4-quinazolinones as hif prolyl hydroxylase 2 inhibitors and uses thereof

Abstract

The application belongs to the field of biological medicine, discloses a HIF prolyl hydroxylase 2 inhibitor as shown in formula (I), relates to a 4-quinazolinone compound and a preparation method thereof, further relates to a pharmaceutical composition containing the compound and purposes. The HIF prolyl hydroxylase mediated disease in the application is selected from the group of uses in anemia secondary to or associated with chronic kidney disease, anemia associated with or caused by chemotherapy or anemia associated with AIDS.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a class of 4-quinazolinone derivatives and their stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, and pharmaceutical compositions thereof, methods of preparation, and their use in the preparation of medicaments for diseases mediated by HIF prolyl hydroxylase. Related diseases include, but are not limited to, anemia secondary to or associated with chronic kidney disease, chemotherapy-related or chemotherapy-induced anemia, or anemia related to AIDS. Technical Background

[0002] Hypoxia-inducible factor (HIF) comprises three isoforms: HIF-1, HIF-2, and HIF-3. HIF-1 and HIF-2 are heterodimers composed of HIF-α and HIF-β. HIF-1α is widely expressed in tissues, while HIF-2α is expressed only in cells such as endothelial cells, cardiomyocytes, hepatocytes, and renal cortical interstitial cells. HIF-1α, as a transcription factor, primarily regulates glycolysis-related enzymes, while HIF-2α plays a crucial role in regulating genes such as EPO, transferrin, and Oct-4. Notably, HIF-2α plays a major role in regulating the expression of blood-related genes such as EPO, thus achieving a therapeutic effect in renal anemia.

[0003] HIF-β is identical to the aryl nucleotransporter (ARNT) in the cell nucleus. Normal hypoxia is characterized by the iron- and 2-oxoglutarate-dependent dioxygenase HIF-proline hydroxylases (HIF-phd, HIF-phd1-3), which hydroxylate certain proline residues in HIF-α, leading to HIF-α recognition by the Von Hippel-Lindau protein (pVHL) and subsequent degradation via the ubiquitin-proteasome system. Simultaneously, the factor inhibiting hypoxia-inducible factor (FIH), an asparagine hydroxylase, prevents HIF-α from binding to the coactivator p300 / CBP, resulting in a reduction in HIF-mediated transcription. Among these HIF-related hydroxylases, HIF-phd2 may play a dominant role in controlling HIF-α-mediated endogenous EPO expression. Therefore, inhibiting HIF-phd2 is considered an effective strategy to stabilize HIF-α and thus increase endogenous EPO levels.

[0004] Patients with chronic kidney disease or cancer often suffer from anemia while undergoing chemotherapy, which severely impacts their quality of life. Clinically, intravenously administered recombinant human erythropoietin (rhEPO) is currently the leading erythropoietin (ESA) on the market and is considered the best treatment for anemia. However, its severe side effects, high cost, and hospitalization requirements deter many patients. Therefore, there is an urgent clinical need for oral active small molecule HIF prolyl hydroxylase 2 inhibitors. Summary of the Invention

[0005] This invention provides compounds of formula (I) or stereoisomers, geometric isomers, tautomers, nitrides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof.

[0006]

[0007] in, Located on any substituted ring atom of the 4-quinazolinone ring;

[0008] R 1 R 2 R 3 Each of the following can be independently H, D, F, Cl, Br, I, Cl, NO2, -COOH, -OH, -NH2, SH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 monosubstituted or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0009] R 4 Selected from the following group: H, D, F, Cl, Br, I, -CN, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or poly-substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, YR a R 4 Can be optionally bounded by 1, 2 or 3 R x Replaced;

[0010] Y is selected from the following group: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-;

[0011] R aSelected from the following group: H, D, F, Cl, Br, I, Cl, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or poly-substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R a Can be optionally bounded by 1, 2 or 3 R y Replaced;

[0012] R x R y Each is independently selected from the following group: H, D, F, Cl, Br, I, -CN, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 monosubstituted or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0013] L is a structure with -[C(R) b R c The connection unit R of )]n- b R c Each of the following is independently selected from hydrogen, methyl, and ethyl; n is an integer from 1 to 3.

[0014] In a preferred embodiment, the compound of formula (I) has the structure shown in formula (Ia) or (Ib):

[0015]

[0016] In the preferred embodiment, R 1 R 2 R 3 Each is independently selected from the following groups: H, D, and halogens;

[0017] In the preferred embodiment, R 4 Selected from the following group: H, C1-C6 alkyl, YR a Wherein, Y is selected from CH2; R h Selected from H, substituted or unsubstituted aryl; R x R y Each of the following groups is selected independently: H, D, CF3;

[0018] In the preferred embodiment, R a Selected from the following groups: H, D, halogens, -CN, -COOH;

[0019] In a preferred embodiment, the compound of formula (I) is selected from:

[0020] (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylpyridinyl)glycine;

[0021] (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-7-yl)pyridinyl)glycine;

[0022] (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine;

[0023] (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-7-yl)pyridinecarboxyl)glycine;

[0024] (5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)-3-hydroxypyridinecarboxyl)glycine;

[0025] (3-hydroxy-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinyl)glycine;

[0026] ((3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinamido)methyl)phosphonic acid;

[0027] (3-hydroxy-5-(4-oxo-3-phenylethyl-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine;

[0028] (3-hydroxy-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine;

[0029] (3-hydroxy-5-(4-oxo-3-phenylethyl-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine;

[0030] (5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0031] (5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazoline-6-yl)-3-hydroxypyridinyl)glycine;

[0032] (3-hydroxy-5-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0033] (3-hydroxy-5-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine;

[0034] (5-(3-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0035] (3-hydroxy-5-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0036] (3-hydroxy-5-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine;

[0037] (3-hydroxy-5-(4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0038] (3-hydroxy-5-(4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine;

[0039] (3-hydroxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0040] (3-hydroxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine;

[0041] (3-hydroxy-5-(3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0042] (5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0043] (5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine;

[0044] (5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0045] (5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinyl)glycine;

[0046] (5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0047] (5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine;

[0048] (5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester;

[0049] (5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinyl)glycine;

[0050] (3-hydroxy-5-(4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0051] (3-hydroxy-5-(4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine;

[0052] (3-hydroxy-5-(4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine;

[0053] (3-hydroxy-5-(4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine;

[0054] (3-hydroxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0055] (3-hydroxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester;

[0056] On one hand, the present invention relates to a pharmaceutical composition comprising the compounds described herein, optionally further comprising any one or any combination thereof of a pharmaceutically acceptable carrier, excipient, adjuvant, or mediator.

[0057] On one hand, the present invention relates to the use of the compound or the pharmaceutical composition of the present invention in the preparation of a medicament; wherein the medicament is used for HIF prolyl hydroxylase, or for the prevention, treatment or relief of anemia.

[0058] In some embodiments, the HIF prolyl hydroxylase described in this invention is HIF-PHD2.

[0059] In some embodiments, the HIF prolyl hydroxylase-regulated disease described in this invention is used in chronic kidney disease or anemia associated with chronic kidney disease, chemotherapy-related or chemotherapy-induced anemia, or anemia associated with AIDS.

[0060] This method is achieved by administering to the subject an effective therapeutic amount of a compound of formula (I) or its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, eutectics, or prodrugs.

[0061] The foregoing description only outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be described in more detail below.

[0062] The present invention also provides a method for synthesizing compounds of general formula (I), including steps such as cyclization, condensation, nucleophilic substitution, reduction, coupling, hydrolysis, and decarboxylation.

[0063] Detailed Implementation

[0064] As used throughout this application, including in the claims, unless otherwise specifically stated, the following terms shall have the meanings defined below as used herein.

[0065] The term “C1-C6 alkyl” refers to a saturated branched or straight-chain alkyl group containing 1 to 6 carbon atoms, such as (but not limited to) methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0066] The term "C1-C6 alkoxy" refers to -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0067] The term "C1-C6 alkylthio" refers to -S-alkyl. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropylthio, and cyclobutylthio.

[0068] The term "C1-C6 haloalkoxy" refers to an alkoxy group substituted with one or more halogens. Non-limiting examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.

