WO2022052924A1 - Preparation method for class of nitrogen-containing fused ring compounds and use thereof - Google Patents

Abstract

A preparation method for a class of nitrogen-containing fused ring compounds and a use thereof, specifically, a nitrogen-containing fused ring compound represented by general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof, a preparation method therefor and a pharmaceutical application thereof, the definition of each group being as described in the description.

Description

Preparation method and use of a kind of nitrogen-containing fused ring compounds technical field

The invention belongs to the field of medicinal chemistry, in particular to a class of nitrogen-containing fused-ring compounds, which have the activity of inhibiting methionine adenosyltransferase (MAT2a) and can be used to prepare diseases related to the activity or expression of MAT2a or MTAP treatment and preventive medicines.

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. Through pharmacological methods, it is 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.

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.

The solution to the above technical problems is as follows:

A nitrogen-containing condensed ring compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, torsion isomer , solvates, polymorphs or prodrugs,

where:

R ¹ and R ³ are independently selected from 5-12-membered monocyclic or bi-cyclic aryl or heteroaryl rings, and the aryl or heteroaryl rings may be substituted by 1-3 different substituents Rn substituted, the Rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ 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;

R ² is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, nitro, amino, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-S-, C ₁ - _C6alkyl -SO-, C1- _C6alkyl - _SO2- , _{C1 - C6alkyl} -O-, _C1 -C6haloalkyl-O-, _{C1 - C6mono} Alkylamino, C ₁ -C ₆ dialkylamino, 3-12-membered cycloalkylamino or heterocycloalkylamino, 3-12-membered cycloalkyl or heterocycloalkyl, 3-12-membered halocycloalkane group 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;

W, X, Y are independently selected from CR ⁴ or N; wherein R ⁴ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, 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 halogenated cycloalkyl or halogenated heterocycloalkyl, 3-12-membered cycloalkyl-O-, 3-12-membered halogenated cycloalkyl-O-, 3-12 membered heterocycloalkyl-O-, 5-12 membered aryl or 5-12 membered heteroaryl; or -X=Y- can be independently selected from -O- or -S-.

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, C ₃ -C ₈ cycloalkyl, Amino, C ₁ -C ₈ alkylamino; wherein, the heteroaryl group contains 1-3 heteroatoms selected from the group consisting of N, O, P or S, and the heterocycloalkyl group contains 1- 3 heteroatoms selected from the group consisting of N, O, P or S, and the ring system includes a saturated or partially unsaturated ring system such as a spiro ring, a bridged ring, a condensed ring, and a fused ring.

In some preferred embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion, or enantiomer thereof Isomers, solvates, polymorphs or prodrugs, which are preferably compounds represented by the general formula (II), or pharmaceutically acceptable salts thereof, or enantiomers and diastereomers thereof isomers, tautomers, torsion isomers, solvates, polymorphs or prodrugs:

wherein R ⁵ , R ⁶ and R ⁷ are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, 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; R ¹ , R ² , R ³ are as defined above.

In some preferred embodiments, it is preferably a compound represented by general formula (III), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, and tautomer , torsion isomer, solvate, polymorph or prodrug:

Wherein: M ₁ is preferably selected from CH or N, M ₂ is preferably selected from O, S, NH, etc.;

Preferably from single bond or double bond; R ⁸ is preferably from hydrogen, deuterium, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ -halogenated alkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; R ³ is preferably selected from phenylcyclyl, pyridinecyclyl, thiazolecyclyl, imidazole ring, indolecyclyl, indazolecyclyl, indoline base, isoindazole ring group, isoindoline ring group, benzofuranyl group, benzodihydrofuranyl group, pyridofuranyl group, pyridodihydrofuranyl group, benzimidazolyl group, benzoxazolyl group, Benzothiazolyl, pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, naphthylcyclyl, quinolinecyclyl, isoquinolinecyclyl, quinazolinylcyclyl, benzomorpholinyl, benzo Dioxane, etc., the above R ³ ring can be substituted by one or more groups selected from the group consisting of 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; R ² , R ³ , W, X, Y are as defined above Show.

In some preferred embodiments, R ¹ is preferably selected from a 5-12-membered monocyclic aryl or heteroaryl ring, which may be substituted by 1-3 substituents Rn, The Rn is selected from hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino; or the above two Rn can form a 3-6 membered saturated ring system through a carbon chain or a heteroatom.

In some preferred embodiments, R ¹ is preferably selected from a 5-6 membered monocyclic aryl or heteroaryl ring, which may be substituted by 1-3 substituents Rn, wherein said Rn is selected from halogen, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy.

In some preferred embodiments, R ² is preferably selected from hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ haloalkyl-O-, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, C ₁ -C ₆ monohaloalkylamino, C ₁ -C ₆ dihaloalkylamino, C ₁ - C ₆ alkyl-S-.

In some preferred embodiments, R ² is preferably selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ haloalkyl- O-, -NR ^a R ^b , C ₁ -C ₆ monohaloalkylamino, C ₁ -C ₆ dihaloalkylamino, C ₁ -C ₆ alkyl-S-, wherein R ^a and R ^b are each independently selected From hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl.

In some preferred embodiments R ² is preferably selected from C ₁ -C ₆ alkyl-O-, -NR ^a R ^b , wherein R ^a and R ^b are each independently selected from hydrogen, deuterium, C ₁ -C ₆ alkane base, C ₁ -C ₆ haloalkyl.

In some preferred embodiments, ^R is preferably selected from 5-12 membered (eg 5, 6, 7, 8, 9, 10, 11, 12) monocyclic or bicyclic aryl or heteroaryl rings, Said aryl or heteroaryl ring may be substituted with 1-3 substituents Rn as defined in the present invention.

In some preferred embodiments, R ³ is preferably selected from phenyl, indazolyl, quinolinyl, benzimidazolyl, benzothiazolyl, which may be replaced by 1-3 substituents Rn as defined in the present invention replaced.

In some preferred embodiments, R ³ is preferably selected from a 5-12-membered bi-cycloaryl or heteroaryl ring, and the bi-cycloaryl or heteroaryl ring may be replaced by 1-3 such as the present Substituent Rn as defined in the invention is substituted.

In some preferred embodiments, R ³ is preferably selected from a 5-12 membered bi-cycloaryl or heteroaryl ring, which may be substituted with 2-3 substituents Rn is substituted, wherein two substituents Rn are adjacent, and the two adjacent Rn may form a substituted or unsubstituted 3-6 membered (eg 3, 4, 5, 6) ring through carbon chains or heteroatoms.

In some preferred embodiments, Rn is preferably selected from the group consisting of hydrogen, deuterium, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, _C1 - _C6 haloalkyl, _C1 - _C6 deuterated Alkyl, C ₁ -C ₆ deuterated alkoxy, alkenyl, alkynyl, C ₁ -C ₆ alkyl-S-, C ₁ -C ₆ alkyl-SO-, C ₁ -C ₆ alkyl- SO _2- .

