Six-membered and five-membered fused ring derivative as well as preparation method and application thereof

Abstract

The invention discloses a six-membered and five-membered fused ring derivative as well as a preparation method and application thereof. The compound provided by the invention is a urate transporter inhibitor, and can effectively increase uric acid excretion in vivo. In some embodiments of the present application, the compounds of the present application have better safety and / or stronger activity compared to similar compounds.

Description

A six-membered and five-membered fused ring derivative and its preparation method and application Technical Field

[0001] The present application belongs to the field of medicine, and specifically relates to a six-membered and five-membered fused ring 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 drugs such as xanthine oxidase / reductase inhibitors allopurinol and febuxostat; the other is to increase uric acid excretion, such as drugs such as uric acid transporter inhibitors probenecid, benzbromarone, and lesinurad. However, these drugs have limiting factors such as insufficient uric acid-lowering effects and insufficient safety, and cannot meet current clinical needs. Verinurad is a new generation of uric acid transporter inhibitors 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 six-membered and five-membered fused ring derivative. To achieve this purpose, the technical solution adopted by the present application is:

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

[0008] In Formula I: Ring G is a six-membered ring, Ring Y is a five-membered ring, Ring Z is 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, R2, and R3 are each independently selected from -CH2- or -S-; a, b, and q are each independently selected from 0, 1, 2, or 3, and not all of a, b, and q are 0; R4 and R5 are each independently selected from an alkyl group or an alkoxy group, and R4 and R5 may or may not form a ring together; a dotted bond represents a single bond or a double bond, and not all of 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, R5, a, b and q are as described above; R6, R7 and R 12 are each independently selected from -C- or -N-; R8, R9, R 10 、R 11 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Each is independently selected from -C-, -N-, -S- or -O-.

[0012] In some embodiments of the present application, at least one of ring G and ring Y is a heterocycle.

[0013] 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.

[0014] In some embodiments of the present application, at least one of ring G and ring Y is an unsaturated ring.

[0015] In some embodiments of the present application, ring Y is a saturated five-membered carbon ring. Preferably, ring Y is cyclopentane.

[0016] In some embodiments of the present application, ring Y is an unsaturated five-membered carbon ring. Preferably, ring Y is cyclopentene.

[0017] In some embodiments of the present application, Ring Y is a saturated five-membered heterocycle. Examples of saturated five-membered heterocycles include those described in the definition section of this application. Preferably, Ring Y is a saturated five-membered heterocycle containing 1-3 nitrogen atoms, and specific examples include pyrrolidine, pyrazolidine, imidazolidine, and the like.

[0018] In some embodiments of the present application, ring Y is an unsaturated five-membered heterocyclic ring. Examples of unsaturated five-membered heterocyclic rings include those described in the definition section of the present application.

[0019] In some embodiments of the present application, the compound of formula I is as shown in formula I-II:

[0020] In formula I-II: Ring G, Ring Z, R1, R2, R3, R4, R5, R7, R8, R9, R 10 、R 11 、R 12 、R 15 、R 16 、R 17 、R 18 、R 19 、R 20, a, b and q are as described above, and ring G, ring Y or ring Z may be further substituted; R 13 and R 14 Each is independently selected from -C- or -N-.

[0021] In some embodiments of the present application, R 13 、R 14 , R7 and R 12 There are 0 to 2 -N-.

[0022] In some embodiments of the present application, ring Y is an unsaturated pentacyclic heterocycle containing 1-3 nitrogen atoms, and specific examples include pyrrole, imidazole, pyrazole, triazole, and the like.

[0023] In some embodiments of the present application, ring Y is selected from formula Y-1, formula Y-2, formula Y-3, formula Y-4, formula Y-5, formula Y-6, formula Y-7, formula Y-8, formula Y-9, formula Y-10 and formula Y-11, wherein the dotted bond represents a single bond or a double bond, and two adjacent dotted bonds are not all double bonds,

[0024] In some embodiments of the present application, ring G is a saturated six-membered carbon ring. Preferably, ring G is cyclohexane.

[0025] In some embodiments of the present application, Ring G 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 is piperidine, piperazine, morpholine, or the like.

[0026] In some embodiments of the present application, Ring G is an unsaturated six-membered carbon ring. Examples of unsaturated six-membered carbon rings include those described in the definition section of the present application. Preferably, Ring G is a benzene ring.