[0069] The term “C1-C6 monosubstituted or polysubstituted alkyl” means that one or more hydrogen atoms in a C1-C6 alkyl group as defined above are replaced by a substituent selected from the following: OH, halogen, alkyl, dialkylamino or heterocyclic group, such as morpholino, piperidinyl, etc.

[0070] The term "C2-C6 alkenyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and having one or more carbon-carbon double bonds, preferably containing 2 to 4 carbon atoms. Non-limiting examples include vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0071] The term "C2-C6 ynyl" refers to a straight-chain or branched monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and having one or more carbon-carbon triple bonds, preferably containing 2 to 4 carbon atoms. Non-limiting examples include ethynyl, propynyl, propynyl, etc.

[0072] The term "C3-C8 cycloalkyl" refers to a cyclic, saturated, monovalent monocyclic or bicyclic hydrocarbon group containing 3 to 8 carbon atoms, with non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. The cycloalkyl group may optionally be substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, and aryl groups.

[0073] The term "3-8 membered heterocyclic alkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic, or tricyclic system containing 3-12 atoms, wherein at least one ring atom is selected from heteroatoms such as nitrogen, sulfur, oxygen, and phosphorus, wherein the heterocyclic group is non-aromatic and does not contain any aromatic rings, and the cyclic system has one or more connection points connected to the rest of the molecule. Non-limiting examples include ethylene oxide, azirrobutyl, oxacyclobutyl, thioheterobutyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolyl, imidazolyl, imidazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, dioxyl, thiaoxyl, thiaoxyl, etc. The heterocyclic alkyl group may optionally be substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, and aryl groups.

[0074] The term "aryl" refers to any carbon monocyclic or fused-ring polycyclic aromatic group containing 6 to 10 carbon atoms and having a conjugated electron system, with phenyl or aryl being non-limiting examples.

[0075] The term "substituted or unsubstituted aryl" means that the 0 to 3 hydrogen atoms on the aryl group are replaced by substituents selected from the following: aryl, halogen, C1-6 alkyl, nitrile, alkyl, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl.

[0076] The term "heteroaryl" refers to a monocyclic or fused-ring polycyclic aromatic heterocyclic group, wherein one or more heteroatomic ring members (ring-forming atoms) in at least one ring are each independently selected from oxygen (O), sulfur (S), and nitrogen (N). Examples of heteroaryl groups include (but are not limited to) 6-membered ring substituents, with non-limiting examples being pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered heteroaryl groups, such as triazolyl, imidazolyl, furanyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5- or 1,3,4-oxadiazolyl, oxazolyl, thiophene, thiazolyl, isothiazolyl, and pyrazolyl; 6 / 5-membered fused-ring substituents, such as indolyl, inzolyl, benzofuranyl, benzimidazolyl, benzothiophene, benzooxadiazolyl, benzothiazolyl, isobenzothiaphene, benzimidazolyl ... Thiopheneyl, benzoisoxazolyl, benzozolyl, benzom-dioxacyclopentenyl, furanopyridyl, purinyl, imidazopyridyl, imidazopyrimidyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidyl, thienenopyridyl, triazolopyrimidyl, triazolopyridyl (e.g., 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl) and o-aminobenzoyl; and 6 / 6-membered fused-ring substituents, such as quinolinyl, isoquinolinyl, cenolinyl, quinazolinyl, oxochromeyl and 1,4-benzoxazinyl.

[0077] The term "substituted or unsubstituted heteroaryl" refers to a heteroaryl group in which 0 to 3 hydrogen atoms are replaced by substituents selected from the following: aryl, halogen, C1-6 alkyl, alkyl, amino, nitro, alkylsulfonyl, ester, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl.

[0078] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0079] The term "solvent" refers to a substance formed by the combination of a compound of the present invention or its salt with a stoichiometric or non-stoichiometric solvent through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0080] The term "pharmaceutical acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components of the formulation and / or the mammals to which it is treated. Preferably, "pharmaceutical acceptable" as used herein means approved by a federal regulatory agency or national government, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, particularly in humans.

[0081] The term "eutectic" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a eutectic formation compound (CCF) through hydrogen bonding or other non-covalent bonds. Both API and CCF are solids in their pure states at room temperature, and a fixed stoichiometric ratio exists between the components. A eutectic is a multi-component substance, encompassing both binary eutectics formed between two neutral solids and multi-component eutectics formed between a neutral solid and a salt or solvate.

[0082] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutical acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutical acceptable carriers, excipients, diluents, binders, fillers, and other excipients, as well as adjunctive therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0083] The term "effective therapeutic dose" refers to the dosage of a compound that, to some extent, reduces one or more symptoms of the condition being treated.

[0084] The term "pharmaceutically acceptable carrier" refers to a carrier that can be used to prepare a pharmaceutical composition. These carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include carriers that are pharmaceutically acceptable to animals and humans. As used in the specification and claims, "pharmaceutically acceptable carrier" includes one or more such carriers in soil.

[0085] The term "carrier" refers to a system that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the given compound, and can change the way a drug enters the body and its distribution in the body, control the rate of drug release, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0086] The term "excipient" refers to an agent that is not itself a therapeutic agent but is used as a diluent, excipient, binder, and / or medium to be added to a pharmaceutical composition to improve its disposal or storage properties or to allow or promote the formation of a unit dosage form of the compound or pharmaceutical composition for administration. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffers, suspending agents, lubricants, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavoring agents, and sweeteners. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and croscarmellose (e.g., sodium croscarmellose); (4) xanthophyll powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter. (9) Oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) pH buffer solution; (21) Polyesters, polycarbonates and / or polyanhydrides; and (22) Other non-toxic compatible substances used in pharmaceutical preparations.

[0087] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0088] Example 1: (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-ylpyridinyl)glycine (E1-1)

[0089]

[0090] Step 1: Preparation of 6-bromoquinazolin-4(3H)-one

[0091] Commercially available 2-amino-5-bromobenzoic acid (10.00 g, 65.30 mmol) was added to a 250 ml round-bottom flask along with 50 ml of formamide. The reaction mixture was then transferred to an oil bath and reacted overnight at 150 °C. TLC analysis confirmed the reaction was complete. The reaction solution was allowed to cool to room temperature, then saturated brine was added. The mixture was placed in a refrigerator below 0 °C to precipitate a solid. The precipitate was filtered, washed three times each with saturated brine and petroleum ether, and dried to obtain a yellow solid (9.03 g, yield 85.27%).

[0092] Step 2: Preparation of 6-bromo-3-methylquinazolin-4(3H)-one

[0093] Weigh 1.50 g (6.67 mmol) of 6-hydroxyquinazolin-4(3H)-one, 1.42 g (10.00 mmol) of potassium iodide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0094] Step 3: Preparation of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0095] Weigh 1.20 g (5.02 mmol) of 6-hydroxyquinazoline-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (985.23 mg, 20.04 mmol), DPPF palladium dichloride (783.64 mg, 250.97 μmol), and pinacol diboronate (3.19 g, 12.22 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0096] Step 4: Preparation of (3-(phenoxy)-5-bromoaminonitrile)

[0097] A methanol (59 mL, 570 mmol) solution in THF (1.8 L) was cooled to 0 °C. Sodium hydroxide (14.4 g, 600 mmol) was slowly added at 0 °C. The mixture was then stirred at room temperature for 1 h, followed by stirring at 35 °C for another 0.5 h. The resulting solution was added to a 5-bromo-3-nitropyridine nitrile (35 g, 100.0 g, 438 mmol) solution in THF (1.3 L), and stirred at room temperature for 24 h. The reaction mixture was quenched with H₂O (200 mL), concentrated to approximately 200 mL, and DCM (1.5 L) was added. The organic layer was separated and washed with saturated NaHCO₃ solution (1.0 L × 1), water (1.0 L × 2), and saturated brine (1.0 L × 1). The solution was concentrated and dried under vacuum at 55 °C to obtain a brown solid.

[0098] Step 5: Preparation of 3-(phenoxy)-5-bromopyridine acid

[0099] Weigh out 53.3 g (184 mmol) of the crude 3-(phenoxy)-5-bromoaminonitrile from the previous step, reflux with methanol (1.0 L) and 30% NaOH (1.0 L) for 2 h, cool to room temperature, concentrate to a volume of about 1.0 L, and acidify with 10% HCl aqueous solution to pH = 2. Collect the precipitate, wash with water, and dry to obtain a pale yellow solid.