In some preferred embodiments, two adjacent Rn can form a 5-6 membered saturated or partially unsaturated or aromatic ring system through a carbon chain or 1-3 heteroatoms selected from N, O, S, preferably A 5-6 membered saturated carbocycle or saturated heterocycle wherein one or more atoms in the saturated carbocycle or saturated heterocycle can be further oxidized to form =O.

In some preferred embodiments, W, X, Y, R1, R2 and R3 are each independently the corresponding groups in compounds 1-94 prepared in the Examples.

In some preferred embodiments, the compound is any one of Compounds 1-94 prepared in the Examples or a pharmaceutically acceptable salt thereof.

A method one for preparing a compound of formula I, the method mainly comprises the following steps a:

A, the compound of general formula (A) and aryl acetic acid or aryl acetyl chloride or aryl acetic acid ester are catalyzed by acid or base or dehydration ring-closing reaction under the condition of a condensing agent generates the compound of general formula (I);

Wherein Ra is hydroxyl, chlorine, ester group; Rb is hydrogen or alkyl; R ¹ , R ² , R ³ , W, X, Y are defined as above.

A method two for preparing a compound of formula I, the method mainly comprises the following steps b;

b. The compound of the general formula (B) is reacted with an aryl keto acid or an aryl keto acid ester under the catalysis of an acid or a base to generate a compound of the general formula (I):

wherein Rc is a hydroxyl group or an ester group; the definitions of R ¹ , R ² , R ³ , X and Y are as shown above.

A method three for preparing a compound of formula I, the method mainly comprises the following steps c and d:

c: compound of general formula (C) and 2-bromophosphoryl acetate (D) are closed under base catalysis to generate intermediate compound of general formula (E);

d: the compound of the general formula (E) is combined with a substituted arylboronic acid (or ester), an aryltin reagent or an arylsilicon reagent to generate a compound of the general formula (I) through a coupling reaction catalyzed by a transition metal complex;

Wherein Ra is hydroxyl, chlorine, alkoxy, ester group; Rb is hydrogen or alkyl; Rd is phosphoryl ester; R ¹ , R ² , R ³ , W, X, Y are defined as above.

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 transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd2(dba) ₃ ), tetrakis(triphenylphosphine)palladium (Pd( _{PPh3 )4 )} , acetic acid Palladium, palladium chloride, bis(triphenylphosphine) palladium dichloro, palladium trifluoroacetate, palladium triphenylphosphine acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium, bis(tri-o-benzylphosphine) palladium dichloride, 1,2-bis(diphenylphosphino)ethane palladium dichloride, or a combination thereof; the catalyst ligand is selected from the group consisting of: Tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-benzylphosphine, tricyclohexylphosphine, tri-o-benzylphosphine, or a combination thereof.

A class of preferred compounds of general formula (I) provided by the present invention includes but is not limited to the following structures:

, and the compound represented by the above general formula (I) does not contain the following structure:

Another object of the present invention is to provide a medicament and its composition for treating or preventing tumors or autoimmune diseases. The technical solutions to achieve the above purpose are as follows:

A pharmaceutical composition for the treatment or prevention of tumors or autoimmune diseases, comprising the nitrogen-containing fused ring compound represented by the above-mentioned general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer thereof , diastereomer, tautomer, torsion isomer, solvate, polymorph or prodrug and a pharmaceutically acceptable carrier.

Another object of the present invention is to provide a use of the above compound. The technical solutions to achieve the above purpose are as follows:

The nitrogen-containing fused ring compound represented by the general formula (I), or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, and torsion isomer Forms, solvates, polymorphs or prodrugs are used to prepare medicines for the treatment of diseases related to the activity or expression of MAT2a or MTAP protein, especially for the prevention or treatment of tumors 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.

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.

It should be understood that, within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be repeated here.

detailed description

After long-term and in-depth research, the inventor has prepared a kind of nitrogen-containing fused-ring compound with novel structure shown in formula I, and found that it has better inhibition of MAT2a enzyme activity, and the compound has a very low concentration ( It can be as low as less than 100 nM), that is, it has a specific inhibitory effect on MAT2a protein, and the inhibitory activity of cell proliferation related to MTAP deletion is quite excellent. Based on the above findings, the inventors have completed the present invention.

the term

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, publications cited throughout this document are incorporated by reference in their entirety unless otherwise indicated.

It is to be understood that both the foregoing brief description and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the invention in any way. In this application, the use of the singular also includes the plural unless specifically stated otherwise. It must be noted that the singular forms used in this specification and the claims include the plural forms of referents unless the context clearly dictates otherwise. It should also be noted that the use of "or" and "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms such as "comprising", "including" and "comprising" is not intended to be limiting.

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.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, _-CH2O- is equivalent to _-OCH2- .

Section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.

In addition to the foregoing, when used in the specification and claims of this application, the following terms have the meanings shown below unless specifically indicated otherwise.

In this application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxy" refers to the -OH group; "hydroxyalkyl" refers to an alkane as defined below substituted with a hydroxyl group (-OH). "carbonyl" refers to a -C(=O)- group; "nitro" refers to _-NO2 ; "cyano" refers to -CN; "amino" refers to _-NH2 ; "substituted amino" means an amino group substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl amino, heteroaralkylamino, wherein the substituted amino group can be further substituted by halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, cyano, alkylamino; "Carboxyl group"" refers to -COOH.

In this application, the term "alkyl" as a group or part of another group (eg, as used in a halogen-substituted alkyl group, etc.) means consisting only of carbon and hydrogen atoms, free from unsaturation A bond, a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.

In this application, the term "alkenyl" as a group or part of another group means consisting of carbon and hydrogen atoms only, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) a straight or branched hydrocarbon chain group, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, butan- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

In this application, the term "alkynyl" as a group or part of another group means consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having eg A straight or branched hydrocarbon chain group of 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl , prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.

In this application, the term "haloalkyl" as part of a group or other group means an alkyl group as described above substituted with 1-3 halogen atoms, such as fluoroalkyl, chloroalkyl, The alkyl group includes any number of carbon atoms, eg, methyl, ethyl, propyl, and the haloalkyl group includes, but is not limited to, trifluoromethyl.

In this application, the term "alkoxy" as part of a group or other group means alkyl-O-, eg, methoxy, ethoxy.

In this application, the term "haloalkoxy" as a group or part of another group means an alkoxy group as described above substituted with 1-3 halogen atoms, eg, trifluoromethoxy and the like.

In this application, the term "deuterated alkyl" as part of a group or other group means an alkyl group as described above substituted with 1-3 deuterium atoms.

