Thioether derivative and preparation method therefor and use thereof

Abstract

The present application discloses a thioether derivative and a preparation method therefor and a use thereof. The compound of the present application is a uric acid transporter inhibitor, and can effectively increase the excretion of uric acid in vivo. In some embodiments of the present application, compared with similar compounds, the compound of the present application has better safety and / or stronger activity.

Description

A thioether derivative and its preparation method and application Technical Field

[0001] The present invention relates to the field of medicine, and specifically relates to a thioether derivative, as well as a preparation method and application thereof. Background Art

[0002] Abnormal uric acid metabolism is a cause or risk factor for many diseases, such as hyperuricemia and gout.

[0003] There are two main approaches to lowering uric acid in the body: one is to reduce uric acid production, such as with xanthine oxidase / reductase inhibitors like allopurinol and febuxostat; the other is to increase uric acid excretion, such as with uric acid transporter inhibitors like probenecid, benzbromarone, and lesinurad. However, these drugs have limitations such as insufficient uric acid-lowering efficacy and insufficient safety, and cannot meet current clinical needs. Verinurad is a new-generation uric acid transporter inhibitor that has been developed. Its ability to bind to the target is better than lesinurad, but it has still encountered repeated setbacks in clinical development.

[0004] Therefore, further development of better uric acid-lowering drugs is needed.

[0005] Summary of the Invention

[0006] The first aspect of the present application is to provide a thioether derivative. To achieve this purpose, the technical solution adopted by the present application is:

[0007] A compound represented by formula I, or a pharmaceutically acceptable salt thereof;

[0008] In Formula I: Ring G, Ring Y and Ring Z are each a six-membered ring, and Ring G and Ring Y are fused via two atoms; Ring G, Ring Y or Ring Z may optionally be further substituted; R1 and R2 are each independently selected from -CH2- or -S-; a and b are each independently selected from 0, 1, 2 or 3; R3 and R4 are each independently selected from an alkyl group or an alkoxy group, and R3 and R4 may or may not form a ring together; a dotted bond represents a single bond or a double bond, and not all two adjacent dotted bonds are double bonds.

[0009] In some embodiments of the present application, ring G, ring Y or ring Z are each independently selected from a carbocyclic ring or a heterocyclic ring.

[0010] In some embodiments of the present application, the compound of formula I is as shown in formula II:

[0011] In formula II: Ring G, Ring Y, Ring Z, R1, R2, R3, R4, a and b are as described above; Ring G, Ring Y or Ring Z may be further substituted; R7, R8, R9, R 10 、R12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 are each independently selected from -C-, -N-, -S- or -O-; R5, R6 and R 11 Each is independently selected from -C- or -N-.

[0012] In some embodiments of the present application, ring G, ring Y or ring Z are each independently selected from a saturated ring or an unsaturated ring.

[0013] In some embodiments of the present application, ring G, ring Y, or ring Z is a saturated six-membered carbon ring, such as cyclohexane.

[0014] In some embodiments of the present application, Ring G, Ring Y, or Ring Z is a saturated six-membered heterocyclic ring. Examples of saturated six-membered heterocyclic rings include those described in the definition section of the present application. Preferably, Ring G, Ring Y, or Ring Z is piperidine, piperazine, or morpholine.

[0015] In some embodiments of the present application, at least one of ring G, ring Y, or ring Z is an unsaturated ring.

[0016] In some embodiments of the present application, Ring G, Ring Y, or Ring Z is an unsaturated six-membered carbocyclic ring. Examples of unsaturated six-membered carbocyclic rings include those described in the definition section of the present application. Preferably, Ring G, Ring Y, or Ring Z is a benzene ring.

[0017] In some embodiments of the present application, Ring G, Ring Y, or Ring Z is an unsaturated six-membered heterocyclic ring. Examples of unsaturated six-membered heterocyclic rings include those described in the definition section of this application. Preferably, Ring G, Ring Y, or Ring Z is an unsaturated six-membered heterocyclic ring containing 1-3 nitrogen atoms, and specific examples include pyridine, pyridazine, pyrimidine, pyrazine, and triazine.

