body, solvate, polymorph or prodrug, or said pharmaceutical composition in the preparation of MAT2a enzyme inhibitor.

The present invention also provides a compound of formula I represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof Use of a form, solvate, polymorph or prodrug, or a pharmaceutical composition as previously described, for the manufacture of a medicament. The medicament can be a medicament for the treatment and/or prevention of diseases related to the activity or expression of MAT2a or MTAP protein; especially a medicament for the prevention or treatment of tumors or autoimmune diseases.

The present invention also provides the aryl ring or aryl heterocyclic pyridone compound represented by the formula (I) according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, A diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug, or a pharmaceutical composition as described in any preceding item in the manufacture of a therapeutic and/or prophylactic treatment with MAT2a or Use in medicines for diseases related to MTAP protein activity or expression; especially medicines for the treatment and/or prevention of tumors or autoimmune diseases.

The present invention also provides a method for treating and/or preventing a disease associated with MAT2a or MTAP protein activity or expression, comprising: administering to an individual in need thereof a therapeutically effective amount of said formula (I) A compound of formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or said drug combination. The disease related to the activity or expression of MAT2a or MTAP protein is especially a preventive or therapeutic drug for tumor or autoimmune disease.

The present invention also provides a method of treating and/or preventing a disease associated with MAT2a or MTAP protein activity or expression, comprising: administering to an individual in need thereof a therapeutically effective amount of a compound of formula (I) as described in any preceding item ) represented by the aromatic ring or aryl heterocyclic pyridone compound, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, torsion isomer body, solvate, polymorph or prodrug, or a pharmaceutical composition as described in any of the preceding items; in particular for the treatment and/or prevention of neoplastic or autoimmune diseases.

The tumor is independently selected from the group consisting of lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal cancer, glioma, bladder cancer carcinoma, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma, etc.; the autoimmune disease is independently selected from Thyroiditis, inflammatory bowel disease, erythematosus, fibrosis, muscle weakness, vasculitis, psoriasis, arthritis, scleroderma, dermatitis, etc.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progressive effect of the present invention is:

The present invention relates to a compound with structural features of general formula (I), which can inhibit the enzymatic activity of MAT2a, significantly inhibit the growth of various tumor cells, especially the tumor cells related to MTAP deletion, and is a therapeutic drug with a new mechanism of action.

Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise stated, conventional methods within the skill in the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are presented, the terms employed herein in the related descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and treatment of patients. For example, the reaction and purification can be carried out using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The techniques and methods described above can generally be carried out according to conventional methods well known in the art from the descriptions in the various general and more specific documents cited and discussed in this specification. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable moieties and compounds.

Unless otherwise specified, the terms used in the present invention have the following meanings:

Those skilled in the art can understand that, according to the conventions used in the art, the present invention describes the groups used in the structural formulae

It means that the corresponding group is connected with other fragments and groups in the compound through this site.

The term "pharmaceutically acceptable" means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for patient use. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. A salt. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine. When compounds of the present invention contain relatively basic functional groups, acid additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent. A salt. The pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like. Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid), amino acids (eg, glutamic acid, arginine), and the like. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.

The term "tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.

Conventional techniques for preparing/separating individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives using, for example, chiral high performance liquid chromatography) ), see for example Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu.Rev.Anal.Chem.3 : 341-63, 2010; Fumiss et al.(eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem .Res.1990, 23, 128.

The term "polymorph" refers to the different solid crystalline phases of certain compounds of the invention in the solid state due to the presence of two or more different molecular arrangements. Certain compounds of the present invention may exist in more than one crystalline form, and the present invention is intended to include each crystalline form and mixtures thereof.

Typically, crystallization results in solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate comprising one or more molecules of a compound of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate is a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. The compounds of the present invention may form true solvates, but in some cases, only indefinite water or mixtures of water plus some indefinite solvent may remain. The compounds of the present invention may be reacted in a solvent or precipitated or crystallized from a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The present invention also includes prodrugs of the above compounds. In the present invention, the term "prodrug" refers to a compound that can be converted to the biologically active compound of the present invention under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of a compound of the present invention. A prodrug may be inactive when administered to an individual in need thereof, but be converted in vivo to an active compound of the present invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compounds of the invention, eg, by hydrolysis in blood. Prodrug compounds generally provide the advantages of solubility, histocompatibility or sustained release in mammalian organisms. Prodrugs include known amino and carboxyl protecting groups. For specific preparation methods of prodrugs, refer to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R. B., et al., J. Med. Chem. 2000, 43, 475.

The term "plurality" means 2, 3, 4 or 5, preferably 2 or 3.

When any variable (such as Rn) appears multiple times in the definition of a compound, the definition that appears at each position of the variable has nothing to do with the definitions that appear at other positions, and their meanings are independent of each other and do not affect each other. Therefore, if a group is substituted with 1, 2 or 3 Rn groups, that is, the group may be substituted with up to 3 Rn groups, the definition of Rn at this position is independent of the definition of Rn at the remaining positions of. Additionally, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and It resembles an alkyl group.

The term "alkoxy" refers to the group -OR ^M , wherein R ^M is an alkyl group as defined above.

The term "alkenyl" refers to a straight-chain or branched alkene of the specified number of carbon atoms containing one or more carbon-carbon double bonds and no carbon-carbon triple bonds, which one or more carbon-carbon double bonds may be internal Also terminal, examples of olefins include vinyl, allyl, methylvinyl, propenyl, butenyl, pentenyl, 1,1-dimethyl-2propenyl, hexenyl, and the like.

The term "alkynyl" refers to a straight or branched chain hydrocarbon group having one or more triple bonds of the specified number of carbon atoms (eg, C2 _- _C8 alkynyl, eg, C2 _- _C4 alkynyl). The one or more carbon-carbon triple bonds may be internal or terminal, such as propynyl where the triple bond is internal

or propynyl with triple bond at the end

Wait.

The term "cycloalkyl" refers to a monocyclic, spirocyclic or bridged saturated cyclic alkyl group, preferably a monocyclic, spirocyclic or bridged monocyclic, spirocyclic or bridged group having 3-12 ring carbon atoms, more preferably 3-6 carbon atoms Saturated cyclic alkyl of the ring, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocycloalkyl" refers to a monocyclic, spirocyclic or bridged saturated cyclic group having a heteroatom, preferably containing 1, 2 or 3 cyclic heterocyclic groups independently selected from N, O and S. A 3- to 10-membered saturated monocyclic, spirocyclic or bridged ring of atoms. Examples of heterocycloalkyl are:

tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomo olinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, and the like. Preferred heterocyclyl groups are

Morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, thiomorpholin-4-yl and 1,1-dioxo-thiomorpholin-4-yl.

The term "aryl" refers to a _C6 - _C10 aryl group, such as phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic or 9-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, When bicyclic, at least one ring is aromatic, such as furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrole base, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benziisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoquinolyl,

Wait.

The term "pharmaceutical composition" refers to the formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of a compound of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing an adverse biological response or Interacts in an undesired manner with any components contained in the composition.

In the present invention, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory authority as acceptable for human or livestock use , diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.

The "tumor", "diseases related to abnormal cell proliferation" and the like in the present invention include but are not limited to leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.

As used herein, the terms "prophylactic", "preventing" and "preventing" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.

As used herein, the term "treatment" and other similar synonyms include the following meanings:

(i) preventing the emergence of a disease or disorder in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease or disorder;

(ii) inhibiting the disease or disorder, i.e. arresting its development;

(iii) alleviating the disease or disorder, i.e. causing the state of the disease or disorder to resolve; or

(iv) alleviating symptoms caused by the disease or disorder.

As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to at least one agent or compound sufficient to alleviate, to some extent, one or more symptoms of the disease or disorder being treated upon administration. amount. The result can be a reduction and/or amelioration of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition. An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.