In this application, the term "alkylamino" as a group or part of another group means an -alkyl-NH ₂ structure or a substituted amino-NR ^a R ^b , where R ^a and R ^b are each independently is hydrogen or an alkyl group as described above. For example, the term "monoalkylamino" refers to a substituted amino group -NR ^a R ^b , wherein one of R ^a and R ^b is hydrogen and the other is an alkyl group as described above; "dialkylamino" refers to a substituted Amino-NR ^a R ^b , wherein R ^a and R ^b are each independently an alkyl group as described above.

In this application, the term "haloalkylamino" as a group or part of another group means an -alkyl- _NH2 structure or ^{a substituted amino-NRaRb, where Ra and Rb are each independently} is hydrogen or haloalkyl as described above. For example, the term "monohaloalkylamino" refers to a substituted amino group -NR ^a R ^b , wherein one of R ^a and R ^b is hydrogen and the other is a haloalkyl group as described above; "dihaloalkylamino" refers to a substituted Amino-NR ^a R ^b , wherein R ^a and R ^b are each independently haloalkyl as described above.

In this application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused Ring systems, bridged ring systems or spiro ring systems, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and which are saturated or unsaturated and can be The carbon atoms are attached to the rest of the molecule by single bonds. Unless specifically stated otherwise in this specification, carbon atoms in a cycloalkyl group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2] octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octa Hydrogen-4,7-methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl, etc.

In this application, the term "heterocyclyl" as a group or part of another group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in this specification, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic or more ring ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of a can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl group can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and through a single bond. In heterocyclyl containing fused rings, one or more of the rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclyl group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonyl Alk-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indoline, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl , phthalimide, etc.

As used herein, as a group or as part of another group, the term "aryl" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or more ring system, and can also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazin-3(4H)-one-7-yl and the like.

In this application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.

In this application, as a group or part of another group, the term "heteroaryl" means a ring having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen 5- to 16-membered conjugated ring system groups of heteroatoms of , oxygen and sulfur. Unless specifically stated otherwise in this specification, a heteroaryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused to a cycloalkyl or heterocyclyl group as defined above, provided that the heterocyclic group The aryl group is attached to the rest of the molecule by a single bond through an atom on the aromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl group can optionally be oxidized; a nitrogen atom can optionally be quaternized. For the purposes of the present invention, a heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 selected heteroatoms. A stable 5- to 10-membered aromatic group from heteroatoms of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furanyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , purinyl, quinolinyl, isoquinolinyl, diazanaphthyl, naphthyridinyl, quinoxalinyl, pteridyl, carbazolyl, carboline, phenanthridine, phenanthroline, acridine base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxtriazolyl, cinnoline, quinazolinyl, phenylthio, indolizine, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]Triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.

In this application, the term "heteroarylalkyl" refers to an alkyl group, as defined above, substituted with a heteroaryl group, as defined above.

In this application, "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl groups.

The terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" as used herein refer to a specific fragment or functional group in a molecule. A chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.

"Stereoisomers" refer to compounds that consist of the same atoms, bonded by the same bonds, but have different three-dimensional structures. The present invention will cover various stereoisomers and mixtures thereof.

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.

"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) ).

In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

"Pharmaceutically acceptable acid addition salts" refers to salts with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include but are not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but are not limited to formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexamethylene Acid, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.

"Pharmaceutically acceptable base addition salts" refers to salts with inorganic or organic bases that retain the biological availability of the free acid without other adverse effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary, secondary and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperazine pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

"Polymorph" refers to the distinct solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more distinct 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 application, the term "prodrug" refers to a compound that can be converted into a 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.

As used herein, a "pharmaceutical composition" refers to a 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.

As used herein, the term "pharmaceutically acceptable" refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.

In this application, "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 a 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. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

The terms "drug combination," "drug combination," "combination," "administration of other treatments," "administration of other therapeutic agents," etc. as used herein refer to drug treatments obtained by admixing or combining more than one active ingredient, It includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or single dosage form. The term "unfixed combination" refers to the simultaneous administration, co-administration, or sequential administration of at least one compound described herein and at least one synergistic formulation at variable intervals to a patient as separate entities. These also apply to cocktail therapy, eg the administration of three or more active ingredients.

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 protecting group can also be a polymeric resin.

The main advantages of the present invention include:

The compounds of the present invention have excellent methionine adenosyltransferase (MAT2a) inhibitory effect, and the IC50 values are all less than 200 nM, and the lowest can be less than 10 nM.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

Example preparation

Example 1: 7-Methoxy-3-(4-methoxyphenyl)-1-phenyl-1,8-naphthyridin-2(1H)-one

The first step: under nitrogen protection, tridibenzylideneacetone dipalladium (Pd ₂ (dba) ₃ ) (477 mg, 0.520 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xantphos (301mg, 0.520mmol) was added sequentially to 2-chloro-6-methoxynicotinic aldehyde (890mg, 5.204mmol), aniline (484mg, 5.204mmol) and cesium carbonate (5.09g, 15.613mmol) ) in 1,4-dioxane (20 mL). The reaction mixture was heated to 120°C and reacted at this temperature for 2 hours. The reaction solution was diluted with ethyl acetate (EA) (100 mL), filtered through celite, the filtrate was concentrated under reduced pressure, and then column chromatography (petroleum ether:ethyl acetate=10:1) was performed to obtain a light yellow oily intermediate (1.02 g, crude product) . LC-MS (ESI) m/z: 229.0 [M+H] ⁺ . ¹ H-NMR (400MHz, DMSO-d ₆ )δ10.87(s, 1H), 9.75(s, 1H), 8.06(d, J=8.4Hz, 1H), 7.76(d, J=7.8Hz, 2H) ), 7.38(t, J=7.9Hz, 2H), 7.09(t, J=7.4Hz, 1H), 6.37(d, J=8.4Hz, 1H), 3.95(s, 3H).

The second step: under ice-water bath cooling, sodium hydride (NaH) (105 mg, 2.628 mmol) was added to a solution of the previous intermediate (200 mg, 0.876 mmol) in tetrahydrofuran (THF) (5 mL). After the reaction was raised to room temperature for half an hour, 2-(4-methoxyphenyl)acetyl chloride (178 mg, 0.964 mmol) was added dropwise. After the reaction mixture was reacted at room temperature for 2 hours, the reaction solution was diluted with ethyl acetate (100 mL), and then the reaction solution was washed with water (50 mL) and aqueous sodium chloride solution (50 mL). The organic phase was collected and dried over anhydrous sodium sulfate, concentrated, and the crude product was isolated to give the compound of Example 1 (off-white solid, 16.8 mg). LC-MS (ESI) m/z: 359.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.14 (t, J=4.2 Hz, 2H), 7.75-7.64 (m, 2H ),7.54(t,J＝7.5Hz,2H),7.49-7.43(m,1H),7.34(dd,J＝5.2,3.3Hz,2H),7.04-6.95(m,2H),6.73(d, J=8.4Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H).

