4-quinazolinone compound serving as thyroid hormone beta receptor agonist and application of 4-quinazolinone compound

Abstract

The invention belongs to the field of biological medicines, and particularly relates to 4-quinazolinone compounds serving as thyroid hormone beta receptor agonists and application of the 4-quinazolinone compounds. The invention discloses a thyroid hormone beta receptor agonist as shown in a formula (I), relates to a 4-quinazolinone compound and a preparation method thereof, and further relates to a pharmaceutical composition containing the compound and application. The compound or the pharmaceutical composition provided by the invention can be used for preventing, treating or relieving diseases regulated by thyroid hormone beta receptors, especially for treating non-alcoholic fatty liver diseases.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a class of 4-quinazolinone compounds as thyroid hormone β receptor agonists and their uses. Background Art

[0002] Thyroid hormones (THs) are the endogenous ligands of thyroid hormone receptors (THRs), including 3,5,3'-L-triiodothyronine (T3) and 3,5,3',5'-L-tetraiodothyronine (T4), and mediate the homeostasis of biological growth, development and metabolism. T4 is the general form of TH, secreted and released by the thyroid gland. Once released, T4 is converted into the active form T3 of TH by type I deiodinase (D1) and type II deiodinase (D2), and can also be converted into the inactive 3,3',5'-L-triiodothyronine (reverse T3 / rT3) by type III deiodinase (D3) to maintain the balance of thyroid hormone function.

[0003] THRs are ligand-dependent transcription factors that belong to the nuclear receptor superfamily and are involved in many important physiological functions. THRs contain multiple subtypes, each of which is composed of four domains shared by nuclear hormone receptors and has a high degree of homology. Among them, Rα is important for heart rate regulation, TRα1 is mainly expressed in myocardial and skeletal muscles, osteoclasts and many areas of the brain, and TRα2 is not regulated by T3; TRβ accounts for about 80% of T3-bound THRs and plays an important role in lipid metabolism and the inhibition of thyroid-stimulating hormone (TSH). TRβ1 is dominant in the liver, and TRβ2 plays a key role in regulating the hypothalamus-pituitary-thyroid axis. TRβ1 (hereinafter referred to as THRβ) is the main subtype of THR in the liver and is mainly responsible for lowering cholesterol levels. Thyrotoxicosis characterized by tachycardia, arrhythmia, and muscle atrophy is mainly mediated by TRα1 (hereinafter referred to as THRα), and the side effects of TSH inhibition are mainly mediated by TRβ2 in the pituitary. The beneficial metabolic effects of THRβ activation include lowering low-density lipoprotein (LDL) cholesterol, increasing liver metabolic rate, and reducing body weight. Therefore, thyroid hormone receptor beta (THRβ) has attracted extensive attention as a molecular target for the treatment of dyslipidemia and NASH.

[0004] Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and THRβ are closely related. THRβ improves metabolic disorders by enhancing fatty acid decomposition, thereby reducing liver fat content. Resmetirom, an oral THRβ agonist, is the only FDA-approved drug for the treatment of non-alcoholic fatty liver disease (NASH) with its excellent Phase III clinical data. Therefore, THRβ is currently widely concerned as a very potential target for the treatment of NASH.

[0005] Currently, THRβ agonists have a single structural type, and it is difficult to separate the toxic side effects caused by THRα activation to achieve selectivity. It is necessary to develop THRβ agonists with stronger effects and higher selectivity. Summary of the invention

[0006] The present invention provides a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I).

[0007]

[0008] wherein, is located on any substitutable ring atom of the 4 - quinazolinone ring;

[0009] X is selected from the group consisting of: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-;

[0010] R 1 , R 2 , R 3 and R 4 are each 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 mono - or poly - substituted alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl, 3 - 8 - membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0011] R 5 is selected from -NHCO(CH) a (R c )COOR d , -CONH(CH) b (R e )COOR f , -CONH(CH) C (R g )CONH2

[0012] R 6 is selected from the group consisting of: 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 heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, YR h , R 6 may optionally be substituted by 1, 2 or 3 R x ;

[0013] Y is selected from the group consisting of: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-;

[0014] a, b, c are selected from 0, 1, 2, 3;

[0015] R aSelected from H, D, F, Cl, Br, I, Cl, NO2, -COOH, -OH, -NH2, -SH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(=O)-C1-C6 alkyl, -C(=O)-C1-C6 alkoxy, -C(=O)NH2, -S(=O)2-C1-C6 alkoxy, -S(=O)2-C1-C6 alkyl, -S(=O)NH2;

[0016] R b Selected from H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0017] R c 、R e 、R g Are each independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0018] R d 、R f Are each independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0019] R h Selected from the group consisting of: H, D, F, Cl, Br, I, Cl, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R h May optionally be substituted by 1, 2 or 3 R y ;

[0020] R x 、R y Are each independently selected from the group consisting of: H, D, F, Cl, Br, I, -CN, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

[0021] In a preferred embodiment, the compound of formula (I) has the structure shown in the following formula (Ia) or (Ib):

[0022]

[0023] In a preferred embodiment, R 1 , R 2 , R 3 and R 4 each independently selected from the group consisting of: H, D, halogen;

[0024] In a preferred embodiment, R a is selected from the group consisting of: H, D, halogen, -CN, -COOH; R b is selected from the group consisting of: H, D;

[0025] In a preferred embodiment, R 6 is selected from the group consisting of: H, C1-C6 alkyl, YR h ; wherein, the Y is selected from CH2; the R h is selected from H, substituted or unsubstituted aryl; R x , R y each independently selected from the group consisting of: H, D, CF3;

[0026] In a preferred embodiment, the compound of formula (I) is selected from:

[0027] 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

[0028] 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

[0029] 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

[0030] 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

[0031] 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

[0032] 2-(3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

[0033] 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

[0034] 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

[0035] 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile;

[0036] 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione;

[0037] Methyl 2-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate;

[0038] 2-((3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetic acid;

[0039] Methyl 3-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionate;

[0040] 3-((3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionic acid;

[0041] Methyl 4-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyrate;

[0042] 4-((3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutanoic acid;

[0043] 3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid;

[0044] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycine methyl ester;

[0045] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycine;

[0046] Methyl 3-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionate;

[0047] 3-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propanoic acid;

[0048] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine ethyl ester;

[0049] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine;

[0050] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine ethyl ester;

[0051] (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine;

[0052] N-(2-Amino-2-oxoethyl)-3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamide;

[0053] 3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid;

[0054] Methyl 2-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate;

[0055] 2-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetic acid;

[0056] Methyl 3-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionate;

[0057] 3-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionic acid;

[0058] Methyl 4-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyrate;

[0059] 4-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyric acid;

[0060] Methyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycinate;

[0061] (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycine;

[0062] Methyl 3-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionate;

[0063] 3-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionic acid;

[0064] Ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine;

[0065] (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine;

[0066] Ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine;

[0067] (3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine;

[0068] N-(2-Amino-2-oxoethyl)-3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamide;

[0069] On the one hand, the present invention relates to a pharmaceutical combination comprising the compound of the present invention, and optionally further comprising any one or any combination of pharmaceutically acceptable carriers, excipients, adjuvants, and vehicles.

[0070] On the one hand, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament; wherein the medicament is used to activate the thyroid hormone receptor, or to prevent, treat or alleviate diseases regulated by the thyroid hormone receptor.

[0071] In some embodiments, the thyroid hormone receptor of the present invention is the thyroid hormone β receptor.

[0072] In some embodiments, the diseases regulated by the thyroid hormone receptor of the present invention are non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, glycogen storage disease type 1A, hypothyroidism or thyroid cancer.

[0073] This method is achieved by administering to a subject an effective therapeutically amount of the compound of formula (I) or its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs.

[0074] The foregoing only outlines certain aspects of the present invention, but is not limited to these aspects. The content of these aspects and other aspects will be described more specifically and completely below.

[0075] The present invention also provides a method for synthesizing the compound of general formula (I), including steps such as ring formation, condensation, nucleophilic substitution, reduction, formation of diazonium salt and addition, amine ester exchange, hydrolysis, decarboxylation, etc.

[0076]

[0077] Detailed implementation mode

[0078] As used throughout this application, including in the claims, unless otherwise specifically indicated, the following terms have the meanings defined below as used herein.

[0079] 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.

[0080] 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-pentyloxy, n-hexyloxy, cyclopropoxy, and cyclobutoxy, etc.

[0081] 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, etc.

[0082] 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.

[0083] The term "C1-C6 mono- or poly-substituted alkyl" refers to one or more hydrogen atoms in the C1-C6 alkyl as defined above being replaced by substituents selected from the following: OH, halogen, alkyl, dialkylamino, or heterocyclic group, such as morpholinyl, piperidinyl, etc.

[0084] The term "C2-C6 alkenyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and having more than one carbon-carbon double bond, preferably containing 2-4 carbon atoms. Non-limiting examples are vinyl, propenyl, allyl, 2-butenyl, 1-butenyl, etc.

[0085] The term "C2-C6 alkynyl" refers to a straight-chain or branched-chain monovalent unsaturated hydrocarbon group containing 2 to 6 carbon atoms and having more than one carbon-carbon triple bond, preferably containing 2-4 carbon atoms. Non-limiting examples are ethynyl, propynyl, propargyl, etc.