[0018] In some embodiments of the present application, the compound of formula I is as shown in formula I-II:

[0019] In formula I-II, ring Z, R1, R2, R3, R4, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 , a and b are as described above, and ring G, ring Y or ring Z may be further substituted; R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 and R14 Each is independently selected from -C- or -N-.

[0020] In some embodiments of the present application, the compound of formula I is as shown in formula I-III:

[0021] In formula I-III, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 , a and b are as described above, and ring G, ring Y or ring Z may be further substituted; R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Each is independently selected from -C- or -N-.

[0022] In some embodiments of the present application, ring G, ring Y, or ring Z are all carbocyclic rings.

[0023] In some embodiments of the present application, ring G, ring Y or ring Z contains at least one heterocycle.

[0024] In some embodiments of the present application, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 There are 0 to 9 -N-.

[0025] In some embodiments of the present application, R5, R6, R 11 、R 12 、R 13 and R 14 There are 0 to 3 -N-.

[0026] In some embodiments of the present application, R6, R7, R8, R9, R 10 and R 11 There are 0 to 3 -N-.

[0027] In some embodiments of the present application, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R13 and R 14 All -C-.

[0028] In some embodiments of the present application, R 15 、R 16 、R 17 、R 18 、R 19 and R 20 All -C-.

[0029] In some embodiments of the present application, R 15 、R 16 、R 17 、R 18 、R 19 and R 20 There are 0 to 3 -N-.

[0030] In some embodiments of the present application, R1 is -CH2-.

[0031] In some embodiments of the present application, R1 is -S-.

[0032] In some embodiments of the present application, R2 is -CH2-.

[0033] In some embodiments of the present application, R2 is -S-.

[0034] In some embodiments of the present application, a is selected from 1, 2 or 3.

[0035] In some embodiments of the present application, a is 0.

[0036] In some embodiments of the present application, b is selected from 1, 2 or 3.

[0037] In some embodiments of the present application, b is 0.

[0038] In some embodiments of the present application, a is selected from 1, 2 or 3, and b is 0.

[0039] In some embodiments of the present application, b is selected from 1, 2 or 3, and a is 0.

[0040] In some embodiments of the present application, a is 0 and b is 0.

[0041] In some embodiments of the present application, the compound of formula I is as shown in formula I-IV:

[0042] In formula I-IV, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 As mentioned above, ring G, ring Y or ring Z may optionally be further substituted.

[0043] In some embodiments of the present application, ring G is further substituted. The substituents may be selected from alkyl, alkoxy, halogen, cyano, hydroxyl, carboxyl, etc. The number of substituents may be one or more.

[0044] In some embodiments of the present application, ring Y is further substituted. The substituent may be selected from alkyl, alkoxy, halogen, cyano, hydroxyl, carboxyl, etc. The number of substituents may be one or more.

[0045] In some embodiments of the present application, ring Z is further substituted. The substituents may be selected from alkyl, alkoxy, halogen, cyano, hydroxyl, carboxyl, etc. The number of substituents may be one or more.

[0046] In some embodiments of the present application, the compound of formula I is as shown in formula IV:

[0047] In Formula IV, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 As mentioned above; Ring Y is R 21 Ring G may optionally be substituted with R 22 substituted, ring Z may optionally be R 23 Replacement; R 21 is selected from alkyl, alkoxy, halogen or cyano; R 22 and R 23 Each is independently selected from alkyl, alkoxy or halogen; p is selected from 1, 2 or 3, and m and n are each independently selected from 0, 1, 2, 3 or 4.

[0048] In some embodiments of the present application, the compound of formula I is as shown in formula I-VI:

[0049] In Formulas I-VI, R3, R4, R5, R6, R7, R8, R9, R 10 、R11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20 、R 21 、R 22 、R 23 , p, m and n are as described above.

[0050] In some embodiments of the present application, R3 and R4 are each independently selected from a C1-C5 alkyl group. Examples of C1-C5 alkyl groups include those described in the definition section of this application. In some embodiments of the present application, R3 and R4 together form a ring, and the resulting ring can be a 3- to 6-membered ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. In some embodiments of the present application, R3 and R4 do not together form a ring.