Example 2-5

Synthesize with reference to the method of Example 1 to obtain the compounds of Examples 2-5;

Example 6: 6-Methoxy-2-(4-methoxyphenyl)-4-phenylpyridin[2,3-b]pyrazin-3(4H)-one

The first step: under nitrogen protection, Pd ₂ (dba) ₃ (984mg, 1.08mmol), Xantphos (622mg, 1.08mmol) were successively added to 2-chloro-6-methoxy-3-nitropyridine (4.04g, 21.42 mmol), aniline (1.0 g, 10.75 mmol) and cesium carbonate ( _{Cs2CO3 )} (10.5 g, 32.22 mmol) in 1,4-dioxane (50 mL). The reaction mixture was heated to 120°C and the reaction was continued at this temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), and then filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain a yellow solid intermediate (2.3 g). LC-MS (ESI) m/z: 246.0 [M+H] ⁺ . ¹ H NMR(400MHz, DMSO-d6)δ10.46(s,1H),8.44(d,J=9.1Hz,1H),7.72(d,J=7.7Hz,2H),7.40(t,J=7.9 Hz, 2H), 7.17 (t, J=7.4Hz, 1H), 6.38 (d, J=9.1Hz, 1H), 3.88 (s, 3H).

The second step: under nitrogen protection, the intermediate of the previous step (3.65 g, 14.88 mmol) and the palladium-carbon catalyst (365 mg, 3.44 mmol) were added to methanol (200 mL). After replacing the hydrogen, the reaction was carried out overnight at room temperature under a hydrogen atmosphere of 1 atm. The reaction solution was filtered with celite, and the filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate volume ratio 20:1 to 10:1) to obtain a black-purple solid intermediate (2.7 g, crude product). LC-MS (ESI) m/z: 216.1 [M+H] ⁺ . ¹ H-NMR(400MHz,DMSO-d6)δ7.72(s,1H),7.65(d,J=7.7Hz,2H),7.23(dd,J=8.4,7.5Hz,2H),6.98(d, J=8.1 Hz, 1H), 6.84 (t, J=7.3 Hz, 1H), 6.07 (d, J=8.1 Hz, 1H), 4.51 (s, 2H), 3.73 (s, 3H).

Step 3: At room temperature, acetic acid (0.6 mL) was added to the previous intermediate (300 mg, 1.395 mmol) and ethyl 4-methoxyphenyl-2-acetoacetate (435 mg, 2.092 mmol) in ethanol (10 mL) in solution. After the tube was sealed, the reaction was continued for 2 hours after the reaction was raised to 100 degrees. After the reaction was detected by liquid chromatography-mass spectrometry (LC-MS), the reaction solution was diluted with dichloromethane (100 mL), and the reaction solution was washed with water (50 mL), and then with aqueous sodium chloride solution (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was isolated by preparative HPLC to give Example 2 (pale yellow solid, 68.2 mg). LC-MS (ESI) m/z: 360.0[M+H]+. ¹ H NMR (400MHz, DMSO-d6) δ 8.35-8.26 (m, 2H), 8.21 (d, J=8.6Hz, 1H) ,7.65-7.54(m,2H),7.50(m,1H),7.43(m,2H),7.12-6.95(m,2H),6.83(d,J＝8.6Hz,1H),3.84(s,3H ), 3.53(s, 3H).

Examples 7-10

Synthesize with reference to the method of Example 6 to obtain the compounds of Examples 7-10:

Examples 11-16

Synthesize with reference to the method of Example 1 to obtain the compounds of Examples 11-16:

Example 17: 7-Methoxy-3-(4-methoxyphenyl)-4-methyl-1-phenyl-1,8-naphthyridin-2(1H)-one

The first step: under nitrogen protection, Pd ₂ (dba) ₃ (411mg, 0.449mmol), Xantphos (260mg, 0.449mmol) were successively added to 2-chloro-6-methoxy-nicotinic acid methyl ester (902mg, 4.49mmol) ), aniline (418 mg, 4.49 mmol) and cesium carbonate (4.39 g, 13.46 mmol) in 1,4-dioxane (20 mL). The reaction mixture was heated to 120°C and the reaction was continued at this temperature for 2 hours. The reaction solution was diluted with ethyl acetate (100 mL), and then filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a yellow solid intermediate (826 mg). LC-MS (ESI) m/z: 259.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.13 (d, J=8.6 Hz, 1H), 7.71 (d, J＝7.8Hz, 2H), 7.35(t, J＝7.8Hz, 2H), 7.05(t, J＝7.3Hz, 1H), 6.27(d, J＝8.6Hz, 1H), 3.91(s , 3H), 3.85(s, 3H).

The second step: under ice bath, lithium bis(trimethylsilyl)amide (3.34 mL, 3.34 mmol) was added to the tetrahydrofuran (20 mL) solution of the above intermediate (430 mg, 1.67 mmol), and the reaction mixture was here The reaction was carried out at temperature for 2 hours. p-Methoxyphenylacetyl chloride (400 mg, 2.17 mmol) was added to the above mixture, and the reaction mixture was continued to react at this temperature for 2 hours. The completion of the reaction was detected by LC-MS. The reaction solution was diluted with ethyl acetate (200 mL), the pH was adjusted to neutrality with 1N aqueous hydrochloric acid solution, and the organic phase was washed with aqueous ammonium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, the filtered filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio 1:1) to obtain a pale yellow solid intermediate (250 mg). LC-MS (ESI) m/z: 375.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.29 (br.s, 1H), 8.29 (d, J=8.6 Hz, 1H) ,7.56-7.46(m,2H),7.45-7.38(m,1H),7.30(m,4H),7.00-6.92(m,2H),6.70(d,J＝8.6Hz,1H),3.79(s , 3H), 3.47(s, 3H).

The third step: under nitrogen protection, trifluoromethanesulfonic anhydride (738 mg, 2.619 mmol) was added to the pyridine (8 mL) solution of the above intermediate (245 mg, 0.655 mmol), and the reaction mixture was reacted at 70 degrees for 16 hours. The reaction was complete by LCMS. The reaction solution was diluted with dichloromethane (200 mL), and the organic phase was washed with aqueous ammonium chloride. The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a pale yellow solid compound (120 mg, 36.2%). LCMS (ESI) m/z: 508.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-D6) δ 8.05 (d, J=8.7 Hz, 1 H), 7.59-7.53 (m, 2H), 7.51 -7.45(m, 1H), 7.42(m, 4H), 7.07-7.00(m, 2H), 6.95(d, J=8.7Hz, 1H), 3.81(s, 3H), 3.52(s, 3H).

