Dihydroquinazolinone compound, preparation method therefor, and use thereof

Abstract

The present invention relates to dihydroquinazolinone compound, a preparation method therefor, and a use thereof. The dihydroquinazolinone compound has an excellent inhibitory effect on GLUT9, can effectively inhibit GLUT9 activity so as to promote uric acid excretion, thereby achieving a uric acid lowering effect, and can be used for treating diseases related to GLUT9 activity or expression. The dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof has no obvious toxicity to organs, can significantly reduce kidney damage caused by hyperuricemia, and alleviates gout symptoms.

Description

Dihydroquinazolinones and methods and uses thereof TECHNICAL FIELD

[0001] The present application is in the field of medicinal chemistry. More specifically, the present application relates to dihydroquinazolinones and methods and uses thereof, which can be used as GLUT9 inhibitors. BACKGROUND

[0002] Currently, the development of new drugs for reducing uric acid at home and abroad mainly focuses on inhibitors of the kidney uric acid reabsorption transporter URAT1. There are more than 10 URAT1 inhibitors in clinical phase 1-3 in China, but none of them has been marketed, including Verinurad developed by AstraZeneca, the main reason being the damage to the kidney. Glucose transporter 9 (GLUT9) is a low-affinity high-capacity uric acid transporter, and its uric acid transport capacity is superior to that of URAT1. Recent studies have found that GLUT9 is the most important transporter of kidney uric acid reabsorption, not URAT1. In the kidney, uric acid is first absorbed from the urine to the cell by URAT1 on the apical membrane, and then transported to the blood by the synergistic transport of GLUT9 on the matrix membrane side. Patients with GLUT9 deficiency have almost complete loss of kidney uric acid excretion, showing more severe hypouricemia than URAT1 patients. GLUT9 and URAT1 are completely opposite in uric acid transport characteristics. It is a high-capacity, low-affinity uric acid transporter, and its regulation of uric acid is much higher than that of URAT1.

[0003] There are few reports on the screening and synthesis of dual-target inhibitors of kidney uric acid transporters URAT1 and GLUT9 in China, but there is currently no report on high-selectivity GLUT9 inhibitors at home and abroad. The development of such new drugs for reducing uric acid is imminent. SUMMARY

[0004] In view of the above prior art problems, the primary object of the present application is to provide dihydroquinazolinones or pharmaceutically acceptable salts thereof.

[0005] A second object of the present application is to provide a pharmaceutical composition comprising the dihydroquinazolinones or pharmaceutically acceptable salts thereof.

[0006] A third object of the present application is to provide the use of dihydroquinazolinones or pharmaceutically acceptable salts thereof or their pharmaceutical compositions in the preparation of GLUT9 inhibitors, especially high-selectivity GLUT9 inhibitors.

[0007] A fourth object of the present application is to provide the use of the dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating diseases related to the activity or expression amount of GLUT9 or in the preparation of a medicament for reducing uric acid.

[0008] A fifth object of the present application is to provide the use of the dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a medicament for treating hyperuricemia, kidney injury, gout or gout complications.

[0009] The above objects of the present application are achieved by the following technical solutions.

[0010] The present application provides a dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof, the structure of which is shown in formula (I):

[0011] wherein R1 is selected from aryl or heteroaryl, hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-8 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl ester, aryl ester, C 1-6 alkyl carbonyl, C 2-6 alkenyl carbonyl and C 2-6 alkynyl carbonyl; wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C 1-6 alkoxy, halogen and C 1-6 alkyl ester;

[0012] R2 and R3 are each independently selected from hydrogen, deuterium, halogen, C 1-8 alkyl, C 1-6 alkoxy, C 1-6 alkylthiol, aryl or C 1-6 alkylsulfonyl, C 3-6 cycloalkyl, C 1-6 alkyl ester, aryl ester, C 1-6 alkyl carbonyl, C 2-8 alkenyl carbonyl, C 2-8 alkynyl carbonyl and aryl, wherein the aryl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C 1-6 alkoxy, halogen and C 1-6 alkyl ester;

[0013] R4 and R5 are each independently selected from hydrogen, halogen, C 2-8 alkenyl, deuterium, cyano, hydroxyl, thiol, amino, C 1-8 alkyl, C 1-6 alkoxy, C3-6 cycloalkyl, C 2-8 alkynyl, C 1-6 alkyl ester, aryl ester, C 1-6 alkyl carbonyl, C 2-8 alkenyl carbonyl and C 2-8 alkynyl carbonyl; the C 2-8 alkenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxyl and -CONR6R7;

[0014] R6and R7are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, heterocyclyl, heterocyclyloxy, C 1-6 alkyl benzyl and aryl; wherein the C 1-8 alkyl, aryl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, heterocyclyl, heterocyclyloxy and C 1-6 alkyl benzyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-6 alkylamino and hydroxyl;

[0015] or, R6, R7and the nitrogen atom to which they are attached together form a heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-6 alkyl, hydroxy C 1-6 alkyl and hydroxyl.

[0016] In some embodiments, R1is selected from the group consisting of phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, benzodioxanyl, quinolinyl and indolyl; wherein the phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, benzodioxanyl, quinolinyl and indolyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, halogen and C 1-6 alkyl ester;

[0017] R2and R3are each independently selected from the group consisting of hydrogen;

[0018] R4and R5are each independently selected from the group consisting of hydrogen, halogen and C 2-6 alkenyl; the C 2-6 alkenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxyl and -CONR6R7;

[0019] R6and R7are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C 1-4 alkylbenzyl and phenyl; wherein the C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyloxy, C 1-4 alkylbenzyl and 3-6 membered heterocyclyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, methylamino and hydroxy;

[0020] or, R6, R7and the nitrogen atom to which they are attached together form a 3-6 membered heterocyclyl, wherein the 3-6 membered heterocyclyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-4 alkyl, hydroxyC 1-4 alkyl and hydroxy.

[0021] In some embodiments, R4and R5are each independently selected from the group consisting of hydrogen, F, Cl, Br, I, vinyl, propenyl, allyl, butenyl and pentenyl, wherein the vinyl, propenyl, allyl, butenyl and pentenyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxyl and -CONR6R7; wherein R 6 and R 7 each have the meaning described herein.

[0022] In some embodiments, R6and R7are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyloxy, pyrrolidinyloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, piperidinyloxy, piperazinyloxy, morpholinoyloxy, methoxybenzyl, ethoxybenzyl and phenyl; wherein the methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyloxy, pyrrolidinyloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, piperidinyloxy, piperazinyloxy, morpholinoyloxy, methoxybenzyl, ethoxybenzyl and methoxy are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, methylamino and hydroxy;

[0023] or, R6, R7and the nitrogen atom to which they are attached together form an azetidinyl, piperidinyl, piperazinyl, morpholinyl or aziridinyl group, wherein the azetidinyl, piperidinyl, piperazinyl, morpholinyl and aziridinyl group is unsubstituted or substituted with one or more substituents independently selected from amino, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxyl.

[0024] In some embodiments, R1is selected from

[0025] In some embodiments, R2, R3are each independently selected from hydrogen.

[0026] In some embodiments, R4, R5are each independently selected from hydrogen, bromo,

[0027] In some embodiments, the compound of the present application is selected from any one of the following structures:

[0028] Further, the present application claims a pharmaceutical composition comprising:

[0029] (a) the dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof, or a combination thereof; and

[0030] (b) a pharmaceutically acceptable carrier and / or excipient.

[0031] Further, the present application claims the use of a dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof in the preparation of a GLUT9 inhibitor.

[0032] Further, the present application claims the use of a dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with GLUT9 activity or expression, or in the preparation of a medicament for lowering uric acid.

[0033] Further, the present application claims the use of a dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hyperuricemia, kidney injury, gout or gout complications.

[0034] In some embodiments, the gout complications include gouty arthritis or uric acid kidney stones, etc.