[0051] Since the compound in the present application is a carboxylic acid, those skilled in the art can easily prepare it into a pharmaceutically suitable salt. Therefore, the present application includes the pharmaceutically acceptable salts of the compound in the present application.

[0052] Since the compound in the present application is a carboxylic acid, those skilled in the art can easily prepare it into an ester. Therefore, the present application also includes the ester of the compound of the present application, such as the compound shown in Formula II:

[0053] In Formula II: Ring Y, Ring G, Ring Z, R1, R2, R3, R4, a and b are as described above; R 24 It is an alkyl group, preferably a C1-C5 alkyl group.

[0054] The carboxylic acid compounds of formula II, formula I-II, formula I-III, formula I-IV, formula IV and formula I-VI may also include the above R 24 Groups, such as:

[0055] The definitions of each ring or each substituent in this application are as described above, but the combination of each ring or each substituent in each technical solution can be arbitrarily combined.

[0056] The second aspect of the present application is to provide a method for preparing the compound represented by the above formula I. In order to achieve this purpose, the technical solution adopted by the present application is:

[0057] A method for preparing the compound represented by formula I is shown in the following reaction formula:

[0058] The compound shown in formula II is subjected to hydrogenation reaction to obtain the compound shown in formula I; wherein ring Y, ring G, ring Z, R1, R2, R3, R4, R 24 , a and b are as described above.

[0059] In some embodiments of the present application, the preparation method of the compound represented by Formula II is as shown in the following reaction formula:

[0060] The compound represented by formula III is reacted with the compound represented by formula IV to obtain the compound represented by formula II; wherein ring Y, ring G, ring Z, R1, R2, R3, R4, R 24 , a and b are as described above, and X in formula IV represents a halogen.

[0061] In some embodiments of the present application, the preparation method of the compound represented by formula IV is as shown in the following reaction formula:

[0062] The compound represented by formula V is reacted with the compound represented by formula VI to obtain the compound represented by formula IV, wherein ring Z, R2, R3, R4, R 24 and b are as described above, and X represents a halogen.

[0063] In some embodiments of the present application, the preparation method of the compound represented by formula V is as shown in the following reaction formula:

[0064] The method comprises reacting a compound represented by formula VII to obtain a compound represented by formula V, wherein ring Z, R2 and b are as described above, and X represents halogen.

[0065] In some embodiments of the present application, the preparation method of the compound represented by formula III is as shown in the following reaction formula:

[0066] The method comprises reacting a compound represented by formula VIII to obtain a compound represented by formula III, wherein ring Y, ring G, R1 and a are as described above, and X represents a halogen.

[0067] Referring to the preparation method of Formula I, compounds represented by Formula II, Formula I-II, Formula I-III, Formula I-IV, Formula IV and Formula I-VI can be prepared.

[0068] The third aspect of the present application is to provide the application of the compound represented by Formula I. In order to achieve this purpose, the technical solution adopted by the present application is:

[0069] Use of the compound represented by the aforementioned formula I in the preparation of a drug for reducing uric acid levels in the body;

[0070] Use of the compound represented by the aforementioned formula I in the preparation of a drug for treating diseases or symptoms associated with abnormal uric acid levels in the body.

[0071] In some embodiments of the present application, the disease is selected from hyperuricemia, gout, renal failure accompanied by abnormal uric acid levels, etc.

[0072] The compounds of the present application are uric acid transporter inhibitors that can effectively increase uric acid excretion in the body. In some embodiments of the present application, the compounds of the present application have better safety than similar compounds. In some embodiments of the present application, the compounds of the present application have stronger inhibitory activity against URAT1 than similar compounds. These situations indicate that the thioether derivatives provided by the present application have unexpectedly superior properties compared to compounds in the prior art. DETAILED DESCRIPTION

[0073] The present application will be described in detail below using specific implementation methods. It should be understood that the content of the specific implementation methods is illustrative rather than restrictive, that is, it does not limit the content of the present application in any way.

[0074] definition:

[0075] A "six-membered ring" refers to a ring having a total of six atoms constituting the ring.

[0076] A "saturated ring" refers to a ring in which all bonds between atoms constituting the ring are single bonds.

[0077] An "unsaturated ring" refers to a ring in which the bonds formed between atoms constituting the ring are not all single bonds but also include double bonds.