The terms "administering," "administering," "administering," and the like, as used herein, refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

It will also be understood by those skilled in the art that in the methods described below, intermediate compound functional groups may need to be protected by suitable protecting groups. Such functional groups include hydroxyl, amino, mercapto, and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable thiol protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.

detailed description

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

Example 1: 2-oxo-1-phenyl-4-(4-pyrrolin-1-yl)-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine- 3-Methyl cyanide

The first step: under nitrogen protection, sodium hydride (NaH) (890 mg, 22.22 mmol) was added to 2-cyanoacetanilide (0.89 g, 5.56 mmol) in tetrahydrofuran (THF) (30 mL), and after stirring at room temperature for 10 minutes, Then a solution of 2-chloro-6-trifluoromethylnicotinyl chloride (1.63 g, 6.67 mmol) in tetrahydrofuran (5 mL) was added slowly. The temperature of the reaction mixture was raised to 70 degrees, and the reaction was continued for 4 hours. After LC-MS detected the completion of the reaction, the reaction solution was diluted with ethyl acetate (EA) (200 mL), and the organic phase was washed with sodium chloride (NaCl) solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio 9/1) to obtain the intermediate product (950 mg, pale yellow solid) . LC-MS (ESI) m/z: 353.9 [M+Na] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.47 (dd, J=7.8, 0.7 Hz, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.41 -7.38(m, 1H), 7.20-7.18(m, 2H).

The second step: N,N-diisopropylethylamine (DIPEA) (0.74 g, 5.738 mmol) was added to a solution of phosphorus oxychloride (POCl ₃ ) (15 mL) of the intermediate product of the previous step at room temperature. Under nitrogen protection, the reaction mixture was reacted at 100 degrees for 16 hours. LC-MS detected that the reaction of the starting materials was complete. Decompression-rotary evaporation-removal of excess phosphorus oxychloride, the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate volume ratio 4/1) to obtain the intermediate product (700mg, light yellow solid) . LC-MS (ESI) m/z: 349.9 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ8.80 (d, J=7.9Hz, 1H), 7.95 (d, J=8.2Hz, 1H), 7.64-7.54 (m, 2H), 7.54-7.46 (m, 1H), 7.34 (dt, J=8.7, 2.6 Hz, 2H).

The third step: at room temperature, tetrahydropyrrole (356mg, 5.01mmol) was added to the previous step intermediate (350mg, 1.0mmol) and N,N-diisopropylethylamine (389mg, 3.01mmol) in tetrahydrofuran (10mL) , the reaction mixture was reacted at room temperature for 2 hours under nitrogen protection. LC-MS detection of raw materials basically disappeared. The excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was prepared by HPLC to give Example 1 (224.7 mg, white solid). LC-MS (ESI) m/z: 385.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.78 (d, J=8.3 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.55-7.47 (m, 2H), 7.44 (dt, J=9.6, 4.3Hz, 1H), 7.24 (dd, J=5.2, 3.2Hz, 2H), 4.05 (t, J=6.4Hz, 4H), 1.99 (t, J=6.4Hz, 4H).

Example 2: 2-oxo-1-phenyl-4-(4-pyrrolin-1-yl)-7-(trifluoromethyl)-1,2-dihydro-1,8-quinoline- 3-Methyl cyanide

The first step: under nitrogen protection, tris(dibenzylideneacetone)dipalladium (Pd2(dba) ₃ ₎ (3.26g, 3.559mmol), 4,5-bis(diphenylphosphine)-9,9 - Dimethyl xanthene (Xantphos) (2.06g, 3.56mmol) was added to methyl 2-amino-4-trifluoromethylbenzoate (7.8g, 35.59mmol), iodobenzene (7.26g, 35.59 mmol) and cesium carbonate (34.79 g, 106.77 mmol) in 1,4-dioxane (150 mL). The reaction mixture was heated to 100°C and reacted at this temperature for 16 hours. The reaction solution was diluted with ethyl acetate (500 mL), filtered through celite, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio 20:1) to obtain the intermediate product (8.6 g, pale yellow solid) ). LC-MS (ESI) m/z: 296.0 [M+H] ⁺ . ¹ H-NMR (400MHz, CDCl ₃ ) δ 9.59(s, 1H), 8.06(d, J=8.3Hz, 1H), 7.45-7.35(m, 3H), 7.21-7.24(m, 2H), 7.17 -7.18(m, 1H), 6.92(dd, J=8.3, 1.3Hz, 1H), 3.94(s, 3H).

Step 2: Under nitrogen protection, sodium hydride (610 mg, 15.24 mmol) was added to the above intermediate (1.5 g, 5.079 mmol) in N,N-dimethylformamide DMF (30 mL). After half an hour of reaction, cyanoacetyl chloride (5.26 g, 50.8 mmol) was added slowly, and the reaction was stirred at room temperature overnight. The reaction was basically complete by LC-MS. Ethyl acetate (200 mL) was added to dilute the reaction solution, and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol volume ratio 9/1) to obtain the intermediate product (670 mg, light red solid). LC-MS (ESI) m/z: 330.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J=8.0 Hz, 1H), 7.57-7.58 (m, 2H), 7.50-7.52 (m, 1H), 7.34 (dd, J=8.1 , 1.1Hz, 1H), 7.27(m, 2H), 6.51(s, 1H).

The third step: N,N-diisopropylethylamine (1.02 g, 7.878 mmol) was added to a solution of the above intermediate (650 mg, 1.970 mmol) in phosphorus oxychloride (15 mL) at room temperature. Under nitrogen protection, the reaction mixture was reacted at 100 degrees for 2 hours. LC-MS detection of raw materials basically disappeared. After the excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate volume ratio 4/1) to obtain the intermediate product (310 mg, pale yellow solid). LC-MS (ESI) m/z: 348.9 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ ) δ 8.37 (d, J=8.5Hz, 1H), 7.81 (dd, J=8.5, 1.3Hz, 1H), 7.74-7.61 (m, 3H), 7.49 -7.41(m, 2H), 6.76(s, 1H).

The fourth step: at room temperature, tetrahydropyrrole (311mg, 4.382mmol) was added to the above intermediate (305mg, 0.876mmol) and N,N-diisopropylethylamine (340mg, 2.628mmol) in tetrahydrofuran (5mL) , the reaction mixture was reacted at room temperature for 2 hours. LC-MS detected that the reaction was basically complete. After the excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was prepared by HPLC to give Example 2 (114.21 mg, white solid). LC-MS (ESI) m/z: 384.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.1, 6.7 Hz, 2H), 7.60-7.54 (m, 1H), 7.50 ( dd, J=8.6, 1.4Hz, 1H), 7.39-7.31(m, 2H), 6.62(s, 1H), 4.04(t, J=6.4Hz, 4H), 1.98(t, J=6.4Hz, 4H) ).

Example 3: 7-Chloro-2-oxo-1-phenyl-4-(4-pyrrolin-1-yl)-1,2-dihydroquinoline-3-methylcyanide

The first step: under argon, methyl 2-amino-4 chlorobenzoate (5g, 26.9mmol), iodobenzene (6.5g, 31.9mmol), 4,5-bis(diphenylphosphine)- To a solution of 9,9-dimethylxanthene (Xantphos) (1.56 g, 2.7 mmol) and cesium carbonate (17.5 g, 53.8 mmol) in 1,4-dioxane (100 mL) was added Pd ₂ (dba) ₃ (1.23 g, 2.7 mmol). The reaction mixture was reacted at 100°C for 16 hours. After the reaction was detected by LC-MS, the mixture solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio 50:1 to 20:1) to give the intermediate product (5.2 g, pale yellow solid). LC-MS: (ESI) m/z=262.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.53 (s, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.37 (m, 2H), 7.24 (t, J=5.4 Hz, 2H), 7.18 -7.11 (m, 2H), 6.67 (dd, J=8.6, 2.0Hz, 1H), 3.88 (d, J=10.5Hz, 3H).

The second step: under ice-water cooling, 2-cyanoacetyl chloride (400 mg, 3.88 mmol) was added dropwise to a mixture of the above intermediate (1 g, 3.8 mmol) and triethylamine (TEA) (405 mg, 4.0 mmol). water in dichloromethane (5 mL), then react at room temperature overnight. After completion of the reaction detected by LC-MS, water (20 mL) was added. The reaction mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio 3:1 to 1:1) to give the intermediate compound (300 mg, pale yellow solid). LC-MS: (ESI) m/z = 329.0 [M+H] ⁺ .

Third step: To a 100 mL solution of the above intermediate (250 mg, 0.8 mmol) and DMF (8 mL) was added potassium carbonate (526 mg, 3.8 mmol) at room temperature. The mixture was reacted at 80°C for 1 hour. After the LC-MS detection was completed, the pH of the solution was adjusted to 4 with (1N) aqueous hydrochloric acid solution, and a pale yellow solid was precipitated. After filtration and drying, the intermediate product (200 mg, pale yellow solid) was obtained. LC-MS: (ESI) m/z=297.0 [M+H] ⁺ .