[0035] Compared with the prior art, the present application has the following beneficial effects:

[0036] The application provides a dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof, which has excellent inhibitory effect on GLUT9 and high selectivity to GLUT9, can effectively inhibit the activity of GLUT9 to promote the excretion of uric acid, and thus achieve the effect of reducing uric acid, and can be used for treating diseases related to the activity or expression amount of GLUT9. The dihydroquinazolinone compound or the pharmaceutically acceptable salt thereof has no obvious toxicity to organs, can significantly reduce the kidney damage caused by high uric acid, and relieve the symptoms of gout. BRIEF DESCRIPTION OF DRAWINGS

[0037] FIG. 1 is a schematic diagram of the inhibitory effect of compounds 1-20 on the activities of GLUT9 and URAT1.

[0038] FIG. 2 is a schematic diagram of the inhibitory effect of compounds 21-40 on the activities of GLUT9 and URAT1.

[0039] FIG. 3 is a schematic diagram of the effects of compounds 6, 9 and 11 on reducing uric acid and kidney damage in vivo. In FIG. 3, A is the blood uric acid level; B is the urine uric acid level; C is the blood creatinine level; and D is the blood urea nitrogen level.

[0040] FIG. 4 is a schematic diagram of the effects of compounds 6 and 9 on kidney damage markers. In FIG. 4, A is the relative mRNA expression content of kidney injury molecule-1 (Kim-1); and B is the relative mRNA expression content of neutrophil gelatinase-associated lipocalin (Ngal). DETAILED DESCRIPTION

[0041] The application will be further explained in conjunction with specific embodiments, but the specific embodiments do not limit the application in any way. Unless otherwise specified, the reagents and methods involved in the embodiments are common reagents and methods in the art.

[0042] In the application, unless otherwise specified in the context, the meanings of the words, phrases and symbols to be used below are as follows. The meanings of the following abbreviations and terms are throughout the text:

[0043] The term "halogen" refers to fluorine, chlorine, bromine and iodine. The term "halo" before a group name means that the group is partially or completely halogenated, that is, substituted with F, Cl, Br or I in any combination.

[0044] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group. The alkyl group is preferably a C1-C8 alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl or the like.

[0045] The term "cycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon groups, including monocyclic or polycyclic groups. Unless otherwise specified, cycloalkyl groups have 3 to 12 carbon atoms. For example, cycloalkyl groups can be monocyclic groups having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-3-enyl, cyclohexenyl, 1-cyclohex-1-enyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, or the like. Cycloalkyl groups can also be bicyclic groups having 4 to 12 carbon atoms, such as bicyclics of [4,5], [5,5], [5,6], and [6,6] ring systems, bridged bicyclics selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane, or the like. The cycloalkyl groups can be saturated or have at least one double bond, but not be fully conjugated, and not be aromatic.

[0046] The term "heterocyclyl" refers to a ring selected from 4- to 12-membered monocyclic, bicyclic and tricyclic saturated or partially unsaturated rings containing at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from O, S and N. The heterocycle can be saturated or contain at least one double bond. The heterocycle can be substituted with oxo, i.e. with the group =O. The heterocyclyl group can be attached to the remainder of the molecule by a carbon atom or a heteroatom. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, azetidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, and the like.

[0047] The term "alkoxy" refers to a saturated straight-chain or branched-chain group attached to the remainder of the molecule through an oxygen atom, usually represented by RO-, wherein R is an alkyl group. Unless otherwise specified, the alkoxy group is an alkoxy group having 1 to 6 carbon atoms, examples of which include, but are not limited to, methoxy.

[0048] The terms "cycloalkyloxy" and "heterocyclyloxy" refer to a cycloalkyl or heterocyclyl group, respectively, attached to the remainder of the molecule through an oxygen atom, wherein the cycloalkyl and heterocyclyl groups have the meanings described herein, respectively.

[0049] The term "hydroxyalkyl" refers to an alkyl group, which has the meaning described herein, substituted with one or more hydroxy groups. Unless otherwise specified, the alkyl group in a hydroxyalkyl group has 1 to 6 carbon atoms, examples of which include, but are not limited to, hydroxymethyl and the like.

[0050] The term "alkylcarbonyl" refers to a group -C(O)R, wherein R is an alkyl group. Unless otherwise specified, the alkyl group in an alkylcarbonyl group has 1 to 6 carbon atoms.

[0051] The term "alkylsulfonyl" refers to a group -S(=O)2alkyl, wherein the alkyl group has the meaning described herein.

[0052] The terms "alkylcarbonyl", "alkenylcarbonyl", and "alkynylcarbonyl" refer to the groups -C(=O)-alkyl, -C(=O)-alkenyl, and -C(=O)-alkynyl, respectively, in which the group is attached to the remainder of the molecule by a carbon atom of the carbonyl group. Unless otherwise indicated, the alkyl, alkenyl, and alkynyl groups have the meanings described herein.

[0053] The term "alkenyl" refers to straight or branched chain hydrocarbon groups containing at least one degree of unsaturation, in which at least one position of a C-C is sp 2 The term "alkenyl" refers to straight or branched chain hydrocarbon groups containing at least one degree of unsaturation, in which at least one position of a C-C is sp

[0054] The term "aryl" refers to a 5-6 membered aromatic ring, a 7-12 membered bicyclic ring system, a 10-15 membered tricyclic ring system, wherein at least one ring in the bicyclic ring system or tricyclic ring system is aromatic. For example, (a) 5-6 membered aromatic rings include, but are not limited to, phenyl; (b) aryl groups of 7-12 membered bicyclic ring systems wherein at least one ring is aromatic, for example, naphthyl; (c) aryl groups of 10-15 membered tricyclic ring systems wherein at least one ring is aromatic, for example, fluorenyl.

[0055] The term "heteroaryl" refers to a 5-6 membered aromatic ring, a 7-12 membered bicyclic ring system, a 10-15 membered tricyclic ring system, wherein at least one ring in the bicyclic ring system or tricyclic ring system is aromatic, and the aromatic ring contains at least one heteroatom selected from O, S, and N. For example, (a) 5-6 membered heteroaryl groups include, but are not limited to, pyridyl or furanyl; (b) heteroaryl groups of 7-12 membered bicyclic ring systems include, but are not limited to, benzodioxanyl or quinolinyl.

[0056] A divalent group derived from a substituted phenyl derivative and having a free valence on a ring atom is referred to as a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon whose name ends in "yl" by removal of one hydrogen atom from a carbon atom having a free valence is named by adding "ylene" to the name of the corresponding monovalent group, e.g., naphthyl having two points of attachment is named naphthylene.

[0057] The term "acceptable salts" refers to salts of the compounds of formula (I) of the present application with suitable acids or bases, including, but not limited to:

[0058] Suitable salts with bases, for example salts of compounds of formula (I) containing carboxyl groups, include alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, ammonium, and salts of amines.

[0059] Suitable acid addition salts, such as those derived from compounds of formula (I) containing amino groups, include those formed from inorganic acids, such as hydrochloric acid, sulphuric acid, sulphurous acid, phosphoric acid, hydrogen phosphoric acid, and nitric acid, and those formed from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, salicylic acid, and oxalic acid, and the like.

[0060] In addition, if the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is the free base, an addition salt can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the conventional manner for preparing acid addition salts from basic compounds. Those skilled in the art will appreciate that various synthetic procedures can be used to prepare the pharmaceutically acceptable addition salts without undue experimentation.

[0061] The present application will be further described in conjunction with the following specific examples, which are intended to be purely exemplary of the application and not in limitation thereof. Unless otherwise indicated, the procedures employed in the following examples are routine procedures and the materials and reagents used are those available commercially, unless otherwise indicated.

[0062] The starting materials known in the present application can be synthesized or purchased from Shanghai Bide Pharmaceutical Technology Co., Ltd., An'ajie Chemical, Beijing Inokai Technology Co., Ltd., and the like, according to methods known in the art. In the present application, thin layer chromatography silica gel plates are used from Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the silica gel plates used in thin layer chromatography (TLC) have a specification of 0.15 mm-0.20 mm, and column chromatography uses Yantai Huanghai silica gel 100-200 mesh silica gel as a carrier; the structure of the compounds is determined by nuclear magnetic resonance (NMR). The NMR shift is given in units of (ppm). The NMR is measured by a (Bruker Avance III 400) nuclear magnetic instrument, and the measuring solvent is deuterated dimethyl sulfoxide (DMSO-de), and the internal standard is tetramethylsilane (TMS).

