Process for the preparation of a class of nitrogen-containing fused ring compounds and uses thereof

Abstract

The application discloses a preparation method and application of a nitrogen-containing fused ring compound, and particularly relates to a nitrogen-containing fused ring compound as shown in a general formula I, or a pharmaceutically acceptable salt, or an enantiomer, diastereoisomer, tautomer, torsion isomer, solvate, polymorph or prodrug thereof, a preparation method and pharmaceutical application thereof, wherein definitions of each group are described in the description.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a class of nitrogen-containing fused ring compounds, which have the activity of inhibiting methionine adenosyltransferase (MAT2a) and can be used for preparing drugs for treating and preventing diseases related to the activity or expression of MAT2a or MTAP. BACKGROUND

[0002] Methionine adenosyltransferase (MAT) (also known as S-adenosylmethionine synthetase) is a cellular enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM or AdoMet) from methionine and ATP, and is considered to be the rate-limiting step of the methionine cycle. SAM is a propylamino donor in polyamine biosynthesis and is the main methyl donor for DNA methylation, and it is involved in gene transcription and cell proliferation as well as the production of secondary metabolites. It is found by pharmacological methods 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.

[0003] Methylthioadenosine phosphorylase (MTAP) is involved in the methionine salvage synthesis pathway, which metabolizes methylthioadenosine (MTA) to generate adenine and methionine. MTAP is located on chromosome 9p21, close to the tumor suppressor gene CDKN2A, and MTAP deficiency exists in various tumors such as leukemia, glioma, melanoma, lung cancer, ovarian cancer, endometrial cancer, breast cancer, etc. Among them, the deletion rate in brain glioma is 41%, in mesothelial carcinoma is 31%, and in pancreatic cancer is 26%. S-adenosyl-L-methionine (SAM) is an enzyme cofactor that can participate in methylation and polyamine biosynthesis, which can be generated by the reaction of ATP and L-methionine under the catalysis of methionine adenosyltransferase family (MAT) protein. In mammalian tissues, there are mainly two different isozymes of MAT gene, which are encoded by MAT1a and MAT2a. MAT1a is only expressed in adult liver tissue and has liver specificity, 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, and studies have shown that upregulation of MAT2a expression exists in various cancer cells and knocking out MAT2a gene can cause cancer cell death, and MTAP-deficient tumors are most sensitive. Therefore, MAT2a is a potential therapeutic target for MTAP-deficient tumors. Finding and searching for MAT2a inhibitors with novel structure and excellent drug properties has become a hot spot for the research and development of drugs for treating MTAP-deficient tumors. SUMMARY

[0004] One of the technical problems to be solved by the present application is to provide a new MAT2a inhibitor for preparing a tumor treatment drug.

[0005] The technical problem is solved by the following solution:

[0006] A nitrogen-containing fused ring compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof,

[0007]

[0008] In the formula:

[0009] R 1 and R 3 are each independently selected from a 5-12 membered monocyclic or bi-cyclic aromatic or heteroaromatic ring, which can be substituted with 1-3 different substituents Rn selected from hydrogen, deuterium, halogen, cyano, nitro, amide, sulfonamide, hydroxyl, amino, ureido, phosphoryl, alkylphosphoryl, alkylsilyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 monoalkylamino, C1-C6 dialkylamino, alkenyl, alkynyl, 3-8 membered cycloalkyl or heterocycloalkyl, C1-C6 alkyl-S-, C1-C6 alkyl-SO-, C1-C6 alkyl-SO2-, etc.; or the two Rn can form a 3-12 membered saturated or partially unsaturated or aromatic ring system through a carbon chain or heteroatom;

[0010] R 2 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, C1-C 12 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S-, C1-C6 alkyl-SO-, C1-C6 alkyl-SO2-, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monoalkylamino, C1-C6 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;

[0011] W, X, Y are each independently selected from CR 4 or N; wherein R 4 is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, C1-C 12Alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S-, C1-C6 alkyl-SO-, C1-C6 alkyl-SO2-, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monoalkylamino, C1-C6 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 -X=Y- can be independently selected from -O- or -S-.

[0012] One or more hydrogen atoms on any of the above groups may be substituted by substituents selected from the group consisting of, but not limited to, deuterium, halogen, C1-C8 alkyl, C3-C8 cycloalkyl, amino, and C1-C8 alkylamino; wherein, the heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, P or S, the heterocycloalkyl group comprises 1-3 heteroatoms selected from the group consisting of N, O, P or S, and the ring system comprises saturated or partially unsaturated ring systems such as spirocyclic, bridged, fused, and fused rings.

[0013] In some preferred embodiments, a compound of general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph, or prodrug thereof, preferably a compound of general formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, torsional isomer, solvate, polymorph, or prodrug thereof:

[0014]

[0015] Where R 5 R 6 R 7 Each group is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, nitro, amino, and C1-C. 12 Alkyl, C1-C6 haloalkyl, C1-C6 alkyl-S-, C1-C6 alkyl-SO-, C1-C6 alkyl-SO2-, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monoalkylamino, C1-C6 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 The definition is as shown above.

[0016] In some preferred embodiments, it is preferably a compound of general formula (III), or a pharmaceutically acceptable salt, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof:

[0017]

[0018] wherein: M1is preferably selected from CH or N, M2is preferably selected from O, S, NH, etc; is preferably selected from a single bond or a double bond; R 8 is preferably selected from hydrogen, deuterium, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; R 3 is preferably selected from phenyl, pyridyl, thiazolyl, imidazolyl, indolyl, indazolyl, indolinyl, isoindazolyl, isoindolinyl, benzofuranyl, benzodihydrofuranyl, pyridofuranyl, pyridodihydrofuranyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, pyridimidazolyl, pyridoxazolyl, pyridothiazolyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, benzomorpholinyl, benzodioxanyl, etc., and the above R 3 may be substituted on the ring by one or more groups selected from hydrogen, deuterium, halogen, cyano, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, 3-8 membered cycloalkyl or heterocycloalkyl; R 2 , R 3 , W, X, Y are defined as above.

[0019] In some preferred embodiments, R 1 is preferably selected from a 5-12 membered monocyclic aryl or heteroaryl ring, which can be substituted by 1-3 substituents Rnselected from hydrogen, deuterium, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, C1-C6monoalkylamino, C1-C6dialkylamino; or the above two Rncan form a 3-6 membered saturated ring system through a carbon chain or a heteroatom.

[0020] In some preferred embodiments, R 1 is preferably selected from a 5-6 membered monocyclic aryl or heteroaryl ring, which can be substituted by 1-3 substituents Rnselected from halogen, C1-C6haloalkyl, C1-C6haloalkoxy.

[0021] In some preferred embodiments, R 2preferably selected from the group consisting of hydrogen, deuterium, halogen, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkyl-O-, Ci-C6-haloalkyl-O-, Ci-C6-monoalkylamino, Ci-C6-dialkylamino, Ci-C6-mono- and dihaloalkylamino, Ci-C6-alkyl-S-.

[0022] In some preferred embodiments, R 2 preferably selected from the group consisting of halogen, Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkyl-O-, Ci-C6-haloalkyl-O-, -NR a R b , Ci-C6-mono- and dihaloalkylamino, Ci-C6-alkyl-S-, wherein R a and R b are each independently selected from the group consisting of hydrogen, deuterium, Ci-C6-alkyl, Ci-C6-haloalkyl.

[0023] In some preferred embodiments, R 2 preferably selected from the group consisting of Ci-C6-alkyl-O-, -NR a R b , wherein R a and R b are each independently selected from the group consisting of hydrogen, deuterium, Ci-C6-alkyl, Ci-C6-haloalkyl.

[0024] In some preferred embodiments, R 3 preferably selected from the group consisting of 5- to 12-membered (e.g. 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-) monocyclic or bi-cyclic aryl or heteroaryl rings, which can be substituted with 1 to 3 substituents Rn, as defined herein.