Fourth step: To a solution of the above intermediate (200 mg, 0.67 mmol) in phosphorus oxychloride (8 mL) was added diisopropylethylamine (474 mg, 5.0 mmol) at room temperature. Under argon, the reaction mixture was reacted at 120°C for 2 hours. Excess phosphorus oxychloride was removed by concentration under reduced pressure to give the crude product (200 mg) as a brown oil. The crude product was directly used in the next reaction without purification. LC-MS: (ESI) m/z = 350.0 [M+H] ⁺ .

The fifth step: at room temperature, tetrahydropyrrole (98 mg, 1.36 mmol) was added to the dichloromethane (8 mL) solution containing the above intermediate (200 mg, 0.63 mmol) and diisopropylethylamine (178 mg, 1.36 mmol). 1.36 mmol). The mixture was reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, water (20 mL) was added to the reaction solution, followed by extraction with dichloromethane (20 mL) three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The crude product was purified by silica gel column chromatography (dichloromethane:methanol volume ratio 40:1 to 20:1) to give the compound of Example 3 (125.9 mg, light white solid). LC-MS: (ESI) m/z = 350.0 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ8.14(d, J=8.9Hz, 1H), 7.65-7.59(m, 2H), 7.59-7.52(m, 1H), 7.34-7.28(m, 2H), 7.24(dd, J＝8.9, 2.2Hz, 1H), 6.36(d, J＝2.2Hz, 1H), 4.02(t, J＝6.4Hz, 4H), 1.97(t, J＝6.4Hz, 4H).

Using different anilines and aliphatic amines as raw materials, the method was synthesized with reference to Examples 1-3 to obtain Examples 4-35;

Preparation of Examples 36-38

The first step: at room temperature, add 4-chloro-2-oxo-1-phenyl-7 trifluoromethyl-1,2-dihydroquinoline-3-methylcyanide (246 mg, 1.43 mmol) To a solution of diisopropylethylamine (178 mg, 1.36 mmol) in tetrahydrofuran (10 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (300 mg, 0.86 mmol). The mixture was reacted at room temperature for 2 hours. After the reaction was detected by LC-MS, water (20 mL) was added to the reaction solution, followed by extraction with dichloromethane (20 mL) three times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. . The crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio from 40:1 to 20:1) to give the compound of Example 36 (125.9 mg, light white solid). LCMS (ESI) m/z: 485.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.60 (d, J=8.4 Hz, 1 H), 7.68-7.56 (m, 4H), 7.36 (d , J=7.6Hz, 2H), 6.63(s, 1H), 4.97(m, 1H), 4.27-4.25(m, 2H), 4.18-4.15(m, 2H), 1.42(s, 9H).

Second step: Trifluoroacetic acid (2 ml) was added to a solution of the above compound (200 mg, 0.286 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (100 mL), and the organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (eluent: dichloromethane/methanol in a volume ratio of 10:1) to obtain the compound of Example 37 (100 mg). LCMS (ESI) m/z: 384.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.65 (d, J=8.2 Hz, 1 H), 7.61 (m, 4H), 7.35 (d, J =7.2Hz, 2H), 6.62(s, 1H), 5.05(m, 1H), 3.86(m, 4H).

The third step: 1 drop of acetic acid was added to the methanol (10 mL) solution of the above compound (50 mg, 0.13 mmol) and aqueous formaldehyde solution (208 mg, 0.286 mmol) at room temperature. The reaction mixture was reacted at room temperature for 1 hour, sodium cyanoborohydride (53 mg, 0.832 mmol) was added to the reaction solution, the reaction at room temperature was continued for 1 hour, the solvent was spin-dried, ethyl acetate (100 mL) was dissolved, saturated sodium bicarbonate solution (100 mL) ), dried, filtered, the organic phase was spin-dried, and the crude product was prepared by HPLC to obtain the compound of Example 38 (12.8 mg). LCMS (ESI) m/z: 399.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.64 (d, J=8.5 Hz, 1H), 8.45 (d, J=5.7 Hz, 1H), 7.70-7.56(m, 4H), 7.36(d, J=7.1Hz, 2H), 6.63(s, 1H), 4.78(m, 1H), 3.64(m, 2H), 3.46-3.38(m, 2H) , 2.33(s, 3H).

Example 39: 4-((1-Isopropylazetidin-3-yl)amino)-2-oxo-1-phenyl-7-trifluoromethyl-1,2-dihydroquinoline Lino-3-methyl cyanide

At room temperature, a drop of acetic acid was added dropwise to a solution of the compound of Example 37 (50 mg, 0.13 mmol), acetone (23 mg, 0.39 mmol) in methanol (10 mL), and the reaction mixture was reacted at room temperature for 2 hours. Sodium cyanoborohydride (25 mg, 0.39 mmol) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. LCMS detected the disappearance of the starting material. The solvent was removed by concentration under reduced pressure, and after ethyl acetate (100 mL) was dissolved, water (100 mL) was added. It was extracted twice with ethyl acetate (100 mL), the combined organic phases were dried and concentrated under reduced pressure, and the obtained crude product was prepared and isolated by HPLC to obtain the compound of Example 39 (19.5 mg) as a white solid. LCMS (ESI) m/z: 427.0 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.64(d,J=8.0Hz,1H),8.41(s,1H),7.65-7.55(m,4H),7.36-7.34(d,J=8.0Hz,2H) ), 6.63(s, 1H), 4.71-4.68(m, 1H), 3.61-3.57(m, 2H), 3.32-3.30(m, 2H), 2.40-2.33(m, 1H), 0.9(d, J =6.8Hz, 6H).

Example 40: 4-((1-Acetylazetidin-3-yl)amino)-2-oxo-1-phenyl-7-trifluoromethyl-1,2-dihydroquinoline -3-Methyl cyanide

At room temperature, the compound of Example 37 (50 mg, 0.13 mmol), 1-ethyl-3(3-dimethylpropylamine) carbodiimide EDCI (50 mg, 0.26 mmol), 1-hydroxybenzotriazole HOBT ( To a solution of 26 mg, 0.195 mmol) in dichloromethane (10 mL) was added acetic acid (32 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction was complete by LCMS. The reaction solution was diluted with dichloromethane (100 mL), and the mixture solution was washed with saturated brine (100 mL). The separated organic phase was dried with anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was prepared and isolated by HPLC to obtain the compound of Example 40 (30.8 mg) as a white solid. LCMS (ESI) m/z: 426.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.60-8.57(m,2H),7.69-7.56(m,4H),7.37-7.35(d,J=8.0Hz,2H),6.64(s,1H),5.02 (m, 1H), 4.57-4.52 (m, 1H), 4.40-4.36 (m, 1H), 4.28-4.24 (m, 1H), 4.19-4.18 (m, 1H), 1.83 (s, 3H).

Taking different aliphatic amines as raw materials, with reference to the method synthesis of Examples 1-3, Examples 41-43 were obtained:

Example 44: 1-(4-Chlorobenzene)-2-oxo-4-((3-oxocyclobutyl)amino)-7-(trifluoromethyl)-1,2-dihydroquinoline -3-Methyl cyanide

The first step: at room temperature, oxalyl chloride (7.24g, 57.02mmol) was added to cyanoacetic acid (2.4g, 28.51mmol) in dichloromethane (30mL), and five drops of N,N-dimethylformamide were added, The reaction mixture was reacted at this temperature for 2 hours. In another reaction flask, sodium hydride (342.1 mg, 8.553 mmol) was added to the N,N- In dimethylformamide (30 mL), after the reaction for half an hour, the concentrated solution of cyanoacetyl chloride prepared above was added, and the reaction was carried out at room temperature overnight. The main reaction product was detected by LCMS, the reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with saturated aqueous sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio of 10:1) to obtain a light red solid intermediate compound (520 mg). LCMS (ESI) m/z: 364.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.17 (d, J=8.1 Hz, 1 H), 7.67-7.61 (m, 2H), 7.38-7.34 (m, 2H), 7.33 (d, J=2.0Hz, 1H), 6.54 (s, 1H).

The second step: at room temperature, N,N-diisopropylethylamine (99.39mg, 5.699mmol) was added to the phosphorus oxychloride (8mL) of the above-mentioned intermediate compound (520mg, 1.426mmol), and the reaction was carried out under nitrogen protection The mixture was reacted at 100°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate in a volume ratio of 4:1) to obtain a pale yellow solid intermediate compound (200 mg). LCMS(ESI) m/z: 382.9[M+H] ⁺ .