[0063] Example 1

[0064] Preparation of intermediate compound 1-2: 2-amino-3-bromobenzamide

[0065] 2-amino-3-bromobenzonitrile (5.0 g, 25.38 mmol) was dissolved in ethanol, and potassium hydroxide (7.12 g, 126.88 mmol) was added, and the resulting reaction solution was refluxed at 80°C for 2 hours. After the reaction was completed, ethanol was removed by rotary evaporation, and the remaining material was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 1-2 (2.94 g) as a white solid, in a yield of 53.9%.

[0066] Preparation of compound 1 : 8-bromo-2-(4-hydroxyphenyl)quinazolin-4(3H)-one:

[0067] Intermediate 1-2 (2.94 g, 13.67 mmol), 4-hydroxybenzaldehyde (1.84 g, 15.04 mmol) and anhydrous copper chloride (5.51 g, 41.01 mmol) were dissolved in 30 mL of ethanol and the resulting reaction was refluxed at 80 °C for 12 hours. After the completion of the reaction, the precipitate was collected by filtration and dried to obtain a red solid (2.97 g), yield: 68.5%. The specific identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.18 (s, 1H), 8.06 (dd, J = 24.9, 6.3 Hz, 4H), 7.28 (s, 1H), 6.85 (d, J = 7.5 Hz, 2H).

[0068] 13 C NMR (101 MHz, DMSO-d6) δ 162.3, 161.3, 153.0, 146.7, 138.3, 130.2, 127.1, 126.1, 123.2, 122.5, 122.2, 115.8.

[0069] LC-MS m / z: [M+H] + Calcd for C 14 H9BrN2O2: 316.9847, Found: 316.8989. HPLC purity: 95.6% (tR= 16.82 min).

[0070] Preparation of compound 2: (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8- yl)acrylic acid:

[0071] Compound 1 (1.0 g, 3.15 mmol), methyl acrylate (325.75 mg, 3.78 mmol), palladium acetate (70.79 mg, 0.32 mmol), triphenylphosphine (248.11 mg, 0.95 mmol) and triethylamine (1.31 mL, 9.46 mmol) were dissolved in N,N-dimethylformamide and the reaction was carried out at 110 °C under nitrogen for 12 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography using dichloromethane / methanol (40:1) to obtain the target intermediate. The obtained intermediate was dissolved in methanol and saturated aqueous sodium hydroxide solution was added and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, methanol was removed under reduced pressure, 3M HC1 was added to adjust the pH of the solution to 4, the precipitate was collected by filtration and dried to obtain off-white solid 2 in 70.4% yield. Specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.43 (s, 1H), 8.60 (d, J = 16.3 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 16.3 Hz, 1H).

[0072] 13 C NMR (101 MHz, DMSO-d6) δ 168.1, 162.5, 161.4, 152.5, 147.4, 139.3, 132.8, 131.0, 130.0, 128.3, 126.1, 123.5, 121.6, 121.1, 116.0.

[0073] LC-MS m / z: [M+H] + Calculated C 17 H 12 N2O4: 309.0797, found: 308.9714. HPLC purity: 95.9% (tR= 14.30 min).

[0074] Compound 3: Preparation of (E)-4-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)but-3-enoic acid:

[0075] Referring to the preparation method of Compound 2, methyl butenoate was used instead of methyl acrylate to prepare an off-white solid. Specific identification results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.35 (s, 1H), 10.17 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 16.3 Hz, 2H), 7.43 (t, J = 7.7 Hz, 1H), 6.92 (dd, J = 8.3, 5.0 Hz, 2H), 3.35 (s, 2H).

[0076] LC-MS m / z: [M-H] calculated for C 18 H 14 N2O4: 321.0797, found: 321.0802. HPLC purity: 97.3% (tR= 14.33 min).

[0077] Compound 4: Preparation of (E)-2-(3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)allyl)malonic acid:

[0078] Following the procedure for the preparation of Reference Compound 2, using allyl malonic acid diethyl ester instead of methyl acrylate, gave a off-white solid. Specific identification results were: 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.25 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 8.12 (dd, J = 7.9, 3.7 Hz, 2H), 7.74 (t, J = 9.3 Hz, 1H), 7.55 (s, 1H), 7.35 (q, J = 7.5, 7.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H).

[0079] LC-MS m / z: [M-H] - calculated for C 20 H 16 N2O6: 379.1008, found: 379.1014. HPLC purity: 97.9% (tR= 16.69 min).

[0080] Example 2

[0081] Compound 6: Preparation of (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide:

[0082] Compound 1 (1.0 g, 3.15 mmol), N-isopropylacrylamide (428.17 mg, 3.78 mmol), palladium acetate (70.79 mg, 0.32 mmol) and triphenylphosphine (248.11 mg, 0.95 mmol) were dissolved in N,N-dimethylformamide, triethylamine (1.31 mL, 9.46 mmol) was added, and the reaction solution was reacted at 110°C under nitrogen protection for 12 h. After the reaction was completed, ethyl acetate was added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography with dichloromethane / methanol (10:1) to obtain compound 6 as an off-white solid in a yield of 43.5%. The specific identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 16.0 Hz, 1H), 8.14 (dd, J = 8.5, 3.4 Hz, 3H), 8.09 (d, J = 7.6 Hz, 1H), 8.04 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.76 (d, J = 16.1 Hz, 1H), 4.00 (dt, J = 13.6, 6.8 Hz, 1H), 1.14 (d, J = 6.5 Hz, 6H).

[0083] 13 C NMR (101 MHz, DMSO-d6) δ 164.5, 162.6, 161.2, 152.1, 147.2, 134.1, 132.1, 131.4, 130.1, 127.3, 126.1, 124.2, 123.6, 121.6, 115.9, 41.0, 22.9.

[0084] LC-MS m / z: [M+H] + Calcd for C 20 H 19 N3O3: 350.1426, found: 350.0724. HPLC purity: 98.8% (tR= 15.11 min).

[0085] Compound 5: Preparation of (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-N,N-dimethylacrylamide:

[0086] Referring to the preparation method of compound 6, N,N-dimethylacrylamide was used instead of N-isopropylacrylamide to prepare an off-white solid. The specific identification results were as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.29 (s, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.14 (t, J = 7.3 Hz, 3H), 7.53 - 7.42 (m, 2H), 7.00 - 6.88 (m, 2H), 3.20 (s, 3H), 2.97 (s, 3H). LC-MS m / z: [M-H] - Calculated C 19 H 17 N3O3: 334.1270, found: 334.1459. HPLC purity: 96.7% (tR= 14.31 min).

[0087] Example 3

[0088] Example 3

[0089] Compound 2 (60 mg, 0.19 mmol) and ethanolamine (14.27 mg, 0.23 mmol) were dissolved in N,N-dimethylformamide, to the reaction solution was added triethylamine (59.08 mg, 0.58 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (41.04 mg, 0.21 mmol) and l-hydroxybenzotriazole (HOBT) (28.93 mg, 0.21 mmol). The resulting reaction solution was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography with dichloromethane / methanol (30: 1) to obtain compound 8 as a white solid at a yield of 50.2%. The specific identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.29 (s, 1H), 8.46 (d, J = 15.7 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.14 (t, J = 7.3 Hz, 3H), 7.53 - 7.42 (m, 2H), 7.00 - 6.88 (m, 2H), 3.20 (s, 3H), 2.97 (s, 3H). LC-MS m / z: [M-H]

[0090] 13C NMR (101 MHz, DMSO-d6) δ 165.7, 162.7, 161.2, 152.1, 147.2, 134.3, 132.0, 131.6, 130.1, 127.4, 126.1, 124.0, 123.6, 121.6, 115.9, 60.3, 42.1.

[0091] LC-MS m / z: [M+H]+calcd for C26H22N5O4: 463.1709, found: 463.1710. + Calcd for C26H22N5O4: 463.1709, found: 463.1710. 19 H 17 N3O4: 352.1219, found: 352.0442. HPLC purity: 97.4% (tR= 12.04 min).