[0027] In some embodiments of the present application, Ring G 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 is an unsaturated six-membered heterocyclic ring containing 1-3 nitrogen atoms, and specific examples include pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like.

[0028] In some embodiments of the present application, the compound of formula I is as shown in formula I-III:

[0029] In formula I-III: Ring Z, R1, R2, R3, R4, R5, R 15 、R 16 、R 17 、R 18 、R 19 、R 20 , a, b and q are as described above, and ring G, ring Y or ring Z may be further substituted; R7, R 12 、R13 and R 14 are each independently selected from -C- or -N-; R8, R9, R 10 and R 11 Each is independently selected from -C- or -N-.

[0030] In some embodiments of the present application, R8, R9, R 10 and R 11 There are 0 to 3 -N-.

[0031] In some embodiments of the present application, ring G is selected from formula G-1, formula G-2, formula G-3, formula G-4, formula G-5, formula G-6, formula G-7, formula G-8, formula G-9, formula G-10 and formula G-11,

[0032] In some embodiments of the present application, ring Z is an unsaturated six-membered carbon ring. Examples of unsaturated six-membered carbon rings include those described in the definition section of the present application. Preferably, ring Z is a benzene ring.

[0033] In some embodiments of the present application, 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 Z is an unsaturated six-membered heterocyclic ring containing 1-3 nitrogen atoms, and specific examples include pyridine, pyridazine, pyrimidine, pyrazine, triazine, and the like.

[0034] In some embodiments of the present application, the compound of formula I is as shown in formula I-IV:

[0035] In formula I-IV: R1, R2, R3, R4, R5, a, b and q are as described above, and ring G, ring Y or ring Z may be further substituted; R7, R 12 、R 13 and R 14 are each independently selected from -C- or -N-; R8, R9, R 10 and R 11 are each independently selected from -C- or -N-; R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Each is independently selected from -C- or -N-.

[0036] 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-.

[0037] In some embodiments of the present application, a is selected from 1, 2 or 3.

[0038] In some embodiments of the present application, a is 0.

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

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

[0041] In some embodiments of the present application, q is selected from 1, 2 or 3.

[0042] In some embodiments of the present application, q is 0.

[0043] In some embodiments of the present application, b is selected from 1, 2, and 3, a is 0, and q is 0.

[0044] In some embodiments of the present application, R1 is -CH2-.

[0045] In some embodiments of the present application, R1 is -S-.

[0046] In some embodiments of the present application, R2 is -CH2-.

[0047] In some embodiments of the present application, R2 is -S-.

[0048] In some embodiments of the present application, R3 is -CH2-.

[0049] In some embodiments of the present application, R3 is -S-.

[0050] In some embodiments of the present application, R1 is -CH2-, R2 is -S-, R3 is -CH2-, a and q are independently selected from 0, 1, 2 or 3, and b is 1.

[0051] In some embodiments of the present application, R2 is -CH2-, b is selected from 1, 2 or 3, a is 0, and q is 0.

[0052] In some embodiments of the present application, the compound of formula I is as shown in formula IV:

[0053] In formula IV: R4 and R5 are as described above, and ring G, ring Y or ring Z may be further substituted; R7, R 12 、R 13 and R 14 are each independently selected from -C- or -N-; R8, R9, R 10 and R 11 are each independently selected from -C- or -N-; R 15 、R 16、R 17 、R 18 、R 19 and R 20 Each is independently selected from -C- or -N-; b is selected from 1, 2 or 3.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] In some embodiments of the present application, the compound of formula I is as shown in formula I-VI:

[0058] In formula I-VI: R4 and R5 are as described above; Ring Y is replaced by R 21 Ring G can be optionally substituted by R 22 Ring Z can be optionally substituted by R 23 Replacement; R7, R 12 、R 13 and R 14 are each independently selected from -C- or -N-; R8, R9, R 10 and R 11 are each independently selected from -C- or -N-; R 15 、R 16 、R 17 、R 18 、R 19 and R 20 Each is independently selected from -C- or -N-; b is selected from 1, 2 or 3; 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 or 2, and m and n are each independently selected from 0, 1, 2, 3 or 4.

[0059] In some embodiments of the present application, the compound of formula I is as shown in formula I-VII:

[0060] In formula I-VII: R4, R5, 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 , b, p, m and n are as described above.