The fourth step: under nitrogen protection, tetrakis (triphenylphosphine) palladium (Pd(PPh ₃ ) ₄ ) (28mg, 0.024mmol) was added to the above-mentioned intermediate (120mg, 0.237mmol), methylboronic acid (142mg, 2.37mmol) ) and potassium phosphate (151 mg, 0.711 mmol) in 1,4-dioxane (20 mL). The reaction mixture was reacted at 100 degrees for 2 hours. The disappearance of starting material was detected by LC-MS. The reaction solution was diluted with ethyl acetate (200 mL), and the organic phase was washed with aqueous sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated, and the crude product was isolated by preparation to give a white solid product (18 mg). LC-MS (ESI) m/z: 373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J=8.7 Hz, 1 H), 7.52 (m, 2H), 7.43 (m,1H),7.35-7.26(d,J=8.4Hz,2H),7.22(d,J=8.7Hz,2H),6.98(d,J=8.7Hz,2H),6.74(d,J= 8.6Hz, 1H), 3.80(s, 3H), 3.47(s, 3H), 2.31(s, 3H).

Example 18: 1-(4-Chlorobenzene)-3-(2-methyl-2H-indazol-5-yl)-7-((2,2,2-trifluoroethyl)amino)- 1,8-Naphthyridin-2(1H)-one

The first step: 6-chloro-2-((4-chlorophenyl)amino)nicotinaldehyde (3.4g, 12.8mmol), 2-bromo-2-phosphoryl acetate triethyl ester (5.1g, 16.6mmol), DBU (2.9 g, 19.2 mmol), lithium chloride (965 mg, 23 mmol) were dissolved in acetonitrile (200 mL), reacted at room temperature for 4 hours, and then refluxed overnight. After the reaction mixture was concentrated, the crude product was purified by silica gel column chromatography (PE/EA=3:1) to obtain a yellow solid product (970 mg). LC-MS [M+H] ⁺ : m/z 368.9.

The second step: under nitrogen protection, the above intermediate (870mg, 2.4mmol), 2-methyl-5-indazole boronic acid pinacol ester (928mg, 3.6mmol), dichloro[1,1'-bis (tert-butylphosphine) ferrocene palladium (78 mg, 0.1 mmol) and potassium phosphate (1.5 g, 7.2 mmol) were dissolved in dioxane (40 mL) and water (8 mL) and reacted at 60° C. for 2 hours. After the reaction solution was concentrated, it was purified by silica gel column chromatography (PE/EA=3:1) to obtain a yellow solid product (600 mg). LC-MS [M+H] ⁺ : m/z 421.0.

The third step: the above intermediate (50mg, 0.1mmol), 2,2,2-trifluoroethylamine (120mg, 1.0mmol), DIEA (46mg, 0.4mmol) were dissolved in N-methylpyrrolidone (2mL) in the microwave at 200°C for 2 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed twice with water (10 mL), and the separated organic phase was dried and concentrated. The crude product was prepared by HPLC to give the compound as a white solid (12.84 mg). LC-MS [M+H] ⁺ : m/z 484.1. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.37 (s, 1H), 8.08 (s, 2H), 7.90 (t, J=7.8 Hz, 2H), 7.65-7.41 (m, 4H), 7.39 -7.18(m, 2H), 6.55(d, J=8.5Hz, 1H), 4.17(s, 3H), 3.77(m, 2H).

Examples 19-39, 43-52

Synthesized according to the method of Example 18 to obtain the compounds of Examples 19-39 and 43-52.

Example 54: 1-(4-Chlorobenzene)-3-(3-methoxy-2-(deuteromethyl)-2H-indazol-5-yl)-7-((2,2,2 -Trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

Step 1: Dissolve 4-bromo-2-(bromomethyl)-1-nitrobenzene (1.2 g, 4.0 mmol) in ethanol (50 mL), add triethylamine (404.1 mg, 4.0 mmol) and deuterium methylamine (2 mL, 4.1 mmol), and the reaction was heated to 80 degrees overnight. After the reaction solution was concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain a white solid compound (201 mg). LC-MS [M+H] ⁺ : m/z 248.0/250.0.

The second step: to the mixed solution of the above compound (50 mg, 0.2 mmol) in MeOH/H ₂ O (9 mL/1 mL), potassium hydroxide KOH (112 mg, 2.0 mmol) was added, and the reaction was carried out at 65 degrees overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=4:1) to obtain a white solid compound (30 mg). LC-MS [M+H] ⁺ : m/z 244.1/246.1.

The third step: under nitrogen protection, to the above compound (100mg, 0.41mmol), pinacol biboronate (117mg, 0.46mmol) and potassium acetate (123.4mg, 1.26mmol) in 1,4-dioxane (20 mL), the catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium Pd(dppf)Cl ₂ (34.1 mg, 0.042 mmol) was added, and the reaction was carried out at 75 degrees for 4 hours . The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE:EA=5:1) to obtain a white solid compound (60 mg). LC-MS [M+H] ⁺ : m/z 292.1.

The fourth step: under nitrogen protection, to the above intermediate compound (60mg, 0.2mmol), 3-bromo 7-chloro-1-(4-chlorobenzene)-1,8-naphthyridin-2(1H)-one (80.0 mg, 0.21 mmol) and potassium phosphate (127.2 mg, 0.6 mmol) in dioxane/ _H2O (12 mL/ ₂ mL) was added Pd(dppf)Cl2 (14.1 mg, 0.02 mmol). The reaction solution was heated to 70°C and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM/MeOH=10:1) to obtain a yellow solid compound (60.1 mg). LC-MS [M+H] ⁺ : m/z 454.0/456.0.

The fifth step: the above intermediate compound (60.0mg, 0.13mmol), 2,2,2-trifluoroethylamine (128.7mg, 1.3mmol), diisopropylethyldiamine DIEA (46mg, 0.4mmol) ) was dissolved in NMP (2 mL), and the reaction was microwaved at 200 °C for 2 h. The crude product was prepared by reverse phase to give the compound as a yellow solid (1.02 mg). LC-MS [M+H] ⁺ : m/z 517.1. ¹ H-NMR (400MHz, DMSO-d ₆ ): δ 8.14 (s, 1H), 8.03 (s, 1H), 7.96 (dd, J=7.6, 1.6 Hz, 1H), 7.90 (m, 2H), 7.52-7.58(m, 3H), 7.33(d, J=8.4Hz, 2H), 6.56(m, 1H), 3.78-3.81(m, 2H), 3.35(s, 3H).

Examples 55-65

Synthesize with reference to the methods of Examples 34, 53, 54, and 66, and replace deuterated methylamine with methylamine, or replace methanol with deuterated methanol, to obtain the compounds of Examples 55-65, 94.