[0100] Step 6: Methyl(3-(benzyloxy)-5-bromoamide)glycine (A1)

[0101] Weigh out 49.3 g (0.16 mol) of 3-(phenoxy)-5-bromopyridine acid from the previous step and dissolve it in DCM (500 mL). Add Et3N (67 mL, 0.48 mol), HOBT (32.4 g, 0.24 mol), EDCI (46.0 g, 0.24 mol), and glycine methyl ester hydrochloride (24.1 g, 0.192 mol). Stir at room temperature for 6 h, add saturated NaHCO3 solution (1.0 L), and remove the aqueous layer. Wash the organic layer with water (1.0 L × 2) and saturated brine (1.0 L × 3), dry with anhydrous MgSO4, filter, and concentrate. Recrystallize the residue oil of petroleum ether / ethyl acetate = 3:1 to obtain white solid Al.

[0102] Step 7: Preparation of (3-benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0103] Weigh out A1 (500.00 mg, 1.32 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (452.74 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0104] Step 8: Preparation of (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0105] Weigh out methyl (3-benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 112.50 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0106] Step 9: Preparation of (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine E1--1

[0107] Weigh out methyl glycine (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl) methyl glycine (20.00 mg, 54.30 μmol), NaOH (8.69 mg, 217.19 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the obtained solids.

[0108] Example 2: (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-7-yl)pyridyl)glycine (E1-2)

[0109]

[0110] Step 1: Preparation of 7-bromoquinazolin-4(3H)-one

[0111] Commercially available 2-amino-4-bromobenzoic acid (10.00 g, 65.30 mmol) was added to a 250 ml round-bottom flask along with 50 ml of formamide. The reaction mixture was then transferred to an oil bath and reacted overnight at 150 °C. TLC analysis confirmed the reaction was complete. The reaction solution was allowed to stand at room temperature, then saturated brine was added. The mixture was placed in a refrigerator below 0 °C to precipitate a solid. The precipitate was filtered, washed three times each with saturated brine and petroleum ether, and dried to obtain a yellow solid (9.03 g, yield 85.27%).

[0112] Step 2: Preparation of 7-bromo-3-methylquinazolin-4(3H)-one

[0113] Weigh 1.50 g (6.67 mmol) of the starting material 7-bromoquinazolin-4(3H)-one, 1.42 g (10.00 mmol) of potassium iodide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 ml round-bottom flask. Add 30 ml of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0114] Step 3: Preparation of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0115] Weigh 1.20 g (5.02 mmol) of 7-bromo-3-methylquinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (985.23 mg, 20.04 mmol), DPPF palladium dichloride (783.64 mg, 250.97 μmol), and pinacol diboronate (3.19 g, 12.22 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0116] Step 4: Preparation of (3-benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine methyl ester

[0117] Weigh out A1 (500.00 mg, 1.32 mmol), 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (452.74 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0118] Step 5: Preparation of (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine methyl ester

[0119] Weigh out methyl (3-benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (50.00 mg, 112.50 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0120] Step 6: Preparation of (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine E1-2

[0121] Weigh out methyl glycine (3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (20.00 mg, 54.30 μmol), NaOH (8.69 mg, 217.19 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was confirmed to be complete by TLC. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 32%. 1 H NMR (400MHz, DMSO-d6) δ12.4 (s, 1H), 9.4 (t, J = 5.8Hz, 1H), 8.6 (d, J = 1.9Hz, 1H), 8.5 (d, J = 2.2Hz , 1H), 8.4 (s, 1H), 8.3 (dd, J=8.0, 2.3Hz, 1H), 7.8-7.8 (m, 2H), 4.0 (d, J=5.9Hz, 2H), 3.5 (s, 3H).

[0122] Example 3: (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine (E2-1)

[0123]

[0124] Step 1: Preparation of 6-bromo-3-isopropylquinazolin-4(3H)-one

[0125] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.36 g (8.00 mmol) of 2-iodopropane, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0126] Step 2: Preparation of 3-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0127] Weigh 1.20 g (4.49 mmol) of 6-bromo-3-isopropylquinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (881.76 mg (8.98 mmol), DPPF palladium dichloride (164.35 mg (554.61 μmol), and pinacol diboronate (2.85 g (11.23 mmol)). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0128] Step 3: Preparation of (3-benzyloxy)-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0129] Weigh out A1 (500.00 mg, 1.32 mmol), 3-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (497.13 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0130] Step 4: Preparation of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0131] Weigh out methyl (3-benzyloxy)-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 102.77 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0132] Step 5: Preparation of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine E2-1. Weigh (20.00 mg, 50.45 μmol) of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-7-yl)pyridinecarboxyl)glycine methyl ester, NaOH (8.07 mg, 201.81 μmol), methanol (5 ml), and H2O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 34%. 1 H NMR (400MHz, DMSO-d6) δ12.4 (s, 1H), 9.4 (t, J = 5.8Hz, 1H), 8.6 (d, J = 1.9Hz, 1H), 8.5 (d, J = 2.2Hz , 1H), 8.4 (s, 1H), 8.3 (dd, J=8.0, 2.3Hz, 1H), 7.8-7.8 (m, 2H), 4.0 (d, J=5.9Hz, 2H), 3.5 (s, 3H).

[0133] Example 4: (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazoline-7-yl)pyridinecarboxyl)glycine (E2-2)

[0134]

[0135] Step 1: Preparation of 7-bromo-3-isopropylquinazolin-4(3H)-one

[0136] Weigh 1.50 g (6.67 mmol) of 7-bromoquinazolin-4(3H)-one, 1.36 g (8.00 mmol) of 2-iodopropane, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0137] Step 2: Preparation of 3-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0138] Weigh 1.20 g (4.49 mmol) of 7-bromo-3-isopropylquinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (881.76 mg 8.98 mmol), DPPF palladium dichloride (164.35 mg 554.61 μmol), pinacol diboronate (2.85 g 11.23 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0139] Step 3: Preparation of (3-benzyloxy)-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine methyl ester

[0140] Weigh out A1 (500.00 mg, 1.32 mmol), 3-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (497.13 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography to obtain a white solid.

[0141] Step 4: Preparation of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine methyl ester

[0142] Weigh out methyl (3-benzyloxy)-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine (50.00 mg, 102.77 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0143] Step 5: Preparation of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine E1-2

[0144] Weigh out methyl glycine (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (20.00 mg, 50.45 μmol), NaOH (8.07 mg, 201.81 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 24%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.1Hz, 1H), 8.7 (d, J=1.9Hz, 1H), 8.5 (s, 1H), 8.3 (d, J=8.3Hz, 1H), 8.1 (d, J=1.8Hz, 1H), 8.0 (dd, J=8.4, 1.8Hz, 1H), 7.9 (d, J=2.0Hz, 1H), 5.0 (p, J=6.8Hz, 1H), 4.0 (d, J=6.1Hz, 2H), 1.5 (d, J=7.0Hz, 6H).

[0145] Example 5: (5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E3-1)

[0146]

[0147] Step 1: Preparation of 6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one

[0148] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 724.26 mg (8.00 mmol) of cyclopropylmethylchloro (2.76 g (20.00 mmol) and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0149] Step 2: Preparation of 3-(cyclopropylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0150] Weigh 1.20 g (4.30 mmol) of 6-bromo-3-(cyclopropylmethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (843.82 mg, 8.60 mmol), DPPF palladium dichloride (157.28 mg, 214.95 μmol), and pinacol diboronate (2.73 g, 10.75 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0151] Step 3: Preparation of (3-benzyloxy)-5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0152] Weigh out A1 (500.00 mg, 1.32 mmol), 3-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (516.13 mg, 1.58 mmol), potassium fluoride (3372.33 mg), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0153] Step 4: Preparation of (3-hydroxy-5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0154] Weigh out methyl (3-benzyloxy)-5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 100.29 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0155] Step 5: Preparation of (3-hydroxy-5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine E1-2

[0156] Weigh out methyl (3-hydroxy-5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl)glycine (20.00 mg, 48.97 μmol), NaOH (7.83 mg, 195.88 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 34%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J = 6.2Hz, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.4Hz, 2H), 8. 3 (dd, J=8.5, 2.3Hz, 1H), 7.9-7.7 (m, 2H), 4.0 (d, J=6.1Hz, 2H), 3.9 (d, J=7.2Hz, 2H), 1.4-1.2 (m, 1H), 0.5-0.4 (m, 4H).