[0061] In some embodiments of the present application, R4 and R5 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, R4 and R5 together form a ring, and the resulting ring can be a 3-6 membered ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. In some embodiments of the present application, R4 and R5 do not form a ring together.

[0062] 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.

[0063] 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:

[0064] In Formula II: Ring Y, Ring G, Ring Z, R1, R2, R3, R4, R5, a, b and q are as described above; R 24 It is an alkyl group, preferably a C1-C5 alkyl group.

[0065] The carboxylic acids of the above formula II, formula I-II, formula I-III, formula I-IV, formula IV, formula I-VI, and formula I-VII may also include the above R 24 Groups, such as:

[0066] 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.

[0067] 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:

[0068] A method for preparing the compound represented by formula I is shown in the following reaction formula:

[0069] The method comprises hydrogenating the compound represented by formula II to obtain the compound represented by formula I; wherein ring Y, ring G, ring Z, R1, R2, R3, R4, R5 and R 24 As mentioned above.

[0070] 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:

[0071] The method comprises reacting a compound represented by formula III with a compound represented by formula IV to obtain a compound represented by formula II; wherein ring Y, ring G, ring Z, R1, R2, R3, R4, R5 and R 24 As mentioned above, X in formula IV represents a halogen.

[0072] 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:

[0073] The compound shown in formula V is reacted to obtain the compound shown in formula IV, wherein ring Z, R1, R2, R3, R4, R5 and R 24 As mentioned above, X in formula IV represents a halogen.

[0074] 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:

[0075] The compound of formula VI is reacted to obtain a compound of formula V, wherein ring Z, R1, R2, R3, R4, R5 and R 24 As defined above.

[0076] In some embodiments of the present application, the preparation method of the compound represented by Formula VI is as shown in the following reaction formula:

[0077] The method comprises reacting a compound represented by formula VII with a compound represented by formula VIII to obtain a compound represented by formula VI; wherein ring Z, R1, R2, R3, R4, R5 and R 24 As mentioned above, X in formula VIII represents halogen.

[0078] In some embodiments of the present application, the preparation method of the compound represented by Formula VII is as shown in the following reaction formula:

[0079] The method comprises reacting a compound represented by formula IX to obtain a compound represented by formula VII; wherein ring Z is as described above, and X in formula IX represents halogen.

[0080] Referring to the preparation method of Formula I, compounds represented by Formula II, Formula I-II, Formula I-III, Formula I-IV, Formula IV, Formula I-VI and Formula I-VII can be prepared.

[0081] 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:

[0082] Use of the compound represented by the aforementioned formula I in the preparation of a drug for reducing uric acid levels in the body;

[0083] 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.

[0084] In some embodiments of the present application, the disease is selected from hyperuricemia, gout, renal failure accompanied by abnormal uric acid levels, etc.

[0085] The compound of the present application is a uric acid transporter inhibitor that can effectively increase uric acid excretion in the body. In some embodiments of the present application, the compound of the present application has better safety than similar compounds. In some embodiments of the present application, the compound of the present application has stronger activity against the uric acid transporter URAT1 compared to similar compounds. These situations show that the six-membered and five-membered fused ring derivatives provided by the present application have unexpected and better properties than the compounds in the prior art. DETAILED DESCRIPTION

[0086] 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.

[0087] definition:

[0088] A "five-membered ring" refers to a ring having a total of five atoms constituting the ring.

[0089] A "six-membered ring" refers to a ring having a total of six atoms constituting the ring.

[0090] A "saturated ring" refers to a ring in which all bonds between atoms constituting the ring are single bonds.

[0091] 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.

[0092] "Carbocycle" refers to a ring in which all atoms constituting the ring are carbon atoms.

[0093] 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.

[0094] "Saturated six-membered carbon ring" includes: cyclohexane.

[0095] "Unsaturated six-membered carbon ring" includes benzene and cyclohexene.

[0096] "Saturated six-membered heterocycle" includes: piperidine, tetrahydropyran (thiohexane), tetrahydrothiopyran (thiane), hexahydropyrimidine, hexahydropyrazine (piperazine), hexahydropyridazine, thiohexane, dithiane (dithiane), dioxane, morpholine, thiomorpholine and the like.