[0086] The term "C3-C8 cycloalkyl" refers to a cyclic saturated monovalent monocyclic or bicyclic hydrocarbon group containing 3 to 8 carbon atoms. Non-limiting examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups. The cycloalkyl may optionally be substituted with one, two, or three substituents selected from halogen atoms, hydroxyl groups, aryl groups.

[0087] The term "3-8 membered heterocycloalkyl" refers to a saturated or partially unsaturated, non-aromatic monocyclic, bicyclic or tricyclic system containing 3 to 12 atoms, wherein at least one ring atom is selected from heteroatoms such as nitrogen, sulfur, oxygen and phosphorus atoms. Among them, the heterocyclic group is non-aromatic and does not contain any aromatic rings, and this ring system has one or more connection points connected to the rest of the molecule. Non-limiting examples are oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, thioxolanyl, etc. The heterocycloalkyl may optionally be substituted by one, two or three substituents selected from halogen atoms, hydroxyl groups, aryl groups.

[0088] The term "aryl" refers to all monocyclic or fused polycyclic aromatic groups containing 6 to 10 carbon atoms and having a conjugated electron system. Non-limiting examples are phenyl or naphthyl.

[0089] The term "substituted or unsubstituted aryl" means that 0 to 3 hydrogen atoms on the aryl are replaced by substituents selected from the following: aryl, halogen, C1-6 alkyl, nitrile, alkyl, amino, nitro, alkylsulfonyl, ester group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenolic hydroxyl group.

[0090] The term "heteroaryl" refers to a monocyclic or fused 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 include (but are not limited to) 6-membered ring substituents, non-limiting examples being pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; 5-membered heteroaryls such as triazolyl, imidazolyl, furyl, isoxazolyl, isothiazolyl, 1,2,3-, 1,2,4, 1,2,5-, or 1,3,4-oxadiazolyl, oxazolyl, thienyl, thiazolyl, isothiazolyl, and pyrazolyl; 6 / 5-membered fused ring substituents such as indolyl, indazolyl, benzofuryl, benzimidazolyl, benzothienyl, benzoxadiazolyl, benzothiazolyl, isobenzothienyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzodioxolyl, furanopyridyl, purinyl, imidazopyridyl, imidazopyrimidinyl, pyrrolopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, thiophenopyridyl, triazolopyrimidinyl, triazolopyridyl (e.g., 5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl), and anthraniloyl; and 6 / 6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, oxochromanyl, and 1,4-benzoxazinyl.

[0091] The term "substituted or unsubstituted heteroaryl" means that 0 to 3 hydrogen atoms on the heteroaryl are replaced by substituents selected from: aryl, halogen, C1-6 alkyl, group, alkyl, amino, nitro, alkanesulfonyl, ester group, trifluoromethyl, trifluoromethoxy, difluoromethoxy, methoxy, fluorine, nitro, phenol hydroxyl.

[0092] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0093] The term "solvate" refers to a substance formed by the compound of the present invention or its salt and a stoichiometric or non-stoichiometric solvent that binds through intermolecular non-covalent forces. When the solvent is water, it is a hydrate.

[0094] The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated therewith. Preferably, "pharmaceutically acceptable" as used in the present invention means approved by a federal regulatory agency or a national government or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, particularly in humans.

[0095] The term "cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) through hydrogen bonding or other non-covalent bonds, where both the pure forms of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A cocrystal is a multi-component crystal, including binary cocrystals formed between two neutral solids, as well as multicomponent cocrystals formed between a neutral solid and a salt or solvate.

[0096] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers, excipients, diluents, binders, fillers and other auxiliary materials, as well as additional therapeutic agents such as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents or lipid-lowering agents. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.

[0097] The term "effective therapeutic amount" refers to the amount of a compound administered that, to some extent, alleviates one or more symptoms of the disorder being treated.

[0098] The term "pharmaceutically acceptable carrier" refers to carriers that can be used in the preparation of pharmaceutical compositions, which are generally safe, non-toxic, not biologically or otherwise undesirable, and include carriers that are pharmaceutically acceptable to animals and humans. The "pharmaceutically acceptable carrier" used in the specification and claims includes one or more such carriers.

[0099] The term "carrier" refers to a system that does not cause significant irritation to an organism, does not eliminate the biological activity and properties of the administered compound, and can change the way a drug enters the body, its distribution in the body, control the release rate of the drug, and deliver the drug to the target organ. Non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0100] The term "excipient" refers to a substance which is not itself a therapeutic agent and which is used as a diluent, adjuvant, binder, and / or vehicle and which is added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate the formation of a unit dosage form for administration of a compound or pharmaceutical composition. As is known to those skilled in the art, pharmaceutical excipients can provide a variety of functions and can be described as wetting agents, buffering agents, suspending agents, lubricants, emulsifying agents, disintegrating agents, absorbents, preservatives, surfactants, coloring agents, flavoring agents, and sweetening agents. 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 cross-linked carboxymethyl cellulose (e.g., sodium cross-linked carboxymethyl cellulose); (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (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) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solutions; (21) polyesters, polycarbonates, and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0101] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only for illustrating the present invention and not for limiting the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0102] Example 1: 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C2e)

[0103]

[0104] Step 1 Preparation of 6-hydroxyquinazolin-4(3H)-one

[0105] Using commercially available raw material 2-amino-5-hydroxybenzoic acid (10.00 g, 65.30 mmol) in a 250 ml eggplant-shaped flask, add 50 ml of formamide, transfer the reaction to an oil bath, and react at 150 °C overnight. TLC detects that the reaction is complete. Let the reaction solution stand to room temperature, add saturated brine, place it in the refrigerator and let it stand below 0 °C to precipitate solids, filter by suction, wash 3 times with saturated brine and petroleum ether respectively, and dry to obtain a yellow solid (9.03 g, yield 85.27%).

[0106] Step 2 Preparation of 6-(2,6-dichloro-4-nitrophenoxy)quinazolin-4(3H)-one

[0107] Weigh the raw materials 6-hydroxyquinazolin-4(3H)-one (3.00 g, 18.50 mmol), 1,2,3-trichloro-5-nitrobenzene (5.02 g, 22.20 mmol), potassium carbonate (3.83 g, 27.75 mmol) into a 250 ml eggplant-shaped flask, add DMF (60 ml), and react at room temperature overnight. TLC detects that the reaction is complete. Add a large amount of saturated brine for dilution, precipitate solids, filter by suction, wash 3 times with saturated brine, dry, and separate by column chromatography to obtain 3.21 g of white solid, yield 49.31%.

[0108] Step 3 Preparation of 6-(4-amino-2,6-dichlorooxy)quinazolin-4(3H)-one

[0109] Weigh the raw material 6-(2,6-dichloro-4-nitrophenoxy)quinazolin-4(3H)-one (2.86 g, 8.12 mmol) into a 250 ml eggplant-shaped flask, dissolve it in DMF (60 ml), slowly add B2(OH)4 (2.18 g, 24.37 mmol), 4,4'-bipyridine (3.17 mg, 20.30 μmol), and stir at room temperature for 10 min. TLC detects that the reaction is complete. Add a large amount of saturated brine for dilution, extract with ethyl acetate (30 mL×3), concentrate under reduced pressure, slurry with petroleum ether and a little ethyl acetate overnight, filter by suction, and separate the filter cake by column chromatography to obtain the white solid 6-(4-amino-2,6-dichlorooxy)quinazolin-4(3H)-one (2.01 g, yield 76.71%).

[0110] Step 4 Preparation of (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate

[0111] Weigh the raw material 6-(4-amino-2,6-dichlorophenoxy)quinazolin-4(3H)-one (1.00 g, 3.10 mmol) into a 100 ml eggplant-shaped flask, add 6 ml of acetic acid and 0.9 ml of hydrochloric acid, and dropwise add an aqueous sodium nitrite solution (235.59 mg, 3.41 mmol, 6 mmol / ml) at 5 - 10 °C. React at room temperature for 30 min. Then add ethyl (2-cyanoacetyl)carbamate (533.16 mg, 3.41 mmol) and an aqueous sodium acetate solution (763.95 mg, 9.31 mmol, 4 mmol / ml), and react for 30 min. Detect the completion of the reaction by TLC. Dilute with water, precipitate a solid, filter by suction, wash the filter cake 3 times with a mixed solution of water and acetic acid, concentrate under reduced pressure to obtain a crude yellow solid, and directly proceed to the next step without purification.