[0157] Example 6: (3-hydroxy-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinyl)glycine (E4-1)

[0158]

[0159] Step 1: Preparation of 6-bromo-3-(2-methoxyethyl)quinazolin-4(3H)-one

[0160] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 756.15 mg (8.00 mmol) of 2-chloroethyl methyl ether, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0161] Step 2: Preparation of 3-(2-methoxyethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0162] Weigh 1.20 g (5.02 mmol) of 6-bromo-3-(2-methoxyethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (985.23 mg, 10.04 mmol), DPPF palladium dichloride (183.64 mg, 250.97 μmol), pinacol diboronate (3.19 g, 12.55 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0163] Step 3: Preparation of (3-benzyloxy)-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0164] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(2-methoxyethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (522.44 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography to obtain a white solid.

[0165] Step 4: Preparation of (3-hydroxy-5-(3-isopropyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0166] Weigh out 50.00 mg (99.50 μmol) of (3-benzyloxy)-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0167] Step 5: Preparation of (3-hydroxy-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine E1-2

[0168] Weigh out methyl (3-hydroxy-5-(3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (20.00 mg, 48.50 μmol), NaOH (7.76 mg, 193.99 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 35%. 1 H NMR (400MHz, DMSO-d6) δ9.2 (s, 1H), 8.6 (s, 1H), 8.5 (s, 1H), 8.4 (s, 1H), 8.3 (d, J = 8.5Hz, 1 H), 7.8 (d, J=9.9Hz, 2H), 4.2 (d, J=6.4Hz, 2H), 3.9 (d, J=5.6Hz, 2H), 3.6 (t, J=5.2Hz, 2H).

[0169] Example 7: ((3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinamido)methyl)phosphonic acid (E5-1)

[0170]

[0171] Step 1: Preparation of methyl 3-benzyloxy-5-bromopyridinecarboxylate

[0172] Weigh out 1 g (3.24 mmol) of 3-(phenoxy)-5-bromopyridine acid. Dissolve it in 10 mL of methanol, add 2 drops of acetyl chloride, reflux for 2 h, and check the reaction is complete by TLC. Separate the product by column chromatography to obtain a white solid.

[0173] Step 2: Preparation of methyl 3-benzyloxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxylate

[0174] Weigh out methyl 3-benzyloxy-5-bromopyridinecarboxylate (500.00 mg, 1.55 mmol), 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (532.91 mg, 1.58 mmol), potassium fluoride (438.26 mg, 4.66 mmol), and tetrakis(triphenylphosphine)palladium (89.68 mg, 77.60 μmol), DME (16 ml), and H₂O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0175] Step 3: Preparation of ((3-(benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinamido)methyl)phosphonic acid

[0176] Weigh out methyl 3-benzyloxy-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxylate (400.00 mg, 996.46 μmol) and aminomethylphosphonic acid (165.94 mg, 1.49 mmol), dissolve them in 20 mL of acetonitrile, slowly add DBU (303.40 mg, 1.99 mmol), heat to 65 °C, and let the reaction complete overnight. Separate the solid by column chromatography to obtain a white solid.

[0177] Step 4: Preparation of ((3-hydroxy-5-(3-methyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinamido)methyl)phosphonic acid (E5-1)

[0178] Weigh 200 mg (416.31 μmol) of ((3-(benzyloxy)-5-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinamido)methyl)phosphonic acid, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Slurry with methanol to obtain a white solid. Yield: 21%. 1 H NMR (400MHz, DMSO-d6) δ12.4 (s, 1H), 8.7 (s, 1H), 8.6 (s, 1H), 8.4 (d, J = 8.5Hz, 2H), 8.2 (d, J=8.5Hz, 1H), 7.8 (d, J=11.0Hz, 2H), 3.6 (dd, J=13.0, 6.1Hz, 2H).

[0179] Example 8: (3-hydroxy-5-(4-oxo-3-phenylethyl-3,4-dihydroquinazoline-6-yl)pyridyl)glycine (E6-1)

[0180]

[0181] Step 1: Preparation of 6-bromo-3-phenylethylquinazolin-4(3H)-one

[0182] Weigh the starting materials 6-bromoquinazolin-4(3H)-one (1.50 g, 6.67 mmol), 1-chloro-2-phenylethane (1.12 g, 8.00 mmol), and potassium carbonate (2.76 g, 20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was monitored by TLC until complete. Dilute with a large amount of saturated saline solution, extract with ethyl acetate without purification, and proceed directly to the next step.

[0183] Step 2: Preparation of 3-phenylethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0184] Weigh 1.20 g (3.65 mmol) of 6-bromo-3-phenylethylquinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (715.50 mg (8.98 mmol), DPPF palladium dichloride (133.36 mg (182.26 μmol), and pinacol diboronate (2.31 g (9.11 mmol)). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0185] Step 3: Preparation of (3-benzyloxy)-5-(3-phenylethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0186] Weigh out A1 (500.00 mg, 1.32 mmol), 3-phenylethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (5953.4 mg, 1.58 mmol), potassium fluoride (372.33 mg, 396 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography to obtain a white solid.

[0187] Step 4: Preparation of (3-hydroxy-5-(3-phenylethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0188] Weigh out methyl (3-benzyloxy)-5-(3-phenylethyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 93.53 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0189] Step 5: Preparation of (3-hydroxy-5-(3-phenylethyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine E1-2

[0190] Weigh out methyl glycine (3-hydroxy-5-(3-phenylethyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinecarboxyl) methyl glycine (20.00 mg, 43.62 μmol), NaOH (6.98 mg, 174.49 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the obtained solids.

[0191] Example 9: (3-hydroxy-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinyl)glycine (E7-1)

[0192]

[0193] Step 1: Preparation of 6-bromo-3-(2-morpholino-2-oxoethyl)quinazolin-4(3H)-one

[0194] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.31 g (8.00 mmol) of 2-chloro-1-morpholinoacet-1-one, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 ml round-bottom flask. Add 30 ml of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0195] Step 2: Preparation of 3-(2-morpholino-2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0196] Weigh 1.20 g (3.41 mmol) of 6-bromo-3-(2-morpholino-2-oxoethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (668.79 mg, 6.81 mmol), DPPF palladium dichloride (124.66 mg, 170.36 μmol), and pinacol diboronate (2.16 g, 8.52 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0197] Step 3: Preparation of (3-benzyloxy)-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazolino-6-yl)pyridinecarboxyl)glycine methyl ester

[0198] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(2-morpholino-2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (631.71 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.18 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0199] Step 4: Preparation of (3-hydroxy-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazolino-6-yl)pyridinecarboxyl)glycine methyl ester

[0200] Weigh 50.00 mg (91.98 μmol) of (3-benzyloxy)-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Step 5 prepares (3-hydroxy-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine E1-2

[0201] Weigh out methyl glycine (3-hydroxy-5-(3-(2-morpholino-2-oxoethyl)-4-oxo-3,4-dihydroquinazolino-7-yl)pyridinyl)glycine (20.00 mg, 41.54 μmol), NaOH (6.65 mg, 116.16 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 27%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.1Hz, 1H), 8.6 (dd, J=4.2, 1.9Hz, 1H), 8.5-8.4 (m, 1H), 8.4-8.2 (m , 2H), 7.8 (dd, J=5.1, 3.3Hz, 2H), 5.0 (s, 2H), 4.0 (d, J=6.1Hz, 2H), 3.8-3.7 (m, 2H), 3.6 (t, J=4.6Hz, 3H), 3.5 (t, J=4.8Hz, 2H).

[0202] Example 10: (3-hydroxy-5-(4-oxo-3-phenylethyl-3,4-dihydroquinazoline-6-yl)pyridyl)glycine (E8-1)

[0203]

[0204] Step 1: Preparation of 6-bromo-3-benzylquinazoline-4(3H)-one

[0205] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.37 g (8.00 mmol) of benzyl bromide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0206] Step 2: Preparation of 3-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0207] Weigh 1.20 g (3.81 mmol) of 6-bromo-3-benzylquinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (747.35 mg (8.98 mmol), DPPF palladium dichloride (139.30 mg (190.37 μmol), and pinacol diboronate (2.42 g (9.53 mmol)). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0208] Step 3: Preparation of (3-benzyloxy)-5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0209] Weigh out A1 (500.00 mg, 1.32 mmol), 3-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (573.14 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography to obtain a white solid.