The third step: at room temperature, 3-aminocyclobutan-1-one (190mg, 1.570mmol) was added to the above-mentioned intermediate compound (120mg, 0.314mmol), N,N,-diisopropylethylamine (122mg, 0.942 mmol) in tetrahydrofuran (5 mL), the reaction mixture was reacted at 20°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated aqueous sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by HPLC to obtain the compound of Example 44 (90 mg) as a white solid. LCMS (ESI): m/z 431.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.58(d,J=8.7Hz,1H),8.53(d,J=6.2Hz,1H),7.79-7.62(m,3H),7.47-7.34(m,2H) ), 6.68(s, 1H), 5.13-4.99(m, 1H), 3.59(d, J=6.4Hz, 4H).

Examples 45a and 45b: 1-(4-Chlorobenzene)-4-((trans-3-fluorocyclobutyl)amino)-2-oxo-7-trifluoromethyl-1,2-dihydro Quinoline-3-methylcyanide and 1-(4-chlorobenzene)-4-((cis-3-fluorocyclobutyl)amino)-2-oxo-7-trifluoromethyl-1,2- Dihydroquinoline-3-methylcyanide

The first step: at room temperature, sodium borohydride (31 mg, 0.810 mmol) was added to the compound of Example 44 (70 mg, 0.16 mmol) in ethanol (5 mL), and the reaction mixture was reacted at 20 degrees for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess ethanol was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by HPLC to obtain the compound of Example 31 (55 mg) as a white solid. LCMS (ESI): m/z 433.9[M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ 8.63(m, 1H), 8.26(m, 1H), 7.68(m, 3H), 7.42(d , J=8.6Hz, 2H), 6.64(s, 1H), 5.23(m, 1H), 4.78(m, 1H), 4.41-4.27(m, 1H), 2.82-2.62(m, 2H), 2.39- 2.25(m, 2H).

The second step: at room temperature, diethylaminosulfur trifluoride (1 mL) was added to the above compound (35 mg, 0.081 mmol) in dichloromethane (5 mL), and the reaction mixture was reacted at 20 degrees for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The reaction was quenched with sodium bicarbonate, the reaction solution was diluted with dichloromethane (100 mL), the organic phase was washed with saturated sodium chloride solution, the separated organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound of Example 45 as a white solid (28 mg) . LCMS (ESI) m/z: 435.9/437.9 [M+H] ⁺ .

The crude product was purified by Prep-TLC (eluent: chloroform/methanol volume ratio of 10:1) to obtain white solids Example 45a (Rf=0.4, 2.39mg) and Example 45b (Rf=0.3, 3.12mg) .

Analysis conditions: analytical column (Waters SunFire C18, 4.6*50mm, 5um); gradient (5%-95% acetonitrile/0.1% formic acid/water, 3.0min, flow rate 2.0mL/min, 2.6min); column temperature: 40°C ; Detection wavelength: 254nM.

Compound 45a: LCMS (Rt=1.894 min) (ESI) m/z: 435.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.60(d,J=8.5Hz,1H),8.43-8.27(m,1H),7.69(t,J=7.8Hz,3H),7.42(d,J=8.6 Hz, 2H), 6.65(s, 1H), 5.00(m, 1H), 4.44-4.31(m, 1H), 3.05-2.89(m, 2H), 2.79-2.58(m, 2H).

Compound 45b: LCMS (Rt=1.872 min) (ESI) m/z: 435.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.57(d,J=8.6Hz,1H),8.31(s,1H),7.69(t,J=9.2Hz,3H),7.42(d,J=8.6Hz, 2H), 6.65(s, 1H), 5.54-5.22(m, 1H), 4.97(s, 1H), 2.90-2.65(m, 4H).

Taking different aliphatic amines as raw materials, with reference to the method synthesis of the above-mentioned embodiment, obtain embodiment 46-63:

Taking different aliphatic amines as raw materials, with reference to the method synthesis of the above-mentioned embodiment, obtain embodiment 64-71:

Using different aliphatic amines such as cyclobutaneamine and azetidine amine as raw materials, with reference to the methods of above-mentioned Examples 1-3, 38, etc., to obtain Examples 72-76;

Preparation of Examples 77a and 77b

The first step: at room temperature, oxalyl chloride (4.97g, 37.0mmol) was added to 2-chloro-6-trifluoromethylnicotinic acid (4.17g, 18.5mmol) in dichloromethane (150mL), and 3 drops of N were added. , N-dimethylformamide, the reaction mixture was reacted at this temperature for 2 hours. In another reaction flask, sodium hydride (3.7 g, 61.66 mmol) was added to N-(4-chlorobenzene)-2-cyanoacetamide (3 g, 15.42 mmol) in N,N-dimethylformamide (80 mL). ), after the reaction for half an hour, the reaction concentrate prepared above was added, and the reaction was stirred at room temperature overnight. The main reaction product was detected by LCMS. After diluting the reaction solution with ethyl acetate (200 mL), the organic phase was washed with saturated sodium chloride solution. The separated organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio of 20:1 to 10:1) to obtain a pale red solid compound (4.1 g, crude product). LCMS (ESI) m/z: 366.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO) δ 8.49 (d, J=7.8Hz, 1H), 7.58-7.49 (m, 3H), 7.31-7.23 (m, 2H).

The second step: at room temperature, N,N-diisopropylethylamine (5.8g, 44.84mmol) was added to the phosphorus oxychloride (20mL) of the above-mentioned intermediate compound (4.1g, 11.21mmol), under nitrogen protection The reaction mixture was reacted at 100°C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. The excess phosphorus oxychloride was removed by rotary evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate in a volume ratio of 4:1) to obtain a pale yellow solid intermediate compound (1.68 g). LCMS (ESI) m/z: 383.9/385.9 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ8.81(d,J=8.1Hz,1H),7.97(d,J=8.2Hz,1H),7.69-7.62(m,2H),7.43-7.36(m,2H) ).

The third step: at room temperature, 3-amino-cyclobutyl-1 ketone (152mg, 1.25mmol) was added to the above intermediate compound (50mg, 0.13mmol), N,N-diisopropylethylamine (162mg, 1.25 mmol) in tetrahydrofuran (5 mL), the reaction mixture was reacted at 20 °C for 2 hours. No starting material was detected by LCMS and most of it was converted to the desired product. After the excess tetrahydrofuran was removed by rotary evaporation under reduced pressure, the reaction solution was diluted with ethyl acetate (100 mL), and the organic phase was washed with saturated sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was purified by HPLC to give Example 77a (white solid, 9.7 mg). LCMS (ESI) m/z: 433.0 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO)δ9.02(d,J=8.3Hz,1H),8.63(d,J=6.1Hz,1H),7.90(d,J=8.3Hz,1H),7.62-7.54( m,2H),7.36-7.29(m,2H),5.04(m,1H),3.64-3.51(m,4H).

The fourth step: under ice cooling, methylmagnesium bromide (50 mg, 0.3 mmol) was added dropwise to a solution of the above intermediate compound (100 mg, 0.23 mmol) in tetrahydrofuran (10 mL). The reaction was carried out under ice cooling for 1 hour. Water (70 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL) twice. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol volume ratio of 10:1) to obtain the compound of Example 77b ( white solid, 70 mg). LC-MS (ESI) m/z: 449.1/451.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.07 (m, 1H), 8.46 (m, 1H), 8.87-8.83 (m, 1H), 7.56(d, J=8.0Hz, 2H), 7.32(d, J=8.0Hz, 2H), 5.16(s, 1H), 4.42(m, 1H), 2.62-2.38(m, 4H), 1.33(s, 3H).

Using different aliphatic amines such as cyclobutaneamine, azetidine amine as raw materials, with reference to the methods of Examples 1-3, 45a/45b, 77a/77b, etc., to obtain Examples 78-85;

Examples 86 and 87: 1-(4-Chlorobenzene)-4-(((cis)-3-fluoro-(3-methylcyclobutyl)amino)-2-oxo-7-(trifluoro Methyl)-1,2-dihydro-1,8-naphthyridine-3-methylcyanide and 1-(4-chlorobenzene)-4-(((trans)-3-fluoro-(3-methyl) Cyclobutyl)amino)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-1,8-naphthyridine-3-methylcyanide

Diethylaminosulfur trifluoride (84 mg, 0.65 mmol) was added to a solution of the compound of Example 77b above (50 mg, 0.13 mmol) in dichloromethane (10 mL) at room temperature. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (100 mL), water (100 mL) was added, and the mixture was extracted twice with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by Prep-TLC (eluent: chloroform/methanol volume ratio 4:1) to obtain the compound of Example 86 (white solid, 1.52 mg) and the compound of Example 87 (white solid, 1.12 mg).