[0112] Step 5 Preparation of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C2e)

[0113] Weigh the crude product C2d from the previous step and charge it according to the theoretical yield of the previous step (1.52 g, 3.10 mmol), and potassium acetate (365.88 mg, 3.73 mmol) into a 100 ml eggplant-shaped flask. Add the solvent DMA (30 ml) to dissolve, and react at 120 °C for 2 h. Detect the completion of the reaction by TLC. Cool to room temperature, add saturated brine, precipitate a solid, filter by suction, wash the filter cake 3 times with saturated brine, and concentrate under reduced pressure. Reflux with acetonitrile for 3 h, filter by suction, wash the filter cake 3 times with acetonitrile, and dry. Pulp overnight with a small amount of a mixed solution of dichloromethane and methanol, filter by suction, wash the filter cake once with dichloromethane, ethyl acetate, and methanol respectively, and concentrate under reduced pressure to obtain a light yellow solid C2e (422.4 mg, yield 95.31%). 1 HNMR(600MHz,DMSO-d6)δ12.34(s,1H),8.05(s,1H),7.88(s,2H),7.76(d,J=8.9Hz,1H),7.62(dd,J=8.9,3.0Hz,1H),7.19(d,J=3.0Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ160.2,155.9,154.2,147.9,145.8,144.8,144.4,137.9,130.0,128.6,127.1,123.5,123.3,122.9,112.6,108.0.LC-MS-ESI + :[M+H] + 442.8.

[0114] Example 2: 2-(3,5-Dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C2g)

[0115]

[0116] Step 1 Preparation of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid

[0117] Weigh the raw material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (300.00 mg, 676.90 μmol) into a 100 ml eggplant-shaped flask, add 2 ml of hydrochloric acid and 8 ml of glacial acetic acid, and react at 120 °C for 16 h. TLC detects that the reaction is complete. Let it stand at room temperature, precipitate solids, and filter to obtain a gray-yellow solid (296.2 mg, yield 94.61%).

[0118] Step 2 Preparation of 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C2g)

[0119] Weigh the raw material 2-(3,5-dichloro-4-((4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid (296.00 mg, 640.43 μmol) into a 50 ml eggplant-shaped flask, dissolve it with mercaptoacetic acid, and react the system at 170 °C for 1 h. TLC detects that the reaction is complete. Let it stand to room temperature, dilute with water, extract with ethyl acetate (30 mL×3), wash the extract three times with saturated sodium bicarbonate aqueous solution, and then wash three times with saturated brine. Combine the organic phases, concentrate under reduced pressure, and separate by column chromatography to obtain a light green solid C2g (174.1 mg, yield 64.97%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 12.33 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 3.5 Hz, 1H), 7.91 (s, 2H), 7.77 (d, J = 8.9 Hz, 1H), 7.73 (s, 1H), 7.62 (dd, J = 8.9, 3.0 Hz, 1H), 7.17 (d, J = 3.0 Hz, 1H). 1313C NMR (151 MHz, DMSO-d6) δ 160.2, 156.9, 154.3, 147.6, 144.9, 144.8, 144.3, 138.4, 136.9, 130.1, 128.2, 126.7, 123.5, 123.4, 107.8. LC-MS-ESI + :[M+H] + 417.8.

[0120] Example 3: 2-(3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C4d)

[0121]

[0122] Step 3 Preparation of 6-(2,6-dichloro-4-nitrophenoxy)-3-methylquinazolin-4(3H)-one

[0123] Weigh the raw materials 6-(2,6-dichloro-4-nitrophenoxy)quinazolin-4(3H)-one (3.15 g, 8.95 mmol) and potassium carbonate (2.47 g, 17.89 mmol) into a 250 ml eggplant-shaped flask, add 100 ml of DMF to dissolve the raw materials, dropwise add potassium iodide (0.84 ml, 13.42 mmol) while stirring, extract with ethyl acetate (30 mL×10), combine the organic layers, concentrate under reduced pressure, and separate by column chromatography to obtain a yellow solid (2.93 g, yield 89.21%).

[0124] Except for the above Step 3, the preparation, separation, and purification were carried out using the method described in Example 1 (total yield 17%). 1 1H NMR (600 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.88 (s, 2H), 7.76 (d, J = 8.9 Hz, 1H), 7.61 (dd, J = 8.9, 3.0 Hz, 1H), 7.23 (d, J = 3.0 Hz, 1H), 3.46 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.6, 157.1, 154.8, 149.0, 147.9, 146.1, 144.7, 138.6, 130.5, 128.9, 127.4, 123.6, 123.4, 122.8, 113.3, 108.5, 34.1. LC-MS-ESI + :[M+H] + 456.9.

[0125] Example 4: 2-(3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C4f)

[0126]

[0127] Using 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, the preparation, separation and purification were carried out by the method described in Example 2 (total yield 43%). 1 HNMR(600MHz,DMSO-d6)δ12.52(s,1H),8.33(s,1H),7.91(s,2H),7.77(d,J = 8.9Hz,1H),7.73(s,1H),7.61(dd,J = 8.9,3.0Hz,1H),7.21(d,J = 3.0Hz,1H),3.46(s,3H). 13 C NMR(151MHz,DMSO-d6)δ160.1,144.9,144.2,138.4,136.9,130.0,128.2,126.7,123.2,122.3,107.8,33.6.LC-MS-ESI + :[M+H] + 431.8.

[0128] Example 5: 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C5d)

[0129]

[0130] Using 1-(bromomethyl)-3-(trifluoromethyl)benzene, the preparation, separation and purification were carried out by the method described in Example 2 (total yield 15%). 1 HNMR(400MHz,DMSO-d6)δ8.63(s,1H),8.59(s,2H),7.82 - 7.79(m,2H),7.67 - 7.65(m,3H),7.59 - 7.55(m,1H),7.27(s,1H),5.24(s,2H). 1313C NMR (151 MHz, DMSO-d6) δ 159.6, 154.1, 150.8, 147.1, 145.4, 144.3, 137.9, 132.0, 130.2, 129.7, 129.5, 129.2 (q, J = 30.2 Hz), 125.4, 124.8 (q, J = 4.5 Hz), 124.5 (q, J = 3.02 Hz), 124.1 (q, J = 271.8 Hz), 123.6, 122.6, 108.7, 108.6748.9. LC-MS-ESI + :[M+H] + 509.8.

[0131] Example 6: 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C5f)

[0132]

[0133] Using 2-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, it was prepared, separated and purified by the method described in Example 2 (total yield 37%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.61 (s, 1H), 7.89 (s, 2H), 7.81 - 7.79 (m, 2H), 7.73 (s, 1H), 7.64 (q, J = 7.7 Hz, 3H), 7.57 (t, J = 7.7 Hz, 1H), 7.21 (d, J = 2.8 Hz, 1H), 5.24 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 160.2, 157.4, 155.1, 148.1, 147.4, 145.3, 144.5, 139.0, 138.4, 137.4, 132.5, 130.6, 130.3, 129.7 (q, J = 31.7 Hz), 128.7, 127.1, 125.2 (q, J = 4.5 Hz), 125.0 (q, J = 3.0 Hz), 124.6 (q, J = 271.8 Hz), 123.98, 123.1, 108.6, 49.3. LC-MS-ESI + :[M+H] + 619.7.

[0134] Example 7: 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C3g)

[0135]

[0136] Step 1: Preparation of 7-methoxyquinazolin-4(3H)-one

[0137] Using the commercially available raw material 2-amino-4-methoxybenzoic acid (20.00 g, 239.28 mmol) in a 100 ml eggplant-shaped flask, add 50 ml of formamide and react at 150 °C overnight. The reaction was monitored by TLC and found to be complete. The reaction solution was allowed to stand to room temperature, saturated brine was added, and the mixture was placed in a refrigerator at 0 °C or below to precipitate a solid. The solid was filtered off, washed three times with saturated brine and petroleum ether respectively, and dried to obtain a brown solid (9.21 g, yield 21.85%).

[0138] Step 2: Preparation of 7-methoxyquinazolin-4(3H)-one

[0139] Weigh the raw materials 7-methoxyquinazolin-4(3H)-one (4.00 g, 22.70 mmol) and potassium carbonate (6.28 g, 45.40 mmol) into a 250 ml eggplant-shaped flask, add 100 ml of DMF to dissolve the raw materials, and while stirring, add potassium iodide (2.12 ml, 34.06 mmol) dropwise. Extract with ethyl acetate (30 mL × 10), combine the organic layers, concentrate under reduced pressure and separate by column chromatography to obtain a light green solid (2.48 g, yield 57.41%).

[0140] Step 3: Preparation of 7-hydroxy-3-methylquinazolin-4(3H)-one

[0141] Weigh the raw material 7-methoxyquinazolin-4(3H)-one (2.48 g, 13.04 mmol) into a 250 ml eggplant-shaped flask, add 100 ml of 48% hydrobromic acid, and react at 150 °C for two days. Allow to stand to room temperature, adjust the pH to neutral with sodium hydroxide and sodium bicarbonate, precipitate a solid, filter it off, wash the filter cake three times with water and three times with petroleum ether, and dry to obtain a gray solid (2.03 g, yield 88.26%).

[0142] Step 4: Preparation of 7-(2,6-dichloro-4-nitrophenoxy)-3-methylquinazolin-4(3H)-one

[0143] Weigh the raw materials 7-hydroxy-3-methylquinazolin-4(3H)-one (1.37 g, 7.78 mmol), 1,2,3-trichloro-5-nitrobenzene (2.64 g, 11.66 mmol), and potassium carbonate (2.15 g, 15.55 mmol) into a 250 ml eggplant-shaped flask, add DMF (60 ml), and react overnight at room temperature. TLC detection shows that the reaction is complete. Add a large amount of saturated brine for dilution, precipitate the solid, filter by suction, wash with saturated brine 3 times, dry, and separate by column chromatography to obtain a white solid (870 mg, yield 32.95%).