[0092] Compound 7: Preparation of (E)-N-(2-(dimethylamino)ethyl)-3-(2-(4- hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)acrylamide:

[0093] Compound 7 was synthesized referring to compound 8, using N,N- dimethylethylenediamine instead of ethanolamine. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 16.0 Hz, 1H), 8.16 (dd, J = 12.4, 7.0 Hz, 4H), 8.08 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 16.0 Hz, 1H), 3.35 (s, 2H), 2.46 (t, J = 6.6 Hz, 2H), 2.25 (s, 6H).

[0094] 13 C NMR (101 MHz, DMSO-d6) δ 165.7, 162.7, 161.2, 152.1, 147.2, 134.3, 132.0, 131.6, 130.1, 127.4, 126.1, 124.0, 123.6, 121.6, 115.9, 60.3, 42.1.

[0095] LC-MS m / z: [M+H]+calcd for C26H22N5O4: 463.1709, found: 463.1710. + Calcd for C26H22N5O4: 463.1709, found: 463.1710. 21 H 22 N4O3: 379.1692, found: 379.0909. HPLC purity: 97.4% (tR= 10.44 min).

[0096] Compound 9: (E)-N-cyclopropyl-3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide:

[0097] Compound 9 was synthesized as per compound 8, with cyclopropylamine as the reactant instead of ethanolamine. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.32 (s, 1H), 8.47 (d, J = 15.9 Hz, 1H), 8.42 - 8.30 (m, 1H), 8.14 (d, J = 8.2 Hz, 3H), 8.05 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 6.95 (d, J = 8.3 Hz, 2H), 6.72 (d, J = 16.0 Hz, 1H), 2.80 (s, 1H), 0.70 (d, J = 6.9 Hz, 2H), 0.50 (s, 2H).

[0098] 13 C NMR (101 MHz, DMSO-d6) δ 166.7, 162.6, 161.2, 152.1, 147.2, 134.3, 132.0, 131.6, 130.1, 127.4, 126.1, 123.7, 123.6, 121.6, 115.9, 29.4, 23.0, 6.3.

[0099] LC-MS m / z: [M+H] + Calculated C 20 H 17 N3O3: 348.1270, found: 348.0491. HPLC purity: 97.2% (tR= 14.39 min).

[0100] Compound 10: (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)-N- (tetrahydro-2H-pyran-4-yl)acrylamide:

[0101] Compound 10 was synthesized as per compound 8, with 4-aminotetrahydropyran as the reactant instead of ethanolamine. The specific identification results are: 1H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.26 (s, 1H), 8.49 (d, J = 16.0 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 8.2 Hz, 3H), 8.06 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 16.0 Hz, 1H), 3.98 - 3.80 (m, 4H), 3.43 (s, 1H), 1.84 - 1.76 (m, 2H), 1.47 (dt, J = 11.6, 5.8 Hz, 2H).

[0102] 13 C NMR (101 MHz, DMSO-d6) δ 164.7, 162.6, 161.2, 152.1, 147.2, 134.4, 132.0, 131.5, 130.1, 127.4, 126.1, 124.0, 123.6, 121.6, 115.9, 66.3, 45.6, 32.9.

[0103] LC-MS m / z: [M+H] + Calculated C 22 H 21 N3O4: 392.1532, found: 392.0806. HPLC purity: 96.5% (tR= 14.16 min).

[0104] Compound 11: Preparation of (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopentylacrylamide:

[0105] Compound 11 was synthesized referring to Compound 8, with isopentylamine instead of ethanolamine. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 10.26 (s, 1H), 8.49 (d, J = 16.0 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.14 (d, J = 8.2 Hz, 3H), 8.06 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 16.0 Hz, 1H), 3.98 - 3.80 (m, 4H), 3.43 (s, 1H), 1.84 - 1.76 (m, 2H), 1.47 (dt, J = 11.6, 5.8 Hz, 2H).

[0106] 13 C NMR (101 MHz, DMSO-d6) δ 165.4, 162.7, 161.2, 152.1, 147.2, 134.2, 132.0, 131.6, 130.1, 127.4, 126.1, 124.1, 123.6, 121.6, 115.9, 38.5, 37.4, 25.6, 22.8.

[0107] LC-MS m / z: [M+H]+calcd for C26H21N4O4: 451.1569, found: 451.1567. + Calculated C 22 H 23 N3O3: 378.1739, found: 378.1011. HPLC purity: 96.8% (tR= 17.20 min).

[0108] Preparation of compound 12: (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-(4-isopropylbenzyl)acrylamide:

[0109] Compound 12 was synthesized referring to compound 8, with 4-isopropylbenzylamine as the reactant instead of ethanolamine. The specific identification results are as follows:

[0110] 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 10.28 (s, 1H), 8.68 (t, J = 5.9 Hz, 1H), 8.53 (d, J = 16.0 Hz, 1H), 8.15 (d, J = 8.3 Hz, 3H), 8.08 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.22 (q, J = 7.9 Hz, 4H), 6.95 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 15.9 Hz, 1H), 4.40 (d, J = 5.8 Hz, 2H), 2.85 (hept, J = 6.9 Hz, 1H), 1.18 (d, J = 6.9 Hz, 6H).

[0111] 13 C NMR (101 MHz, DMSO-d6) δ 165.5, 162.6, 161.2, 152.2, 147.5, 147.2, 137.2, 134.7, 132.0, 131.7, 130.1, 127.9, 127.5, 126.6, 126.1, 123.8, 123.6, 121.6, 115.9, 42.6, 33.5, 24.3.

[0112] LC-MS m / z: [M+H]+calcd for C26H21N4O4: 451.1569, found: 451.1567. + Calculated C 27 H25 N3O3: 440.1896, found: 440.1061. HPLC purity: 98.4% (tR= 18.80 min).

[0113] Compound 13: (E)-N-(1,3-dihydroxy-2-methylpropan-2-yl)-3-(2-(4- hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)acrylamide:

[0114] Compound 13 was synthesized as for Compound 8, using 2-amino-2-methyl-1,3- propanediol instead of ethanolamine. The specific identification results were:

[0115] 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 10.31 (s, 1H), 8.46 (d, J = 15.9 Hz, 1H), 8.19 - 8.10 (m, 3H), 8.08 (d, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.00 - 6.88 (m, 3H), 4.93 (t, J = 5.7 Hz, 2H), 3.57 (dd, J = 12.7, 5.2 Hz, 4H), 1.23 (s, 3H).

[0116] LC-MS m / z: [M - H] - Calculated C 21 H 21 N3O5: 394.1481, found: 394.1663. HPLC purity: 95.5% (tR= 12.78 min).

[0117] Compound 14: (E)-8-(3-(3,3-dimethylazetidin-1-yl)-3-oxoprop-1-en-1-yl)-2-(4- hydroxyphenyl)quinazolin-4(3H)-one:

[0118] Compound 14 was synthesized as for Compound 8, using 3,3-dimethylazetidine hydrochloride instead of ethanolamine. The specific identification results were: 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.33 (s, 1H), 8.38 (d, J = 15.9 Hz, 1H), 8.20 (d, J = 7.6 Hz, 1H), 8.13 (t, J = 7.4 Hz, 3H), 7.47 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 15.9 Hz, 1H), 6.93 (d, J = 8.4 Hz, 2H), 4.00 (s, 2H), 3.66 (s, 2H), 1.27 (s, 6H).

[0119] 13 C NMR (101 MHz, DMSO-d6) δ 166.0, 162.6, 161.2, 152.3, 147.4, 135.7, 133.1, 131.7, 130.1, 127.6, 126.0, 123.6, 121.5, 119.4, 115.9, 62.2, 60.1, 30.9, 27.0.

[0120] LC-MS m / z: [M+H]+calcd for C 22 H 21 N3O3: 376.1583, found: 376.0779. HPLC purity: 97.9% (tR= 16.65 min).

[0121] Preparation of compound 15: (E)-8-(3-(3-hydroxy-3-methylazetidin-l-yl)-3-oxoprop-l-en-l-yl)-2-(4-hydroxyphenyl)quinazolin-4(3H)-one:

[0122] Compound 15 was synthesized referring to compound 8, with 3-methyl-3-azetidinol hydrochloride instead of ethanolamine. The specific identification results are:

[0123] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.31 (s, 1H), 8.38 (d, J = 15.9 Hz, 1H), 8.23 (d, J = 7.6 Hz, 1H), 8.13 (t, J = 8.6 Hz, 3H), 7.48 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 15.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.78 (s, 1H), 4.25 - 4.08 (m, 2H), 3.85 (t, J = 7.5 Hz, 2H), 1.42 (s, 3H).