[0210] Step 4: Preparation of (3-hydroxy-5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0211] Weigh out methyl (3-benzyloxy)-5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 93.53 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates.

[0212] Step 5: Preparation of (3-hydroxy-5-(3-benzyl-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine E1-2

[0213] Weigh out methyl glycine (3-hydroxy-5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (20.00 mg, 45.00 μmol), NaOH (7.20 mg, 180.00 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 27%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.1Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 ( d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.9-7.8 (m, 2H), 7.4-7.2 (m, 5H), 5.2 (s, 2H), 4.0 (d, J=6.2Hz, 2H).

[0214] Example 11: (5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E10-1)

[0215]

[0216] Step 1: Preparation of 6-bromo-3-(4-(tert-butyl)benzyl)quinazolin-4(3H)-one

[0217] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.82 g (8.00 mmol) of 4-(tert-butyl)bromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0218] Step 2: Preparation of 3-(4-(tert-butyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0219] Weigh 1.20 g (4.49 mmol) of 6-bromo-3-(4-(tert-butyl)benzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (634.41 mg, 8.98 mmol), DPPF palladium dichloride (118.25 mg, 161.60 μmol), pinacol diboronate (2.05 g, 8.08 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0220] Step 3: Preparation of (3-benzyloxy)-5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0221] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-(tert-butyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (661.92 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0222] Step 4: Preparation of (3-hydroxy-5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0223] Weigh out 50.00 mg (93.53 μmol) of (3-benzyloxy)-5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 24%. 1 HNMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J = 6.1Hz, 1H), 8.7 (s, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.2Hz, 1H), 8 .3(dd, J=8.5, 2.2Hz, 1H), 7.8-7.8(m, 2H), 7.4-7.3(m, 4H), 5.2(s, 2H), 4.1(d, J=6.1Hz, 2H), 3.7(s, 3H), 1.2(s, 9H).

[0224] Example 12: (5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E10-2)

[0225]

[0226] Step 1: Preparation of ((5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E10-2)

[0227] Weigh out methyl glycine (3-hydroxy-5-(3-(4-(tert-butyl)benzyl)-4-oxo-3,4-dihydroquinazolin-7-yl)pyridinyl)glycine (20.00 mg, 45.00 μmol), NaOH (7.20 mg, 180.00 μmol), methanol (5 ml), and H₂O (5 ml). Stir overnight at room temperature. The reaction was monitored by TLC until complete. Concentrate to approximately 5 ml and acidify with 10% HCl aqueous solution to pH 2. Collect the precipitate, wash with water, evaporate to dryness, and slurry with DCM and methanol respectively. Dry the solids. Yield: 32%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2 .3Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.8 (dd, J=5.2, 3.3Hz, 2H), 7.5-7.2 (m, 4H), 4.0 (d, J=6.1Hz, 2H), 1.2 (s, 9H).

[0228] Example 13: (3-hydroxy-5-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E11-1)

[0229]

[0230] Step 1: Preparation of 6-bromo-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one

[0231] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.91 g (8.00 mmol) of 3-(trifluoromethyl)bromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0232] Step 2: Preparation of 3-(3-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0233] Weigh 1.20 g (3.13 mmol) of 6-bromo-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (614.72 mg, 6.26 mmol), DPPF palladium dichloride (114.58 mg, 156.59 μmol), pinacol diboronate (1.99 g, 7.83 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0234] Step 3: Preparation of (3-benzyloxy)-5-(3-(3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0235] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(3-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (680.73 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0236] Step 4: Preparation of (3-hydroxy-5-(3-(3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0237] Weigh 50.00 mg (82.98 μmol) of (3-benzyloxy)-5-(3-(3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 34%. 1 HNMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J = 6.1Hz, 1H), 8.7 (s, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.2Hz, 1H), 8 .3(dd, J=8.5, 2.2Hz, 1H), 7.8-7.8(m, 2H), 7.4-7.3(m, 4H), 5.2(s, 2H), 4.1(d, J=6.1Hz, 2H), 3.7(s, 3H), 1.2(s, 9H).

[0238] Example 14: (3-hydroxy-5-(4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (E11-2)

[0239]

[0240] Refer to Example 12, yield 26%. 1H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J = 6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.3Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.8 (dd, J=5.2, 3.3Hz, 2H), 7.5-7.2 (m, 4H), 5.2 (s, 2H), 4.0 (d, J=6.1Hz, 2H), 1.2 (s, 9H).

[0241] Example 15: (5-(3-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E9-1)

[0242]

[0243] Step 1: Preparation of 6-bromo-3-3-([1,1′-biphenyl]-4-ylmethyl)quinazolin-4(3H)-one

[0244] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.98 g (8.00 mmol) of 4-bromomethylbiphenyl, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0245] Step 2: Preparation of 3-([1,1′-biphenyl]-4-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0246] Weigh 1.20 g (4.49 mmol) of 6-bromo-3-([1,1′-biphenyl]-4-ylmethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (602.00 mg, 6.13 mmol), DPPF palladium dichloride (112.21 mg, 153.35 μmol), pinacol diboronate (1.95 g, 7.67 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0247] Step 3: Preparation of (3-benzyloxy)-5-(3-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0248] Weigh out A1 (500.00 mg, 1.32 mmol), 3-([1,1′-biphenyl]-4-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (693.55 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0249] Step 4: Preparation of (3-hydroxy-5-(3-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0250] Weigh out 50.00 mg (81.88 μmol) of (3-benzyloxy)-5-(3-([1,1′-biphenyl]-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Yield: 35%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J = 6.2Hz, 1H), 8.7 (d, J = 5.5Hz, 1H ), 8.6 (d, J = 2.0Hz, 1H), 8.5 (t, J = 2.7Hz, 1H), 8.3 (dt, J = 8.6, 2.4Hz, 1H), 7.8 ( dd, J=5.1, 3.1Hz, 2H), 7.7-7.6(m, 2H), 7.5-7.4(m, 3H), 7.3-7.2(m, 2H), 7.2( dd, J=16.0, 7.8Hz, 2H), 5.3 (d, J=7.1Hz, 2H), 4.1 (d, J=6.2Hz, 2H), 3.7 (s, 3H).

[0251] Example 16: (3-hydroxy-5-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E12-1)

[0252]

[0253] Step 1: Preparation of 6-bromo-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one

[0254] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.91 g (8.00 mmol) of 4-(trifluoromethyl)bromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0255] Step 2: Preparation of 3-(4-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0256] Weigh 1.20 g (3.13 mmol) of 6-bromo-3-(4-(trifluoromethyl)benzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (614.72 mg, 6.26 mmol), DPPF palladium dichloride (114.58 mg, 156.59 μmol), and pinacol diboronate (1.99 g, 7.83 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0257] Step 3: Preparation of (3-benzyloxy)-5-(3-(4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0258] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (680.73 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0259] Step 4: Preparation of (3-hydroxy-5-(3-(4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0260] Weigh 50.00 mg (82.98 μmol) of (3-benzyloxy)-5-(3-(4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 43%. 1 HNMR (400MHz, DMSO-d6) δ12.7 (s, 1H), 8.5 (s, 1H), 8.3 (d, J = 2.2Hz, 1H), 8.1 (dd, J = 8.4, 2.2Hz, 1H), 7.8 (t, J = 7.0 Hz, 3H), 7.6 (t, J=7.6Hz, 1H), 7.5 (t, J=7.6Hz, 1H), 7.2-7.0 (m, 2H), 5.4 (s, 2H), 4.1 (d, J=5.7Hz, 2H), 3.6 (s, 3H).