[0144] Step 5 Preparation of 7-(4-amino-2,6-dichlorophenoxy)-3-methylquinazolin-4(3H)-one

[0145] Weigh the raw material 7-(2,6-dichloro-4-nitrophenoxy)-3-methylquinazolin-4(3H)-one (850 mg, 2.32 mmol) into a 250 ml eggplant-shaped flask, dissolve it in DMF (60 ml), slowly add B2(OH)4 (624.33 mg, 6.96 mmol) and 4,4'-bipyridine (1.82 mg, 11.60 μmol), and stir at room temperature for 10 min. TLC detection shows that the reaction is complete. Add a large amount of saturated brine for dilution, extract with ethyl acetate (30 mL×3), concentrate under reduced pressure, slurry with petroleum ether and a little ethyl acetate overnight, filter by suction, and separate the filter cake by column chromatography to obtain a white solid (540.2 mg, yield 69.22%).

[0146] Step 6 Preparation of (Z)-(2-cyano-2-(2-(3,5-dichloro-4-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)hydrazono)acetyl)ethyl carbamate

[0147] Weigh the raw material 7-(4-amino-2,6-dichlorophenoxy)-3-methylquinazolin-4(3H)-one (540.0 g, 1.61 mmol) into a 100 ml eggplant-shaped flask, add 6 ml of acetic acid and 0.9 ml of hydrochloric acid, and dropwise add an aqueous solution of sodium nitrite (121.91 mg, 1.77 mmol, dissolved in 0.5 ml of water) at 5-10 °C, and react at room temperature for 30 min. Then add (2-cyanoacetyl)ethyl carbamate (275.89 mg, 1.77 mmol) and an aqueous solution of sodium acetate (395.32 mg, 4.82 mmol, dissolved in 0.5 ml of water), and react for 30 min. TLC detection shows that the reaction is complete. Dilute with water, precipitate the solid, filter by suction, wash the filter cake 3 times with a mixed solution of water and acetic acid, concentrate under reduced pressure, and obtain a yellow solid (419.5 mg, 83.34%).

[0148] Step 7 Preparation of 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C3g)

[0149] Weigh 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (419.5 mg, 833.51 μmol) and potassium acetate (98.16 mg, 1.00 mmol) into a 100 ml eggplant-shaped flask, add the solvent DMA (30 ml) to dissolve, and react at 120 °C for 2 h. TLC detection shows that the reaction is complete. Adjust the pH to acidic with acetic acid, dilute with water, extract with ethyl acetate (30 mL×3), combine the organic layers, wash 3 times with hydrochloric acid aqueous solution, then wash 3 times with saturated brine, concentrate under reduced pressure, and separate by column chromatography to obtain a pale yellow solid C3g (283.8 mg, 74.47%). 1 HNMR(600MHz,DMSO-d6)δ13.30(s,1H),8.37(s,1H),8.19(d,J=8.9Hz,1H),7.87(s,2H),7.21(dd,J=8.9,2.6Hz,1H),6.90(d,J=2.6Hz,1H),3.47(s,3H). 13 C NMR(151MHz,DMSO-d6)δ160.0,159.9,154.6,150.2,149.7,147.0,145.7,137.5,128.8,128.6,127.1,123.0,117.3,115.4,112.2,110.3,33.5.LC-MS-ESI + :[M+H] + 456.8.

[0150] Example 8: 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C3i)

[0151]

[0152] Use 2-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile and prepare, separate and purify it by the method described in Example 2 (total yield 32%). 1HNMR(600MHz, DMSO-d6) δ 12.52 (s, 1H), 8.36 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.90 (s, 2H), 7.74 (s, 1H), 7.20 (dd, J = 8.8, 2.6 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 3.47 (s, 3H). 13 CNMR(151MHz, DMSO-d6) δ 160.1, 160.0, 156.9, 150.2, 149.7, 147.6, 144.5, 138.5, 136.9, 128.8, 128.1, 126.6, 117.2, 115.4, 110.2, 33.5. LC-MS-ESI + :[M + H] + 431.8.

[0153] Example 9: 2-(3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (C6f)

[0154]

[0155] Prepared and isolated and purified using 1-(bromomethyl)-3-(trifluoromethyl)benzene by the method described in Example 7 (total yield 11%). 1 H NMR(600MHz, DMSO-d6) δ 13.30 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.88 (s, 2H), 7.80 (s, 1H), 7.69–7.63 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.23 (dd, J = 8.9, 2.6 Hz, 1H), 6.94 (d, J = 2.6 Hz, 1H), 5.26 (s, 2H). 13 C NMR(151MHz, DMSO-d6) δ 160.2, 159.5, 154.5, 150.0, 149.3, 146.9, 145.6, 138.1, 137.5, 131.9, 129.8 129.2 (q, J = 31.7 Hz), 129.1, 128.6, 127.2, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 3.02 Hz), 124.1 (q, J = 271.8 Hz), 123.0, 117.4, 115.7, 112.1, 110.5, 48.7. LC-MS-ESI + :[M + H] +600.8.

[0156] Example 10: 2-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-1,2,4-triazine-3,5(2H,4H)-dione (C6h)

[0157]

[0158] Using 2-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, it was prepared, separated and purified by the method described in Example 2 (total yield 45%). 1 H NMR (600 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.64 (s, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.90 (s, 2H), 7.80 (s, 1H), 7.74 (s, 1H), 7.66 (t, J = 7.2 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 5.26 (s, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 160.4, 159.5, 156.9, 145.0, 149.3, 147.6, 144.4, 138.6, 138.1, 136.9, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.1, 126.6, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 4.5 Hz), 124.1 (q, J = 271.8 Hz), 117.3, 115.7, 110.4, 48.7. LC-MS-ESI + :[M+H] + 576.7.

[0159] Example 11: Methyl 2-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate (C7a)

[0160]

[0161] Weigh the raw material 7-(4-amino-2,6-dichlorophenoxy)-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one (200.0 mg, 416.43 μmol) and dissolve it in DMF (50 ml) in a 100-ml eggplant-shaped flask. After adding triethylamine (69.46 mmol, 499.72 μmol), slowly add methyl 2-chloro-2-oxoacetate (45.96 mmol, 499.72 μmol), and react overnight. TLC detects that the reaction is complete. Add water to precipitate the solid, filter by suction, wash the filter cake 3 times with water and then 3 times with petroleum ether, dry it, collect the filter cake, and separate it by column chromatography to obtain white solid C7a (131.0 mg, yield 55.55%). 1 HNMR (600 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.63 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.11 (s, 2H), 7.79 (s, 1H), 7.66 (t, J = 8.0 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.20 (dd, J = 8.9, 2.4 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 5.25 (s, 2H), 3.88 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 160.7, 160.3, 159.5, 155.4, 150.0, 149.2, 141.6, 138.1, 136.8, 131.9, 129.8, 129.2 (q, J = 30.2 Hz), 129.0, 128.3, 124.6 (q, J = 3.0 Hz), 124.5 (q, J = 4.53 Hz), 124.1 (q, J = 271.8 Hz), 121.0, 117.1, 115.8, 110.3, 53.5, 48.6. LC-MS-ESI + :[M+H] + 566.0.

[0162] Example 12: 2-((3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetic acid (C7b)

[0163]

[0164] Weigh the raw material methyl 2-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate (100.0 mg, 176.58 μmol) and dissolve it in MeOH (50 ml) in a 100 ml eggplant-shaped flask. Add aqueous sodium hydroxide solution (1.06 ml, 1.06 mmol, 1.00 M) and react overnight. TLC detection shows that the reaction is complete. Concentrate under reduced pressure, adjust the pH to neutral with water, extract with dichloromethane (30 ml × 3), combine the organic phases, concentrate under reduced pressure, and separate by column chromatography to obtain white solid C7b (53.2 mg, yield 54.55%). 1 HNMR(600MHz,DMSO-d6)δ8.61(s,1H),8.14(d,J=8.9Hz,1H),7.79(s,1H),7.69–7.63(m,2H),7.58(d,J=7.7Hz,1H),7.15(dd,J=8.9,2.5Hz,1H),6.78(d,J=2.4Hz,1H),6.75(s,2H),5.24(s,2H). 13 C NMR(151MHz,DMSO-d6)δ161.3,159.0,149.4,148.5,147.8,137.6,133.5,131.3,129.2,128.6(q,J=31.7Hz),128.2,127.6,124.0(q,J=3.02Hz),123.9(q,J=4.5Hz),123.5(q,J=271.8Hz),116.1,115.3,112.7,109.3,48.0.LC-MS-ESI + :[M+H] + 552.1.

[0165] Example 13: Methyl 3-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionate (C8a)

[0166]

[0167] Using methyl 3-chloro-3-oxopropionate, the preparation, separation and purification were carried out by the method described in Example 11 (total yield 74.07%). 11H NMR (600 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.63 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.86 (s, 2H), 7.80 (s, 1H), 7.66 (t, J = 7.7 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 6.87 (s, 1H), 5.25 (s, 2H), 3.68 (s, 3H), 3.54 (s, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 167.1, 164.2, 160.3, 159.0, 149.4, 148.6, 140.1, 137.6, 137.3, 131.3, 129.2, 128.6 (q, J = 31.7 Hz), 128.4, 127.8, 124.0 (q, J = 3.0 Hz), 123.9 (q, J = 3.0 Hz), 123.5 (q, J = 271.8 Hz), 118.9, 116.5, 115.2, 109.7, 51.5, 48.1, 43.0. LC-MS-ESI + :[M+H] + 580.1.