[0124] 13 C NMR (101 MHz, DMSO-d6) δ 166.0, 162.6, 161.2, 152.3, 147.4, 135.9, 133.2, 131.6, 130.1, 127.7, 126.0, 123.6, 121.6, 119.7, 115.9, 67.3, 64.5, 62.3, 26.7.

[0125] LC-MS m / z: [M+H]+calcd for C 22 H 19N3O4: 378.1376, found: 378.0694. HPLC purity: 97.4% (tR= 13.64 min).

[0126] Compound 16: Preparation of (E)-N-(4-hydroxyphenyl)-3-(2-(4- hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-8-yl)acrylamide:

[0127] Compound 16 was synthesized as for Compound 8, using 4- aminophenol instead of ethanolamine. The specific identification results were:

[0128] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.24 (s, 1H), 10.06 (s, 1H), 9.25 (s, 1H), 8.60 (d, J = 15.9 Hz, 1H), 8.27 - 8.08 (m, 4H), 7.60 - 7.46 (m, 3H), 7.03 - 6.92 (m, 3H), 6.75 (d, J = 8.4 Hz, 2H).

[0129] LC-MS m / z: [M - H]~calcd for C 23 H 17 N3O4: 398.1219, found: 398.1623. HPLC purity: 95.7% (tR= 14.78 min).

[0130] Compound 17: Preparation of (E)-3-(2-(4-hydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide:

[0131] Compound 17 was synthesized as for Compound 8, using O-(tetrahydro- 2H-pyran-2-yl)hydroxylamine instead of ethanolamine, to give a white solid. Yield: 55.8%. The specific identification results were: 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 11.39 (s, 1H), 10.28 (s, 1H), 8.54 (dd, J = 17.0, 10.3 Hz, 1H), 8.14 (dq, J = 19.0, 11.7, 9.1 Hz, 4H), 7.50 (dt, J = 12.6, 7.7 Hz, 1H), 6.96 (t, J = 6.2 Hz, 2H), 6.73 (t, J = 13.3 Hz, 1H), 4.97 (d, J = 9.7 Hz, 1H), 4.00 (d, J = 10.5 Hz, 1H), 3.57 (d, J = 10.8 Hz, 1H), 1.72 (d, J = 9.9 Hz, 3H), 1.55 (d, J = 10.1 Hz, 3H).

[0132] 13 C NMR (101 MHz, DMSO-d6) δ 162.6, 161.2, 152.3, 147.3, 135.3, 131.9, 131.6, 130.1, 127.7, 126.1, 123.5, 121.6, 120.4, 115.9, 101.5, 61.9, 28.2, 25.1, 18.7.

[0133] LC-MS m / z: [M+H]+calcd for C 22 H 21 N3O5: 408.1481, found: 408.0677. HPLC purity: 95.1% (tR= 15.28 min).

[0134] Preparation of compound 18: (E)-2-(4-hydroxyphenyl)-8-(3-(4- hydroxypiperidin-l-yl)-3-oxoprop-l-en-l-yl)quinazolin-4(3H)-one:

[0135] Compound 18 was synthesized referring to compound 8, with 4- hydroxypiperidine replacing ethanolamine. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.27 (s, 1H), 8.46 (d, J = 15.6 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 8.14 (t, J = 6.9 Hz, 3H), 7.57 - 7.46 (m, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.79 (d, J = 4.1 Hz, 1H), 4.04 (d, J = 13.3 Hz, 2H), 3.81 - 3.71 (m, 1H), 3.17 (s, 2H), 1.80 (s, 2H), 1.39 - 1.32 (m, 2H).

[0136] LC-MS m / z: [M+H]+calcd for C 22 H 21 N3O4: 392.1532, found: 392.0826. HPLC purity: 96.1% (tR= 13.45 min).

[0137] Preparation of compound 19: (E)-8-(3-(3-hydroxyazetidin-l-yl)-3-oxoprop-l-en-l- yl)-2-(4-hydroxyphenyl)quinazolin-4(3H)-one:

[0138] Compound 19 was synthesized referring to compound 8, with azetidin-3-ol instead of ethanolamine. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.29 (s, 1H), 8.38 (d, J = 15.7 Hz, 1H), 8.23 (d, J = 7.5 Hz, 1H), 8.14 (t, J = 8.1 Hz, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 15.9 Hz, 1H), 6.94 (d, J = 8.3 Hz, 2H), 5.92 - 5.71 (m, 1H), 4.53 (d, J = 5.7 Hz, 2H), 4.18 (dd, J = 11.3, 5.8 Hz, 1H), 4.05 (q, J = 7.5 Hz, 1H), 3.08 (q, J = 7.3 Hz, 1H).

[0139] 13 C NMR (101 MHz, DMSO-d6) δ 165.8, 162.6, 161.3, 152.3, 147.4, 135.8, 133.2, 131.7, 130.1, 127.6, 126.0, 123.6, 121.6, 119.6, 115.9, 60.4, 60.2, 58.0.

[0140] LC-MS m / z: [M-H]"calcd for C 20 H 17 N3O4: 362.1219, found: 362.1248. HPLC purity: 95.7% (tR= 12.65 min).

[0141] Preparation of compound 20: (E)-8-(3-(4-(hydroxymethyl)piperidin-l-yl)-3-oxoprop-l-en-l- yl)-2-(4-hydroxyphenyl)quinazolin-4(3H)-one:

[0142] Compound 20 was synthesized referring to compound 8, with 4-hydroxymethylpiperidine instead of ethanolamine. The specific identification results are:1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.25 (s, 1H), 8.46 (d, J = 15.6 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.20 - 8.08 (m, 3H), 7.59 - 7.42 (m, 2H), 6.94 (d, J = 8.3 Hz, 2H), 4.66 - 4.48 (m, 2H), 4.45 - 4.24 (m, 1H), 3.29 (t, J = 5.5 Hz, 2H), 3.09 (d, J = 13.3 Hz, 1H), 2.67 (t, J = 12.7 Hz, 1H), 1.76 (d, J = 11.9 Hz, 2H), 1.69 - 1.61 (m, 1H), 1.16 - 1.02 (m, 2H).

[0143] 13 C NMR (101 MHz, DMSO-d6) δ 164.9, 162.6, 161.2, 152.1, 147.2, 136.8, 132.9, 132.1, 130.1, 127.4, 125.9, 123.7, 121.6, 120.7, 115.9, 65.9, 45.6, 38.9, 28.9.

[0144] LC-MS m / z: [M+H]+calcd for C 23 H 23 N3O4: 406.1689, found: 406.0894. HPLC purity: 99.3% (tR= 14.15 min).

[0145] Example 4

[0146] Preparation of intermediate compound VI: 8-bromo-2-(naphthalen-2-yl)quinazolin-4(3H)-one

[0147] Intermediate 1-2 (0.5 g, 2.33 mmol), 2-naphthaldehyde (0.40 g, 2.56 mmol) and anhydrous copper chloride (0.94 g, 6.98 mmol) were dissolved in 30 mL of ethanol, and the resulting reaction solution was refluxed at 80 °C for 12 hours. After the reaction was completed, the precipitate was collected by filtration and dried to obtain a white solid (0.18 g), yield: 22.0%.

[0148] Preparation of compound 21: (E)-N-isopropyl-3-(2-(naphthalen-2-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide:

[0149] Intermediate VI (50.0 mg, 0.14 mmol), N-isopropylacrylamide (19.3 mg, 0.17 mmol), palladium acetate (3.2 mg, 0.01 mmol) and triphenylphosphine (11.2 mg, 0.04 mmol) were dissolved in N,N-dimethylformamide, triethylamine (0.06 mL, 0.43 mmol) was added, and the reaction solution was reacted at 110°C for 12 hours under nitrogen atmosphere. After the reaction was completed, ethyl acetate was added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane / methanol (50:1) to obtain Compound 21 as an off-white solid in a yield of 55.7%. The specific identification results were as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.85 (s, 1H), 8.53 (d, J = 16.1 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.14 (dd, J = 37.2, 27.5 Hz, 6H), 7.63 (d, J = 33.0 Hz, 3H), 6.82 (d, J = 16.1 Hz, 1H), 4.01 (s, 1H), 1.15 (d, J = 6.7 Hz, 6H).