[0261] Example 17: (3-hydroxy-5-(4-oxo-3-(4-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (E12-2)

[0262]

[0263] Reference Example 12: Yield 24%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J = 6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.2Hz, 1 H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.9-7.8 (m, 2H), 7.7 (d, J=8.1Hz, 2H), 7.6 (d, J=8.0Hz, 2H), 5.3 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0264] Example 18: (3-hydroxy-5-(4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E13-1)

[0265]

[0266] Step 1: Preparation of 6-bromo-3-(2-(trifluoromethyl)benzyl)quinazolin-4(3H)-one

[0267] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.91 g (8.00 mmol) of 3-(trifluoromethyl)bromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0268] Step 2: Preparation of 3-(2-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0269] Weigh 1.20 g (3.13 mmol) of 6-bromo-3-(2-(trifluoromethyl)benzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (614.72 mg, 6.26 mmol), DPPF palladium dichloride (114.58 mg, 156.59 μmol), pinacol diboronate (1.99 g, 7.83 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0270] Step 3: Preparation of (3-benzyloxy)-5-(3-(2-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0271] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-(trifluoromethyl)benzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (680.73 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0272] Step 4: Preparation of (3-hydroxy-5-(3-(2-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0273] Weigh out 50.00 mg (82.98 μmol) of (3-benzyloxy)-5-(3-(4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 23%. 1 HNMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.1Hz, 1H), 8.6-8.5 (m, 2H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.2H z, 1H), 7.9-7.8 (m, 3H), 7.6 (dt, J=32.9, 7.6Hz, 2H), 7.1 (d, J=7.7Hz, 1H), 5.4 (s, 2H), 4.1 (d, J=6.0Hz, 2H), 3.7 (s, 3H).

[0274] Example 19: (3-hydroxy-5-(4-oxo-3-(2-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (E13-2)

[0275]

[0276] Refer to Example 12, yield 34%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.1Hz, 1H), 8.7-8.6 (m, 2H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.3 Hz, 1H), 7.9 (d, J=8.5Hz, 1H), 7.8-7.8 (m, 2H), 7.6 (dt, J=33.1, 7.6Hz, 2H), 7.1 (d, J=7.8Hz, 1H), 5.4 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0277] Example 20: (3-hydroxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E14-1)

[0278]

[0279] Step 1: Preparation of 6-bromo-3-(3-(4-methoxybenzyl))quinazolin-4(3H)-one

[0280] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.61 g (8.00 mmol) of 4-methoxybenzyl bromide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0281] Step 2: Preparation of 3-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0282] Weigh 1.20 g (3.13 mmol) of 6-bromo-3-(4-methoxybenzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (682.34 mg, 6.95 mmol), DPPF palladium dichloride (127.18 mg, 173.81 μmol), pinacol diboronate (2.21 g, 8.69 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography to obtain a white solid.

[0283] Step 3: Preparation of (3-benzyloxy)-5-(3-(4-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0284] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (620.65 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0285] Step 4: Preparation of (3-hydroxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0286] Weigh out 50.00 mg (82.98 μmol) of (3-benzyloxy)-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 32%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.2Hz, 1H), 8.6 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2.3Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1 H), 7.9-7.8 (m, 2H), 7.3 (q, J=10.4, 9.2Hz, 1H), 7.2-7.0 (m, 1H), 7.0-6.8 (m, 3H), 5.2 (s, 2H), 4.1 (d, J=6.1Hz, 2H), 3.7 (s, 3H), 3.7 (s, 3H).

[0287] Example 21: (3-hydroxy-5-(3-(4-methoxybenzyl)-4-oxo-3,4-dihydroquinazoline-6-yl)pyridinecarboxyl)glycine (E14-2)

[0288]

[0289] See Example 12. Yield: 23%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.6 ( s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.8(dd, J=5.2, 3.3Hz, 2H), 7.3(t, J=7.9Hz, 1H), 7.0-7.0(m, 1H), 6.9-6.9(m, 1H), 6.9 (dd, J=8.3, 2.6Hz, 1H), 5.2 (s, 2H), 4.0 (d, J=6.1Hz, 2H), 3.7 (s, 3H).

[0290] Example 22: (3-hydroxy-5-(3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E15-1)

[0291]

[0292] Step 1: Preparation of 6-bromo-3-(3-(3-methoxybenzyl))quinazolin-4(3H)-one

[0293] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.61 g (8.00 mmol) of 4-methoxybenzyl bromide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0294] Step 2: Preparation of 3-(3-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0295] Weigh 1.20 g (3.13 mmol) of 6-bromo-3-(3-methoxybenzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (682.34 mg, 6.95 mmol), DPPF palladium dichloride (127.18 mg, 173.81 μmol), and pinacol diboronate (2.21 g, 8.69 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0296] Step 3: Preparation of (3-benzyloxy)-5-(3-(3-(trifluoromethyl)benzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0297] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(3-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (620.65 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0298] Step 4: Preparation of (3-hydroxy-5-(3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0299] Weigh out 50.00 mg (82.98 μmol) of (3-benzyloxy)-5-(3-(3-methoxybenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 23%. 1 H NMR (400MHz, DMSO-d6) δ12.6 (s, 1H), 8.3 (d, J=2.1Hz, 1H), 8.1 (s, 2H), 8.0-7.9 (m, 1H), 7 .8 (s, 1H), 7.6 (d, J = 8.5Hz, 2H), 7.0 (s, 1H), 6.9 (s, 1H), 4.1 (d, J = 5.5Hz, 4H), 3.6 (s, 6H).

[0300] Example 23: 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E17-1)

[0301]

[0302] Step 1: Preparation of 6-bromo-3-(4-fluoromethylbenzyl)quinazolin-4(3H)-one

[0303] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.51 g (8.00 mmol) of 4-fluorobromobenzyl (2.76 g (20.00 mmol) and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0304] Step 2: Preparation of 3-(4-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0305] Weigh 1.20 g (3.60 mmol) of 6-bromo-3-(4-(fluorobenzyl)benzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (706.99 mg, 9.00 mmol), DPPF palladium dichloride (131.78 mg, 180.09 μmol), pinacol diboronate (2.29 g, 9.00 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0306] Step 3: Preparation of (3-benzyloxy)-5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0307] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (601.61 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0308] Step 4: Preparation of (3-hydroxy-5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0309] Weigh out 50.00 mg (90.49 μmol) of (3-benzyloxy)-5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 23% 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J = 6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J = 2.0Hz, 1H), 8.5 (d, J = 2.2Hz, 1H), 8.3 ( dd, J=8.5, 2.3Hz, 1H), 7.9-7.8 (m, 2H), 7.5-7.4 (m, 2H), 7.3-7.1 (m, 2H), 5.2 (s, 2H), 4.1 (d, J=6.1Hz, 2H), 3.7 (s, 3H).

[0310] Example 24: 5-(3-(4-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E17-2)

[0311]

[0312] Reference Example 12: Yield 43%. 1H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2.2Hz, 1H ), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.8 (dd, J=5.3, 3.3Hz, 2H), 7.6-7.3 (m, 2H), 7.3-6.9 (m, 2H), 5.2 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0313] Example 25: (5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E18-1)

[0314]

[0315] Step 1: Preparation of 6-bromo-3-(2-fluoromethylbenzyl)quinazolin-4(3H)-one

[0316] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.51 g (8.00 mmol) of 2-fluorobromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0317] Step 2: Preparation of 3-(2-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0318] Weigh 1.20 g (3.60 mmol) of 6-bromo-3-(2-fluorobenzylbenzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (706.99 mg, 9.00 mmol), DPPF palladium dichloride (131.78 mg, 180.09 μmol), pinacol diboronate (2.29 g, 9.00 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0319] Step 3: Preparation of (3-benzyloxy)-5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0320] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (601.61 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0321] Step 4: Preparation of (3-hydroxy-5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0322] Weigh out 50.00 mg (90.49 μmol) of (3-benzyloxy)-5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 43%. 1 H NMR (400MHz, DMSO-d6) δ12.6 (s, 1H), 8.3 (d, J=2.1Hz, 1H), 8.1 (dd, J=8.5, 2.2Hz, 1H), 7. 9-7.7 (m, 2H), 7.4-7.1 (m, 5H), 7.1 (s, 1H), 5.3 (s, 2H), 4.1 (d, J=5.7Hz, 2H), 3.6 (s, 3H).

[0323] Example 26: (5-(3-(2-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E18-2)

[0324]

[0325] Reference Example 12, yield 24%. ¹H NMR (400MHz, DMSO-d⁶) δ 12.8 (s, ¹H), 12.4 (s, ¹H), 9.4 (t, J = 6.2 Hz, ¹H), 8.7–8.6 (m, 2H), 8.5 (d, J = 2.3 Hz, 1H), 8.3 (dd, J = 8.6, 2.3 Hz, 1H), 7.9–7.7 (m, 2H), 7.3 (q, J = 7.9 Hz, 2H), 7.3–7.1 (m, 2H), 5.3 (s, 2H), 4.0 (d, J = 6.1 Hz, 2H).