[0097] "Unsaturated six-membered heterocycle" includes: dihydropyridine, tetrahydropyridine, pyridine, dihydropyran, pyran, dihydrothiopyran, thiopyran, dihydropyrimidine, pyrimidine, dihydropyrazine, pyrazine, dihydropyridazine, pyridazine, oxazine, thiazine, triazine and the like.

[0098] "Saturated five-membered carbon ring" includes: cyclopentane.

[0099] "Unsaturated five-membered carbon ring" includes: cyclopentene.

[0100] "Saturated five-membered heterocycle" includes pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, oxathiol and the like.

[0101] "Unsaturated five-membered heterocycle" includes: pyrroline, pyrrole, dihydrofuran, furan, dihydrothiophene, thiophene, dihydropyrazole (pyrazoline), pyrazole, dihydroimidazole (imidazoline), imidazole, dihydrooxazole, oxazole, dihydroisoxazole, isoxazole, dihydrothiazole, thiazole, dihydroisothiazole, isothiazole, triazole, tetrazole, etc.

[0102] "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, amino, etc. 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.

[0103] "Alkoxy" includes straight-chain alkoxy, branched-chain alkoxy, or cycloalkyloxy. It includes saturated alkoxy and unsaturated alkoxy. It includes substituted or unsubstituted alkoxy groups, for example, substituted with halogen, alkyl, alkoxy, hydroxy, carboxyl, amino, etc.

[0104] "Halogen" includes fluorine, chlorine, bromine and iodine.

[0105] "Hydroxy" includes substituted or unsubstituted hydroxy groups, for example, substituted by alkyl, alkoxy, carboxyl, amino, etc.

[0106] The "carboxyl group" includes substituted or unsubstituted carboxyl groups, for example, substituted by an alkyl group, an amino group, or the like.

[0107] 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.

[0108] Example 1: Preparation of Compound F-02

[0109] 1.1 Preparation of F201:

[0110] Sodium hydrosulfide hydrate (17.3 g) and dimethylformamide (200 mL) were added to a reaction flask and stirred to dissolve. 2-bromobenzaldehyde (20.8 g) was added and reacted at 70°C until the reaction was complete as determined by thin-layer chromatography (TLC). Water, ethyl acetate, and acetic acid were added for extraction. The organic phase was washed, dried, and concentrated to yield 2-mercaptobenzaldehyde.

[0111] Dimethylformamide (100 mL) and potassium carbonate (29.8 g) were added to 2-mercaptobenzaldehyde, and methyl 2-bromoisobutyrate (23.5 g) was added with stirring. The mixture was allowed to react at room temperature for 2 hours. Water and ethyl acetate were added for extraction. The organic phase was washed, dried, concentrated, and purified by column chromatography to obtain product F201 (15.2 g).

[0112] 1.2 Preparation of F202:

[0113] F201 (15.2 g, prepared according to the method in 1.1 above) and methanol (100 mL) were added to a reaction flask. Sodium borohydride (2.4 g) was added portionwise at -10°C. After reacting for 0.5 hours, the reaction was quenched by adding water. The methanol was removed by concentration under reduced pressure, and water and ethyl acetate were added for extraction. The organic phase was washed, dried, concentrated, and purified by column chromatography to obtain the product F202 (9 g).

[0114] 1.3 Preparation of F203:

[0115] F202 (1.2 g, prepared according to the method in 1.2 above) and dichloromethane (13 mL) were added to a reaction flask. Phosphorus tribromide (1.35 g) was added at -10°C and allowed to react at room temperature until the starting materials were completely reacted. Ethyl acetate and brine were added for extraction. The organic phase was dried and purified by column chromatography to obtain product F203.

[0116] 1.4 Preparation of F204:

[0117] 3-Cyanoindole (0.736 g), sodium hydroxide (0.4 g), and dimethylformamide (10 mL) were added to a reaction flask and stirred at room temperature for 1 hour. F203 (prepared according to the method in 1.3 above) was then added and the reaction continued at room temperature until the starting materials were completely reacted. Ethyl acetate was added for extraction, and the organic phase was washed with brine, dried, concentrated, and purified by column chromatography to obtain the product F204 (0.845 g).