[0150] Preparation of intermediate Compound VII: (E)-ethyl 3-(2-(naphthalen-2-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)acrylate

[0151] Intermediate VI (130.0 mg, 0.37 mmol), ethyl acrylate (48.3 μL, 0.44 mmol), palladium acetate (8.31 mg, 0.04 mmol) and triphenylphosphine (29.13 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide, triethylamine (0.15 mL, 1.11 mmol) was added, and the reaction solution was reacted at 110°C for 12 hours under nitrogen atmosphere. After the reaction was completed, ethyl acetate was added for extraction. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane / methanol (50:1) to obtain intermediate VII as a white solid in a yield of 60.8%.

[0152] Preparation of intermediate Compound VIII: (E)-3-(2-(naphthalen-2-yl)-4-oxo-3,4-dihydroquinazolin-8-yl)acrylic acid

[0153] Intermediate VII was dissolved in methanol, saturated sodium hydroxide aqueous solution was added, and the resulting reaction solution was reacted at 60°C for 2 hours. After the reaction was completed, methanol was evaporated, the remaining material was adjusted to pH 4 using 3M hydrochloric acid aqueous solution, and suction filtration was performed to obtain the corresponding carboxylic acid intermediate VIII.

[0154] Preparation of compound 22: (E)-N-cyclopropyl-3-(2-(naphthalen-2-yl)-4-oxo- 3,4-dihydroquinazolin-8-yl)acrylamide

[0155] Compound 22 was synthesized according to compound 8, using intermediate VIII and cyclopropylamine instead of compound 2 and ethanolamine, respectively. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.56 (t, J = 18.3 Hz, 1H), 8.36 (d, J = 9.9 Hz, 1H), 8.26 - 8.17 (m, 2H), 8.15 - 8.00 (m, 4H), 7.66 (s, 2H), 7.60 - 7.51 (m, 1H), 6.77 (d, J = 15.6 Hz, 1H), 2.82 (s, 1H), 0.71 (s, 2H), 0.51 (s, 2H).

[0156] Preparation of compound 23: (E)-N-isopropyl-3-(2-(naphthalen-1-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide

[0157] Compound 23 was synthesized according to compound 21, using 1-naphthaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.32 (d, J = 16.3 Hz, 1H), 8.23 (t, J = 9.2 Hz, 2H), 8.19 - 8.05 (m, 3H), 8.01 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.62 (s, 3H), 6.73 (d, J = 15.9 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 1.08 (d, J = 6.5 Hz, 6H).

[0158] Preparation of compound 24: (E)-N-isopropyl-3-(2-(4-methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide

[0159] Compound 24 was synthesized according to compound 21, using p-methoxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.49 (d, J = 16.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H), 8.12 (dt, J = 34.0, 7.5 Hz, 3H), 7.53 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 16.2 Hz, 1H), 4.06 - 3.95 (m, 1H), 3.87 (s, 3H), 1.14 (d, J = 6.4 Hz, 6H).

[0160] Preparation of compound 25: (E)-N-cyclopropyl-3-(2-(4-methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide

[0161] Compound 25 was synthesized according to compound 22, using p-methoxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.48 (s, 1H), 8.21 (d, J = 46.2 Hz, 4H), 7.84 - 7.67 (m, 1H), 7.54 (s, 2H), 7.25 - 7.10 (m, 1H), 6.72 (s, 1H), 3.87 (s, 3H), 2.80 (s, 1H), 0.70 (s, 2H), 0.49 (s, 2H).

[0162] Preparation of compound 26: (E)-N-isopropyl-3-(4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)acrylamide

[0163] Compound 26 was synthesized according to compound 21, using benzaldehyde instead of 2-naphthaldehyde. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (d, J = 20.0 Hz, 1H), 8.45 (d, J = 18.1 Hz, 1H), 8.31 - 7.98 (m, 5H), 7.72 - 7.44 (m, 4H), 6.77 (t, J = 16.3 Hz, 1H), 3.99 (s, 1H), 1.14 (d, J = 16.0 Hz, 6H).

[0164] Preparation of compound 27: (E)-N-cyclopropyl-3-(4-oxo-2-phenyl-3,4-dihydroquinazolin-8- yl)acrylamide

[0165] Compound 27 was synthesized according to compound 22, using benzaldehyde instead of 2-naphthaldehyde. The specific identification results are: 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.48 (d, J = 16.3 Hz, 1H), 8.25 (t, J = 23.7 Hz, 4H), 8.08 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 26.1 Hz, 4H), 6.74 (d, J = 16.1 Hz, 1H), 2.81 (s, 1H), 0.71 (s, 2H), 0.50 (s, 2H).

[0166] Preparation of compound 28: (E)-N-isopropyl-3-(4-oxo-2-(pyridin-3-yl)-3,4- dihydroquinazolin-8-yl)acrylamide

[0167] Compound 28 was synthesized according to compound 21, using 2-pyridinecarboxaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.48 (d, J = 16.3 Hz, 1H), 8.25 (t, J = 23.7 Hz, 4H), 8.08 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 26.1 Hz, 4H), 6.74 (d, J = 16.1 Hz, 1H), 2.81 (s, 1H), 0.71 (s, 2H), 0.50 (s, 2H).

[0168] Preparation of compound 29: (E)-3-(2-(2,3-dihydrobenzo[b][l,4]dioxan-6-yl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0169] Compound 29 was synthesized according to compound 21, using 1,4-benzo[d]ioxan-6- carboxaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.48 (d, J = 16.3 Hz, 1H), 8.25 (t, J = 23.7 Hz, 4H), 8.08 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 26.1 Hz, 4H), 6.74 (d, J = 16.1 Hz, 1H), 2.81 (s, 1H), 0.71 (s, 2H), 0.50 (s, 2H).

[0170] Preparation of compound 30: (E)-N-cyclopropyl-3-(2-(2,3-dihydrobenzo[b][l,4]dioxan-6-yl)- 4-oxo-3,4-dihydroquinazolin-8-yl)acrylamide

[0171] Compound 30 was synthesized according to compound 22, using 1,4-benzo- dioxan-6-carboxaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.48 (d, J = 16.0 Hz, 1H), 8.31 (s, 1H), 8.10 (dd, J = 37.1, 7.7 Hz, 2H), 7.82 (d, J = 11.9 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 4.34 (d, J = 4.5 Hz, 4H), 2.80 (td, J = 7.2, 3.6 Hz, 1H), 0.70 (t, J = 6.3 Hz, 2H), 0.55 - 0.45 (m, 2H).

[0172] Compound 31: Preparation of (E)-N-isopropyl-3-(4-oxo-2-(quinolin-4-yl)-3,4- dihydroquinazolin-8-yl)acrylamide

[0173] Compound 31 was synthesized according to compound 21, using 4-quinoline carboxaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.48 (d, J = 16.0 Hz, 1H), 8.31 (s, 1H), 8.10 (dd, J = 37.1, 7.7 Hz, 2H), 7.82 (d, J = 11.9 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 4.34 (d, J = 4.5 Hz, 4H), 2.80 (td, J = 7.2, 3.6 Hz, 1H), 0.70 (t, J = 6.3 Hz, 2H), 0.55 - 0.45 (m, 2H).

[0174] Compound 32: Preparation of (E)-3-(2-(4-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0175] Compound 32 was synthesized according to compound 21, using 4-fluorobenzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.46 (d, J = 16.0 Hz, 1H), 8.30 (t, J = 6.9 Hz, 2H), 8.21 - 8.01 (m, 3H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8.5 Hz, 2H), 6.78 (d, J = 16.0 Hz, 1H), 3.99 (dd, J = 13.6, 7.1 Hz, 1H), 1.14 (d, J = 6.6 Hz, 6H).