Example 86: LCMS (Rt=1.867 min) (ESI) m/z: 451.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO)δ9.03(d,J=8.3Hz,1H),8.50(d,J=6.6Hz,1H),7.87(d,J=8.3Hz,1H),7.57(d, J=8.6Hz, 2H), 7.31 (d, J=8.6Hz, 2H), 4.46 (m, 1H), 2.82-2.69 (m, 4H), 1.49 (d, J=22.4Hz, 3H).

Example 87: LCMS (Rt=1.855 min) (ESI) m/z: 451.0 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO)δ9.02(d,J=8.0Hz,1H),8.40(m,1H),7.87(d,J=7.8Hz,1H),7.57(d,J=8.5Hz, 2H), 7.31(d, J=8.4Hz, 2H), 4.92(m, 1H), 2.85-2.76(m, 2H), 2.70-2.55(m, 2H), 1.55(d, J=20Hz, 3H) .

Using different aliphatic amines such as cyclobutaneamine and azetidinamine as raw materials, with reference to the methods of Examples 1-3, 77, 87, etc., to obtain Examples 88-103;

The following comparative compounds 1-4 were synthesized with reference to the synthesis method of the patent document WO2020123395A1.

Test Example 1MAT2a Enzyme Inhibitory Activity Test

Colorimetric Assay was used to test the enzymatic inhibitory activity of the compounds of the examples on MAT2a, and the test steps were as follows: 1), using standard reaction buffer (Tris, pH 8.0, 50mM KCl, 15mM MgCl ₂ , 300uM EDTA, 0.005% w/v bovine blood Clean albumin) configure 10 compound concentration gradients: the test compound test concentration is 10uM starting, 3-fold dilution, 10 concentrations, single-well test. 10 different concentration solutions were serially diluted to 100-fold final concentration in 384-well plates. Then use Echo 550 to transfer 250nL to 384 reaction plate for use. 250nL of 100% DMSO was added to negative control wells and positive control wells, respectively. 2), prepare 1.67 times the final concentration of enzyme solution with standard reaction buffer. 3) Add 15 μL of enzyme solution of 1.67 times the final concentration to compound wells and positive control wells respectively; add 15 μL of standard reaction buffer to negative control wells. 4) Centrifuge at 1000 rpm for 60 seconds, and incubate for 15 minutes after shaking and mixing. 5), prepare 2.5 times the final concentration of substrate mixed solution with standard reaction buffer. 6), add 10 μL of 2.5 times the final concentration of the substrate mixed solution to start the reaction. 7) Centrifuge the 384-well plate at 1000 rpm for 60 seconds, shake and mix well and incubate for 150 minutes. 8) Add 50 μL of Biomol to stop the reaction, centrifuge at 1000 rpm for 60 seconds and then incubate for 15 minutes. Read the OD620 and process the data. 9), data analysis: calculation formula %Inhibition=(OD ₆₂₀ _max-OD ₆₂₀ _sample)/(OD ₆₂₀ _max-OD ₆₂₀ _min) x 100; wherein: OD ₆₂₀ _sample is the absorbance value of the sample hole; OD ₆₂₀ _min: negative control Well absorbance value, representing the reading of the well without enzymatic activity; _{OD620_max} : absorbance value of the positive control well, representing the reading of the well without compound inhibition. 10) Fit the dose-response curve: take the log value of the concentration as the X-axis and the percentage inhibition rate on the Y-axis, and use the log(inhibitor) vs.response-Variable slope of the analysis software GraphPad Prism 5 to fit the dose-response curve, thereby obtaining The _IC50 value of each compound for enzymatic activity was calculated.

Results: Most of the compounds in the examples of the present invention have high MAT2a inhibitory activity, and the IC ₅₀ is less than 200nM, and the IC ₅₀ of some examples is even less than 20nM, which is obviously better than that of the comparative compounds 3 and 4. (A<100nM, 100nM≤B<500nM, C≥500nM)

编号serial number	MAT2a IC ₅₀(nM) MAT2a _IC50 (nM)	编号serial number	MAT2a IC ₅₀(nM) MAT2a _IC50 (nM)	编号serial number	MAT2a IC ₅₀(nM) MAT2a _IC50 (nM)
11	119.7119.7	22	75.575.5	33	69.969.9
44	CC	55	BB	66	CC
77	CC	88	BB	99	CC
1010	CC	1111	CC	1212	BB

1313	CC	1414	CC	1515	CC
1616	CC	1717	CC	1818	CC
1919	CC	2020	CC	21twenty one	76.976.9
22twenty two	CC	23twenty three	CC	24twenty four	407407
2525	17.117.1	2626	20.820.8	2727	32.232.2
2828	305305	2929	31.931.9	3030	74.674.6
3131	16.616.6	3232	AA	3333	178178
3434	17.317.3	3535	42.042.0	3636	56.756.7
3737	BB	3838	19.119.1	3939	BB
4040	38.638.6	4141	25.525.5	4242	CC
4343	13.313.3	4444	18.518.5	4545	AA
45a45a	16.316.3	45b45b	16.116.1	4646	AA
4747	AA	4848	AA	4949	BB
5050	20.820.8	5151	AA	5252	24twenty four
5353	BB	5454	31.631.6	5555	48.748.7
5656	38.638.6	5757	BB	5858	BB
5959	BB	6060	BB	6161	20.820.8
6262	AA	6363	AA	6464	3333
6565	BB	6666	BB	6767	AA
6868	AA	6969	AA	7070	AA
7171	AA	7272	15.315.3	7373	23.523.5
7474	23.123.1	7575	AA	7676	AA
77a/77b77a/77b	18.6/20.118.6/20.1	7878	AA	7979	AA
8080	AA	8181	13.613.6	8282	17.217.2
8383	16.316.3	8484	17.317.3	8585	15.815.8
8686	16.316.3	8787	14.714.7	8888	15.715.7
8989	BB	9090	BB	9191	AA
9292	AA	9393	3232	9494	7676
9595	BB	9696	25.125.1	9797	26.526.5
9898	AA	9999	4141	100100	BB

101101	77.977.9	102102	65.565.5	103103	BB
104104	BB	对照1Control 1	10.910.9	对照2Control 2	11.111.1
对照3Control 3	BB	对照4Control 4	39.139.1

Test Example 2: Proliferation-inhibitory effects of Example compounds on HCT-116 ^wt and HCT-116 ^MTAP -cells.

1), experimental reagents

2. Cell line

细胞系cell line	培养类型Culture type	来源source	培养基culture medium
HCT116 MTAPHCT116 MTAP	贴壁型Adherent	HorizonHorizon	RPMI-1640+10％FBSRPMI-1640+10%FBS
HCT116wtHCT116wt	贴壁型Adherent	HorizonHorizon	RPMI-1640+10％FBSRPMI-1640+10%FBS

3. Test method: 1) Take HCT-116 ^wt /HCT116 ^MTAP -cells (Horizon) in logarithmic growth phase and inoculate them into a 96-well culture plate at an appropriate density, 80 μL per well, and after culturing overnight, add compounds of different concentrations Act for 4hr, and set solvent control group (negative control). 2) After the compound acts on the cells for 120 hr, the effect of the compound on the cell proliferation was detected by CTG cell counting kit. 40 μL of CTG reagent was added to each well, and placed in a 37°C incubator for 60 min, and then used a Multilabel Reader microplate reader of PerkinElmer Company. reading. 3) Calculate the inhibition rate (%) of the compound on tumor cell growth using the following formula: inhibition rate (%)=(OD negative control well-OD administration well)/OD negative control well×100%. IC ₅₀ values were obtained by four-parameter regression using the software GraphPad Prism5 that came with the microplate reader.

Results: The IC ₅₀ of most of the example compounds of the present invention is less than 1 uM for HCT-116 ^MTAP -cell proliferation inhibition, such as Examples 25, 26, 34, 45b, 72, 77a, 81, 82, 83, 85, 86, 88, etc. The inhibitory activity IC ₅₀ of HCT-116 wt cells was less than 200nM, which was significantly better than that of the comparative compound 4; and the proliferation inhibitory activity IC ₅₀ of some example compounds of the present invention on HCT-116 ^wt cells was greater than 5uM, showing high cell selectivity.