[0025] In some preferred embodiments, R 3 preferably selected from the group consisting of phenyl, indazolyl, quinolinyl, benzimidazolyl, benzothiazolyl, which can be substituted with 1 to 3 substituents Rn, as defined herein.

[0026] In some preferred embodiments, R 3 preferably selected from the group consisting of 5- to 12-membered bi-cyclic aryl or heteroaryl rings, which can be substituted with 1 to 3 substituents Rn, as defined herein.

[0027] In some preferred embodiments, R 3Preferably selected from a 5-12 membered bi-cyclic aryl or heteroaryl ring, which can be substituted with 2-3 substituents Rn, wherein two substituents Rn are adjacent and the two adjacent Rn can form a substituted or unsubstituted 3-6 membered (e.g. 3, 4, 5, 6) ring by a carbon chain or heteroatom.

[0028] In some preferred embodiments, Rn is preferably selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, alkenyl, alkynyl, C1-C6 alkyl-S-, C1-C6 alkyl-SO-, C1-C6 alkyl-SO2-.

[0029] In some preferred embodiments, two adjacent Rn can form a 5-6 membered saturated or partially unsaturated or aromatic ring system by a carbon chain or 1-3 heteroatoms selected from N, O, S, preferably a 5-6 membered saturated carbocyclic or saturated heterocyclic ring, wherein one or more atoms in the saturated carbocyclic or saturated heterocyclic ring can be further oxidized to form =O.

[0030] In some preferred embodiments, W, X, Y, R1, R2 and R3 are each independently the corresponding group in any one of compounds 1-94 prepared in the Examples.

[0031] In some preferred embodiments, the compound is any one of compounds 1-94 prepared in the Examples or a pharmaceutically acceptable salt thereof.

[0032] A method one for preparing a compound of formula I, the method mainly comprising the following step a:

[0033] a. cyclizing a compound of general formula (A) with aryl acetic acid or aryl acetyl chloride or aryl acetate under acid or base catalysis or dehydrating agent to form a compound of general formula (I);

[0034] wherein Ra is hydroxyl, chloro, ester; Rb is hydrogen or alkyl; R 1 , R 2 , R 3 , W, X, Y are defined as above.

[0035] A method two for preparing a compound of formula I, the method mainly comprising the following step b;

[0036] b. reacting a compound of general formula (B) with aryl keto acid or aryl keto acid ester under acid or base catalysis to form a compound of general formula (I):

[0037] wherein Rc is hydroxyl or ester; R 1 , R2 , R 3 , X, Y are as defined above.

[0038] A process three for preparing a compound of formula I, said process mainly comprising the following steps c and d:

[0039] c: ring closure of a compound of general formula (C) with 2-bromophosphonoacetic acid ester (D) catalyzed by a base to give an intermediate compound of general formula (E);

[0040] d: coupling reaction of a compound of general formula (E) with a substituted aryl boronic acid (or ester), aryl stannane or aryl silane catalyzed by a transition metal complex to give a compound of general formula (I);

[0041] wherein Ra is hydroxyl, chloro, alkoxy, ester; Rb is hydrogen or alkyl; Rd is phosphonoester; R 1 , R 2 , R 3 , W, X, Y are as defined above.

[0042] Preferably, said step is carried out in a solvent and said solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, ethylene glycol methyl ether, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, or a combination thereof.

[0043] Preferably, said 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, potassium bicarbonate, sodium carbonate, sodium bicarbonate, or a combination thereof; said 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 hexamethyldisilyl, sodium hexamethyldisilyl, dimethylpyridine, or a combination thereof.

[0044] Preferably, said 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 a combination thereof.

[0045] Preferably, the transition metal catalyst is selected from the group consisting of tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate, palladium chloride, dichlorobis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphine palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, bis(tri-o-tolylphosphine)dichloropalladium, 1,2-bis(diphenylphosphino)ethanedichloropalladium, or combinations thereof; and the catalyst ligand is selected from the group consisting of tri-tert-butylphosphine, tri-tert-butylphosphine tetrafluoroborate, tri-n-butylphosphine, triphenylphosphine, tri-p-tolylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine, or combinations thereof.

[0046] The present application provides a class of preferred compounds of general formula (I), including but not limited to the following structures:

[0047]

[0048]

[0049]

[0050] and the compound represented by the above general formula (I) does not include the following structure:

[0051]

[0052] Another object of the present application is to provide a medicine for treating or preventing tumors or autoimmune diseases and its composition. The technical solution to achieve the above object is as follows:

[0053] A pharmaceutical composition for treating or preventing tumors or autoimmune diseases, which is composed of the nitrogen-containing fused ring compound represented by the above general formula (I), or its pharmaceutically acceptable salt, or its enantiomer, diastereoisomer, tautomer, atropisomer, solvate, polymorph or prodrug, and a pharmaceutically acceptable carrier.

[0054] Another object of the present application is to provide the use of the above-mentioned compound. The technical solution to achieve the above object is as follows:

[0055] The nitrogen-containing fused ring compound shown in the general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, rotamer, solvate, polymorph or prodrug thereof, is used for preparing a drug for treating a disease related to MAT2a or MTAP protein activity or expression, in particular a prophylactic or therapeutic drug for a tumor or an autoimmune disease. The tumor is independently selected from lung cancer, pancreatic cancer, liver cancer, colorectal cancer, cholangiocarcinoma, gallbladder cancer, brain cancer, gastric cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal carcinoma, 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 disease is independently selected from thyroiditis, inflammatory bowel disease, lupus erythematosus, fibrosis, myasthenia, vasculitis, psoriasis, arthritis, scleroderma, dermatitis, etc.

[0056] The present application relates to a compound having the structural characteristics of general formula (I), which can inhibit the enzyme activity of MAT2a, significantly inhibit the growth of various tumor cells, and in particular, tumor cells related to MTAP deletion, and is a therapeutic drug with a completely new mechanism of action.

[0057] It should be understood that, within the scope of the present application, each of the technical features described above and in the following (such as the examples) can be combined with each other to form a new or preferred technical solution. Due to the limited space, they are not listed one by one here. DETAILED DESCRIPTION

[0058] The inventors have prepared a novel nitrogen-containing fused ring compound having the structure shown in formula I through long-term and in-depth research, and found that it has good MAT2a enzyme activity inhibition, and the compound has specific inhibition effect on MAT2a protein at very low concentration (as low as less than 100 nM), and has quite excellent cell proliferation inhibition activity related to MTAP deletion. Based on the above findings, the inventors have completed the present application.

[0059] TERMS

[0060] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter of the claims belongs. Unless otherwise indicated, all patents, patent applications, publications cited herein are hereby incorporated by reference in their entirety.

[0061] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this application, unless specifically stated otherwise, the singular is used to include the plural. It must be noted that unless clearly stated otherwise, the singular form used in this specification and claims includes the plural form of the referred to. It should also be noted that unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0062] Unless otherwise stated, conventional methods within the scope of the art, such as mass spectrometry, NMR, IR and UV / VIS spectroscopy, and pharmacological methods, are employed. Unless specifically defined, the terminology used herein in the relevant descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry is known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and in the treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for use of kits, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein are generally carried out according to conventional methods well known in the art, based on descriptions in several summary 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 structural moieties and compounds.

[0063] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0064] The chapter headings used in this document are for organizational purposes only and should not be construed as limiting the subject matter. All references or portions thereof cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and papers, are incorporated herein by reference in their entirety.

[0065] Certain chemical groups defined herein are preceded by simplified symbols to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to alkyl groups having a total of 1 to 6 carbon atoms as defined below. The total number of carbon atoms in the simplified symbols does not include carbons that may be present in substituents of the group.