Example 40: 1-(4-Chlorobenzene)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-((2,2,2-trifluoroethyl) amino)-1,8-naphthyridin-2(1H)-one

The first step: The compound 4-chloroaniline (6.4 g, 50.0 mmol) was dissolved in THF (60 mL), and lithium hexamethyldisilazide LiHMDS (76 mL, 76.0 mmol) was added dropwise at -60 °C, and the reaction was performed for 1 h. , and 2,6-dichloro-5-fluoronicotinic acid (5.0 g, 23.8 mmol) was added. After the dropwise addition, the reaction was returned to room temperature for 4 hours. After quenching with water (10 mL), the pH was adjusted to 2 with 5M aqueous hydrochloric acid and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine, dried and concentrated. The obtained crude product was slurried with ethyl acetate (30 mL) to obtain a yellow solid intermediate product (6.1 g). LC-MS [M+H] ⁺ : m/z 301.0.

The second step: The above intermediate product (6.1 g, 20.3 mmol) was dissolved in THF (40 mL), and borane tetrahydrofuran solution (61 mL, 61 mmol) was added dropwise at 0°C. After the dropwise addition, the reaction was carried out at room temperature for 2 hours. It was quenched by adding methanol (50 mL), stirred for half an hour, and then concentrated. The crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain a yellow crude intermediate (5.8 g). LC-MS [M+H] ⁺ : m/z 287.1.

The third step: the above intermediate product (5.8 g, 20.2 mmol) was dissolved in DCM (50 mL), Dess-Martin reagent (17.2 g, 40.4 mmol) was added at 0° C., and the reaction was carried out at room temperature for 2 hours. It was quenched with Na2S2O3 ₍ 30 mL ₎ followed by _NaHCO3 (30 mL) and extracted _three times with dichloromethane (50 mL). The combined organic phases were washed with saturated brine, dried and concentrated. The obtained crude product was purified by silica gel column chromatography (PE:EA=10:1) to obtain a yellow solid intermediate (2.2 g). LC-MS [MH] ^- : m/z 283.0.

The fourth step: the above-mentioned intermediate compound (2.2g, 7.7mmol), 2-bromo-2-(diethoxyphosphoryl) ethyl acetate (3.1g, 10.1mmol), DBU (1.8g, 11.6mmol) , LiCl (583 mg, 13.9 mmol) was dissolved in acetonitrile (50 mL), reacted at room temperature for 4 hours, and then refluxed overnight. The reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column chromatography (PE:EA=2:1) to obtain a yellow solid intermediate product (300 mg). LC-MS[M+H] ⁺ : m/z 386.9

Step 5: Dissolve the above intermediate compound (700mg, 1.8mmol) in DMSO (4mL), add potassium fluoride (526mg, 9.1mmol) and 2,2,2-trifluoroethylamine (2mL), microwave The reaction was carried out at 150°C for 1.5 hours. Water (10 mL) was added to dilute, and the mixture was extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine and dried. After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (PE:EA=2:1) to obtain a yellow solid product (500 mg). LC-MS [M+H] ⁺ : m/z 450.0.

The sixth step: compound the above intermediate product (60mg, 0.13mmol), 2-methyl-5-indazole boronic acid pinacol ester (36mg, 0.14mmol), dichloro[1,1'-bis(tert-butyl) phosphine) ferrocene palladium (8 mg, 0.01 mmol), potassium phosphate (85 mg, 0.39 mmol) were dissolved in dioxane/H ₂ O (10 mL/2 mL), and reacted at 60° C. for 1 h under nitrogen protection. Concentration and reverse phase preparation gave the desired product as a yellow solid (23 mg). LC-MS [M+H] ⁺ : m/z 502.0. ¹ H NMR(400MHz, DMSO)δ8.38(s,1H),8.08-8.05(m,3H),7.94(d,J=10.8Hz,1H),7.69-7.44(m,4H),7.33(d , J=8.8Hz, 2H), 4.18(s, 3H), 3.88-3.61(m, 2H).

Synthesized according to the method of Example 40 to obtain Examples 41-42, 53, 66-67.

Example 68: 1-(4-Chlorobenzene)-3-(3,4-dihydro-2H-[1,3]oxazin[3,2-b]indazol-9-yl)-7-( (2,2,2-Trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

Step 1: Dissolve 5-bromo-2-nitrobenzaldehyde (1.0g, 2mmol) and 3-amino-1-propanol (625mg, 8.7mmol) in ethanol (20mL), add tetraisopropyl titanate After the ester (4.9 g, 17.2 mmol) was reacted at room temperature overnight, sodium borohydride (245 mg, 6.5 mmol) was added, and the reaction was continued at room temperature for 6 hours. Ammonia water (6 mL) was added to quench the reaction, the reaction solution was filtered, the filtrate was dried and concentrated, and the obtained crude product was purified by silica gel column chromatography (eluted with pure EtOAc) to obtain a yellow solid (780 mg). LC-MS [M+H] ⁺ : m/z 289.0.

The second step: KOH (607 mg, 10.8 mmol) was added to the mixed solution of the above compound (780 mg, 2.7 mmol) in tert-butanol and water (15 mL/5 mL), and reacted at 85° C. for 5 hours. Diluted with water (45 mL), extracted three times with ethyl acetate (50 mL), the combined organic phases were dried over MgSO ₄ , after filtration, the organic phases were concentrated and the resulting crude product was purified by silica gel column chromatography (eluting with pure EtOAc) to give a yellow solid (540mg). LC-MS [M+H] ⁺ : m/z 252.9.

The third step: under nitrogen protection, the above intermediate compound (540mg, 2.1mmol), pinacol biboronate (707mg, 2.7mmol), potassium acetate KOAc (617mg, 6.3mmol) was dissolved in 1,4-di Oxane (10 mL), catalyst Pd(dppf)Cl ₂ (146 mg, 0.2 mmol) was added, and the reaction was carried out at 90° C. overnight. After cooling to room temperature, the reaction solution was filtered, and the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (100% EA) to obtain a yellow crude product (520 mg). LC-MS [M+H] ⁺ : m/z 301.1.

The fourth step: under nitrogen protection, to the above intermediate compound (123mg, 0.41mmol), 3-bromo 7-chloro-1-(4-chlorobenzene)-1,8-naphthyridin-2(1H)-one (150 mg, 0.41 mmol) and potassium phosphate (260 mg, 1.31 mmol) in dioxane/ _H2O (3 mL/0.5 mL) was added Pd(dppf)Cl2 ( ₂₆ mg, 0.04 mmol). The reaction solution was heated to 70°C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with pure ethyl acetate) to give a yellow solid compound (84 mg). LC-MS [M+H] ⁺ : m/z 463.0.

The fifth step: the above intermediate compound (84mg, 0.18mmol), 2,2,2-trifluoroethylamine (1mL), potassium fluoride KF (54mg, 0.90mmol) was dissolved in DMSO (2mL), microwave 150 ℃ reaction 4h. The crude product was prepared by reverse phase to give the compound as a yellow solid (22 mg). LC-MS [M+H] ⁺ : m/z 526.0. ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.08(s, 1H), 7.94(s, 1H), 7.90-7.85(m, 2H), 7.59-7.55(m, 3H), 7.37(d, J=9.2Hz, 1H), 7.35-7.30(m, 2H), 6.55(d, J=8.4Hz, 1H), 4.53(t, J=5.2Hz, 2H), 4.39(t, J=6.0Hz, 2H), 3.80-3.73 (m, 2H), 2.37-2.31 (m, 2H).