Test Example 3: ADMET Test of Example Compounds

(1) Metabolic stability test: 150 μL of liver microsomes (final concentration 0.5 mg/mL) were used for metabolic stability incubation, and the system contained NADPH (final concentration 1 mM), 1 μM test compound and positive control midazole The reaction was terminated with acetonitrile containing tinidazole at 0min, 5min, 10min, 20min and 30min, respectively, vortexed for 10min, centrifuged at 15000rmp for 10min, and 50 μL of supernatant was injected into a 96-well plate. Compound metabolic stability was calculated by determining the relative reduction of the parent drug.

Results: The compounds of the examples of the present invention have high stability to liver microsomes of various genera (such as rat, mouse, dog, monkey, human), and the half-life is more than 30min, such as compounds 25, 43, 83, 85, 86 of the examples. , 88, etc.

Test Example 4: Pharmacokinetic Parameter Test of Example Compounds in Mice

Six male SPF Balb c mice (Shanghai Sipple-Bike laboratory animals) were divided into two groups, and the test compounds were formulated into appropriate solutions or suspensions; one group was administered intravenously, and the other group was administered orally. Blood was collected by jugular vein puncture, each sample was collected about 0.2 mL/time point, and heparin sodium was anticoagulated. 24h; blood samples were placed on ice after collection, centrifuged to separate plasma (centrifugation conditions: 8000 rpm, 6 minutes, 2-8°C), and the collected plasma was stored at -80°C before analysis. Plasma samples were analyzed by LC-MS/MS.

According to the plasma concentration data of the drug, the pharmacokinetic parameters AUC _0-t , AUC _0-∞ , MRT _0-∞ , C _max of the test substance were calculated using the non-compartmental model of the pharmacokinetic calculation software WinNonlin5.2 , T _max , T _1/2 and V _d parameters and their mean and standard deviation. In addition, the bioavailability (F) will be calculated by the following formula.

For samples whose concentration is lower than the lower limit of quantification, in the calculation of pharmacokinetic parameters, the samples taken before reaching Cmax should be calculated as zero value, and the samples at the sampling point after reaching _Cmax should be calculated as non-quantitative (BLQ).

The results show that the compounds of the examples of the present invention show good pharmacokinetic properties, and the pharmacokinetic parameters of the representative examples are shown below.

The mouse PK data results of Example 25 are as follows:

The mouse PK data results of Example 43 are as follows:

The mouse PK data results of Example 72 are as follows:

The mouse PK data results of Example 83 are as follows:

The mouse PK data results of Example 85 are as follows:

The mouse PK data results of Example 86 are as follows:

The mouse PK data results of Example 88 are as follows:

Test Example 5: Inhibitory effect of example compounds on the growth of human colon cancer HCT116 MTAP ^-/- nude mice subcutaneous xenograft tumor in vivo

(1) BALB/c nude mice (6-8 weeks old, Shanghai Lingchang Biotechnology Co., Ltd.) were raised in SPF environment, temperature 20-25°C, relative humidity 30-70%, 12:12h light and dark lighting; free Drinking water and eating food. Animals were adaptively reared before experimental treatment; (2) HCT116 MTAP ^-/- cells (Horizon) were cultured and expanded in vitro, and the cells in logarithmic growth phase were collected and resuspended in serum-free RPMI1640 medium, and the cell concentration was adjusted to 1.33×10 ⁷ /mL; (3) Inject the cell suspension subcutaneously into the axilla of the front right limb of BALB/c nude mice with a 1 mL syringe, and inject 150 μL into each animal; observe the growth of the animals and the transplanted tumor regularly; (4) When the average tumor volume grows to At about 100-150 mm ³ , animals with too large, too small or irregular tumor shape were eliminated and grouped by random block method; the solvent control group was intragastrically administered with solvent (1% HPMC) once a day; the administration group was administered by intragastric administration once a day Different volumes of 1% HPMC drug suspension were administered to the stomach; (5) During the administration period, the tumor diameter was measured twice a week, the weight of the animals was weighed, the living conditions of the animals were observed, and abnormal conditions were recorded; When the tumor volume exceeded 2000 mm, the animals were euthanized; ( ⁶ ) At the end of the test, the animals were euthanized with _CO , and the subcutaneous tumor tissue was excised and weighed, and then photographed to calculate the tumor weight and tumor inhibition rate; Observe and record whether there is any abnormality in animal organs; (7) Tumor volume (TV): the calculation formula is TV=1/2×a×b ² , where a represents the long diameter of the tumor; b represents the short tumor path. Relative tumor volume (RTV): the calculation formula is RTV=V _t /V _initial × 100 (%); where, V _initial is the tumor volume measured during group administration (ie d _initial ), and V _t is each tumor volume. Tumor volume at one measurement. Relative tumor proliferation rate T/C (%): the calculation formula is T/C (%)=(T _RTV /C _RTV )×100%; where T _RTV represents the relative tumor volume of the treatment group, and C _RTV represents the solvent control group The tumor volume inhibition rate (GI): the calculation formula is GI=[1–(TV _t –TV _initial )/(CV _t –CV _initial )]×100%; where, TV _t represents each treatment group The tumor volume at the time of measurement; TV _initial represents the tumor volume of the treatment group during group administration; CV _t represents the tumor volume of the solvent control group at each measurement; CV _initial represents the tumor volume of the solvent control group during group administration. Body weight loss rate of animals: the calculation formula is body weight loss rate=100%×(BW _initial -BW _final )/BW _initial ; wherein, BW _initial represents the animal body weight at the time of group administration; BW _final represents the animal body weight at the end of the test. Tumor weight inhibition rate (IR): The calculation formula is: IR=(WC-WT)/WC×100%; wherein, WC represents the tumor weight in the solvent control group; WT represents the tumor weight in the treatment group. (8) Statistical analysis method: The test data were calculated and related statistical processing with Microsoft Office Excel 2010 software. Unless otherwise specified, data are expressed as mean ± standard error (Mean ± SE), and t-test was used for comparison between two groups.

The results show that the example of the present invention has obvious growth inhibitory effect on the subcutaneous xenograft tumor of human colon cancer HCT116 MTAP ^-/- nude mice. At a dose of 300 mg/kg, intragastric administration once a day for 35 consecutive days inhibited the growth of subcutaneous xenograft tumors in HCT116 MTAP ^-/- nude mice in a dose-dependent manner (tumor inhibition rate was 30% to 93%), and the body weight of the animals was similar to that of the mice. There was no significant difference compared to the solvent control group.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application. Although the specific embodiments of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes may be made to these embodiments without departing from the principle and essence of the present invention. Revise. Accordingly, the scope of protection of the present invention is defined by the appended claims.

Claims

An aromatic ring or aryl heterocyclic pyridone compound represented by formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or tautomer thereof isomers, torsion isomers, solvates, polymorphs or prodrugs,

where:

Ar is selected from 5-12-membered monocyclic or cycloaryl, monocyclic or cycloaryl substituted by 1-3 Rn, "heteroatom is selected from one or more of N, O, P and S" , 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms" and "heteroatoms substituted by 1-3 Rn" selected from one or more of N, O, P and S Species, 5-12-membered monocyclic or heterocyclic heteroaryl with 1-3 heteroatoms";

The Rn is independently selected from deuterium, halogen, cyano, amide, sulfonamide, hydroxyl, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C 1 -C 12 alkyl, C 1 - C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy, -NRz 1 Rz 2 , alkenyl, alkynyl, 3-12 membered monocyclic, spirocyclic or bridged cycloalkanes base, "heteroatoms selected from one or more of N, O, P and S, and 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl groups with 1-3 heteroatoms", C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl-SO-, C 1 -C 12 alkyl-SO 2 -, 3-12-membered cycloalkyl ether, 3-12-membered heterocycloalkane base ether, 5-10-membered monocyclic or cyclic aryl and "heteroatoms selected from one or more of N, O, P and S, and 3-12-membered monocyclic rings with 1-3 heteroatoms Or cycloheteroaryl"; or any two of the above Rn can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through a carbon chain or a heteroatom; Rz 1 and Rz 2 are independently selected from H and C 1 -C 12 alkyl;