[0326] Example 27: (5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E19-1)

[0327]

[0328] Step 1: Preparation of 6-bromo-3-(3-fluoromethylbenzyl)quinazolin-4(3H)-one

[0329] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.51 g (8.00 mmol) of 3-fluorobromobenzyl (2.76 g (20.00 mmol) into a 100 mL round-bottom flask, add 30 mL of DMF, and react overnight at room temperature. The reaction was confirmed to be complete by TLC. The mixture was diluted with a large amount of saturated brine, precipitating a solid. The solid was filtered, washed three times with saturated brine, dried, and separated by column chromatography to obtain 3.21 g of a white solid (yield 49.31%).

[0330] Step 2: Preparation of 3-(3-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0331] Weigh 1.20 g (3.60 mmol) of 6-bromo-3-(3-(fluorobenzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (706.99 mg, 9.00 mmol), DPPF palladium dichloride (131.78 mg, 180.09 μmol), pinacol diboronate (2.29 g, 9.00 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0332] Step 3: Preparation of (3-benzyloxy)-5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0333] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-fluorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (601.61 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0334] Step 4: Preparation of (3-hydroxy-5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0335] Weigh out methyl (3-benzyloxy)-5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (50.00 mg, 90.49 μmol), add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 34%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1 H), 7.9-7.8 (m, 2H), 7.4 (td, J=8.0, 6.1Hz, 1H), 7.3-7.2 (m, 2H), 7.1 (td, J=8.6, 2.6Hz, 1H), 5.2 (s, 2H), 4.1 (d, J=6.2Hz, 2H), 3.7 (s, 3H).

[0336] Example 28: (5-(3-(3-fluorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E19-2)

[0337]

[0338] See Example 12. Yield: 25%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.1Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=2.0Hz, 1H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J= 8.5, 2.3Hz, 1H), 7.9-7.8 (m, 2H), 7.4 (td, J=7.9, 6.0Hz, 1H), 7.3-7.2 (m, 2H), 7.1 (td, J=8.7, 2.7Hz, 1H), 5.2 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0339] Example 29: (5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine methyl ester (E20-1)

[0340]

[0341] Step 1: Preparation of 6-bromo-3-(4-chlorobenzyl)quinazolin-4(3H)-one

[0342] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.64 g (8.00 mmol) of 4-chlorobenzyl bromide, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0343] Step 2: Preparation of 3-(4-chlorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0344] Weigh 1.20 g (3.43 mmol) of 6-bromo-3-(4-chlorobenzyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (673.72 mg, 6.86 mmol), DPPF palladium dichloride (125.58 mg, 171.62 μmol), and pinacol diboronate (2.18 g, 8.58 mmol). Add 30 mL of 1,4-dioxane, and under argon protection, react overnight at 120 °C until complete. Filter with diatomaceous earth, evaporate the solvent, and separate by column chromatography to obtain a white solid.

[0345] Step 3: Preparation of (3-benzyloxy)-5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0346] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(4-chlorobenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (627.64 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0347] Step 4: Preparation of (3-hydroxy-5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0348] Weigh out 50.00 mg (87.87 μmol) of (3-benzyloxy)-5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 32%. 1 H NMR (400MHz, DMSO-d6) δ12.6 (s, 1H), 8.6 (s, 1H), 8.3 (d, J = 2.2Hz, 1H), 8.1 (dd, J = 8.5, 2.2Hz , 1H), 7.9-7.7(m, 2H), 7.4(s, 4H), 7.1(s, 1H), 5.2(s, 2H), 4.1(d, J=5.7Hz, 2H), 3.6(s, 3H).

[0349] Example 30: (5-(3-(4-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-6-yl)-3-hydroxypyridinecarboxyl)glycine (E20-2)

[0350]

[0351] Refer to Example 12, yield 23%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.7 (s, 1H), 8.6 (d, J=1.9Hz, 1H), 8. 5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.9-7.8 (m, 2H), 7.4 (s, 4H), 5.2 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0352] Example 31: (3-hydroxy-5-(4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E21-1)

[0353]

[0354] Step 1: Preparation of 6-bromo-3-(3-(pyridin-4-ylmethyl)quinazolin-4(3H)-one

[0355] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.31 g (8.00 mmol) of 4-chloromethylpyridine hydrochloride, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0356] Step 2: Preparation of 3-(pyridin-4-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0357] Weigh 1.20 g (3.80 mmol) of 6-bromo-3-(pyridin-4-ylmethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (745.01 mg, 7.59 mmol), DPPF palladium dichloride (138.86 mg, 189.78 μmol), pinacol diboronate (2.41 g, 9.49 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0358] Step 3: Preparation of (3-benzyloxy)-5-(3-(pyridin-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0359] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(pyridin-4-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (574.71 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0360] Step 4: Preparation of (3-hydroxy-5-(3-(pyridin-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0361] Weigh 50.00 mg (93.36 μmol) of (3-benzyloxy)-5-(3-(pyridin-4-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 27%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.2Hz, 1H), 8.7-8.7 (m, 2H), 8.6 (d, J=2.0Hz, 1H), 8.5-8.4 (m, 2H), 8 .3 (dd, J=8.5, 2.3Hz, 1H), 7.9-7.8 (m, 3H), 7.4 (dd, J=7.9, 4.7Hz, 1H), 5.3 (s, 2H), 4.1 (d, J=6.1Hz, 2H), 3.7 (s, 3H).

[0362] Example 32: (3-hydroxy-5-(4-oxo-3-(pyridin-4-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E21-2)

[0363]

[0364] Refer to Example 12, yield 25%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.7-8.7 (m, 2H), 8.6 (d, J=1.9Hz, 1H), 8.5 (dd, J=4.8, 1.6Hz , 1H), 8.5 (d, J=2.2Hz, 1H), 8.3 (dd, J=8.5, 2.2Hz, 1H), 7.8-7.8 (m, 3H), 7.4 (dd, J=7.9, 4.8Hz, 1H), 5.3 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0365] Example 33: (3-hydroxy-5-(4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E22-1)

[0366]

[0367] Step 1: Preparation of 6-bromo-3-(3-(pyridin-2-ylmethyl)quinazolin-4(3H)-one

[0368] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.31 g (8.00 mmol) of 2-chloromethylpyridine hydrochloride, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0369] Step 2: Preparation of 3-(pyridin-2-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0370] Weigh 1.20 g (3.80 mmol) of 6-bromo-3-(pyridin-2-ylmethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (745.01 mg, 7.59 mmol), DPPF palladium dichloride (138.86 mg, 189.78 μmol), pinacol diboronate (2.41 g, 9.49 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0371] Step 3: Preparation of (3-benzyloxy)-5-(3-(pyridin-2-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0372] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(pyridin-2-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (574.71 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0373] Step 4: Preparation of (3-hydroxy-5-(3-(pyridin-2-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0374] Weigh out 50.00 mg (93.36 μmol) of (3-benzyloxy)-5-(3-(pyridin-2-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 37%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.2Hz, 1H), 8.6 (d, J=2.6Hz, 2H), 8.5-8.4 (m, 2H), 8.3 (dd, J=8.5, 2.3H z, 1H), 7.9-7.7 (m, 3H), 7.5 (d, J=7.8Hz, 1H), 7.3 (dd, J=7.6, 4.9Hz, 1H), 5.4 (s, 2H), 4.1 (d, J=6.1Hz, 2H), 3.7 (s, 3H).

[0375] Example 34: (3-hydroxy-5-(4-oxo-3-(pyridin-2-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (E22-2)

[0376]

[0377] Refer to Example 12, yield 34%. 1 H NMR (400MHz, DMSO-d6) δ12.8 (s, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.6 (s, 2H), 8.5 (dd, J=11.3, 3.6Hz, 2H), 8.3 (dd , J=8.6, 2.3Hz, 1H), 7.9-7.7 (m, 3H), 7.4 (d, J=7.8Hz, 1H), 7.3 (dd, J=7.5, 4.8Hz, 1H), 5.3 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0378] Example 35: (3-hydroxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester (E23-1)

[0379]

[0380] Step 1: Preparation of 6-bromo-3-(3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one

[0381] Weigh 1.50 g (6.67 mmol) of 6-bromoquinazolin-4(3H)-one, 1.31 g (8.00 mmol) of 3-chloromethylpyridine hydrochloride, and 2.76 g (20.00 mmol) of potassium carbonate into a 100 mL round-bottom flask. Add 30 mL of DMF and react overnight at room temperature. The reaction was confirmed to be complete by TLC. Dilute with a large amount of saturated brine, precipitate the solid, filter, wash three times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid (yield 49.31%).