The following boronic acid (or boronic acid) and bromo-pyrimidopyridone intermediates of the indazolo ring were synthesized with reference to Example 68 and the synthetic methods reported in the literature:

Examples 69-93

Synthesized according to the method of Example 68, using different boronic ester (or boronic acid) intermediates of indazolo ring instead of 3,4-dihydro-2H-[1,3]oxazine[3,2-b]indium oxazole-9-boronic acid pinacol ester to give Examples 69-93.

Test Example 1 MAT2a Enzyme Inhibitory Activity Test

Colorimetric Assay was used to test the enzymatic inhibitory activity of the compounds in the examples against 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 serum Albumin) was configured with 10 compound concentration gradients: the test compound test concentration was 10uM initial, 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 Echo550 to transfer 250nL to 384 reaction plate for use. Add 250nL of 100% DMSO-D6 to the negative control wells and positive control wells respectively. 2) Use standard reaction buffer to prepare an enzyme solution with a final concentration of 1.67 times. 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. (A represents _IC50 <100nM, B represents _100nM≤IC50 <500nM, C represents _IC50≥500nM ).

Results: Most of the example compounds of the present invention have high MAT2a inhibitory activity, the IC ₅₀ of most example compounds is less than 200 nM, and the IC ₅₀ of some examples is even less than 10 nM.

serial number	MAT2a IC50 (nM)	serial number	MAT2a IC50 (nM)	serial number	MAT2a IC50 (nM)
1	55.1	2	101.7	3	A
4	A	5	A	6	A
7	A	8	A	9	A
10	A	11	24.9	12	24.5
13	97.6	14	23.4	15	61.7
16	160.5	17	132	18	6.9
19	7.9	20	7.2	twenty one	C
twenty two	7.7	twenty three	7.3	twenty four	19.6
25	17.1	26	17.3	27	27.3
28	10.8	29	20.3	30	A
31	A	32	A	33	A
34	16.1	35	19.1	36	C
37	16.9	38	20.1	39	A
40	11.0	41	A	42	A
43	13.9	44	16.2	45	29
46	18.3	47	16.7	48	A
49	A	50	A	51	A
52	A	53	A	54	18.7
55	A	56	A	57	A
58	14.4	59	18.0	60	31.6
61	22.0	62	20.6	63	A
64	A	65	A	66	17.8
67	A	68	A	69	A

70	A	71	A	72	A
73	A	74	20.7	75	A
76	17.2	77	A	78	A
79	A	80	A	81	A
82	A	83	A	84	A
85	A	86	A	87	A
88	A	89	A	90	A
91	A	92	A	93	A
94	A

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

1. Experimental reagents:

2. Cell line:

cell line	Culture type	source	culture medium
HCT116MTAP	Adherent	Horizon	RPMI-1640+10%FBS
HCT116wt	Adherent	Horizon	RPMI-1640+10%FBS

3. Test steps: 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, with 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: Most of the example compounds of the present invention are examples 11, 12, 14, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 34, 35, 37, 38, 40, 43-62, the IC ₅₀ for inhibiting HCT-116 ^MTAP -cell proliferation is less than 1 uM, as in Examples 18, 34, 37, 38, 39, 40, 42, 43, 44, 48, 49, 50, 53-78, etc. The inhibitory activity IC ₅₀ is less than 100nM; and the proliferation inhibitory activity IC ₅₀ of all the example compounds of the present invention on HCT-116 ^wt cells is greater than 5uM, and some example compounds are such as Examples 12, 14, 18, 20, 22, 23 , 34, 37, 40, 46, 47, 50, 53, 55-62, and 68 had an IC ₅₀ of inhibiting proliferation of HCT-116 ^wt cells, which was more than 10uM, 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 (rat, mouse, dog, monkey, human), and the half-life is more than 20min, such as example compounds 18, 34, 40, 54, 58, 59, 74, 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 (1 mg/kg), and the other group was orally administered Dosing (5 mg/kg). 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, when calculating the pharmacokinetic parameters, the sample taken before reaching _Cmax should be calculated as zero value, and the sample at the sampling point after reaching _Cmax should be calculated as non-quantitative (BLQ).

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.

Claims (21)

1. A nitrogen-containing condensed ring compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or its enantiomer, diastereomer, tautomer, torsion isomer , solvates, polymorphs or prodrugs,

   

   In the formula: R ¹ and R ³ are independently selected from 5-12-membered monocyclic or bi-cyclic aromatic or heteroaryl rings, and the aromatic or heteroaromatic rings may be substituted by 1-3 different is substituted by Rn, the Rn is selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, urea, phosphoryl, alkylphosphooxy, alkylsilyl, C ₁ - _C6 alkyl, _C1 - _C6 alkoxy, haloalkyl, haloalkoxy, _C1 - _C6 monoalkylamino, _C1 - _C6 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.; or two of the above Each Rn can form a 3-12-membered saturated or partially unsaturated or aromatic ring system through carbon chains or heteroatoms;

   R ² is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, nitro, amino, C ₁ -C ₁₂ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-S-, C ₁ - _C6alkyl -SO-, C1- _C6alkyl - _SO2- , _{C1 - C6alkyl} -O-, _C1 -C6haloalkyl-O-, _{C1 - C6mono} Alkylamino, C ₁ -C ₆ dialkylamino, 3-12-membered cycloalkylamino or heterocycloalkylamino, 3-12-membered cycloalkyl or heterocycloalkyl, 3-12-membered halocycloalkane group 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;

   W, X, Y are independently selected from CR ⁴ or N; wherein R ⁴ is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, 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 halogenated cycloalkyl or halogenated heterocycloalkyl, 3-12-membered cycloalkyl-O-, 3-12-membered halogenated cycloalkyl-O-, 3-12-membered heterocycloalkyl-O-, 5-12-membered aryl or 5-12-membered heteroaryl; or -X=Y- can be independently selected from -O- or -S-;

   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.
2. The compound according to claim 1, characterized in that it is preferably a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or isomer thereof. Variant, torsion isomer, solvate, polymorph or prodrug:

   

   wherein R ⁵ , R ⁶ and R ⁷ are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, 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; R ¹ , R ² , R ³ are as defined in claim 1 .
3. The compound according to claim 1, characterized in that it is preferably a compound represented by the general formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or isomer thereof. Variant, torsion isomer, solvate, polymorph or prodrug:

   

   Wherein: M ₁ is preferably selected from CH or N, M ₂ is preferably selected from O, S, NH, etc.;