R 1 is selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy, C 1 -C 12 monoalkylamino, C 1 -C 12 dialkylamino, C 1 -C 12 haloalkylamino, 3-12-membered monocyclic, spiro or bridged cycloalkyl, "heteroatom selected from N, O, P and S One or more of 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms, C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl-SO-, C 1 -C 12 alkyl-SO 2 -, 3-12-membered cycloalkyl ether, 3-12-membered heterocycloalkyl ether, 5-10-membered monocyclic or cyclic aryl and "The heteroatom is selected from one or more of N, O, P and S, and the 3-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms";

R 2 is selected from halogen, cyano, amide, sulfonamide, phosphoryl, alkylphosphooxy, alkylsilyl, C 1 -C 12 haloalkyl and C 1 -C 12 haloalkoxy;

R 3a is selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 monoalkylaminoalkyl, C 1 -C 12 dialkylaminoalkyl, cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 membered monocyclic, spirocyclic or bridged ring Cycloalkyl, 3-12-membered monocyclic, spirocyclic or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 selected from N, O, P and S One or more of 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl groups with 1-3 heteroatoms";

R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12Monoalkylaminoalkyl, C1 - C12dialkylaminoalkyl , cycloalkylaminoalkyl, heterocycloalkylaminoalkyl, 3-12 -membered monocyclic, spirocyclic or bridged cycloalkane base, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one or more of N, O, P and S, heteroatom A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1 to 3 "heterocycloalkyl groups" and "heteroatoms substituted by one or more Rm 3 are selected from one of N, O, P and S. One or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";

Alternatively, the above-mentioned R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl", "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms are selected from one or more of N, O, P and S, and 3-heteroatoms with 1-3 heteroatoms 12-membered monocyclic or heterocyclic heteroaryl" or "heteroatoms substituted by one or more Rm 5 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic or heterocyclic heteroaryl";

The Rm 1 , Rm 2 , Rm 3 , Rm 4 and Rm 5 are independently selected from deuterium, oxo (=O), halogen, cyano, amide, sulfonamide, hydroxyl, urea, phosphoryl, alkyl Phosphoroxy, alkylsilyl, C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Ry 1 , C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl , C 1 -C 12 haloalkoxy, alkenyl, alkynyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl, 3-12-membered monocyclic, spiro substituted by one or more Ry 2 Ring or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged rings with 1-3 heteroatoms "Heterocycloalkyl", "heteroatoms substituted by one or more Ry 3 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3 3-12-membered units Ring, spirocyclic or bridged heterocycloalkyl", C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl-SO-, C 1 -C 12 alkyl-SO 2 -, -NRz 1 Rz 2 and
Or the above-mentioned two Rm 1 , two Rm 2 , two Rm 3 , two Rm 4 or two Rm 5 can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through carbon chains or heteroatoms;

Rx is selected from C 1 -C 12 alkyl and C 1 -C 12 alkoxy;

Ry 1 is independently hydroxyl;

Ry 2 is independently selected from C 1 -C 12 alkyl and hydroxy-substituted C 1 -C 12 alkyl;

Ry 3 is independently selected from C 1 -C 12 alkyl and C 1 -C 12 haloalkyl;

W, Z, Y are independently selected from O, S, CR 4 and N; wherein R 4 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amido, sulfonamido, C 1 -C 12 Alkyl, C 1 -C 12 haloalkyl, C 1 -C 12 alkyl-S-, C 1 -C 12 alkyl -SO-, C 1 -C 12 alkyl -SO 2 -, C 1 -C 12 Alkyl-O-, C 1 -C 12 haloalkyl-O-, -NRz 1 Rz 2 , 3-12-membered cycloalkylamino, 3-12-membered heterocycloalkylamino, 3-12-membered monocyclic, spiro Ring or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic or bridged rings with 1-3 heteroatoms "Heterocycloalkyl", 3-12-membered halogenated cycloalkyl or halogenated heterocycloalkyl, 3-12-membered cycloalkyl-O-, 3-12-membered halogenated cycloalkyl-O-, 3- 12-membered heterocycloalkyl-O-, 5-12-membered monocyclic or cycloaryl and 5-12-membered monocyclic or cycloheteroaryl;

Or -Y=Z- can form =CH-, =N-, -O-, -S- or -NR 5 ; R 5 is selected from hydrogen, C 1 -C 12 alkyl, 3-12 membered monocyclic, spiro Ring or bridged cycloalkyl and "hetero atoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spiro or bridged rings with 1-3 heteroatoms. Heterocycloalkyl";

The above-mentioned aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) does not include the following compounds:
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1) Rn is independently selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10 A monocyclic cycloalkyl;

(2) R 1 is selected from halogen, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10-membered monocyclic cycloalkyl;

(3) R 2 is cyano;

(4) R 3a is selected from hydrogen and C 1 -C 12 alkyl;

R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 dialkylaminoalkyl, 3-12 membered monocyclic ring, spirocyclic ring or bridged cycloalkyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one of N, O, P and S or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 are selected from N, O, One or more of P and S, a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";

Alternatively, the above-mentioned R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl"

(5) said Rm 1 , Rm 2 , Rm 3 and Rm 4 are independently selected from oxo (=O), halogen, cyano, hydroxyl, C 1 -C 12 alkyl, a group consisting of one or more Ry 1 Substituted C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, 3-8 membered monocyclic, spiro or bridged cycloalkyl, replaced by one or more Ry 2 -substituted 3-8-membered monocyclic, spirocyclic or bridged cycloalkyl, "heteroatoms selected from one or more of N, O, P and S, and 3 with 1-3 heteroatoms. -12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms substituted by one or more Ry3 " selected from one or more of N, O, P and S, the number of heteroatoms 1-3 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", -NRz 1 Rz 2 and

(6) Rz 1 and Rz 2 are independently selected from C 1 -C 12 alkyl;

(7) Y is CH or N;

(8) Z is CH;

(9) W is CH or N.
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs, wherein Ar is selected from 5-12-membered monocyclic or cyclic aryl, monocyclic substituted by 13 Rn Ring or cycloaryl, "heteroatoms selected from one or more of N, O, P and S, 5-12-membered monocyclic or cycloheteroaryl with 1-3 heteroatoms" and "The heteroatom is selected from one or more of N, O, P and S, and the 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms is substituted by 1-3 Rn" ;

Said Rn is independently selected from halogen, C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10 membered monocyclic ring cycloalkyl;

for

R 1 is selected from halogen, C 1 -C 12 haloalkyl, C 1 -C 12 haloalkoxy and 3-10-membered monocyclic cycloalkyl;

R 2 is cyano;

R 3a is selected from hydrogen and C 1 -C 12 alkyl;

R 3b is selected from C 1 -C 12 alkyl, C 1 -C 12 alkyl substituted by one or more Rm 1 , C 1 -C 12 dialkylaminoalkyl, 3-12 membered monocyclic ring, spirocyclic ring or bridged cycloalkyl, 3-12-membered monocyclic, spiro or bridged cycloalkyl substituted by one or more Rm 2 , "heteroatom selected from one of N, O, P and S or more, 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" and "heteroatoms substituted by one or more Rm 3 are selected from N, O, One or more of P and S, a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms";

Alternatively, the above-mentioned R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, Spirocyclic or bridged ring heterocycloalkyl" or "heteroatoms substituted by one or more Rm 4 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl";

Said Rm 1 , Rm 2 , Rm 3 and Rm 4 are independently selected from oxo (=O), halogen, cyano, hydroxyl, C 1 -C 12 alkyl, C substituted by one or more Ry 1 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 1 -C 12 haloalkyl, 3-8 membered monocyclic, spiro or bridged cycloalkyl, substituted by one or more Ry 2 3-8 membered monocyclic, spirocyclic or bridged cycloalkyl, "heteroatom selected from one or more of N, O, P and S, 3-12 membered with 1-3 heteroatoms Monocyclic, spirocyclic or bridged heterocycloalkyl", "heteroatoms substituted by one or more Ry 3 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1- 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", -NRz 1 Rz 2 and

Rx is C 1 -C 12 alkyl or C 1 -C 12 alkoxy;

Ry 1 is independently hydroxyl;

Ry 2 is independently C 1 -C 12 alkyl or hydroxy-substituted C 1 -C 12 alkyl;

Ry 3 is independently C 1 -C 12 alkyl or C 1 -C 12 haloalkyl;

Rz 1 and Rz 2 are independently selected from C 1 -C 12 alkyl.
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1) In Ar, Rn, R 1 and R 4 , the aryl group is independently a 6-10-membered monocyclic or paracyclic aryl group, such as phenyl or naphthyl;