[0118] 1.5 Preparation of F-02:

[0119] F204 (0.845 g, prepared according to the method in 1.4 above), methanol (10 mL), water (2 mL), and lithium hydroxide (0.195 g) were added to a reaction flask and reacted at 50°C for 1.5 hours. Dilute hydrochloric acid was added to adjust the pH to 5, and the mixture was concentrated under reduced pressure. Water and ethyl acetate were added for extraction. The organic phase was dried, concentrated, and purified by column chromatography to obtain the product F-02 (0.660 g). Mass spectrum: [M+H] + :351.11; NMR: 1 H NMR (400MHz, DMSO-d6) δ12.86(br,1H), δ8.33(s,1H),7.71-7.68(m,1H),7.60-7.57(m, 1H),7.54-7.51(m,1H),7.33-7.28(m,4H),6.77-6.73(m,1H),5.71(s,2H),1.46(s,6H).

[0120] Example 2: Preparation of Compound F-07

[0121] 2.1 Preparation of F704:

[0122] 3-Cyano-7-azaindole (0.5 g), sodium hydroxide (0.69 g), dimethylformamide (10 mL) and intermediate F203 (1.58 g, prepared according to the method of Example 1) were added to a reaction flask, reacted at room temperature for 0.5 hour, and extracted with water and ethyl acetate. The organic phase was taken and washed with brine, dried, concentrated and purified by column chromatography to obtain product F704 (0.51 g).

[0123] 2.2 Preparation of F-07:

[0124] Intermediate F704 (0.9 g, prepared according to the method in 2.1 above), tetrahydrofuran (10 mL), methanol (15 mL), water (10 mL), and lithium hydroxide (0.21 g) were added to a reaction flask and reacted at 60°C for 4 hours. Acetic acid was added to adjust the pH to 7, and the mixture was concentrated. Ethyl acetate was added for extraction, and the organic phase was concentrated and purified by column chromatography to obtain product F-07 (0.640 g). Mass spectrum: [M+H] + :352.13; NMR: 1H NMR (400MHz, DMSO-d6) δ12.81(s,1H),8.47(s,1H),8.45(dd,J=4.8,1.5Hz,1H),8.20(dd,J=8.0,1.5Hz,1H),7 .58-7.53(m,1H),7.37(dd,J=8.0,4.7Hz,1H),7.34-7.29(m,2H),6.85-6.80(m,1H),5.79(s,2H),1.45(s,6H).

[0125] Example 3: Preparation of Compound F-09

[0126] 3.1 Preparation of F901:

[0127] Sodium hydrosulfide (4.4 g), dimethylformamide (100 mL) and potassium carbonate (10.4 g) were added to a reaction flask, and 5-fluoro-2-bromobenzaldehyde (10.2 g) was added under stirring. The reaction was carried out at 70° C. After detecting that the raw materials were basically reacted, the mixture was cooled.

[0128] Methyl 2-bromoisobutyrate (10 g) was added and the mixture was allowed to react at room temperature for 20 minutes. Water and ethyl acetate were added for extraction. The organic phase was collected and washed with aqueous copper acetate and brine, dried, concentrated, and purified by column chromatography to obtain product F901 (4 g).

[0129] 3.2 Preparation of F902:

[0130] F901 (4 g, prepared according to the method in 3.1 above) and methanol (25 mL) were added to a reaction flask. Sodium borohydride (0.42 g) was added at -10°C. After reacting for 0.5 hours, the reaction was quenched by adding water. The methanol was removed by concentration under reduced pressure, and water and ethyl acetate were added for extraction. The organic phase was washed with aqueous copper acetate and brine, dried, concentrated, and purified by column chromatography to obtain the product F902 (3 g).

[0131] 3.3 Preparation of F903:

[0132] F902 (3 g, prepared according to the method in 3.2 above) and dichloromethane (20 mL) were added to a reaction flask. Phosphorus tribromide (3.14 g) was added at -10°C and allowed to react for 0.5 hours. The reaction was then continued at room temperature until the reaction of the starting materials was complete. The reaction was quenched with water. The organic phase was extracted with ethyl acetate, washed, dried, concentrated, and purified by column chromatography to obtain product F903.

[0133] 3.4 Preparation of F904:

[0134] 3-Cyanoindole (1.4 g), sodium hydroxide (0.7 g), and dimethylformamide (25 mL) were added to a reaction flask and reacted at room temperature for 1 hour. F903 obtained in step 3.3 was then added and allowed to react at room temperature until the starting materials were completely reacted. Water and ethyl acetate were added for extraction. The organic phase was washed, dried, concentrated, and purified by column chromatography to obtain product F904 (2 g).