[0066] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0067] In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine; "hydroxy" means an -OH group; "hydroxyalkyl" means an alkyl group as defined below which is substituted with a hydroxy (-OH) group; "carbonyl" means a -C(=O)- group; "nitro" means -NO2; "cyano" means -CN; "amino" means -NH2; "substituted amino" means an amino group which is substituted with one or two alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkylamino, heteroaralkylamino groups, wherein the substituted amino group can be further substituted with a member selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, cyano, alkylamino; "carboxy" means -COOH.

[0068] In the present application, the term "alkyl" as a group or part of a group (for example in the groups halo-substituted alkyl and the like) means a straight or branched chain hydrocarbon group consisting exclusively of carbon and hydrogen atoms, containing no unsaturated linkages, having for example from 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and being attached to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl and the like.

[0069] In the present application, the term "alkenyl" as a group or part of a group means a straight or branched chain hydrocarbon group consisting exclusively of carbon and hydrogen atoms, containing at least one double bond, having for example from 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being attached to the rest of the molecule by a single bond, for example, but not limited to, ethenyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.

[0070] In the present application, the term "alkynyl" as a group or part of a group means a straight or branched chain hydrocarbon group consisting exclusively of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having for example from 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and being attached to the rest of the molecule by a single bond, for example, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1- en-4-ynyl and the like.

[0071] In the present application, the term "haloalkyl" as a group or part of a group means an alkyl group as defined above substituted with 1 to 3 halogen atoms, for example fluoroalkyl, chloroalkyl, the alkyl group including any number of carbon atoms, for example methyl, ethyl, propyl, the haloalkyl group including, but not limited to, trifluoromethyl.

[0072] In the present application, the term "alkoxy" as a group or part of a group means an alkyl-O- group, for example methoxy, ethoxy.

[0073] In the present application, the term "haloalkoxy" as a group or part of a group means an alkoxy group as defined above substituted with 1-3 halogen atoms, for example trifluoromethoxy and the like.

[0074] In the present application, the term "deuteroalkyl" as a group or part of a group means an alkyl group as defined above substituted with 1-3 deuterium atoms.

[0075] In the present application, the term "alkylamino" as a group or part of a group means an -alkyl-NH2 structure or substituted amino group -NR a R b wherein R a and R b are each independently hydrogen or alkyl as defined above. For example, the term "monoalkylamino" means a substituted amino group -NR a R b wherein R a and R b are each independently hydrogen or alkyl as defined above. For example, the term "monoalkylamino" means a substituted amino group -NR a R b wherein R a and R b are each independently alkyl as defined above.

[0076] In the present application, the term "haloalkylamino" as a group or part of a group means an -alkyl-NH2 structure or substituted amino group -NR a R b wherein R a and R b are each independently hydrogen or haloalkyl as defined above. For example, the term "monohaloalkylamino" means a substituted amino group -NR a R b wherein R a and R b are each independently hydrogen or haloalkyl as defined above. For example, the term "monohaloalkylamino" means a substituted amino group -NR a R b wherein R a and R b are each independently haloalkyl as defined above.

[0077] In the present application, the term "cycloalkyl" as a group or part of a group refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, which can include fused ring, bridged ring or spiro ring systems, having from 3 to 15 carbon atoms, preferably having from 3 to 10 carbon atoms, more preferably having from 3 to 8 carbon atoms, and which is saturated or unsaturated and can be attached to the remainder of the molecule via a single bond through any suitable carbon atom. Unless otherwise specifically noted in the specification, the carbon atoms in a cycloalkyl group can optionally be oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzocyclohepten-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, octahydro-4,7-methano-1H-indenyl, and octahydro-2,5-methano-indenyl, and the like.

[0078] In the present application, the term "heterocyclyl" as a group or as part of a group means a stable 3- to 20-membered non-aromatic ring radical consisting of two to fourteen carbon atoms and one to six heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. Unless stated otherwise specifically in the present specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or more ring ring system, which can include fused, bridged or spiro ring systems; the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can optionally be oxidized; the nitrogen atom can optionally be quaternized; and the heterocyclyl radical can be partially or fully saturated. The heterocyclyl radical can be attached to the remainder of the molecule via a carbon atom or a heteroatom and by a single bond. In a heterocyclyl radical comprising fused rings, one or more rings can be an aryl or heteroaryl group as defined below, provided that the point of attachment to the remainder of the molecule is a non-aromatic ring atom. For the purposes of the present application, the heterocyclyl radical is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro radical comprising one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocyclyl radicals include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinolizinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indolinyl, octahydroindolinyl, octahydroisoindolinyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.

[0079] In the present application, the term "aryl" as a group or as part of a group means a conjugated hydrocarbon ring system radical having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present application, the aryl radical can be a monocyclic, bicyclic, tricyclic or more ring ring system, which can also be fused with a cycloalkyl or heterocyclyl radical as defined above, provided that the aryl radical is attached to the remainder of the molecule via an atom on the aromatic ring by a single bond. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1 H-isoindolyl, 2-benzoxazolinonyl, 2H-1,4-benzoxazin-3(4H)-on-7-yl, and the like.

[0080] In the present application, the term "arylalkyl" means an alkyl radical as defined above substituted by an aryl radical as defined above.

[0081] In the present application, the term "heteroaryl" as a group or part of a group refers to a 5- to 16-membered, conjugated ring system having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Unless specifically indicated otherwise in the present specification, the heteroaryl group can be a monocyclic, bicyclic, tricyclic or more ring ring system, and can also be fused with a cycloalkyl or heterocyclyl group as defined above, provided that the heteroaryl group is attached to the remainder of the molecule via a single bond through an atom of the aromatic ring. The nitrogen, carbon or sulfur atoms in the heteroaryl group can optionally be oxidized; the nitrogen atoms can optionally be quaternized. For the purposes of the present application, the heteroaryl group is preferably a stable 5- to 12-membered aromatic radical containing 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, more preferably a stable 5- to 10-membered aromatic radical containing 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic radical containing 1 to 3 heteroatoms selected from the group consisting of 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, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolyl, isoquinolyl, naphthyridinyl, cinnolinyl, quinazolinyl, benzothiophenyl, indolizinyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thiophenyl, naphthpyridinyl, [l,2,4]triazolo[4,3-b]pyridazine, [l,2,4]triazolo[4,3-a]pyrazine, [l,2,4]triazolo[4,3-c]pyrimidine, [l,2,4]triazolo[4,3-a]pyridine, imidazo[l,2-a]pyridine, imidazo[l,2-b]pyridazine, imidazo[l,2-a]pyrazine, and the like.

[0082] In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above which is substituted with a heteroaryl group as defined above.

[0083] In the present application, "optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description is to be construed as including both the event or circumstance occurring and not occurring. For example, "an optionally substituted aryl group" means that the aryl group is substituted or unsubstituted, and that the description is to be construed as including both substituted aryl groups and unsubstituted aryl groups.

[0084] The terms "moiety," "structural moiety," "chemical moiety," "group," "chemical group" as used herein refer to a specific fragment or functional group within a molecule. Chemical moieties are generally recognized chemical entities that are embedded or appended to a molecule.

[0085] "Stereoisomers" refer to compounds which have the same atomic constituents, bonded by the same bonds, but have different three-dimensional structures. The present invention will encompass all such stereoisomers and mixtures thereof.

[0086] When the compounds of the present invention contain alkenyl double bonds, the compounds of the present invention are intended to include the E- and Z- geometric isomers, unless otherwise noted.

[0087] "tautomers" refer to isomers that differ in the protonation site. All tautomeric forms of the compounds of the present invention are also intended to be included within the scope of the present invention.

[0088] The compounds of the present invention, or pharmaceutically acceptable salts thereof, can contain one or more chiral carbon atoms and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined, based on its stereochemistry, as either the (R)- or (S)-isomer. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The preparation of the compounds of the present invention can select a racemic, diastereomeric, or enantiomeric form as starting material or intermediate. The optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chromatography on chiral supports.