[0078] "Carbocycle" refers to a ring in which all atoms constituting the ring are carbon atoms.

[0079] A "heterocycle" is a ring whose atoms are not all carbon atoms but include other atoms (called heteroatoms). The heteroatoms can be selected from one or more of sulfur, nitrogen, and oxygen. The number of heteroatoms can be one or more.

[0080] "Saturated six-membered carbon ring" includes: cyclohexane.

[0081] "Unsaturated six-membered carbon ring" includes benzene and cyclohexene.

[0082] "Saturated six-membered heterocycle" includes: piperidine, tetrahydropyran (thiohexane), tetrahydrothiopyran (thiane), hexahydropyrimidine, hexahydropyrazine (piperazine), hexahydropyridazine, thiohexane, dithiane (dithiane), dioxane, morpholine and thiomorpholine, etc.

[0083] "Unsaturated six-membered heterocycle" includes: dihydropyridine, tetrahydropyridine, pyridine, dihydropyran, pyran, dihydrothiopyran, thiopyran, dihydropyrimidine, pyrimidine, dihydropyrazine, pyrazine, dihydropyridazine, pyridazine, oxazine, thiazine and triazine, etc.

[0084] "Alkyl" refers to a group consisting entirely of carbon atoms; including straight-chain alkyl, branched-chain alkyl or cycloalkyl; including saturated alkyl or unsaturated alkyl; including substituted or unsubstituted alkyl, for example, substituted by halogen, alkyl, alkoxy, hydroxy, carboxyl or amino. The C1-C5 alkyl group also includes a linear, branched or cyclic C1-C5 alkyl group, including a saturated or unsaturated C1-C5 alkyl group, and specifically includes at least: methyl, methylene, ethyl, vinyl, alkynyl, n-propyl, isopropyl, cyclopropyl, propenyl, methyl-substituted vinyl, propynyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, methyl-substituted propyl, butenyl, methyl-substituted propenyl, butynyl, methyl-substituted propynyl, n-pentyl, isopentyl, cyclopentyl, methyl-substituted butyl, dimethyl-substituted propyl, ethyl-substituted propyl, pentenyl, methyl-substituted butenyl, ethyl-substituted propenyl, dimethyl-substituted propenyl, pentynyl, methyl-substituted butynyl, ethyl-substituted propynyl and dimethyl-substituted propynyl, and also includes the case where these groups are further substituted by alkyl or halogen.

[0085] "Alkoxy" includes straight-chain alkoxy, branched-chain alkoxy or cycloalkyloxy; includes saturated alkoxy or unsaturated alkoxy; includes substituted or unsubstituted alkoxy, for example, substituted by halogen, alkyl, alkoxy, hydroxy, carboxyl or amino.

[0086] "Halogen" includes fluorine, chlorine, bromine and iodine.

[0087] "Hydroxy" includes substituted or unsubstituted hydroxy groups, for example, substituted by alkyl, alkoxy, carboxyl or amino groups.

[0088] The "carboxyl group" includes substituted or unsubstituted carboxyl groups, for example, substituted by an alkyl group or an amino group.

[0089] In addition, "-C-" and "-N-" are generalizations. "-C-" means that the carbon atom forms at least two primary bonds, which can be single or double bonds. This notation also omits hydrogen atoms, thus including cases where the carbon atom is bonded to zero, one, or two hydrogen atoms. "-N-" means that the nitrogen atom forms at least two primary bonds, which can be single or double bonds. This notation also omits hydrogen atoms, thus including cases where the nitrogen atom is bonded to zero or one hydrogen atom.

[0090] Example 1: Preparation of Compound E-02

[0091] 1.1 Preparation of E201:

[0092] 3-Bromo-4-chloropyridine (2 g), sodium hydrosulfide (2.4 g), and dimethylformamide (20 mL) were added to a reaction flask and reacted at 100°C for 5 hours. Dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5-6, and ethyl acetate and water were added for extraction. The organic phase was collected and concentrated to obtain the product E201 (2 g).