[0168] Example 14: 3 - ((3,5 - Dichloro - 4 - ((4 - oxo - 3 - (3 - (trifluoromethyl)benzyl)-3,4 - dihydroquinazolin - 7 - yl)oxy)phenyl)amino)-3 - oxopropanoic acid (C8b)

[0169]

[0170] Methyl 3 - ((3,5 - dichloro - 4 - ((4 - oxo - 3 - (3 - (trifluoromethyl)benzyl)-3,4 - dihydroquinazolin - 7 - yl)oxy)phenyl)amino)-3 - oxopropanoate was used and prepared, separated and purified by the method described in Example 12 (total yield 81.06%). 1 1H NMR (600 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.62 (s, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.87 (s, 2H), 7.79 (s, 1H), 7.66 (t, J = 8.2 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.19 (dd, J = 8.9, 2.6 Hz, 1H), 6.87 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H). 1313C NMR (151 MHz, DMSO-d6) δ 168.2, 164.7, 160.3, 159.0, 149.4, 148.6, 140.0, 137.6, 137.5, 131.3, 129.2, 128.6 (q, J = 31.7 Hz), 128.4, 127.8, 124.0 (q, J = 3.02 Hz), 123.9 (q, J = 3.02 Hz), 123.5 (q, J = 271.8 Hz), 118.8, 116.5, 115.2, 109.7, 48.1, 43.5. LC-MS-ESI + :[M+H] + 566.0.

[0171] Example 15: Methyl 4-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutanoate (C9a)

[0172]

[0173] Prepared, separated and purified using methyl 4-chloro-4-oxobutanoate by the method described in Example 11 (total yield 18.22%). 1 1H NMR (600 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.62 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.87 (s, 2H), 7.79 (s, 1H), 7.66 (t, J = 8.2 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.18 (dd, J = 8.9, 2.4 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 5.25 (s, 2H), 3.61 (s, 3H), 2.69–2.60 (m, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.7, 170.7, 160.9, 159.5, 150.0, 149.2, 140.2, 138.4, 138.1, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 128.9, 128.2, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 4.5 Hz), 124.1 (q, J = 271.8), 119.2, 117.1, 115.8, 110.2, 51.4, 48.6, 31.0, 28.3. LC-MS-ESI + :[M+H] + 593.7.

[0174] Example 16: 4-((3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyric acid (C9b)

[0175]

[0176] Methyl 4-((3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyrate was used and prepared, separated and purified by the method described in Example 12 (total yield 72.29%). 1 HNMR(600MHz,DMSO-d6)δ12.93(s,1H),8.62(s,1H),8.15(d,J = 8.9Hz,1H),7.82(s,2H),7.80(s,1H),7.65(t,J = 8.2Hz,2H),7.58(t,J = 7.8Hz,1H),7.18(dd,J = 8.9,2.5Hz,1H),6.85(d,J = 2.4Hz,1H),5.25(s,2H),2.43(t,J = 6Hz,2H),2.25(t,J = 6Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ175.5,173.3,161.0,159.6,145.0,149.2,139.6,139.3,138.2,131.8,129.8,129.2(q,J = 31.7Hz),128.9,128.2,124.6(q,J = 4.5Hz),124.4(q,J = 4.5Hz),124.1(q,J = 271.8Hz),118.8,117.0,115.8,110.2,48.6,34.8,33.8.LC-MS-ESI + :[M+H] + 580.6.

[0177] Example 17: 3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid (C10b)

[0178]

[0179] Step 1 Preparation of methyl 3,5-dichloro-4-fluorobenzoate

[0180] Weigh the raw material 3,5-dichloro-4-fluorobenzoic acid (5.00 g, 23.92 mmol) into a 250 ml eggplant-shaped flask, add 100 ml of methanol, dropwise add 1 drop of concentrated sulfuric acid, and reflux the reaction overnight. Monitor the reaction completion by TLC. Let it stand to room temperature, precipitate white solid, filter by suction, wash the filter cake with methanol 3 times, and dry it to obtain a white solid (4.97 g, yield 93.07%).

[0181] Step 2 Preparation of methyl 3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoate

[0182] Weigh the raw materials 7-hydroxy-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one (2.00 g, 6.24 mmol), methyl 3,5-dichloro-4-fluorobenzoate (1.67 g, 7.50 mmol), and potassium carbonate (1.29 g, 9.36 mmol) into a 250 ml eggplant-shaped flask, add 100 ml of DMF, and react overnight. Monitor the reaction completion by TLC. Add water, extract with ethyl acetate (50 ml × 3), combine the organic phases, concentrate under reduced pressure, and separate by column chromatography to obtain a white solid (1.99 g, yield 61.04%).

[0183] Step 3 Preparation of 3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid

[0184] Weigh the raw material methyl 3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoate (1.99 g, 3.80 mmol) into a 250 ml eggplant-shaped flask, dissolve the raw material with 100 ml of methanol, add an aqueous sodium hydroxide solution (15.21 ml, 45.63 mml, 3 M), and react overnight. Monitor the reaction completion by TLC. Concentrate under reduced pressure, add water, adjust the pH to neutral, extract with dichloromethane (50 ml × 3), combine the organic phases, and concentrate under reduced pressure to obtain a white solid C10b (1.82 g, yield 93.81%). 1 HNMR(600MHz,DMSO-d6)δ8.63(s,1H),8.19–8.14(m,2H),8.09(s,1H),7.80(s,1H),7.66(t,J=6.7Hz,2H),7.58(t,J=7.7Hz,1H),7.25–7.16(m,1H),6.93–6.86(m,1H),5.25(s,2H),3.91(s,1H). 1313C NMR (151 MHz, DMSO-d6) δ 163.7, 160.3, 159.5, 150.0, 149.3, 149.2, 138.1, 131.9, 130.4, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.5, 124.6 (q, J = 3.0 Hz), 124.5 (q, J = 4.5 Hz), 124.1 (q, J = 271.8 Hz), 117.3, 115.8, 110.5, 53.0, 48.7. LC-MS-ESI + :[M-H] + 507.0.

[0185] Example 18: Methyl (3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycinate (C11a)

[0186] Weigh the raw material 3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid (200.0 mg, 392.75 μmol) into a 100 ml eggplant-shaped flask, add DMF (40 ml) to dissolve the raw material, then add DIPEA (342.0 mml, 1.9 mml), HATU (223.99 mg, 589.09 μmol). After reacting for 30 min, add glycine methyl ester hydrochloride (59.2 mg, 471.27 μmol), and react overnight. Monitor the completion of the reaction by TLC. Dilute with water, extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with 1 M hydrochloric acid aqueous solution 3 times, then wash with saturated brine 3 times, concentrate under reduced pressure, and separate by column chromatography (the first time PE / EA = 1:1, the second time DCM / MeOH = 19:1) to obtain white solid C11a (80.0 mg, yield 35.10%). 1 1H NMR (600 MHz, DMSO-d6) δ 9.29 (t, J = 5.8 Hz, 1H), 8.64 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.15 (s, 2H), 7.80 (s, 1H), 7.66 (t, J = 7.3 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H), 4.07 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H). 13CNMR(151MHz, DMSO-d6) δ 170.0, 163.5, 160.2, 159.5, 150.0, 149.3, 147.6, 138.1, 133.1, 131.9, 129.8, 129.2 (q, J = 31.7Hz), 128.8, 124.6 (q, J = 4.5Hz), 124.5 (q, J = 3.0Hz), 124.1 (q, J = 271.8Hz), 117.3, 115.8, 110.5, 51.9, 48.7, 41.4.. LC-MS-ESI + :[M - H] + 577.8.

[0187] Example 19: (3,5 - Dichloro - 4 - ((4 - oxo - 3 - (3 - (trifluoromethyl)benzyl)-3,4 - dihydroquinazolin - 7 - yl)oxy)benzoyl)glycine (C11b)

[0188]

[0189] Using methyl (3,5 - dichloro - 4 - ((4 - oxo - 3 - (3 - (trifluoromethyl)benzyl)-3,4 - dihydroquinazolin - 7 - yl)oxy)benzoyl)glycinate, it was prepared, separated and purified by the method described in Example 12 (total yield 72.63%). 1 HNMR(600MHz, DMSO - d6) δ 12.79 (s, 1H), 9.14 (t, J = 5.7Hz, 1H), 8.63 (s, 1H), 8.17 (d, J = 8.9Hz, 1H), 8.15 (s, 2H), 7.80 (s, 1H), 7.66 (t, J = 7.5Hz, 2H), 7.58 (t, J = 7.7Hz, 1H), 7.22 (dd, J = 8.9, 2.5Hz, 1H), 6.93 (d, J = 2.5Hz, 1H), 5.25 (s, 2H), 3.96 (d, J = 5.8Hz, 2H). 13 CNMR(151MHz, DMSO - d6) δ 170.3, 162.8, 159.7, 159.0, 149.4, 148.7, 146.9, 137.5, 132.8, 131.3, 129.2, 128.6 (d, J = 31.7Hz), 128.5, 128.2, 128.1, 124.0 (q, J = 3.0Hz), 123.9 (q, J = 3.0Hz), 123.5 (q, J = 30.2Hz), 116.7, 115.2, 110.0, 48.1, 40.9. LC-MS-ESI + :[M - H] + 565.7.