[0089] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0090] In the present application, the term "pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0091] "Pharmaceutically acceptable acid addition salt" refers to salts of the free base which retain the biological effectiveness and non-toxicity of the free amine and which are formed with inorganic acids or with organic acids. Inorganic acids from which salts can be derived include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, but are not limited to, formic acid, acetic acid, 2,2-dichloroacetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-aminosalicylic acid, naphthalene-2-sulfonic acid, and the like. These salts can be prepared by methods known in the art.

[0092] "Pharmaceutically acceptable base addition salt" refers to salts of the free acid which retain the biological effectiveness and non-toxicity of the free acid and which are formed with inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion-exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.

[0093] "Polymorph" refers to different solid crystalline phases of certain compounds of the application that arise due to the presence of two or more different molecular arrangements in the solid state. Certain compounds of the application can exist in more than one crystal form, and the present application is intended to cover all such polymorphs and mixtures thereof.

[0094] In general, crystallization will produce solvates of the compounds of the application. The term "solvate" as used throughout this application refers to an aggregate that comprises one or more molecules of a compound of the present application with one or more molecules of solvent. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present application can exist in a hydrate form, including monohydrates, dihydrates, hemi-hydrates, sesqui-hydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. The compounds of the present application can form true solvates but in some cases can only retain a mixture of solvent molecules that are not stoichiometrically bound to the compound. The compounds of the present application can be reacted or precipitated out of a solvent or crystallized from a solvent. Solvates of the compounds of the present application are also within the scope of the application.

[0095] The present application also includes prodrugs of the above-mentioned compounds. In this application, the term "prodrug" means a compound that is convertible in vivo into a biologically active compound of the present application. The term "prodrug" thus refers to a pharmacologically acceptable metabolic precursor of a compound of the present application. When administered to a subject in need thereof, a prodrug can not be active, but is converted in vivo to an active compound of the present application. Prodrug compounds are typically rapidly transformed in vivo to yield the parent compound of the present application, for example, by hydrolysis in blood. Prodrug compounds often provide an advantage in solubility, tissue compatibility, or sustained release. Prodrugs include known amino- and carboxy-protecting groups.

[0096] In this application, "pharmaceutical composition" means a formulation of a compound of the present application and a medium generally accepted for the delivery of biologically active compounds to mammals, e.g., humans. The medium includes a pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject and to enhance the biological effectiveness of the active ingredient.

[0097] The term "pharmaceutically acceptable" as used herein means a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compounds of the present application, and is relatively nontoxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0098] In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsor that is nontoxic to the subject intended to receive the composition.

[0099] The "tumors", "cell proliferation abnormality-related diseases" and the like described in the present application 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, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, renal cancer, oral cancer and the like.

[0100] The terms "preventing", "prevention" and "prevent" as used herein include reducing the likelihood of the occurrence or worsening of a disease or condition in a subject.

[0101] The terms "treatment" and other grammatical equivalents as used herein include the following meanings:

[0102] (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed or has yet to be diagnosed as having the disease or condition;

[0103] (ii) inhibiting the disease or condition, i.e., arresting its development;

[0104] (iii) relieving the disease or condition, i.e., causing the state of the disease or condition to regress; or

[0105] (iv) alleviating the symptoms of the disease or condition.

[0106] The terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refer to the amount of at least one agent or compound that, upon administration, is sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. For example, an "effective amount" for therapy is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief of symptoms of a condition. Techniques for determining appropriate effect amounts in any individual case are known in the art, e.g., by using dose escalation studies.

[0107] The terms "administration", "administering", "administered" and the like, as used herein, refer to methods allowing delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, transduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injections or infusion), topical administration and transrectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

[0108] The terms "pharmaceutical combination," "pharmaceutical combinations," "combination," "co-administration," "co-administration of another therapeutic," "co-administration of another therapeutic agent," and the like, as used herein, refer to administration of more than one active ingredient, including fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that at least one compound described herein and at least one co-agent are arranged together in a single entity or dosage form. The term "non-fixed combination" means that at least one compound described herein and at least one co-agent are administered to the patient simultaneously, in close succession, or at different times, provided that they reach the patient's blood stream before they become substantially inactivated. These also apply to cocktail therapies, e.g., administration of three or more active ingredients.

[0109] It will also be appreciated by one of ordinary skill in the art that in the methods described below, intermediate compounds can require protection of certain functional groups. Such functional groups include hydroxyl, amino, thiol, and carboxylic acid. Suitable protecting groups for hydroxyl include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl, or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidine, and guanidine include tert-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for thiol include -C(O)-R" (where R" is alkyl, aryl, or aralkyl), p-methoxybenzyl, trityl, and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl, or aralkyl esters.

[0110] Protecting groups can be introduced and removed in accordance with standard techniques known to those skilled in the art and as described herein. Protecting groups can also be polymeric resins.

[0111] The main advantages of the present application include:

[0112] The compounds described herein have excellent methionine adenosyltransferase (MAT2a) inhibitory effects, with IC50 values of less than 200 nM, and the lowest of less than 10 nM.

[0113] The present application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not limit the scope of the application. Unless otherwise indicated, the methods of the following examples were carried out in accordance with conventional procedures or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are percent by weight and parts by weight.

[0114] Example Preparation

[0115] Example 1: 7-Methoxy-3-(4-methoxyphenyl)-1-phenyl-1,8-naphthyridin-2(1H)-one

[0116]

[0117] First Step: To a solution of 2-chloro-6-methoxybenzaldehyde (890 mg, 5.204 mmol), aniline (484 mg, 5.204 mmol) and cesium carbonate (5.09 g, 15.613 mmol) in 1,4-dioxane (20 mL) was added Pd2(dba)3(477 mg, 0.520 mmol) and Xantphos (301 mg, 0.520 mmol) sequentially. The reaction mixture was heated to 120 °C and stirred at this temperature for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL), filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the intermediate (1.02 g, crude) as a yellow oil. LC-MS (ESI) m / z: 229.0 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.75 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.09 (t, J = 7.4 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 3.95 (s, 3H).

[0118] Second Step: To a solution of the intermediate from the previous step (200 mg, 0.876 mmol) in THF (5 mL) was added NaH (105 mg, 2.628 mmol) under ice-water bath cooling. After the reaction mixture was allowed to warm to room temperature and stirred for half an hour, 2-(4-methoxyphenyl)acetyl chloride (178 mg, 0.964 mmol) was added dropwise. The reaction mixture was stirred at room temperature for another 2 hours, then diluted with ethyl acetate (100 mL), 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 purified to give the compound of Example 1 (off-white solid, 16.8 mg). LC-MS (ESI) m / z: 359.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 4.2 Hz, 2H), 7.75-7.64 (m, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.49-7.43 (m, 1H), 7.34 (dd, J = 5.2, 3.3 Hz, 2H), 7.04-6.95 (m, 2H), 6.73 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H), 3.48 (s, 3H).

[0119] Example 2-5

[0120] Reference to the method of Example 1 to synthesize the compounds of Example 2-5;

[0121]

[0122] Example 6: 6-methoxy-2-(4-methoxyphenyl)-4-phenylpyridine[2,3-b]pyrazin-3(4H)- one

[0123]

[0124] First step: Pd2(dba)3(984 mg, 1.08 mmol), Xantphos (622 mg, 1.08 mmol) were added successively to a solution of 2-chloro-6-methoxy-3-nitropyridine (4.04 g, 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) under nitrogen atmosphere. The reaction mixture was heated to 120 °C and the reaction was continued at this temperature for 2 h. 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 give the intermediate (2.3 g) as a yellow solid. LC-MS (ESI) m / z: 246.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.44 (d, J = 9.1 Hz, 1H), 7.72 (d, J = 7.7 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 6.38 (d, J = 9.1 Hz, 1H), 3.88 (s, 3H).