[0093] 1.2 Preparation of E202:

[0094] E01 (2 g, prepared according to the method in 1.1 above), methyl 2-bromoisobutyrate (2 g), and dimethylformamide (20 mL) were added to a reaction flask and reacted at room temperature for 5 hours. Water and ethyl acetate were added and stirred to dissolve the solid. The organic and aqueous phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed, dried, concentrated, and purified by column chromatography to obtain the product E202 (2.5 g).

[0095] 1. Preparation of 3E203:

[0096] 4-Bromo-1-naphthocarbonitrile (1 g), sodium hydrosulfide (0.520 g), and dimethylformamide (10 mL) were added to a reaction flask and reacted at 100°C for 4 hours. After cooling, water and ethyl acetate were added to the reaction solution for extraction. The aqueous phase was collected and the pH was adjusted to 4-5 with dilute hydrochloric acid. Ethyl acetate was then added for extraction. The organic phase was collected and concentrated to dryness to obtain the product E203 (0.500 g).

[0097] 1.4E204 preparation:

[0098] E203 (0.500 g, prepared according to the method in 1.3 above), E202 (0.783 g, prepared according to the method in 1.2 above), bis(dibenzylideneacetone)palladium (0.750 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (0.781 g), diisopropylethylamine (1 g), and 1,4-dioxane (10 mL) were added to a reaction flask and stirred at 80°C overnight. After cooling, the reaction solution was filtered and extracted with water and ethyl acetate. The organic phase was collected, washed, dried, concentrated, and purified by column chromatography to obtain the product E204 (0.300 g).

[0099] Preparation of 1.5E-02:

[0100] E204 (0.300 g, prepared according to the method in 1.4 above), lithium hydroxide (0.096 g), methanol (1 mL), tetrahydrofuran (2 mL), and water (1 mL) were added to a reaction flask and reacted at room temperature for 4 hours. The reaction solution was concentrated, extracted with water and ethyl acetate, and the aqueous phase was collected. The pH was adjusted to 5-6 with hydrochloric acid, and extracted with ethyl acetate. The organic phase was collected and concentrated to dryness to obtain the product E-02 (0.250 g). Mass spectrum: [M+H] + :381.09; NMR: 1 H NMR (400MHz, DMSO-d6) δ13.29(bs,1H),8.56(d,J=5.2Hz,1H),8.46(s,1H),8.39(d,J=8.8Hz,1H),8.19(d,J=8.4Hz,1H) ,8.04(d,J=8.0Hz,1H),7.94–7.89(m,1H),7.87-7.83(m,1H),7.47(d,J=5.6Hz,1H),7.04(d,J=8.0Hz,1H),1.54(s,6H).

[0101] Example 2: Efficacy test

[0102] The test compounds were tested for their inhibition on the uric acid transporter URAT1.

[0103] Compounds: The compounds of the present application were prepared according to the methods in the examples; Verinurad was purchased commercially; CDER167 was prepared according to the method in the literature (doi:10.1038 / s41401-021-00640-5).

[0104] Cells: Flp-In-T-REx-293-hURAT1 cells are cells that express human urate transporter 1 (hURAT1) and are available from Pharmaron. They can also be prepared (for example, commercially available Flp-In-T-REx-293 cells are transfected with the hURAT1 gene using methods such as reference literature doi:10.1124 / dmd.106.012187. hURAT1 gene expression can be verified by methods such as Western blotting).