[0176] Preparation of compound 33: (E)-N-cyclopropyl-3-(2-(4-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)acrylamide

[0177] Compound 33 was synthesized referring to compound 22, with 4-fluorobenzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.46 (d, J = 16.0 Hz, 1H), 8.30 (t, J = 6.9 Hz, 2H), 8.21 - 8.01 (m, 3H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8.5 Hz, 2H), 6.78 (d, J = 16.0 Hz, 1H), 3.99 (dd, J = 13.6, 7.1 Hz, 1H), 1.14 (d, J = 6.6 Hz, 6H).

[0178] Preparation of compound 34: (E)-3-(2-(2-chloro-6-fluorophenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0179] Compound 34 was synthesized referring to compound 21, with 2-chloro-6-fluoro- benzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.46 (d, J = 16.0 Hz, 1H), 8.30 (t, J = 6.9 Hz, 2H), 8.21 - 8.01 (m, 3H), 7.56 (t, J = 7.8 Hz, 1H), 7.45 (t, J = 8.5 Hz, 2H), 6.78 (d, J = 16.0 Hz, 1H), 3.99 (dd, J = 13.6, 7.1 Hz, 1H), 1.14 (d, J = 6.6 Hz, 6H).

[0180] Preparation of compound 35: (E)-3-(2-(4-hydroxy-3-methoxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0181] Compound 35 was synthesized according to compound 21, using vanillin instead of 2- naphthaldehyde. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 9.92 (s, 1H), 8.43 (d, J = 16.1 Hz, 1H), 8.15 (t, J = 8.8 Hz, 2H), 8.05 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 2.1 Hz, 1H), 7.82 (dd, J = 8.3, 2.1 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.84 (d, J = 16.1 Hz, 1H), 4.02 - 3.97 (m, 1H), 3.91 (s, 3H), 1.13 (d, J = 6.5 Hz, 6H).

[0182] Preparation of compound 36: (E)-3-(2-(2,4-dihydroxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0183] Compound 36 was synthesized according to compound 21, using 2,4-dihydroxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.31 - 8.00 (m, 5H), 7.52 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 15.9 Hz, 1H), 6.41 (s, 1H), 3.99 (d, J = 7.1 Hz, 1H), 1.14 (d, J = 6.4 Hz, 6H).

[0184] Preparation of compound 37: (E)-3-(2-(3,5-dimethoxyphenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)-N-isopropylacrylamide

[0185] Compound 37 was synthesized according to compound 21, using 3,5-dimethoxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are: 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (t, J = 13.5 Hz, 1H), 8.02 (d, J = 57.9 Hz, 3H), 7.79 - 7.34 (m, 3H), 6.91 - 6.63 (m, 1H), 4.00 (s, 1H), 3.85 (s, 6H), 1.13 (s, 6H).

[0186] Preparation of compound 38: (E)-N-cyclopropyl-3-(2-(3,5-dimethoxyphenyl)-4-oxo- 3,4-dihydroquinazolin-8-yl)acrylamide

[0187] Compound 38 was synthesized referring to compound 22 with 3,5-dimethoxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.46 (d, J = 16.0 Hz, 1H), 8.31 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 2.2 Hz, 2H), 6.75 (dd, J = 9.2, 6.7 Hz, 2H), 3.87 (s, 6H), 2.80 (tq, J = 7.8, 4.1 Hz, 1H), 0.70 (dt, J = 7.3, 3.6 Hz, 2H), 0.55 - 0.44 (m, 2H).

[0188] Preparation of compound 39: (E)-methyl 3-(8-(3-(isopropylamino)-3-oxoprop-1-en-1-yl)- 4-oxo-3,4-dihydroquinazolin-2-yl)benzoate

[0189] Compound 39 was synthesized referring to compound 21 with methyl 3-formylbenzoate instead of 2-naphthaldehyde. The specific identification results are as follows: 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 8.80 (s, 1H), 8.50 - 8.42 (m, 2H), 8.19 (d, J = 7.9 Hz, 2H), 8.10 (dd, J = 7.7, 5.2 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H), 4.03 - 3.97 (m, 1H), 3.94 (s, 3H), 1.14 (d, J = 6.6 Hz, 6H).

[0190] Preparation of compound 40: (E)-N-isopropyl-3-(4-oxo-2-(3,4,5-trimethoxyphenyl)- 3,4-dihydroquinazolin-8-yl)acrylamide

[0191] Compound 40 was synthesized referring to compound 21 with 3,4,5-trimethoxybenzaldehyde instead of 2-naphthaldehyde. The specific identification results are as follows: 1H NMR (400 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.37 (d, J = 16.1 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.66 (s, 2H), 7.54 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 16.1 Hz, 1H), 4.01 (dt, J = 13.7, 6.7 Hz, 1H), 3.93 (s, 6H), 3.77 (s, 3H), 1.12 (d, J = 6.6 Hz, 6H).

[0192] Example 5 In vitro inhibition of GLUT9 activity of compounds

[0193] The in vitro inhibition of GLUT9 activity of the compounds of the present application was demonstrated using the following method. These effects show that the compounds of the present application can effectively inhibit GLUT9 activity. The specific testing method is as follows:

[0194] GLUT9 plasmid (Mirus Bio, Cat No. P16767) was transfected into human embryonic kidney cells HEK293 cells (Shanghai PrimoSue, Cat No. CL-0001), and the cells in better condition were selected under the inverted microscope of the patch clamp. The electrode was mounted on the electrode holder, a certain positive pressure was given, and then it was moved into the liquid surface. It was observed that the entry resistance was about 3-5 MΩ, which was better. The liquid junction potential compensation was carried out. The electrode tip was slowly moved close to the top of the selected cell under direct vision using a micro manipulator. When the cell was contacted, the resistance increased by about 0.2-0.4 MΩ. The positive pressure was stopped and a negative pressure was given. After the electrode and the HEK293 cell membrane overexpressing GLUT9 formed a “giga seal”, fast capacitance compensation was carried out. Then a short and powerful negative pressure was applied to break the membrane, and slow capacitance compensation was carried out. The whole cell transient charging current was adjusted to 0 position using the control key of the clamping amplifier.

[0195] In this experiment, the patch clamp whole cell mode was used to record the current change. A suitable sample prepared with extracellular fluid was added gently above the cell using a perfusion system, a working voltage was given, and the current change was recorded. The experiment was repeated 3 times, and the current curve was plotted using clampfit and origin. The drug inhibition rate was calculated according to the formula (1- current density after drug administration / original current density)*100%.

[0196] Experimental results: The test results of compounds 1-20 are shown in Figure 1, and the test results of compounds 21-40 are shown in Figure 2. All the compounds showed obvious GLUT9 inhibition at a concentration of 10 μM, far exceeding the existing marketed URAT1 inhibitors benzbromarone and lesinurad.

[0197] Example 6 Study on URAT1 Inhibition Activity of Compounds in Example 6

[0198] The human URAT1 plasmid (Wuhan Moli Biological Company, item number P23457) was transfected into HEK293 cells by transfection with liposome Lipo3000 (Shanghai Yingwei Jieji Company, item number L3000015) to make it overexpress, and then 1 x 10 5 cells were seeded at a density of 1 x 104cells / well into 96-well plates adhered by poly-D-lysine, and cell experiments were performed after 24 hours of culture. First, the cells were incubated with or without the uptake buffer containing the test compound for 30 minutes. Then, the uptake test was performed by adding 25 mM of 14 C-uric acid. After 15 minutes, the extracellular 14 C-uric acid was removed, and the cells were washed with ice-cold DPBS to terminate the reaction. The cells were lysed by adding 25 mL of 0.1M sodium hydroxide, followed by the addition of 0.1 mL of scintillation fluid (PerkinElmer, item number 6013321). The radioactivity of the intracellular 14 C-uric acid was determined using a liquid scintillation counter.

[0199] Experimental results: the test results of compounds 1-20 are shown in Figure 1, and the test results of compounds 21-40 are shown in Figure 2. The results show that the compounds have no obvious inhibition effect on URAT1 at 10 mM, indicating that these compounds have strong selectivity for GLUT9.