[0125] Second step: The intermediate (3.65 g, 14.88 mmol) from the previous step and palladium on carbon catalyst (365 mg, 3.44 mmol) were added to methanol (200 mL) under nitrogen atmosphere. After replacing the hydrogen atmosphere, the reaction was continued at room temperature overnight under 1 atm of hydrogen. The reaction solution was filtered through celite and the filtrate was concentrated and purified by column chromatography (petroleum ether / ethyl acetate in the ratio of 20: 1 to 10: 1) to give the intermediate (2.7 g, crude) as a black purple solid. LC-MS (ESI) m / z: 216.1 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.65 (d, J = 7.7 Hz, 2H), 7.23 (dd, J = 8.4, 7.5 Hz, 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).

[0126] Step 3: To a solution of the intermediate from Step 2 (300 mg, 1.395 mmol) and 4-methoxyphenyl-2-acetylacetate (435 mg, 2.092 mmol) in ethanol (10 mL) was added acetic acid (0.6 mL) at room temperature. After the vial was sealed, the reaction was heated to 100 °C for 2 hours. After the reaction was complete by LC-MS, the reaction was diluted with dichloromethane (100 mL), washed with water (50 mL), and then washed with a saturated aqueous sodium chloride solution (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated 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 (400 MHz, DMSO-d6) δ 8.35-8.26 (m, 2H), 8.21 (d, J = 8.6 Hz, 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 = 8.6 Hz, 1H), 3.84 (s, 3H), 3.53 (s, 3H).

[0127] Examples 7-10

[0128] Examples 7-10 were synthesized by the method described in Reference Example 6:

[0129]

[0130] Examples 11-16

[0131] Examples 11-16 were synthesized by the method described in Reference Example 1:

[0132]

[0133]

[0134] Example 17: 7-Methoxy-3-(4-methoxyphenyl)-4-methyl-1-phenyl-1,8-naphthyridin-2(1H)-one

[0135] Example 17: 7-Methoxy-3-(4-methoxyphenyl)-4-methyl-1-phenyl-1,8-naphthyridin-2(1H)-one

[0136] First step: Pd2(dba)3(411 mg, 0.449 mmol), Xantphos (260 mg, 0.449 mmol) were added successively to a solution of 2-chloro-6-methoxy-nicotinic acid methyl ester (902 mg, 4.49 mmol), aniline (418 mg, 4.49 mmol) and cesium carbonate (4.39 g, 13.46 mmol) in 1,4-dioxane (20 mL) under nitrogen. 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 over celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the intermediate (826 mg) as a yellow solid. LC-MS (ESI) m / z: 259.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 2H), 7.35 (t, J = 7.8 Hz, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.27 (d, J = 8.6 Hz, 1H), 3.91 (s, 3H), 3.85 (s, 3H).

[0137] Second step: Lithium bis(trimethylsilyl)amide (3.34 mL, 3.34 mmol) was added to a solution of the above intermediate (430 mg, 1.67 mmol) in tetrahydrofuran (20 mL) under ice-bath. The reaction mixture was stirred at this temperature for 2 hours. p-Methoxyphenylacetyl chloride (400 mg, 2.17 mmol) was added to the above mixture and the reaction mixture was stirred at this temperature for 2 hours. LC-MS was used to check the completion of the reaction. The reaction solution was diluted with ethyl acetate (200 mL) and then the pH was adjusted to neutral with 1 N aqueous hydrochloric acid solution. The organic phase was washed with aqueous ammonium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1: 1) to give the intermediate (250 mg) as a light yellow solid. LC-MS (ESI) m / z: 375.0 [M+H] + . 1 1H 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 = 8.6 Hz, 1H), 3.79 (s, 3H), 3.47 (s, 3H).

[0138] Step 3: To a solution of the above intermediate (245 mg, 0.655 mmol) in pyridine (8 mL) was added triflic anhydride (738 mg, 2.619 mmol) under nitrogen atmosphere. The reaction mixture was heated at 70 °C for 16 h. LCMS indicated the reaction was complete. The reaction mixture was diluted with dichloromethane (200 mL) and washed with aqueous ammonium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the compound (120 mg, 36.2%) as a light yellow solid. LCMS (ESI) m / z: 508.9 [M+H] + . 1 H NMR (400 MHz, DMSO-D6) δ 8.05 (d, J = 8.7 Hz, 1H), 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 = 8.7 Hz, 1H), 3.81 (s, 3H), 3.52 (s, 3H).

[0139] Step 4: To a solution of the above intermediate (120 mg, 0.237 mmol), methylboronic acid (142 mg, 2.37 mmol) and potassium phosphate (151 mg, 0.711 mmol) in 1,4-dioxane (20 mL) was added Pd(PPh3)4 (28 mg, 0.024 mmol) under nitrogen atmosphere. The reaction mixture was heated at 100 °C for 2 h. LC-MS indicated the starting material was consumed. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with aqueous sodium chloride solution. The separated organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated. The crude product was purified by preparative separation to give the product (18 mg) as a white solid. LC-MS (ESI) m / z: 373.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 8.7 Hz, 1H), 7.52 (m, 2H), 7.43 (m, 1H), 7.35-7.26 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.6 Hz, 1H), 3.80 (s, 3H), 3.47 (s, 3H), 2.31 (s, 3H).

[0140] Example 18: 1-(4-chlorophenyl)-3-(2-methyl-2H-indazol-5-yl)-7-((2,2,2- trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

[0141]

[0142] First step: 6-chloro-2-((4-chlorophenyl)amino)nicotinaldehyde (3.4 g, 12.8 mmol), 2-bromo-2-oxoethyl acetate (5.1 g, 16.6 mmol), DBU (2.9 g, 19.2 mmol), lithium chloride (965 mg, 23 mmol) were dissolved in acetonitrile (200 mL) and reacted at room temperature for 4 hours, 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.

[0143] Second step: The above intermediate (870 mg, 2.4 mmol), 2-methyl-5-indazoleboronic acid pinacol ester (928 mg, 3.6 mmol), dichloro[l,l'-bis(tert-butylphosphine)ferrocenepalladium (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 under nitrogen protection. 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 (600 mg). LC-MS [M+H] + : m / z 421.0.

[0144] Third step: The above intermediate (50 mg, 0.1 mmol), 2,2,2-trifluoroethylamine (120 mg, 1.0 mmol), DIEA (46 mg, 0.4 mmol) were dissolved in N-methylpyrrolidone (2 mL) and reacted at 200°C for 2 hours under microwave. After the reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL) twice, the separated organic phase was dried and concentrated. The crude product was prepared by HPLC to obtain a white solid compound (12.84 mg). LC-MS [M+H] + : m / z 484.1. 1 HNMR (400 MHz, DMSO-d6): 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 = 8.5 Hz, 1H), 4.17 (s, 3H), 3.77 (m, 2H).

[0145] Examples 19-39, 43-52

[0146] The compounds of Examples 19-39, 43-52 were synthesized according to the method of Reference Example 18.

[0147]

[0148]

[0149]

[0150]

[0151] Example 54: 1-(4-chlorophenyl)-3-(3-methoxy-2-(methyl)-2H-indazol-5-yl)-7-((2,2,2- trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

[0152]

[0153] First Step: 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 deuterated methylamine (2 mL, 4.1 mmol), heat the reaction to 80 degrees overnight. Concentrate the reaction under reduced pressure, then purify the crude product 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.

[0154] Second Step: To the above compound (50 mg, 0.2 mmol) in a mixture of MeOH / H2O (9 mL / 1 mL), add potassium hydroxide KOH (112 mg, 2.0 mmol), and react at 65 degrees overnight. Concentrate the reaction under reduced pressure, then purify the crude product 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.

[0155] Third Step: Under nitrogen protection, to the above compound (100 mg, 0.41 mmol), bis(pinacolato)diboron (117 mg, 0.46 mmol), and potassium acetate (123.4 mg, 1.26 mmol) in 1,4-dioxane (20 mL), add a catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Pd(dppf)Cl2 (34.1 mg, 0.042 mmol), and react at 75 degrees for 4 hours. Concentrate the reaction under reduced pressure, then purify the crude product 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.