[0105] Incubate at 75 cm in 5% CO2 and 37°C. 2Flp-In-T-REx-293-hURAT1 cells were cultured in DMEM medium in a culture flask and passaged every 2 days. When the cells were routinely cultured to a saturation of 80% to 90%, the cells were digested and collected by centrifugation at 200×g for 5 minutes. The cells were resuspended in DMEM medium and counted to prepare a cell suspension of appropriate density. The cells were seeded into a 96-well plate and cultured in a 37°C and 5% CO2 incubator for 24 hours. The culture medium was removed, and DMEM medium containing 200 ng / mL doxycycline was added, and then cultured in a 37°C and 5% CO2 incubator for 18 hours. The test compound was diluted 3-fold with DMSO starting from 10 mmol / L into 10 concentrations to prepare 10 stock solutions of different concentrations. Prepare a buffer solution containing 125 mmol / L sodium gluconate, 4.8 mmol / L potassium gluconate, 5.6 mmol / L glucose, 1.2 mmol / L potassium dihydrogen phosphate, 1.2 mmol / L magnesium sulfate, 1.3 mmol / L calcium gluconate, and 25 mmol / L HEPES (pH = 7.4). Take 1.2 μL of the test compound stock solution and mix it with 119 μL of buffer to form the assay buffer. After 16 hours of induction, remove the culture medium and wash the cells with preheated buffer and incubate at 37°C for 10 minutes. Remove the buffer and add 50 μmol / L 14 C-uric acid and the test compound assay buffer were incubated at 37°C for 5 minutes. The buffer was removed, and the cells were washed three times with pre-cooled buffer, followed by lysis with 100 mmol / L NaOH for 20 minutes. The lysate was transferred to a 96-well plate, 200 μL of UltimaGold XR scintillation fluid was added, and the plate was read using a MicroBeta2 (PerkinElmer). The half-maximal inhibitory concentration (IC50) of the test compound was calculated using a nonlinear fitting formula using GraphPad Prism 8 software. 50 ). IC 50 The values ​​are expressed as follows: C: <1 μmol / L; D: 1-2 μmol / L; E: >2 μmol / L. The results are shown in Table 1.

[0106] Table 1: Inhibitory effects of the compounds of the present application on uric acid transporter (IC 50 )

[0107] This experiment shows that compared with similar compounds, the compounds of the present application have stronger inhibitory activity against URAT1.

[0108] Example 3: Toxicology test

[0109] Compounds were tested for toxicity in mice following repeated 28-day dosing.

[0110] Methods: ICR mice that passed the quarantine were taken, half male and half female, and randomly divided into groups according to body weight and gender, with 8 mice in each group. The test substances were the compounds of this application and the positive drug Verinurad. The animals were given the test substances by gavage at a dose of 200 mg / kg once a day for 28 consecutive days. Detailed clinical observations were performed after each administration. The animals were observed for at least 2 hours after the first administration or when the animals showed abnormalities. Cage-side observations were performed once every afternoon. Observations included: clinical symptoms (animal appearance, behavior, diet, response to stimuli, secretions and excretions) and death (time of death or time of death discovered, pre-mortem reactions, etc.), and the symptoms of the animals and the onset, severity and duration of the symptoms were recorded. The animals were euthanized after blood was drawn on the 28th day of administration, and a gross autopsy was performed. The liver and left kidney were taken for paraffin sectioning and HE staining. Histopathological examination was performed to observe tissue lesions, paying attention to glomerular and tubular degeneration, inflammatory changes and urea crystals. During the experiment, animals that were euthanized due to dying or died were promptly subjected to gross autopsy.

[0111] Results: After repeated administration of E-02 for 28 days, histopathological examination of all mice showed no liver and kidney toxicity. After repeated administration of Verinurad for 28 days, histopathological examination of three out of eight mice showed kidney toxicity.

[0112] The test results suggest that the compound of the present application has better safety than similar compounds.

[0113] The above describes the present application in detail using general descriptions and specific implementation methods. On this basis, those skilled in the art may make some changes or improvements thereto. These changes or improvements made without departing from the protection of the present application are all within the content required to be protected by the present application.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, in, Ring G, ring Y and ring Z are each a six-membered ring, and ring G and ring Y are fused via two atoms; ring G, ring Y or ring Z is optionally further substituted; R1 and R2 are each independently selected from -CH2- or -S-; a and b are each independently selected from 0, 1, 2 or 3; R3 and R4 are each independently selected from alkyl or alkoxy, and R3 and R4 may or may not form a ring together.

2. The compound according to claim 1, wherein ring G, ring Y or ring Z is each independently selected from a carbocyclic ring or a heterocyclic ring.

3. The compound according to claim 1, wherein the compound of formula I is as shown in formula II: in, Ring G, Ring Y, Ring Z, R1, R2, R3, R4, a and b are as defined in claim 1; R7, R8, R9, R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 are each independently selected from -C-, -N-, -S- or -O-; R5, R6 and R 11 Each is independently selected from -C- or -N-.