[0200] Example 7 Study on Uric Acid-lowering and Kidney Protection of Compounds in Example 7 in vivo

[0201] Experimental method: the experimental animals were male Kunming mice weighing 20±2g, and the blank control group, model group, drug administration group, and positive drug control group were set up, with 8 mice in each group. After the mice were adaptively fed for seven days, the experiment was started, and the mice were fasted the day before the experiment. Except for the blank control group, the mice in each group were subcutaneously injected with 350mg / kg of oxypurinol solution (solvent: 0.5% CMC-Na), and the blank control group was given the same volume of 0.5% CMC-Na. After 0.5 hours, the blank control group and the model group were given the same amount of solvent by gavage, and each drug administration group was given the corresponding drug and 600mg / kg of hypoxanthine by gavage. The compounds were given at a dose of 10mg / kg by gavage, and the positive controls benzbromarone and lesinurad were also 10mg / kg. After 3 hours of gavage of the drugs, the mice in each group were taken blood from the eye sockets, and the blood was centrifuged after standing for 30 minutes to obtain the serum, which was detected for blood uric acid, creatinine, and urea nitrogen levels using a kit. At the same time, the mice were placed in metabolic cages, and the urine collected over the next 12 hours was measured for uric acid levels.

[0202] The activity results are shown in Figure 3, and the data are shown as mean ± SD, n = 8. Compared with the blank group, ***P < 0.001; compared with the model group, #P < 0.05, ##P < 0.01. As can be seen from Figure 3, it is shown that at a dose of 10 mg / kg, compounds 6, 9 and 11 have obvious effects of reducing blood uric acid and promoting uric acid excretion. The detection results of renal function indexes such as blood creatinine and urea nitrogen show that the compounds have less damage to the kidney and are safer than the positive drugs benzbromarone and lesinurad.

[0203] Effect of the compound of Example 8 on the markers of kidney damage

[0204] The animal experiment method is the same as that of Example 7. After the mice were sacrificed by cervical dislocation, about 20 mg of kidney tissue was taken on ice, and the kidney RNA of each group of mice was extracted according to the RNA extraction kit instructions (Chengdu Fujian Biological, item number RE-030104). The reaction system was configured according to the reverse transcription reaction reagent (Japan Takara Company, item number RR047A) instructions, and the PCR reaction conditions were 37℃, 15 min; 85℃, 5 sec; 4℃, +∞. The RNA was reverse transcribed into cDNA. The reaction system was configured according to the qPCR reaction reagent instructions (Hunan Aikuerui Biological, item number AG11711), and after mixing, it was added to the qPCR 96-well plate. Real-time fluorescent quantitative PCR reaction was carried out in LC480, and the reaction conditions were set according to the instructions. The Ct value of gene amplification was obtained, the internal reference was selected as β-actin, and the relative expression amount of mRNA was calculated by 2 -ΔΔCt

[0205] The experimental results are shown in Figure 4. Compared with the blank group, the mRNA relative expression contents of Kim-1 and Ngal in the model group were significantly increased, indicating that the model group had acute kidney injury. Compared with the model group, the mRNA expression of Kim-1 and Ngal in compounds 6 and 9 was significantly reduced, the positive drugs allopurinol and lesinurad had no obvious improvement, and benzbromarone aggravated the kidney damage.

[0206] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples. Any changes, modifications, substitutions, combinations and simplifications made without departing from the spirit and principles of the present application shall be equivalent replacement modes and shall be within the scope of protection of the present application.​

Claims

A dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof, characterized in that, The structure is shown in formula (I): wherein R1is selected from aryl or heteroaryl, hydrogen, deuterium, halogen, cyano, hydroxyl, thiol, amino, C 1-8 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-6 alkyl ester, aryl ester, C 1-6 alkyl carbonyl, C 2-6 alkenyl carbonyl, and C 2-6 alkynyl carbonyl; wherein said aryl is unsubstituted or substituted with one or more substituents independently selected from hydroxyl, C 1-6 alkoxy, halogen, and C 1-6 alkyl ester; R2 and R3 are each independently selected from hydrogen, deuterium, halogens, and carbon. 1-8 Alkyl, C 1-6 Alkoxy, C 1-6 alkylthio, aryl or C 1-6 alkylsulfonyl, C 3-6 cycloalkyl, C 1-6 Alkyl ester group, aryl ester group, C 1-6 alkyl carbonyl, C 2-8 alkenyl carbonyl, C 2-8 Alkyne carbonyl and aryl, wherein the aryl group is unsubstituted or has one or more derivatives independently selected from hydroxyl, C 1-6 Alkoxy, halogen and C 1-6 Substitution of alkyl ester groups; R4and R5are each independently selected from the group consisting of hydrogen, halogen, C 2-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 1-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 1-6 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 3-6 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 2-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 1-6 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 1-6 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 2-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 2-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C 2-8 alkyl, deuterium, cyano, hydroxyl, thiol, amino, C R6and R7are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, heterocyclyl, heterocyclyloxy, C 1-6 alkylbenzyl, and aryl; wherein C 1-8 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, heterocyclyl, heterocyclyloxy, and C 1-6 alkylbenzyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-6 alkylamino, and hydroxyl; or R6, R7and the nitrogen atom to which they are attached collectively form a heterocyclyl group, wherein said heterocyclyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-6 alkyl, hydroxyC 1-6 alkyl and hydroxy. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1is selected from the group consisting of phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, benzodioxanyl, quinolinyl, and indolyl; wherein each instance of phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, pyrazinyl, pyrimidinyl, benzodioxanyl, quinolinyl, and indolyl is independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of hydroxy, C 1-4 alkoxy, halogen, and C 1-6 alkyl ester; R2 and R3 are each independently selected from hydrogen; R4and R5are each independently selected from the group consisting of hydrogen, halogen, and C 2-6 alkenyl; said C 2-6 alkenyl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of carboxyl and -CONR6R7; R6and R7are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyloxy, C 1-4 alkylbenzyl, and phenyl; wherein the C 1-4 alkyl, phenyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3- to 6-membered heterocyclyloxy, C 1-4 alkylbenzyl, and 3- to 6-membered heterocyclyl are each independently unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, methylamino, and hydroxyl; or R6, R7and the nitrogen atom to which they are attached collectively form a 3-6 membered heterocyclyl group, wherein said 3-6 membered heterocyclyl group is unsubstituted or substituted with one or more substituents independently selected from the group consisting of amino, C 1-4 alkyl, hydroxyC 1-4 alkyl and hydroxy. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R4 and R5 are each independently selected from hydrogen, F, Cl, Br, I, vinyl, propenyl, allyl, butenyl and pentenyl, wherein each of the vinyl, propenyl, allyl, butenyl and pentenyl is independently unsubstituted or substituted with one or more substituents independently selected from carboxyl and -CONR6R7; R6 and R7 are each independently selected from hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyloxy, pyrrolidinyloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, methoxybenzyloxy, ethoxybenzyloxy and phenyl; wherein each of the methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, tetrahydrofuranyloxy, pyrrolidinyloxy, tetrahydrothienyloxy, tetrahydropyranyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, methoxybenzyloxy and ethoxybenzyloxy is independently unsubstituted or substituted with one or more substituents independently selected from amino, methylamino and hydroxy; or R6, R7 and the nitrogen atom to which they are attached together form azetidinyl, piperidinyl, piperazinyl, morpholinyl or aziridinyl, wherein the azetidinyl, piperidinyl, piperazinyl, morpholinyl and aziridinyl are unsubstituted or substituted with one or more substituents independently selected from amino, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R1is selected from The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-4, wherein R4and R5are each independently selected from hydrogen, bromo, The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein selected from any one of the following structures: A pharmaceutical composition, characterized in that, comprising: (a) the dihydroquinazolinone compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, or a combination thereof; and (b) a pharmaceutically acceptable carrier and / or excipient. Use of the dihydroquinazolinone compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a GLUT9 inhibitor. Use of the dihydroquinazolinone compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for treating a disease associated with GLUT9 activity or expression, or in the manufacture of a medicament for lowering uric acid. Use of the dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for treating hyperuricemia, renal impairment, gout or a complication of gout. Optionally, the complication of gout is gouty arthritis or uric acid nephrolithiasis.

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