[0135] 3.5 Preparation of F-09:

[0136] F904 (2 g, prepared according to the method in 3.4 above) and tetrahydrofuran (20 mL) were added to a reaction flask and dissolved. Methanol (10 mL), water (10 mL), and lithium hydroxide (0.42 g) were added and reacted at 60°C for 1 hour. Dilute hydrochloric acid was added to adjust the pH to 4, and the mixture was concentrated under reduced pressure. Ethyl acetate was added for extraction, and the product F-09 (1.53 g) was obtained after concentration and column chromatography purification. Mass spectrum: [M+H] + :369.11; NMR: 1 H NMR (400MHz, DMSO-d6) δ12.86(s,1H),8.34(s,1H),7.70(dd,J=6.8,1.7Hz,1H),7.64(dd,J=8.6,5.9Hz,1H),7.54(d, J=7.3Hz,1H),7.36-7.29(m,2H),7.22(td,J=8.5,2.9Hz,1H),6.59(dd,J=9.8,2.9Hz,1H),5.70(s,2H),1.46(s,6H).

[0137] Example 4: Preparation of Compound F-12

[0138] 4.1 Preparation of F1201:

[0139] Sodium hydrosulfide hydrate (8.3 g), dimethylformamide (200 mL), and potassium carbonate (19.6 g) were added to a reaction flask and stirred. 2,5-dibromobenzaldehyde (25 g) was added and allowed to react at 70°C until TLC showed complete reaction of the starting material. The mixture was then cooled. Methyl 2-bromoisobutyrate (18.8 g) was added and allowed to react at room temperature for 20 minutes. Water and ethyl acetate were added for extraction. The organic phase was washed with aqueous copper acetate and brine, dried, concentrated, and purified by column chromatography to obtain product F1201 (22.5 g).

[0140] 4.2 Preparation of F1202:

[0141] F1201 (22.5 g, prepared according to the method in 4.1 above) and 50 mL of methanol were added to a reaction flask. Sodium borohydride (1.9 g) was added at -10°C. After the reaction was complete, the reaction was quenched with water. The methanol was removed by concentration under reduced pressure, and water and ethyl acetate were added for extraction. The organic phase was washed with aqueous copper acetate and brine, dried, concentrated, and purified by column chromatography to obtain the product F1202 (15.9 g).

[0142] 4.3 Preparation of F1203:

[0143] F1202 (15.9 g, prepared according to the method in 4.2 above) and 100 mL of dichloromethane were added to a reaction flask. Phosphorus tribromide (13.5 g) was added at -10°C and allowed to react for 0.5 hours. The mixture was then brought to room temperature and allowed to react until the starting material was completely reacted. The reaction was quenched with water. Extraction was performed with ethyl acetate, and the organic phase was washed, dried, concentrated, and purified by column chromatography to obtain the product F1203.

[0144] 4.4 Preparation of F1204:

[0145] 3-Cyanoindole (6 g), sodium hydroxide (3 g), and dimethylformamide (100 mL) were added to a reaction flask and reacted at room temperature for 1 hour. F1203 obtained in step 4.3 was added and the reaction was continued at room temperature for 0.5 hour before stopping. Water and ethyl acetate were added for extraction. The organic phase was washed, dried, concentrated, and purified by column chromatography to obtain the product F1204 (12.1 g).

[0146] 4.5 Preparation of F1205:

[0147] F1204 (3 g, prepared according to the method of 4.4 above), methylboric acid (0.49 g), potassium carbonate (1.4 g), dioxane (30 mL) and water (6 mL) were added to the reaction flask, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl2) (0.29 g) was added under nitrogen. The reaction was carried out at 100°C under nitrogen protection overnight, filtered, and extracted with ethyl acetate. The organic phase was washed, dried, concentrated and purified by column chromatography to obtain the product F1205 (1.8 g).