4. The compound according to claim 1, wherein ring G, ring Y or ring Z is each independently selected from a saturated ring or an unsaturated ring. The compound according to claim 1 , wherein ring G, ring Y or ring Z is cyclohexane. The compound according to claim 1 , wherein ring G, ring Y or ring Z is a saturated six-membered heterocyclic ring.

7. The compound according to claim 1, wherein ring G, ring Y or ring Z is piperidine, piperazine or morpholine.

8. The compound according to claim 1, wherein ring G, ring Y or ring Z is an unsaturated six-membered heterocyclic ring.

9. The compound according to claim 1, wherein the compound of formula I is as shown in formula I-II: in, Ring Z, R1, R2, R3, R4, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , a and b are as defined in claim 3, and ring G, ring Y or ring Z is optionally further substituted; R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 and R 14 Each is independently selected from -C- or -N-.

10. The compound according to claim 1, wherein the compound of formula I is as shown in formula I-III: in, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , a and b are as defined in claim 9, and ring G, ring Y or ring Z is optionally further substituted; R 15 , R 16 , R 17 , R 18 , R 19 and R 20 Each is independently selected from -C- or -N-.

11. The compound according to claim 10, wherein R5, R6, R 11 , R 12 , R 13 and R 14 There are 0 to 3 -N- in it.

12. The compound according to claim 10, wherein R6, R7, R8, R9, R 10 and R 11 There are 0 to 3 -N- in it.

13. The compound according to claim 10, wherein R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 and R 14 All -C-.

14. The compound according to claim 10, wherein R 15 , R 16 , R 17 , R 18 , R 19 and R 20 There are 0 to 3 -N- in it.

15. The compound according to claim 10, wherein R 15 , R 16 , R 17 , R 18 , R 19 and R 20 All -C-.

16. The compound according to claim 1, wherein at least one of ring G, ring Y or ring Z is a heterocyclic ring.

17. The compound according to claim 1, wherein ring G, ring Y or ring Z is a benzene ring.

18. The compound according to claim 1, wherein ring G, ring Y or ring Z is an unsaturated six-membered heterocyclic ring.

19. The compound according to claim 1, wherein ring G, ring Y or ring Z is pyridine, pyridazine, pyrimidine, pyrazine or triazine.

20. The compound according to claim 1, wherein a is selected from 1, 2 or 3, and b is 0.

21. The compound according to claim 1, wherein b is selected from 1, 2 or 3, and a is 0.

22. The compound according to claim 1, wherein a is 0 and b is 0.

23. The compound according to claim 1, wherein the compound of formula I is as shown in formula I-IV: in, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 As defined in claim 10, ring G, ring Y or ring Z is optionally further substituted.

24. The compound according to claim 1, wherein ring G, ring Y or ring Z is optionally further substituted by one or more alkyl, alkoxy, halogen, cyano, hydroxyl or carboxyl groups.

25. The compound according to claim 1, wherein ring Y is further substituted.

26. The compound according to claim 1, wherein the compound of formula I is represented by formula IV: in, R3, R4, R5, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 As defined in claim 10; Ring Y is R 21 Ring G is optionally substituted by R 22 substituted, ring Z is optionally replaced by R 23 Replacement; R 21 is selected from alkyl, alkoxy, halogen or cyano; R 22 and R 23 Each is independently selected from alkyl, alkoxy or halogen; p is selected from 1, 2 or 3, and m and n are each independently selected from 0, 1, 2, 3 or 4.

27. The compound according to claim 1, wherein R3 and R4 do not form a ring together, and R3 and R4 are each independently selected from C1-C5 alkyl.

28. The compound according to claim 1, wherein R3 and R4 are cyclically linked, and R3 and R4 are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

29. The compound represented by formula II: in, Ring Y, Ring G, Ring Z, R1, R2, R3, R4, a and b are as described in claim 1; R 24 It is an alkyl group.

30. Use of the compound according to any one of claims 1 to 29 in the preparation of a medicament for reducing uric acid levels in the body or a medicament for treating a disease or symptom associated with abnormal uric acid levels in the body.

31. The use according to claim 30, wherein the disease is selected from hyperuricemia, gout or renal failure accompanied by abnormal uric acid level.

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