[0382] Step 2: Preparation of 3-(pyridin-3-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)quinazolin-4(3H)-one

[0383] Weigh 1.20 g (3.80 mmol) of 6-bromo-3-(pyridin-3-ylmethyl)quinazolin-4(3H)-one into a 100 mL three-necked flask, add potassium acetate (745.01 mg, 7.59 mmol), DPPF palladium dichloride (138.86 mg, 189.78 μmol), pinacol diboronate (2.41 g, 9.49 mmol), and 30 mL of 1,4-dioxane. Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0384] Step 3: Preparation of (3-benzyloxy)-5-(3-(pyridin-3-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0385] Weigh out A1 (500.00 mg, 1.32 mmol), 3-(pyridin-3-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)quinazolin-4(3H)-one (574.71 mg, 1.58 mmol), potassium fluoride (372.33 mg, 3.96 mmol), and tetraphenylphosphine palladium (76.78 mg, 65.93 μmol), DME (16 ml), and H2O (4 ml). Under argon protection, the reaction was carried out overnight at 120 °C until complete. The mixture was filtered through diatomaceous earth, the solvent was evaporated, and the solid was separated by column chromatography.

[0386] Step 4: Preparation of (3-hydroxy-5-(3-(pyridin-3-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester

[0387] Weigh out 50.00 mg (93.36 μmol) of (3-benzyloxy)-5-(3-(pyridin-3-ylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine methyl ester, add an appropriate amount of trifluoroacetic acid, and reflux for two hours. Dry the trifluoroacetic acid by rotary evaporation, adjust the pH to neutral with NaHCO3, and a white solid precipitates. Pulverize with methanol. Dry by rotary evaporation to obtain the product. Yield: 46%. 1 H NMR (400MHz, DMSO-d6) δ12.3 (s, 1H), 9.5 (t, J=6.2Hz, 1H), 8.7-8.6 (m, 2H), 8.6 (d, J=1.9Hz, 1H), 8.5-8.4 (m, 2H), 8.3 (dd, J=8.6, 2.3Hz, 1H), 7.9-7.7 (m, 3H), 7.4 (dd, J=7.9, 4.8Hz, 1H), 4.1 (d, J=6.1Hz, 2H), 3.7 (s, 3H).

[0388] Example 36: (3-hydroxy-5-(4-oxo-3-(pyridin-3-ylmethyl)-3,4-dihydroquinazolin-6-yl)pyridinecarboxyl)glycine (E23-2)

[0389]

[0390] Refer to Example 12, yield 24%. 1 H NMR (400MHz, DMSO-d6) δ13.0-12.6 (m, 1H), 12.4 (s, 1H), 9.4 (t, J=6.2Hz, 1H), 8.7 (d, J=9.0Hz, 2H), 8.6 (d, J=2.0Hz, 1H), 8.5 (dd, J=1 5.0, 3.5Hz, 2H), 8.3 (dd, J=8.5, 2.3Hz, 1H), 7.8 (dt, J=5.0, 3.1Hz, 3H), 7.4 (dd, J=7.9, 4.8Hz, 1H), 5.3 (s, 2H), 4.0 (d, J=6.1Hz, 2H).

[0391] Biological testing experiments

[0392] Compound preparation and processing:

[0393] Compound DMSO stock preparation:

[0394] All compounds were reconstituted into 20 mM stock solutions using DMSO.

[0395] Compound storage:

[0396] All cpd in DMSO is stored in a desiccator at room temperature for short-term storage (up to 3 months).

[0397] Compound screening:

[0398] a) Use an Echo 655 to transfer 40 nmol of the compound dilution into each well of the assay plate;

[0399] b) Seal the analytical plate and the centrifugal composite plate at 1000 rpm for 1 minute.

[0400] c) Prepare 4 μL of 2X PHD2 enzyme and add it to a single well of the assay plate.

[0401] d) Seal the analysis plate and equilibrate it at room temperature for 30 minutes.

[0402] e) Prepare 4 μl of 2X PHD2 substrate and add it to each well of the analysis plate.

[0403] f) Incubate at room temperature for 30 minutes.

[0404] g) Using A-Eu code protein, streptoacid-D2, and hydroxy-HIF-1α(Pro564)(D43B5) Prepare 2X detection solution using rabbit monoclonal antibody. (h) Add 8 μL of 2X detection solution (prepared in step g) to each well of the assay plate. Incubate at room temperature for 1 hour.

[0405] i) Read HTRF665 / 615 on the BMG reader.

[0406] Data Analysis

[0407] Calculate the ratio of each pore (Ratio665nm / 615nm).

[0408] Plot the effect-dose curve of cmpds and calculate IC50. 50 The IC was calculated by fitting the % inhibition value and the logarithm of the compound concentration to a nonlinear regression (dose-response-variable slope) using Graphpad 8.0. 50 .

[0409] Y = bottom + (top - bottom) / (1 + 10^((LogIC50 - X) * slope))

[0410] X: Logarithm of inhibitor concentration; Y: Inhibition percentage.

[0411] Biological testing experiment results

[0412] Preliminary in vitro PHD2 inhibitory activities of the synthesized compounds were investigated at the molecular level. The results showed that several compounds exhibited good PHD2 inhibitory activity.

[0413] Table 1. Activity data of some compounds in the in vitro molecular evaluation system.

[0414]

[0415] Table 2. Activity data of some compounds in the in vitro molecular evaluation system.

[0416]

[0417] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound that is a stereoisomer, geometric isomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof of a compound of formula (I). in, Located on any substituted ring atom of the 4-quinazolinone ring; R 1 R 2 R 3 Each of the following can be independently H, D, F, Cl, Br, I, Cl, NO2, -COOH, -OH, -NH2, SH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 monosubstituted or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 4 Selected from the following group: H, D, F, Cl, Br, I, -CN, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or poly-substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, YR a R 4 Can be optionally bounded by 1, 2 or 3 R x Replaced; Y is selected from the following group: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-; R a Selected from the following group: H, D, F, Cl, Br, I, C1, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or poly-substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R a Can be optionally bounded by 1, 2 or 3 R y Replaced; R x R y Each is independently selected from the following group: H, D, F, Cl, Br, I, -CN, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 monosubstituted or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocyclic alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; L is a structure with -[C(R) b R c The connection unit R of )]n- b R c Each of the following is independently selected from hydrogen, methyl, and ethyl; n is an integer from 1 to 3.

2. The compound according to claim 1, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, characterized in that, The compound of formula (I) has the structure shown in formula (Ia) or (Ib):

3. The compound according to claims 1-2, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, characterized in that, R 1 R 2 R 3 and R 4 Each is independently selected from the following groups: H, D, and halogens.

4. The compound according to claims 1-3, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, characterized in that, R a Selected from the following groups: H, D, halogens, -CN, -COOH; R b Selected from the following groups: H, D.

5. The compound according to claims 1-4, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals, or prodrugs, characterized in that, R 4 Selected from the group consisting of: H, C1-C6 alkyl, YRa; wherein, Y is selected from CH2; and R is selected ... a Selected from H, substituted or unsubstituted aryl; R x R y Each of them is independently selected from the following groups: H, D, CF3.

6. The compound according to claims 1-5, wherein its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, cocrystal, or prodrug is selected from:

7. A drug combination, characterized in that, include: The compound or stereoisomer of any one of claims 1-6, a deuterated compound, a solvate, a metabolite, a pharmaceutically acceptable salt, a eutectic, or a prodrug.

8. Use of the compound or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, eutectic, or prodrug according to any one of claims 1-7 in the preparation of a medicament; wherein, The drug is used for HIF prolyl hydroxylase, or for the prevention, treatment or relief of anemia.

9. The use as described in claim 8, characterized in that, The diseases mediated by HIF prolyl hydroxylase mentioned are selected from the group consisting of: anemia secondary to or associated with chronic kidney disease, anemia associated with or caused by chemotherapy, or anemia associated with AIDS.

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