[0148] 4.6 Preparation of F-12:

[0149] F1205 (1.8 g, prepared according to the method in 4.5 above) and tetrahydrofuran (20 mL) were added to a reaction flask to dissolve. Methanol (10 mL), water (10 mL), and lithium hydroxide (0.4 g) were added and reacted at 60°C until the starting materials reacted completely. Dilute hydrochloric acid was added to adjust the pH to 4, the mixture was concentrated, and ethyl acetate was added for extraction. After concentration and column chromatography purification, the product F-12 (1.55 g) was obtained. Mass spectrum: [M+H] + :365.14; NMR: 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),8.31(s,1H),7.69-7.66(m,1H),7.53(dd,J=7.1,1.3Hz,1H),7.46(d,J=7.9Hz ,1H),7.34-7.26(m,2H),7.14(dd,J=7.9,1.4Hz,1H),6.72(d,J=1.5Hz,1H),5.66(s,2H),2.17(s,3H),1.42(s,6H).

[0150] Example 5: Preparation of Compound F-14

[0151] 5.1 Preparation of F1401:

[0152] 4-Fluoroindole-3-carbaldehyde (0.815 g), hydroxylamine hydrochloride (0.416 g), and methanol (15 ml) were added to a reaction flask and reacted at 80°C until the starting materials were completely reacted. The mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain the product F1401 (0.854 g).

[0153] 5.2 Preparation of F1402:

[0154] F1401 (0.845 g, prepared according to the method in 5.1 above) and thionyl chloride (5 ml) were added to a reaction flask, reacted at 80°C for 30 minutes, cooled, concentrated, extracted with water and ethyl acetate, and the organic phase was washed and concentrated to obtain the product F1402 (0.660 g).

[0155] 5.3 Preparation of F1403:

[0156] F1402 (0.320 g, prepared according to the method in 5.2 above), sodium hydroxide (80 mg), and dimethylformamide (5 ml) were added to a reaction flask and reacted at 50°C for 10 minutes. F203 (0.606 g, prepared according to the method in Example 1) was then added and allowed to react for 30 minutes. The reaction was then quenched with water. Extraction was performed with ethyl acetate, and the organic phase was dried and concentrated to obtain the product F1403 (0.911 g).

[0157] 5.4 Preparation of F-14:

[0158] F1403 (0.911 g, prepared according to the method in 5.3 above), tetrahydrofuran (4 ml), methanol (2 ml), water (2 ml), and lithium hydroxide (0.168 g) were added to a reaction flask. After reacting at 50°C for 40 minutes, the reaction was quenched by adding water. Citric acid was added to adjust the pH to acidic. Extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by column chromatography to obtain the product F-14 (0.649 g). Mass spectrum: [M+H] + :369.13; NMR: 1 H NMR(400MHz,DMSO-d6)δ12.83(br,1H),δ8.41(s,1H),7.59-7.56(m,1H),7.38 -7.29(m,4H),7.11-7.06(m,1H),6.80-6.77(m,1H),5.72(s,2H),1.45(s,6H).

[0159] Example 6: Preparation of Compound F-16

[0160] 6.1 Preparation of F1601:

[0161] 6-Fluoroindole-3-carbaldehyde (1.63 g), hydroxylamine hydrochloride (0.83 g), and methanol (30 ml) were added to a reaction flask and reacted at 80°C for 3 hours. The mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain the product F1601 (1.684 g).

[0162] 6.2 Preparation of F1602:

[0163] F1601 (1.684 g, prepared according to the method in 6.1 above) and thionyl chloride (5 ml) were added to a reaction flask and reacted at 80°C for 30 minutes. The mixture was concentrated, extracted with water and ethyl acetate, and the organic phase was washed, concentrated, and purified by column chromatography to obtain the product F1602 (1.054 g).

[0164] 6.3 Preparation of F1603:

[0165] F1602 (0.320 g, prepared according to the method in 6.2 above), sodium hydroxide (80 mg), and dimethylformamide (5 ml) were added to a reaction flask and reacted at 50°C for 10 minutes. F203 (0.606 g, prepared according to the method in Example 1) was then added and allowed to react for 30 minutes. The reaction was then quenched with water. Extraction was performed with ethyl acetate, and the organic phase was dried and concentrated to obtain crude F1603 (0.900 g).