[0156] Fourth Step: To the above intermediate compound (60 mg, 0.2 mmol), 3-bromo 7-chloro-1-(4-chlorophenyl)-1,8-naphthyridin-2(1H)-one (80.0 mg, 0.21 mmol) and potassium phosphate (127.2 mg, 0.6 mmol) in dioxane / H20 (12 mL / 2 mL) was added Pd(dppf)Cl2(14.1 mg, 0.02 mmol) under nitrogen. The reaction was heated to 70 °C and stirred for 3 h. The reaction was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (DCM / MeOH = 10:1) to give the compound (60.1 mg) as a yellow solid. LC-MS [M+H] + : m / z 454.0 / 456.0.

[0157] Fifth Step: The above intermediate compound (60.0 mg, 0.13 mmol), 2,2,2- trifluoroethylamine (128.7 mg, 1.3 mmol), diisopropylethylamine DIEA (46 mg, 0.4 mmol) were dissolved in NMP (2 mL) and reacted at 200 °C for 2 h in microwave. The crude product was purified by reverse phase prep to give the compound (1.02 mg) as a yellow solid. LC-MS [M+H] + : m / z 517.1. 1 H-NMR (400 MHz, DMSO-d6): 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 = 8.4 Hz, 2H), 6.56 (m, 1H), 3.78-3.81 (m, 2H), 3.35 (s, 3H).

[0158] Examples 55-65

[0159] Refer to the method of Example 34, 53, 54, 66, replace deuterated methylamine with methylamine or deuterated methanol with methanol to synthesize Examples 55-65, 94.

[0160]

[0161]

[0162] Example 40: 1-(4-chlorophenyl)-6-fluoro-3-(2-methyl-2H-indazol-5-yl)-7-((2,2,2- trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

[0163]

[0164] First step: Dissolve compound 4-chloroaniline (6.4 g, 50.0 mmol) in THF (60 mL), add lithium hexamethyldisilazide (LiHMDS) (76 mL, 76.0 mmol) dropwise at -60 °C, after 1 h, add 2,6-dichloro-5-fluoro-nicotinic acid (5.0 g, 23.8 mmol). After the addition is complete, allow the reaction to warm to room temperature and stir for 4 h. Quench with water (10 mL), adjust the pH to 2 with 5 M aqueous HCl, and extract with ethyl acetate (50 mL) three times. Wash the combined organic phases with saturated aqueous brine, dry, and concentrate. Triturate the resulting crude product with ethyl acetate (30 mL) to obtain the yellow solid intermediate product (6.1 g). LC-MS [M+H] + : m / z 301.0.

[0165] Second step: Dissolve the above intermediate product (6.1 g, 20.3 mmol) in THF (40 mL), and add borane-tetrahydrofuran solution (61 mL, 61 mmol) dropwise at 0 °C. After the addition is complete, allow the reaction to warm to room temperature and stir for 2 h. Quench with methanol (50 mL), stir for 0.5 h, and concentrate. Purify the resulting crude product by silica gel column chromatography (PE:EA = 10:1) to obtain the yellow crude intermediate (5.8 g). LC-MS [M+H] + : m / z 287.1.

[0166] Third step: Dissolve the above intermediate product (5.8 g, 20.2 mmol) in DCM (50 mL), and add Dess-Martin reagent (17.2 g, 40.4 mmol) at 0 °C. Allow the reaction to warm to room temperature and stir for 2 h. Add Na2S2O3 (30 mL) and NaHCO3 (30 mL) sequentially, extract with dichloromethane (50 mL) three times, wash the combined organic phases with saturated aqueous brine, dry, and concentrate. Purify the resulting crude product by silica gel column chromatography (PE:EA = 10:1) to obtain the yellow solid intermediate (2.2 g). LC-MS [M-H] - : m / z 283.0.

[0167] Fourth step: Dissolve the above intermediate compound (2.2 g, 7.7 mmol), 2-bromo-2-(diethoxyphosphoryl)acetic acid ethyl ester (3.1 g, 10.1 mmol), DBU (1.8 g, 11.6 mmol), and LiCl (583 mg, 13.9 mmol) in acetonitrile (50 mL), and allow the reaction to proceed at room temperature for 4 h, then overnight at reflux. Concentrate the reaction mixture directly, and purify the resulting crude product by silica gel column chromatography (PE:EA = 2:1) to obtain the yellow solid intermediate product (300 mg). LC-MS [M+H] + : m / z 386.9

[0168] Step 5: The above intermediate compound (700 mg, 1.8 mmol) was dissolved in DMSO (4 mL), potassium fluoride (526 mg, 9.1 mmol) and 2,2,2-trifluoroethylamine (2 mL) were added, and the mixture was reacted at 150 °C for 1.5 h under microwave. Diluted with water (10 mL), extracted with ethyl acetate (50 mL) for three times, the combined organic phase was washed with saturated brine, dried. After concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography (PE:EA = 2:1) to obtain yellow solid product (500 mg). LC-MS [M+H] + m / z 450.0.

[0169] Step 6: The above intermediate product (60 mg, 0.13 mmol), 2-methyl-5-indazole boronic acid pinacol ester (36 mg, 0.14 mmol), dichloro[1,1'-bis(tert-butylphosphine) ferrocenepalladium (8 mg, 0.01 mmol), potassium phosphate (85 mg, 0.39 mmol) were dissolved in dioxane / H2O (10 mL / 2 mL), and the mixture was reacted at 60 °C for 1 h under nitrogen protection. Concentration, reversed phase preparation to obtain yellow solid target product (23 mg). LC-MS [M+H] + m / z 502.0. 1 H NMR (400 MHz, DMSO) δ 8.38 (s, 1H), 8.08-8.05 (m, 3H), 7.94 (d, J = 10.8 Hz, 1H), 7.69-7.44 (m, 4H), 7.33 (d, J = 8.8 Hz, 2H), 4.18 (s, 3H), 3.88-3.61 (m, 2H).

[0170] Synthesized by the method of reference example 40 to obtain examples 41-42, 53, 66-67.

[0171]

[0172] Example 68: 1-(4-chlorophenyl)-3-(3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazol-9-yl)-7-((2,2,2-trifluoroethyl)amino)-1,8-naphthyridin-2(1H)-one

[0173]

[0174] First Step: Dissolve 5-bromo-2-nitrobenzaldehyde (1.0 g, 2 mmol) and 3-amino-1-propanol (625 mg, 8.7 mmol) in ethanol (20 mL), after adding tetraisopropyl titanate (4.9 g, 17.2 mmol), the reaction was carried out at room temperature overnight, then sodium borohydride (245 mg, 6.5 mmol) was added, and the reaction was continued at room temperature for 6 hours. The reaction was quenched by adding ammonia water (6 mL), the reaction solution was filtered, and the filtrate was dried and concentrated. 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.

[0175] Second Step: To the mixture of the above compound (780 mg, 2.7 mmol) in t-butanol and water (15 mL / 5 mL), KOH (607 mg, 10.8 mmol) was added, and the reaction was carried out at 85 °C for 5 hours. The reaction was diluted with water (45 mL) and extracted with ethyl acetate (50 mL) three times. The combined organic phase was dried with MgSO4, filtered, and the organic phase was concentrated. The obtained crude product was purified by silica gel column chromatography (eluted with pure EtOAc) to obtain a yellow solid (540 mg). LC-MS [M+H] + : m / z 252.9.

[0176] Third Step: Under nitrogen protection, the above intermediate compound (540 mg, 2.1 mmol), bis(pinacolato)diboron (707 mg, 2.7 mmol), potassium acetate KOAc (617 mg, 6.3 mmol) were dissolved in 1,4-dioxane (10 mL), and a catalyst Pd(dppf)Cl2 (146 mg, 0.2 mmol) was added. 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.