[0190] Example 20: Methyl 3-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionate (C12a)

[0191]

[0192] Prepared, separated, and purified using methyl 3-aminopropionate hydrochloride by the method described in Example 18 (total yield 55.22%). 1 HNMR (600 MHz, DMSO-d6) δ 8.85 (t, J = 5.4 Hz, 1H), 8.63 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.11 (s, 2H), 7.80 (s, 1H), 7.66 (t, J = 7.7 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 8.9, 2.6 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 5.25 (s, 2H), 3.62 (s, 3H), 3.52 (dd, J = 12.4, 6.8 Hz, 2H), 2.62 (t, J = 6.9 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 171.6, 163.1, 160.3, 159.5, 145.0, 149.3, 147.3, 138.1, 133.8, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.7, 128.6, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 4.5 Hz), 124.1 (q, J = 271.8 Hz), 117.3, 115.8, 110.5, 51.5, 48.7, 35.7, 33.2. LC-MS-ESI + :[M-H] + 593.7.

[0193] Example 21: 3-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionic acid (C12b)

[0194]

[0195] Prepared, separated, and purified using methyl 3-(3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionate by the method described in Example 12 (total yield 57.31%). 1HNMR (600 MHz, DMSO-d6) δ 12.27 (s, 1H), 8.84 (t, J = 5.4 Hz, 1H), 8.63 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.12 (s, 2H), 7.80 (s, 1H), 7.66 (t, J = 7.6 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.21 (dd, J = 8.9, 2.6 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 5.25 (s, 2H), 3.49 (dd, J = 12.4, 6.9 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 172.7, 163.0, 160.3, 159.5, 150.0, 149.3, 147.3, 138.1, 133.9, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.7, 128.6, 124.6 (q, J = 3.0 Hz), 124.5 (q, J = 3.0 Hz), 124.1 (q, J = 271.8 Hz), 117.3, 115.8, 110.5, 48.7, 35.8, 33.5. LC-MS-ESI + :[M - H] + 579.7.

[0196] Example 22: Ethyl (3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alaninate (C13a)

[0197]

[0198] Using D-alanine ethyl ester hydrochloride, it was prepared, separated and purified by the method described in Example 18 (total yield 23.11%). 1 HNMR (600 MHz, DMSO-d6) δ 9.07 (d, J = 6.8 Hz, 1H), 8.63 (s, 1H), 8.21–8.15 (m, 3H), 7.80 (s, 1H), 7.66 (t, J = 6.9 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.22 (dd, J = 8.9, 2.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H), 4.55–4.38 (m, 1H), 4.16–4.09 (m, 2H), 1.42 (d, J = 7.3 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 172.3, 163.1, 160.2, 159.5, 150.0, 149.3, 147.5, 138.1, 133.2, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.9, 128.7, 124.6 (q, J = 3.0 Hz), 124.5 (q, J = 3.0 Hz), 124.1 (q, J = 271.8 Hz), 124.99 (s), 124.87–124.36 (m), 123.18 (s), 121.38 (s), 117.3, 115.8, 110.5, 60.59, 48.7, 48.6, 16.61, 14.07. LC-MS-ESI + :[M-H] + 607.8.

[0199] Example 23: (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine (C13b)

[0200]

[0201] Using ethyl (3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alaninate, it was prepared, separated and purified by the method described in Example 12 (total yield 57.31%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.98 (d, J = 7.1 Hz, 1H), 8.63 (s, 1H), 8.19 - 8.15 (m, 3H), 7.80 (s, 1H), 7.66 (t, J = 7.6 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.22 (dd, J = 8.9, 2.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H), 4.43 (p, J = 7.3 Hz, 1H), 1.41 (d, J = 7.3 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 173.8, 162.9, 160.3, 159.5, 150.0, 149.3, 147.5, 138.1, 133.4, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.9, 128.6, 124.6 (q, J = 3.0 Hz), 124.5 (q, J = 4.5 Hz), 124.1 (q, J = 273.3 Hz), 117.3, 115.8, 110.5, 48.7, 48.5, 16.8. LC-MS-ESI + : [M-H] + 579.8.

[0202] .3, 115.8, 110.5, 48.7, 35.8, 33.5. LC-MS-ESI + : [M-H] + 579.7.

[0203] Example 24: Ethyl (3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alaninate (C14a)

[0204]

[0205] Prepared, separated and purified by the method described in Example 18 using L-alanine ethyl ester hydrochloride (total yield 22.36%). 1 1H NMR (600 MHz, DMSO-d6) δ 9.07 (d, J = 6.8 Hz, 1H), 8.63 (s, 1H), 8.20–8.15 (m, 3H), 7.80 (s, 1H), 7.66 (t, J = 7.2 Hz, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.22 (dd, J = 8.9, 2.6 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 5.25 (s, 2H), 4.47 (p, J = 7.3 Hz, 1H), 4.13 (qd, J = 7.1, 2.4 Hz, 2H), 1.42 (d, J = 7.3 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 172.3, 163.1, 160.2, 159.5, 150.0, 149.3, 147.5, 138.1, 133.2, 131.9, 129.8, 129.2 (q, J = 31.7), 129.1, 128.9, 128.7, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 3.0 Hz), 124.1 (q, J = 271.8), 117.3, 115.8, 110.5, 60.6, 48.7, 48.6, 16.6, 14.1. LC-MS-ESI + :[M-H] + 607.8.

[0206] Example 25: (3,5-Dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine (C14b)

[0207]

[0208] Using ethyl (3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alaninate, it was prepared, separated and purified by the method described in Example 12 (total yield 65.23%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.66 (s, 1H), 8.98 (d, J = 7.1 Hz, 1H), 8.63 (s, 1H), 8.19–8.16 (m, 3H), 7.80 (s, 1H), 7.66 (t, J = 7.4 Hz, 2H), 7.58 (t, J = 7.7 Hz, 1H), 7.22 (dd, J = 8.9, 2.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 5.25 (s, 2H), 4.44 (p, J = 7.3 Hz, 1H), 1.42 (d, J = 7.4 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.8, 162.9, 160.3, 159.5, 150.0, 149.3, 147.5, 138.1, 133.4, 131.9, 129.8, 129.2 (q, J = 31.7 Hz), 129.1, 128.9, 128.6, 124.6 (q, J = 4.5 Hz), 124.5 (q, J = 3.0 Hz), 124.1 (q, J = 271.8), 117.3, 115.8, 110.5, 48.7, 48.5, 16.8. LC-MS-ESI +:[M-H] + 579.8.

[0209] Example 26: N-(2-Amino-2-oxoethyl)-3,5-dichloro-4-((4-oxo-3-(3-(trifluoromethyl)benzyl)-3,4-dihydroquinazolin-7-yl)oxy)benzamide (C15)

[0210]

[0211] It was prepared, separated and purified by the method described in Example 18 using 2-aminoacetamide hydrochloride (total yield 78.15%). 1 HNMR(600MHz,DMSO-d6)δ9.04(s,1H),8.63(s,1H),8.18(d,J = 8.9Hz,1H),8.17(s,2H),7.80(s,1H),7.66(t,J = 7.4Hz,2H),7.58(t,J = 7.7Hz,1H),7.44(s,1H),7.22(dd,J = 8.9,2.6Hz,1H),7.10(s,1H),6.89(d,J = 2.6Hz,1H),5.25(s,2H),3.84(d,J = 5.9Hz,2H). 13 C NMR(151MHz,DMSO-d6)δ170.6,163.4,160.3,159.5,150.0,149.3,147.3,138.1,133.8,131.9,129.8,129.2(q,J = 31.7Hz),129.1,128.9,128.5,124.6(q,J = 4.5Hz),124.5(q,J = 3.0Hz),124.1(q,J = 271.8),117.3,115.8,110.4,48.7,42.6.LC-MS-ESI + :[M-H] + 564.7.

[0212] Example 27: 3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid (D1b)

[0213]

[0214] It was prepared, separated and purified by the method described in Example 17 using 7-hydroxy-3-methylquinazolin-4(3H)-one (total yield 78.85%). 11H NMR (600 MHz, DMSO-d6) δ 13.77 (s, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.11 (s, 2H), 7.21 (dd, J = 8.8, 2.5 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 3.47 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 164.1, 159.4, 159.3, 149.6, 149.1, 148.1, 130.3, 129.9, 128.3, 128.2, 116.7, 115.0, 109.7, 32.9. LC-MS-ESI + :[M-H] + 364.8.