   

   Preferably from single bond or double bond; R ⁸ is preferably from hydrogen, deuterium, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ -halogenated alkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; R ³ is preferably selected from phenylcyclyl, pyridinecyclyl, thiazolecyclyl, imidazole ring, indolecyclyl, indazolecyclyl, indoline base, isoindazole ring group, isoindoline ring group, benzofuranyl group, benzodihydrofuranyl group, pyridofuranyl group, pyridodihydrofuranyl group, benzimidazolyl group, benzoxazolyl group, Benzothiazolyl, pyridoimidazolyl, pyridooxazolyl, pyridothiazolyl, naphthylcyclyl, quinolinecyclyl, isoquinolinecyclyl, quinazolinylcyclyl, benzomorpholinyl, benzo Dioxane, etc., the above R ³ ring can be substituted by one or more groups selected from the group consisting of 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; R ² , R ³ , W, X, Y are as defined in the claims as defined in 1.
4. The compound of claim 1, wherein R ¹ is selected from a 5-12-membered monocyclic aryl or heteroaryl ring, and the aryl or heteroaryl ring may be substituted by 1-3 substituents Replaced by Rn, the Rn is selected from hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino; or the above two Rn can form a 3-6 membered saturated ring system through a carbon chain or a heteroatom.
5. The compound of claim 1, wherein R ¹ is selected from a 5-6 membered monocyclic aryl or heteroaryl ring, and the aryl or heteroaryl ring may be substituted by 1-3 groups substituted by Rn, wherein said Rn is selected from halogen, _C1 - _C6 haloalkyl, _C1 - _C6 haloalkoxy.
6. The compound of claim 1, wherein R ² is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ haloalkyl-O-, C ₁ -C ₆ monoalkylamino, C ₁ -C ₆ dialkylamino, C ₁ -C ₆ monohaloalkylamino, C ₁ -C ₆ dihaloalkylamino , C ₁ -C ₆ alkyl-S-.
7. The compound of claim 1, wherein R ² is selected from halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-O-, C ₁ -C ₆ haloalkyl-O-, -NR ^a R ^b , C ₁ -C ₆ monohaloalkylamino, C ₁ -C ₆ dihaloalkylamino, C ₁ -C ₆ alkyl-S-, wherein R ^a and R ^b Each is independently selected from hydrogen, deuterium, _C1 - _C6 alkyl, _C1 - _C6 haloalkyl.
8. The compound of claim 1, wherein R ² is selected from C ₁ -C ₆ alkyl-O-, -NR ^a R ^b , wherein R ^a and R ^b are each independently selected from hydrogen, deuterium, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl.
9. The compound of claim 1, wherein R ³ is selected from 5-12 membered (eg 5, 6, 7, 8, 9, 10, 11, 12) monocyclic or bicyclic aryl or heterocyclic Aryl ring, said aryl or heteroaryl ring may be substituted by 1-3 substituents Rn as claimed in claim 1.
10. The compound of claim 1, wherein R ³ is selected from phenyl, indazolyl, quinolyl, benzimidazolyl, benzothiazolyl, which can be composed of 1-3 as claimed in claim 1 Substituted with the defined substituents Rn.
11. The compound of claim 1, wherein R ³ is selected from a 5-12-membered bi-cycloaryl or heteroaryl ring, and the bi-cycloaryl or heteroaryl ring can be replaced by a 1- Substituted by 3 substituents Rn as defined in claim 1.
12. The compound of claim 1, wherein R ³ is selected from a 5- to 12-membered bi-cycloaryl or heteroaryl ring, and the bi-cycloaryl or heteroaryl ring can be replaced by a 2- Substituted by 3 substituents Rn, wherein two substituents Rn are adjacent, and the two adjacent Rn constitute a substituted or unsubstituted 3-6-membered (such as 3, 4, 5, 6) through carbon chains or heteroatoms. )ring.
13. The compound of claim 1, wherein Rn is selected from the group consisting of hydrogen, deuterium, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ - C ₆ deuterated alkyl, C ₁ -C ₆ deuterated alkoxy, alkenyl, alkynyl, C ₁ -C ₆ alkyl-S-, C ₁ -C ₆ alkyl-SO-, C ₁ -C ₆ alkyl-SO ₂ -.
14. The compound of claim 12, wherein the two adjacent Rn form a 5-6-membered saturated or partially unsaturated or Aromatic ring systems in which one or more atoms in the ring system can be further oxidized to form =O.
15. The compound of claim 12, wherein the two adjacent Rn form a 5-6 membered saturated carbocycle or a saturated heterocycle through a carbon chain or 1-3 heteroatoms selected from N, O, and S , wherein one or more atoms in the saturated carbocyclic or saturated heterocyclic ring can be further oxidized to form =O.
16. The compound of claim 1, wherein W, X, Y, R1, R2 and R3 are each independently the corresponding groups in the compounds 1-94 prepared in the examples.
17. The compound of claim 1, wherein the compound is any one of Compounds 1-94 prepared in the Examples or a pharmaceutically acceptable salt thereof.
18. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer, A solvate, polymorph or prodrug, characterized in that the compound has the following structure:

    

    

    

    , and the compound represented by the above general formula (I) does not contain the following structure:

    
19. A method for preparing a compound of formula I, characterized in that the method mainly comprises the following steps c and d:

    c: compound of general formula (C) and 2-bromophosphoryl acetate (D) are closed under base catalysis to generate intermediate compound of general formula (E);

    d: the compound of the general formula (E) is combined with a substituted arylboronic acid (or ester), an aryltin reagent or an arylsilicon reagent to generate a compound of the general formula (I) through a coupling reaction catalyzed by a transition metal complex;

    

    Wherein Ra is hydroxyl, chlorine, alkoxy, ester group; Rb is hydrogen or alkyl; Rd is phosphoryl ester; R ¹ , R ² , R ³ , W, X, Y are defined as in claim 1 .
20. Comprising a compound of formula I as claimed in any one of claims 1-3 or 18, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion thereof A pharmaceutical composition composed of isomers, solvates, polymorphs or prodrugs, characterized in that 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.
21. A compound of formula I as claimed in any one of claims 1-3 or 18, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsion isomer thereof Constituents, solvates, polymorphs or prodrugs or the use of the pharmaceutical composition according to claim 20, characterized in that, for the preparation of drugs for treating or preventing diseases related to MAT2a or MTAP protein activity or expression , especially the therapeutic drug of tumor or autoimmune disease; Said tumor is independently selected from 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, astrocytoma, basal cell carcinoma, osteosarcoma, head and neck cancer, chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma and mesothelioma etc.; the autoimmune diseases are independently selected from thyroiditis, inflammatory bowel disease, erythematosus, fibrosis, myasthenia, vasculitis, psoriasis, arthritis, scleroderma, dermatitis and the like.