[0177] Fourth Step: Under nitrogen protection, to the above intermediate compound (123 mg, 0.41 mmol), 3-bromo 7-chloro-1-(4-chlorophenyl)-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), Pd(dppf)Cl2 (26 mg, 0.04 mmol) was added. The reaction was heated to 70 °C and stirred for 2 hours. The reaction was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with pure ethyl acetate) to obtain a yellow solid compound (84 mg). LC-MS [M+H] + : m / z 463.0.

[0178] Step 5: The above intermediate compound (84 mg, 0.18 mmol), 2,2,2-trifluoroethylamine (1 mL), potassium fluoride KF (54 mg, 0.90 mmol) were dissolved in DMSO (2 mL) and reacted in microwave at 150 °C for 4 h. The crude product was purified by reverse phase prep to give compound (22 mg) as a yellow solid. LC-MS [M+H] + : m / z 526.0. 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 1H), 7.94 (s, 1H), 7.90-7.85 (m, 2H), 7.59-7.55 (m, 3H), 7.37 (d, J = 9.2 Hz, 1H), 7.35-7.30 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 4.53 (t, J = 5.2 Hz, 2H), 4.39 (t, J = 6.0 Hz, 2H), 3.80-3.73 (m, 2H), 2.37-2.31 (m, 2H).

[0179] The following indazolocyclic boronic acid (or boronic acid) and bromo-pyrimidopyridinone intermediates were synthesized according to the synthetic methods of Reference Example 68 and literature reports:

[0180]

[0181]

[0182] Examples 69-93

[0183] The compounds of Examples 69-93 were synthesized according to the method of Reference Example 68, using different indazolocyclic boronate ester (or boronic acid) intermediates in place of 3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazole-9-boronic acid pinacol ester.

[0184]

[0185]

[0186]

[0187]

[0188] Test Example 1 MAT2a enzyme inhibitory activity test

[0189] The Colorimetric Assay was used to test the enzymatic inhibition activity of the compounds of the examples on MAT2a, and the test steps were as follows: 1) using a standard reaction buffer (Tris, pH 8.0, 50 mM KCl, 15 mM MgCl2, 300 uM EDTA, 0.005% w / v bovine serum albumin) to prepare 10 concentration gradients of the compounds: the test concentration of the tested compound was 10 uM, 3-fold dilution, 10 concentrations, single-hole test. Gradient dilution of 10 different concentrations of solutions to 100-fold final concentration in a 384-well plate. Then 250 nL was transferred to a 384-reaction plate by Echo550 for standby. 250 nL of 100% DMSO-D6 was added to the negative control hole and the positive control hole, respectively. 2) The enzyme solution was prepared with a standard reaction buffer at a final concentration of 1.67 times. 3) 15 uL of the enzyme solution at a final concentration of 1.67 times was added to the compound hole and the positive control hole, respectively; 15 uL of the standard reaction buffer was added to the negative control hole. 4) Centrifugation at 1000 rpm for 60 seconds, and incubation for 15 minutes after shaking. 5) The substrate mixed solution was prepared with a standard reaction buffer at a final concentration of 2.5 times. 6) 10 uL of the substrate mixed solution at a final concentration of 2.5 times was added to start the reaction. 7) The 384-well plate was centrifuged at 1000 rpm for 60 seconds, and incubated for 150 minutes after shaking. 8) 50 uL of Biomol was added to terminate the reaction, and incubated for 15 minutes after centrifugation at 1000 rpm for 60 seconds. OD620 was read, and the data was processed. 9) Data analysis: the calculation formula %Inhibition = (OD 620 _max–OD 620 _sample) / (OD 620 _max–OD 620 _min)x 100; wherein: OD 620 _sample is the absorbance of the sample hole; OD 620 _min: the absorbance of the negative control hole, representing the reading of the hole without enzyme activity; OD 620 _max: the absorbance of the positive control hole, representing the reading of the hole without compound inhibition. 10) Fitting the dose-effect curve: taking the log value of the concentration as the X axis and the percentage inhibition rate as the Y axis, the dose-effect curve was fitted by the analysis software GraphPad Prism 5 log(inhibitor) vs. response-Variable slope, so as to obtain the IC 50 value of each compound on the enzyme activity. (A represents IC 50 <100 nM, B represents 100 nM≤IC 50 <500 nM, C represents IC 50 ≥500 nM).

[0190] Results: Most of the example compounds of the present application have high MAT2a inhibitory activity, most of the example compounds have IC 50 less than 200nM, some of the example compounds have IC 50 even less than 10nM.

[0191]

[0192]

[0193] Test Example 2: Proliferation inhibition effect of the example compounds on HCT-116 wt and HCT-116 MTAP- cells.

[0194] 1. Experimental reagents:

[0195] 2. Cell lines:

[0196] Cell line Culture type Origin Culture medium HCT116 MTAP Adherent Horizon RPMI-1640 + 10% FBS HCT116 wt Adherent Horizon RPMI-1640 + 10% FBS

[0197] 3. Test steps: 1) HCT-116 wt / HCT116 MTAP- cells (Horizon) in the logarithmic growth phase were inoculated into a 96-well culture plate at an appropriate density of 80μL per well, and after overnight culture, different concentrations of compounds were added for 4hr, and a solvent control group (negative control) was set. 2) After the compound acted on the cells for 120hr, the effect of the compound on cell proliferation was detected using a CTG cell counting kit, 40μL of CTG reagent was added to each well, and after being placed in a 37℃ incubator for 60min, the Multilabel Reader enzyme label reader of PerkinElmer company was read. 3) The inhibition rate (%) of the compound on tumor cell growth was calculated using the following formula: inhibition rate (%) = (OD negative control well-OD dosing well) / OD negative control well x 100%. IC 50 values were obtained by four-parameter regression using the random software GraphPad Prism5 attached with the enzyme label instrument.

[0198] Results: Most of the example compounds of the present application, such as examples 11, 12, 14, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 34, 35, 37, 38, 40, 43-62, have IC MTAP- on HCT-116 50 cells less than 1uM, such as examples 18, 34, 37, 38, 39, 40, 42, 43, 44, 48, 49, 50, 53-78, etc. have inhibitory activity IC 50More than 100 nM; and all the compounds of the present application have IC50 wt proliferation inhibition activity on HCT-116 cells 50 More than 10 uM, showing higher cell selectivity. wt proliferation inhibition activity on HCT-116 cells 50 More than 10 uM, showing higher cell selectivity.

[0199] Test Example 3: ADMET test of the compounds of the present application

[0200] (1) Metabolic stability test: metabolic stability incubation was carried out in a system of 150 μL of liver microsomes (final concentration 0.5 mg / mL) containing NADPH (final concentration 1 mM), 1 μM of the test compound and positive control midazolam or negative control atenolol, and the reaction was terminated at 0 min, 5 min, 10 min, 20 min and 30 min with acetonitrile containing tizoxazone, vortexed for 10 min, centrifuged at 15000 rpm for 10 min, and 50 μL of supernatant was taken for injection into a 96-well plate. The metabolic stability of the compound was calculated by determining the relative decrease in the amount of the original drug.

[0201] Results: The compounds of the present application have high stability to liver microsomes of various species (rat, mouse, dog, monkey, human), with a half-life of more than 20 min, such as compounds 18, 34, 40, 54, 58, 59 and 74.

[0202]

[0203] Test Example 4: Pharmacokinetic parameter test of the compounds of the present application in mice

[0204] Six male SPF Balb c mice (Shanghai Xipu-Bike Experimental Animal) were divided into two groups, and the test compound was prepared into a suitable solution or suspension; one group was administered intravenously (1 mg / kg), and one group was administered orally (5 mg / kg). Blood was collected by neck venipuncture, with about 0.2 mL / sample / time point, and heparin sodium was used for anticoagulation. The blood collection time points were as follows: before administration and 5, 15 and 30 min, 1, 2, 4, 6, 8 and 24 h after administration; the blood samples were placed on ice after collection, and the plasma was separated by centrifugation (centrifugation conditions: 8000 rpm / min, 6 min, 2-8°C), and the collected plasma was stored at -80°C before analysis. The plasma samples were analyzed by LC-MS / MS.