[0215] Example 28: Methyl 2-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate (D2a)

[0216]

[0217] Weigh the raw material 7-(4-amino-2,6-dichlorophenoxy)-3-(3-(trifluoromethyl)benzyl)quinazolin-4(3H)-one (200.0 mg, 594.93 μmol) and dissolve it in DMF (50 ml) in a 100 ml eggplant-shaped flask. After adding potassium carbonate (164.45 mmol, 1.19 mmol), slowly add methyl 2-chloro-2-oxoacetate (82.07 mmol, 892.40 μmol), and react overnight. TLC detects that the reaction is complete. Add water to precipitate the solid, filter by suction, wash the filter cake 3 times with water and then 3 times with petroleum ether, dry it, collect the filter cake, and separate it by column chromatography to obtain white solid D2a (81.7 mg, yield 32.53%). 1 1H NMR (600 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 8.11 (s, 2H), 7.17 (dd, J = 8.8, 2.5 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 3.89 (s, 3H), 3.46 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 159.8, 159.7, 159.4, 154.8, 149.6, 149.1, 141.1, 136.2, 128.1, 127.7, 120.4, 116.4, 114.9, 109.5, 52.9, 32.9. LC-MS-ESI + :[M-H]+ 421.8.

[0218] Example 29: 2-((3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetic acid (D2b)

[0219]

[0220] Methyl 2-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-2-oxoacetate was used and prepared, separated and purified by the method described in Example 12 (total yield 58.80%). 1 HNMR(600MHz,DMSO-d6)δ11.17(s,1H),8.50(s,1H),8.17(d,J = 8.9Hz,1H),8.13(s,2H),7.19(dd,J = 8.8,2.4Hz,1H),6.87(s,1H),3.47(s,3H). 13 C NMR(151MHz,DMSO-d6)δ161.8,161.0,160.3,157.6,150.4,149.5,141.9,137.5,129.3,128.7,121.3,117.3,116.1,109.9,34.1.LC-MS-ESI + :[M-H] + 408.6.

[0221] Example 30: Methyl 3-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropionate (D3a)

[0222]

[0223] Methyl 3-chloro-3-oxopropionate was used and prepared, separated and purified by the method described in Example 28 (total yield 24.85%). 1 HNMR(600MHz,DMSO-d6)δ10.65(s,1H),8.35(s,1H),8.16(d,J = 8.9Hz,1H),7.86(s,2H),7.17(dd,J = 8.8,2.6Hz,1H),6.83(d,J = 2.5Hz,1H),3.68(s,3H),3.53(s,2H),3.46(s,3H). 1313C NMR (151 MHz, DMSO-d6) δ 167.7, 164.8, 160.6, 160.0, 150.1, 149.6, 140.8, 137.9, 128.6, 128.4, 119.5, 117.0, 115.5, 110.1, 52.1, 43.5, 33.4. LC-MS-ESI + :[M-H] + 435.8.

[0224] Example 31: 3-((3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropanoic acid (D3b)

[0225]

[0226] Using methyl 3-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-3-oxopropanoate, it was prepared, separated and purified by the method described in Example 12 (total yield 66.54%). 1 1H NMR (600 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.37 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.88 (s, 2H), 7.17 (dd, J = 8.8, 2.5 Hz, 1H), 6.84 (d, J = 2.5 Hz, 1H), 3.46 (s, 3H), 2.13 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 169.3, 165.8, 161.1, 160.5, 150.5, 150.1, 141.1, 138.5, 129.1, 128.8, 119.8, 117.4, 116.0, 110.5, 44.6, 34.0. LC-MS-ESI + :[M-H] + 421.8.

[0227] Example 32: Methyl 4-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutanoate (D4a)

[0228]

[0229] Using methyl 4-chloro-4-oxobutanoate, it was prepared, separated and purified by the method described in Example 28 (total yield 34.38%). 11H NMR (600 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.86 (s, 2H), 7.16 (dd, J = 8.8, 2.6 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 3.61 (s, 3H), 3.46 (s, 3H), 2.64 (td, J = 8.7, 2.9 Hz, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 172.1, 170.1, 160.0, 159.4, 149.6, 149.0, 139.7, 137.7, 128.1, 127.7, 118.6, 116.4, 114.9, 109.5, 50.8, 32.9, 30.4, 27.7. LC-MS-ESI + :[M-H] + 449.8.

[0230] Example 33: 4-((3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyric acid (D4b)

[0231]

[0232] Using methyl 4-((3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)phenyl)amino)-4-oxobutyrate, it was prepared, separated and purified by the method described in Example 12 (total yield 77.96%). 1 1H NMR (600 MHz, DMSO-d6) δ 8.37–8.35 (m, 1H), 8.17–8.13 (m, 1H), 7.89 (s, 1H), 7.13 (dd, J = 8.8, 2.5 Hz, 1H), 6.76 (s, 2H), 6.75 (d, J = 2.5 Hz, 1H), 3.46 (s, 3H), 1.23 (s, 4H). 13 13C NMR (151 MHz, DMSO-d6) δ 173.1, 170.4, 161.0, 159.4, 148.9, 147.7, 133.6, 127.9, 127.6, 118.6, 116.0, 115.0, 112.7, 109.1, 59.2, 32.9, 28.4. LC-MS-ESI + :[M-H] + 436.7.

[0233] Example 34: Methyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycinate (D5a)

[0234]

[0235] Weigh 3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoic acid (200.0 mg, 547.70 μmol) into a 100 ml eggplant-shaped flask, add DMF (40 ml) to dissolve the raw material, then add DIPEA (477.01 mml, 2.74 mml), HATU (416.51 mg, 1.1 mmol). After reacting for 30 min, add glycine methyl ester hydrochloride (103.15 mg, 821.54 μmol), and react overnight. Monitor the completion of the reaction by TLC. Dilute with water, extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with 1 M hydrochloric acid aqueous solution 3 times, then wash with saturated brine 3 times, concentrate under reduced pressure, and separate by column chromatography to obtain white solid D5a (117.3 mg, yield 49.1%). 1 HNMR (600 MHz, DMSO-d6) δ 9.29 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.15 (s, 2H), 7.20 (dd, J = 8.8, 2.6 Hz, 1H), 6.89 (d, J = 2.6 Hz, 1H), 4.07 (d, J = 5.8 Hz, 2H), 3.68 (s, 3H), 3.47 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 170.0, 163.5, 160.0, 159.9, 150.2, 149.7, 147.7, 133.0, 128.8, 128.7, 117.2, 115.5, 110.4, 51.9, 41.4, 33.5. LC-MS-ESI + :[M-H] + 435.8.

[0236] Example 35: (3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycine (D5b)

[0237]

[0238] Using methyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)glycinate, prepare, separate and purify it by the method described in Example 12 (total yield 49.48%).1 1H NMR (600 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.18 (t, J = 5.7 Hz, 1H), 8.37 (s, 1H), 8.18 (d, J = 8.9 Hz, 1H), 8.16 (s, 2H), 7.20 (dd, J = 8.8, 2.3 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 3.98 (d, J = 5.8 Hz, 2H), 3.47 (s, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.4, 163.9, 160.5, 160.4, 150.6, 150.2, 148.1, 133.8, 129.2, 129.2, 117.7, 116.0, 110.9, 41.9, 34.0. LC-MS-ESI + :[M-H] + 421.8.

[0239] Example 36: Methyl 3-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propionate (D6a)

[0240]

[0241] Prepared, separated and purified by the method described in Example 34 using methyl 3-aminopropionate hydrochloride (total yield 29.23%). 1 1H NMR (600 MHz, DMSO-d6) δ 8.84 (t, J = 5.3 Hz, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 8.10 (s, 2H), 7.19 (dd, J = 8.9, 2.5 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 3.62 (s, 3H), 3.52 (dd, J = 12.5, 6.7 Hz, 2H), 3.46 (s, 3H), 2.62 (t, J = 6.9 Hz, 2H). 13 13C NMR (151 MHz, DMSO-d6) δ 171.6 163.1, 160.0, 160.0, 150.2, 149.7, 147.4, 133.8, 128.8, 128.7, 128.6, 117.2, 115.5, 110.3, 51.5, 35.7, 33.5, 33.3. LC-MS-ESI + :[M-H] + 451.9.

[0242] Example 37: 3-(3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propanoic acid (D6b)

[0243]

[0244] Methyl 3-(3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamido)propanoate was used and prepared, separated and purified by the method described in Example 12 (total yield 66.27%). 1 H NMR (600 MHz, DMSO-d6) δ 8.88 (t, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.12 (s, 2H), 7.18 (dd, J = 8.9, 2.5 Hz, 1H), 6.86 (d, J = 2.5 Hz, 1H), 3.49–3.45 (m, 5H), 2.52–2.50 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.6, 163.4, 160.5, 150.6, 150.2, 147.8, 134.4, 129.2, 129.1, 129.0, 117.7, 116.0, 110.8, 36.6, 34.5, 33.9. LC-MS-ESI + :[M-H] + 435.8.