(2) In Ar, Rn, R 1 , R 3a , R 3b and R 4 , the heteroaryl group is independently "one or more heteroatoms selected from N, O and S, and the number of heteroatoms is 1-3 5-12-membered monocyclic or heterocyclic heteroaryl";

( 3 ) in Rn, R1, R2, Rm1 , Rm2 , Rm3 , Rm4 , Rm5 and R4 , the halogen is independently F, Cl , Br or I;

(4) Among Rn, Rz 1 , Rz 2 , R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , Rx, Ry 2 , Ry 3 , R 4 and R 5 , The alkyl groups are independently C 1 -C 6 alkyl groups;

(5) In Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 and Rx, the alkoxy group is independently a C 1 -C 6 alkoxy group;

( 6 ) Among Rn, R1, R2, R3a , R3b , Rm1 , Rm2 , Rm3 , Rm4 , Rm5 , Ry3 and R4 , the haloalkyl is independently C1 - C haloalkyl of 6 ;

(7) In Rn, R 1 , R 2 , Rm 1 , Rm 2 , Rm 3 , Rm 4 and Rm 5 , the haloalkoxy is independently a C 1 -C 6 haloalkoxy;

(8) Among Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , R 4 and R 5 , the cycloalkyl group is a 3-6 membered monocyclic, spiro cyclic or bridged cycloalkyl;

(9) In Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , R 4 and R 5 , the heterocycloalkyl group is "heteroatoms selected from N, One or more of O and S, 3-10-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms".
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1) In Ar, Rn, R 1 and R 4 , the aryl group is independently phenyl or naphthyl;

(2) In Ar, the "heteroatoms are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3 5-12-membered monocyclic or heterocyclic heteroaryl groups" And by 1-3 Rn substituted "heteroatoms are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 5-12-membered monocyclic or heterocyclic heteroaryl groups "Heteroatoms are selected from one or more of N, O, P and S, and a 5-12-membered monocyclic or heterocyclic heteroaryl group with 1-3 heteroatoms" is independently pyridyl (E.g
) or imidazo[1,2-a]pyridine (e.g.
);

( 3 ) in Rn, R1, R2, Rm1 , Rm2 , Rm3 , Rm4 , Rm5 and R4 , the halogen is independently F or Cl ;

(4) Among Rn, Rz 1 , Rz 2 , R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , Rx, Ry 2 , Ry 3 , R 4 and R 5 , The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

(5) In Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 and Rx, the alkoxy groups are independently methoxy, ethoxy, n-propyl Oxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, for example methoxy;

(6) Among Rn, R 1 , R 2 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , Ry 3 and R 4 , the haloalkyl group is independently CF 3 or CH 2CF3 ;

(7) In Rn, R 1 , R 2 , Rm 1 , Rm 2 , Rm 3 , Rm 4 and Rm 5 , the haloalkoxy is independently OCF 3 ;

(8) Among Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , R 4 and R 5 , the cycloalkyl group is a 3- to 6-membered monocyclic ring Alkyl such as cyclopropyl or cyclobutyl;

(9) In Rn, R 1 , R 3a , R 3b , Rm 1 , Rm 2 , Rm 3 , Rm 4 , Rm 5 , R 4 and R 5 , the heterocycloalkyl group is "heteroatom selected from N and One or more of O, a 4-10-membered monocyclic or spirocyclic heterocycloalkyl with 1-2 heteroatoms", such as azetidinyl (such as
), oxetanyl (e.g.
), pyrrolidinyl (e.g.
), piperidinyl (such as
)or
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1) In R 3a and R 3b , when R 3b is "a heteroatom selected from one or more of N, O, P and S, and a 3-12-membered monocyclic ring with 1-3 heteroatoms, spirocyclic or bridged ring heterocycloalkyl", the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3 3-12-membered monocyclic ring , spirocyclic or bridged heterocycloalkyl" is

When R 3b is substituted by one or more Rm 3 "heteroatoms are selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro ring or bridged ring heterocycloalkyl", the "heteroatoms substituted by one or more Rm 3 are selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3. A 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl" is

When R 3a and R 3b together with the atoms to which they are attached form "heteroatoms selected from one or more of N, O, P and S, 3-12-membered monocyclic, spirocyclic rings with 1-3 heteroatoms or bridged ring heterocycloalkyl", the "heteroatom is selected from one or more of N, O, P and S, the number of heteroatoms is 1-3 3-12-membered monocyclic, spiro cyclic or bridged heterocycloalkyl" is

When R 3a and R 3b together with the atoms to which they are attached, form a "heteroatom selected from one or more of N, O, P and S, which is substituted by one or more Rm 4 , and the number of heteroatoms is 1-3. 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl", the "heteroatom substituted by one or more Rm 4 is selected from one or more of N, O, P and S , a 3-12-membered monocyclic, spirocyclic or bridged heterocycloalkyl with 1-3 heteroatoms" is

(2) In Rm 1 , Rm 2 , Rm 3 and Rm 4 , the "heteroatom is selected from one or more of N, O, P and S, and the number of heteroatoms is 1-3 in 3-12 A monocyclic, spirocyclic or bridged heterocycloalkyl" is
The "heteroatom substituted by one or more Ry 3 is selected from one or more of N, O, P and S, and the 3-12-membered monocyclic, spirocyclic or Bridged ring heterocycloalkyl" is
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1)
for

E.g

(2) Ar is selected from phenyl,
Rn is independently selected from halogen (eg Cl, F), C 1 -C 6 haloalkyl (eg CF 3 ), C 1 -C 6 haloalkoxy (eg OCF 3 ) and 3-6 membered cycloalkyl (eg cyclo propyl);

(3) R 1 is Cl or CF 3 ;

R 3a is hydrogen;

R 3b is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted with 1-3 Rm 1 , C 1 -C 6 dialkylaminoalkyl, 3-6 membered monocyclic Cycloalkyl, 3-6-membered monocyclic cycloalkyl substituted by 1-3 Rm 2 , "heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1-2 The 3-6-membered monocyclic or spirocyclic heterocycloalkyl" and the "heteroatoms substituted by 1-3 Rm 3 are selected from one or more of N, O and S, and the number of heteroatoms is 1- 2 3-6 membered monocyclic or spirocyclic heterocycloalkyl";

Alternatively, the above R 3a and R 3b together with the atoms to which they are attached form "the heteroatom is selected from N, a 3-5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms" or is surrounded by 1-3 Rm 4 Substituted "heteroatoms are selected from N, 3-5-membered monocyclic heterocycloalkyl with 1-2 heteroatoms", wherein, when the above R 3a and R 3b together with the atoms to which they are attached, form "hetero atoms selected from From N, 5-membered monocyclic heterocycloalkyl with 1-3 heteroatoms" or "heteroatoms substituted with 1-3 Rm 4 " from N, 5-membered heteroatoms with 1-2 heteroatoms "monocyclic heterocycloalkyl", Ar is phenyl or
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone represented by formula (I) The compound satisfies one or more of the following conditions:

(1)
for

(2) R 1 is selected from Cl, CF 3 , OCF 3 and cyclopropyl;

(3) Ar is selected from phenyl,

(4)
selected from
The aromatic ring or aryl heterocyclic pyridone compound represented by the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof isomers, tautomers, torsional isomers, solvates, polymorphs or prodrugs, characterized in that the aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) is selected from any of the following compounds:
A pharmaceutical composition, characterized in that the pharmaceutical composition comprises:

(1) The aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof isomers, diastereomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs, and

(2) A pharmaceutically acceptable carrier.
The aromatic ring or aryl heterocyclic pyridone compound represented by formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, or an enantiomer thereof, Use of diastereomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs, or the pharmaceutical composition of claim 10, in the preparation of a medicament; the medicament It can be a drug for the treatment and/or prevention of diseases related to MAT2a or MTAP protein activity or expression; the drug is especially a drug for the treatment and/or prevention of tumors or autoimmune diseases.
The use according to claim 11, wherein the tumor is independently selected from the group consisting of lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, and melanoma , thyroid cancer, nasopharyngeal cancer, glioma, bladder cancer, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma ;

The autoimmune disease is independently selected from the group consisting of thyroiditis, inflammatory bowel disease, erythematosus, fibrosis, myasthenia, vasculitis, psoriasis, arthritis, scleroderma and dermatitis.