[0205] From the blood concentration data of the drug, the pharmacokinetic parameters AUC 0-t , AUC 0-∞ , MRT 0-∞ , C max , T max , T 1 / 2 and V d and their mean and standard deviation were calculated using the pharmacokinetic calculation software WinNonlin 5.2 non-compartment model for the test sample.

[0206]

[0207] For samples with concentrations below the lower limit of quantification, in the calculation of the pharmacokinetic parameters, samples taken before reaching C max should be calculated as zero, and samples taken after reaching C max should be calculated as below the limit of quantification (BLQ).

[0208]

[0209] All documents referred to in this disclosure are incorporated herein by reference as if each were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that these equivalents ype within the scope of the appended claims.

Claims

1. A nitrogen-containing fused-ring compound as shown in general formula I, or a pharmaceutically acceptable salt thereof, The compound is a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof. In the formula: W, X, and Y are defined as shown in general formula II; R 1 It is selected from a 6-membered monocyclic aryl group or a 5-6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the aryl or heteroaryl ring is optionally substituted by 1 to 3 different substituents Rn, wherein the Rn is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy; R 3 The aryl or heteroaryl ring is selected from 6-membered monocyclic aryl, 6-membered monocyclic heteroaryl, or 7-12-membered dicyclic heteroaryl rings, wherein the aryl or heteroaryl ring is optionally substituted by 1-3 different substituents Rn, wherein Rn is selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, or C1-C6 alkyl-SO2-; or two adjacent Rn may optionally form a 5-6 membered saturated carbide ring or saturated heterocycle by a carbon chain or 1-3 heteroatoms selected from N, O, or S, wherein one or more atoms in the saturated carbide ring or saturated heterocycle may optionally be further oxidized to form =O; wherein, The heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, or S; R 2 Selected from halogens, C1-C6 alkyl-S-, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 monohaloalkylamino, C1-C6 dihaloalkylamino, and 3-8 membered cycloalkylamino. R 5 It is hydrogen; R 6 Selected from hydrogen and halogens; R 7 Selected from hydrogen and C1-C6 alkyl groups.

2. The compound according to claim 1, characterized in that, R 5 R 7 All are hydrogen; R 6 It is hydrogen or halogen.

3. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is a compound represented by general formula (III): in: The compound is a compound represented by general formula (II), or a pharmaceutically acceptable salt thereof. The definitions of W, X, and Y are shown in General Formula II; M1 is selected from CH or N; M2 is selected from O and S; It is a single bond; R 8 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 3 The aryl or heteroaryl ring is selected from 6-membered monocyclic aryl, 6-membered monocyclic heteroaryl, or 7-12-membered dicyclic heteroaryl rings, wherein the aryl or heteroaryl ring is optionally substituted by 1-3 different substituents Rn, wherein Rn is selected from deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy, C1-C6 alkyl-SO2-; or two adjacent Rn may optionally form a 5-6 membered saturated carbon ring or saturated heterocycle by a carbon chain or 1-3 heteroatoms selected from N, O, and S, wherein one or more atoms in the saturated carbon ring or saturated heterocycle may optionally be further oxidized to form =O; wherein the heteroaryl group comprises 1-3 heteroatoms selected from the group consisting of N, O, or S. R 2 Selected from halogens, C1-C6 alkyl-S-, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monoalkylamino, C1-C6 dialkylamino, C1-C6 monohaloalkylamino, C1-C6 dihaloalkylamino, and 3-8 membered cycloalkylamino. R 5 It is hydrogen; R 6 Selected from hydrogen and halogens; R 7 Selected from hydrogen and C1-C6 alkyl groups.

4. The compound according to claim 3, characterized in that, The compound is a compound represented by general formula (III): Wherein: M1 is selected from CH or N; M2 is 0; It is a single bond; R 8 Selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 3 Selected from phenylcycloyl, pyridinecycloyl, indazolecycloyl, benzodihydrofuranyl, benzimidazolyl, benzothiazolyl, quinolinecycloyl, the above R 3 The ring may be optionally substituted by one or more groups selected from the group consisting of: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy. R 2 The definitions of W, X, and Y are as defined in claim 3.

5. The compound according to claim 1, characterized in that, R 1 The radical is selected from phenyl or pyridyl, wherein the phenyl or pyridyl is optionally replaced by 1 to 3 different substituents Rn, wherein the Rn is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy.

6. The compound according to claim 1, characterized in that, R 1 The aryl or heteroaryl ring is selected from a 6-membered monocyclic aryl group or a 5-6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the aryl or heteroaryl ring is optionally substituted by 1 to 3 different substituents Rn, wherein the Rn is selected from halogens, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups.

7. The compound according to claim 1, characterized in that, R 1 The phenyl group is optionally substituted with 1-3 different substituents Rn, wherein the Rn is selected from halogens, C1-C6 haloalkyl groups, and C1-C6 haloalkoxy groups.

8. The compound according to claim 1, characterized in that, R 2 Selected from halogens, C1-C6 alkyl-O-, C1-C6 haloalkyl-O-, C1-C6 monohaloalkylamino, and C1-C6 alkyl-S-.

9. The compound according to claim 1, characterized in that, R 3 The group is selected from phenyl, indazole, quinolinyl, benzimidazolyl, benzothiazolyl, and benzopyrazolyl, and is optionally substituted with 1 to 3 different substituents Rn, wherein Rn is as defined in claim 1.

10. The compound according to claim 1, characterized in that, R 3 The heteroaryl ring is selected from 7-12 bis-cyclic heteroaryl rings, wherein the heteroaryl ring is optionally replaced by 2-3 different substituents Rn.

11. The compound according to claim 1, characterized in that, R 3 The indazole group is optionally replaced by 2-3 different substituents Rn.

12. The compound according to claim 1, characterized in that, R 2 For Cl, 13. The compound according to claim 1, characterized in that, R 1 for 14. The compound according to claim 1, characterized in that, R 3 for 15. A compound, or a pharmaceutically acceptable salt thereof, characterized in that, The compounds are selected from the group consisting of:

16. A method for preparing a compound of formula I, characterized in that, The method mainly includes the following steps c and d: c: Compound of general formula C is cyclized with triethyl 2-bromo-2-phosphorylacetate under base catalysis to generate intermediate compound of general formula E; d: Compound of general formula E is reacted with pinacol ester of 2-methyl-5-indazoleboronic acid via a coupling reaction catalyzed by a transition metal complex to generate compound of general formula (I); Where Rb is hydrogen; R 1 R 2 R 3 The definitions of W, X, and Y are as described in claim 1.

17. A pharmaceutical composition comprising the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutical composition comprises: (i) an effective amount of the compound, or a pharmaceutically acceptable salt thereof; and (ii) Pharmaceutically acceptable carriers.

18. The use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, characterized in that, This is used to prepare drugs for the treatment or prevention of diseases related to the activity or expression of MAT2a or MTAP proteins.

19. The use of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 17, characterized in that, Used to prepare drugs for treating tumors or autoimmune diseases.

20. The use as described in claim 19, characterized in that, The tumors mentioned are selected from: lung cancer, pancreatic cancer, liver cancer, colorectal cancer, bile duct cancer, gallbladder cancer, brain cancer, stomach cancer, leukemia, lymphoma, melanoma, thyroid cancer, nasopharyngeal carcinoma, 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 diseases mentioned are selected from thyroiditis, inflammatory bowel disease, lupus erythematosus, fibrosis, myasthenia gravis, vasculitis, psoriasis, arthritis, scleroderma, and dermatitis.

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