[0245] Example 38: Ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine (D7a)

[0246]

[0247] D-Alanine ethyl ester hydrochloride was used and prepared, separated and purified by the method described in Example 34 (total yield 31.14%). 1 HNMR (600 MHz, DMSO-d6) δ 9.07 (d, J = 6.8 Hz, 1H), 8.36 (s, 1H), 8.22–8.14 (m, 3H), 7.20 (dd, J = 8.9, 2.5 Hz, 1H), 6.88 (d, J = 2.5 Hz, 1H), 4.47 (p, J = 7.2 Hz, 1H), 4.25–3.98 (m, 2H), 3.47 (s, 3H), 1.42 (d, J = 7.3 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H). 1313C NMR (151 MHz, DMSO-d6) δ 172.3, 163.1, 160.0, 160.0, 150.2, 149.7, 147.6, 133.1, 128.9, 128.8, 128.7, 117.2, 115.5, 110.3, 60.6, 48.7, 33.5, 16.6, 14.1. LC-MS-ESI + :[M-H] + 463.8.

[0248] Example 39: (3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine (D7b)

[0249]

[0250] Using ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-D-alanine, it was prepared, separated and purified by the method described in Example 12 (total yield 63.82%). 1 1H NMR (600 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.99 (d, J = 7.1 Hz, 1H), 8.37 (s, 1H), 8.21–8.15 (m, 3H), 7.19 (dd, J = 8.8, 2.4 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 4.44 (p, J = 7.3 Hz, 1H), 3.47 (s, 3H), 1.42 (d, J = 7.3 Hz, 3H). 13 13C NMR (151 MHz, DMSO-d6) δ 174.3, 163.4, 160.5, 150.6, 150.2, 148.0, 133.8, 129.4, 129.2, 129.1, 117.7, 116.0, 110.8, 49.0, 34.0, 17.3. LC-MS-ESI + :[M-H] + 435.8.

[0251] Example 40: Ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine (D8a)

[0252]

[0253] Using L-alanine ethyl ester hydrochloride, it was prepared, separated and purified by the method described in Example 34 (total yield 31.97%). 1HNMR(600MHz, DMSO-d6) δ 9.06 (d, J = 6.8Hz, 1H), 8.36 (s, 1H), 8.20–8.14 (m, 3H), 7.20 (dd, J = 8.8, 2.5Hz, 1H), 6.88 (d, J = 2.5Hz, 1H), 4.47 (p, J = 7.2Hz, 1H), 4.19–4.09 (m, 2H), 3.47 (s, 3H), 1.42 (d, J = 7.3Hz, 3H), 1.21 (t, J = 7.1Hz, 3H). 13 C NMR(151MHz, DMSO-d6) δ 172.8, 163.6, 160.5, 160.4, 150.6, 150.2, 148.1, 133.6, 129.4, 129.2, 129.2, 117.7, 116.0, 110.8, 61.1, 49.2, 34.0, 17.1, 14.6. LC-MS-ESI + :[M-H] + 463.8.

[0254] Example 41: (3,5-Dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine (D8b)

[0255]

[0256] Using ethyl (3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzoyl)-L-alanine, it was prepared, separated and purified by the method described in Example 12 (total yield 93.77%). 1 HNMR(600MHz, DMSO-d6) δ 12.66 (s, 1H), 8.98 (d, J = 7.1Hz, 1H), 8.37 (s, 1H), 8.17 (d, J = 8.0Hz, 3H), 7.19 (dd, J = 8.8, 2.5Hz, 1H), 6.89 (d, J = 2.5Hz, 1H), 4.44 (p, J = 7.3Hz, 1H), 3.47 (s, 3H), 1.42 (s, 3H). 13 C NMR(151MHz, DMSO-d6) δ 173.8, 162.9, 160.0, 150.1, 149.7, 147.6, 133.3, 128.9, 128.8, 128.7, 117.2, 115.5, 110.3, 48.5, 33.5, 16.8. LC-MS-ESI + :[M-H] + 435.8.

[0257] Example 42: N-(2-Amino-2-oxoethyl)-3,5-dichloro-4-((3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)oxy)benzamide (D9)

[0258]

[0259] Using 2-aminoacetamide hydrochloride, it was prepared, separated and purified by the method described in Example 34 (total yield 77.63%). 1H NMR (600 MHz, DMSO-d6) δ 9.03 (t, J = 5.9 Hz, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 8.16 (s, 2H), 7.45 (s, 1H), 7.19 (dd, J = 8.9, 2.6 Hz, 1H), 7.10 (s, 1H), 6.85 (d, J = 2.5 Hz, 1H), 3.84 (d, J = 5.9 Hz, 2H), 3.47 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 170.0, 162.8, 159.4, 149.6, 149.2, 146.8, 133.1, 128.3, 128.2, 127.9, 116.6, 114.9, 109.6, 42.1, 32.9. LC-MS-ESI + :[M-H] + 420.7.

[0260] Biological test experiment

[0261] At the molecular level, the binding ability of the compound to THRβ / THRα was determined by the AlphaScreen detection method. First, recombinant GST-THRβ / GST-THRα fusion proteins were constructed respectively, and then the reaction of the compound with the receptor was carried out in a 384-well plate. The mixture of the recombinant protein, agonist, co-regulator, receptor beads and donor beads was reacted in a buffer containing: 50 mM Tris-HCl (pH 7.4), 50 mM NaCl, 0.1% BSA, 1 mM DTT. If the compound can bind to the receptor protein, the relative positions of the receptor beads and the donor beads change, and then fluorescence of a specific wavelength will be emitted. We detected the fluorescence signal intensity at a wavelength of 570 nm by a fluorescence detector Envision to characterize the binding activity of the compound to THRβ. And the compound EC 50 .

[0262] Experimental results of biological test experiment

[0263] The synthesized compounds were preliminarily tested for in vitro THRβ agonist activity and selectivity at the molecular level. It was found that multiple compounds had good THRβ agonist activity and good selectivity for THRα. Among them, the activity of compound C6h on THRβ EC 50 was 88.8 ± 11.5 nM, showing significant agonist activity compared to Resmetirom. The selectivity of C6h reached 40-fold, significantly better than Resmetirom. Almost no THRα agonist activity was detected for C5d and C5f, and they maintained moderate THRβ agonist activity, showing complete selectivity.

[0264] Table 1 Activity data of the in vitro molecular evaluation system of the compounds

[0265]

[0266]

[0267]

[0268] EC 50 :A: 0 - 100 nM, B: 100 - 500 nM, C: 500 - 1000 nM, D: >1000 nM

[0269] Selectivity: -: 0 - 1, +: 1 - 10, ++: 10 - 100, +++: >100

[0270] NT: Not detected

[0271] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill 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 which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, N-oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I), Among them, at any substitutable ring atom of the 4-quinazolinone ring; X is selected from the group consisting of: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-; R 1 、R 2 、R 3 and R 4 each independently is 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 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R 5 Selected from -NHCO(CH) a (R c )COOR d 、-CONH(CH) b (R e )COOR f 、-CONH(CH) C (R g )CONH2 R 6 Selected from the group consisting of: H, D, F, Cl, Br, I, -CN, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, YR h R 6 may optionally be substituted by 1, 2 or 3 R x groups; Y is selected from the group consisting of: -O-, -CH2-, -C(=O)-, -CH(OH)-, -S-; a, b, c are selected from 0, 1, 2, 3; R a selected from H, D, F, Cl, Br, I, Cl, NO2, -COOH, -OH, -NH2, -SH2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -C(=O)-C1-C6 alkyl, -C(=O)-C1-C6 alkoxy, -C(=O)NH2, -S(=O)2-C1-C6 alkoxy, -S(=O)2-C1-C6 alkyl, -S(=O)NH2; R b selected from H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R c 、R e 、R g are each independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R d 、R f are each independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; R h Selected from the group consisting of: H, D, F, Cl, Br, I, Cl, CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R h may optionally be substituted by 1, 2 or 3 R y groups; R x 、R y each independently selected from the group consisting of: H, D, F, Cl, Br, I, -CN, -CF3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 mono- or polysubstituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

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 the following formula (Ia) or (Ib):

3. The compound according to claim 1-2, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs, characterized in that, R 1 、R 2 、R 3 and R 4 are each independently selected from the group consisting of: H, D, halogen.

4. The compound according to any one of claims 1-3, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, characterized in that, R a selected from the group consisting of: H, D, halogen, -CN, -COOH; R b selected from the group consisting of: H, D.

5. The compound according to any one of claims 1-4, its stereoisomers, deuterated compounds, solvates, metabolites, pharmaceutically acceptable salts, cocrystals or prodrugs, characterized in that, R 6 selected from the group consisting of: H, C1-C6 alkyl, YR h ; wherein, said Y is selected from CH2; said R h is selected from H, substituted or unsubstituted aryl; R x , R y are each independently selected from the group consisting of: H, D, CF 3。 6. The compound according to any one of claims 1-5, its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug, which is selected from:

7. A pharmaceutical composition, characterized in that, Including: The compound according to any one of claims 1-6 or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug.

8. Use of the compound according to any one of claims 1-6 or its stereoisomer, deuterated compound, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug in the preparation of a medicament for treating an activated thyroid hormone receptor or for preventing, treating or alleviating a thyroid hormone receptor-regulated disease.

9. The use according to claim 8, wherein, The thyroid hormone receptor-mediated diseases are selected from the group consisting of: non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, atherosclerosis, coronary heart disease, hypertension, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, dyslipidemia, obesity, diabetes, metabolic disorder, lipid metabolism disorder, type 1A glycogen storage disease, hypothyroidism or thyroid cancer.

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