[0166] 6.4 Preparation of F-16:

[0167] F1603 (0.900 g, prepared according to the method in 6.3 above), tetrahydrofuran (4 ml), methanol (2 ml), water (2 ml), and lithium hydroxide (0.168 g) were added to a reaction flask. After reacting at 50°C for 40 minutes, the reaction was quenched by adding water. Citric acid was added to adjust the pH to acidic. Extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by column chromatography to obtain the product F-16 (0.820 g). Mass spectrum: [M+H] + :369.13; NMR: 1 H NMR (400MHz, DMSO-d6) δ12.85(br,1H),8.31(s,1H),7.74-7.70(m,1H),7.60-7.57(m,1H),7.46(dd,J=10Hz ,2.4Hz,1H),7.37-7.34(m,2H),7.18(td,J=10Hz,2.4Hz,1H),6.80-6.77(m,1H),5.67(s,2H),1.46(s,6H).

[0168] Example 7: Preparation of Compound F-17

[0169] 7.1 Preparation of F1701:

[0170] 7-Fluoroindole-3-carbaldehyde (0.490 g), hydroxylamine hydrochloride (0.333 g), and methanol (10 ml) were added to a reaction flask and reacted at 80°C until the starting materials were completely reacted. The mixture was concentrated under reduced pressure, extracted with water and ethyl acetate, and the organic phase was dried and concentrated to obtain the product F1701 (0.600 g).

[0171] 7.2 Preparation of F1702:

[0172] F1701 (1.085 g, prepared according to the method of 7.1 above) and dichlorothionyl (5 ml) were added to a reaction flask, reacted at 80°C for 30 minutes, concentrated, extracted with water and ethyl acetate, and the organic phase was washed and concentrated to obtain the product F1702 (1.01 g).

[0173] 7.3 Preparation of F1703:

[0174] F1702 (0.82 g, prepared according to the method in 7.2 above), sodium hydroxide (0.24 g), and dimethylformamide (8 ml) were added to a reaction flask and reacted at 50°C for 10 minutes. F203 (1.56 g, prepared according to the method in Example 1) was then added and stirred for 1 hour. The reaction was then quenched with water. Extraction was performed with ethyl acetate, and the organic phase was washed, dried, and concentrated to obtain crude F1703 (2 g).

[0175] 7.4 Preparation of F-17:

[0176] F1703 (2 g, prepared according to the method in 7.3 above), tetrahydrofuran (4 ml), methanol (2 ml), and water (2 ml) were added to a reaction flask. Lithium hydroxide was added to adjust the pH of the reaction solution to 14. After reacting at 50°C for 40 minutes, the reaction was quenched by adding water. Citric acid was added to adjust the pH to acidic. Extraction was performed with ethyl acetate, and the organic phase was dried, concentrated, and purified by column chromatography to obtain the product F-17 (0.449 g). Mass spectrum: [M+H] + :369.20; NMR 1 HNMR(400MHz,DMSO-d6)δ12.85(br,1H),8.35(s,1H),7.57-7.51(m,2H),7.34 -7.24(m,3H),7.15-7.10(m,1H),6.57-6.59(m,1H),5.82(s,2H),1.44(s,6H).

[0177] Example 8: Preparation of Compound F-20

[0178] 8.1 Preparation of F2001:

[0179] 2-Bromobenzaldehyde (15.00 g), sodium hydrosulfide (6.49 g), potassium carbonate (16.79 g) and dimethylformamide (80 mL) were added to a reaction flask and reacted at 70° C. After detecting that the raw materials were basically reacted, the mixture was cooled to room temperature.

[0180] Ethyl 1-bromocyclobutanecarboxylate (16.77 g) was added and the reaction was allowed to proceed at room temperature. After the reaction of the starting material was substantially complete, aqueous copper acetate was added to quench the reaction. Ethyl acetate was added for extraction, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography to obtain product F2001 (12.41 g).

[0181] 8.2 Preparation of F2002:

[0182] F2001 (12.41 g, prepared according to the method in 8.1 above) and methanol (60 ml) were added to a reaction flask and stirred below 0°C. Sodium borohydride (0.888 g) was added. After complete consumption of the starting material, the reaction was quenched by adding water. The mixture was concentrated under reduced pressure to remove the methanol. The pH was adjusted to 6 with citric acid. Aqueous copper acetate and ethyl acetate were added for extraction. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was collected, concentrated, and purified by column chromatography to obtain the product F2002 (10.51 g).

[0183] 8.3 Preparation of F2003:

[0184] F2002 (2.66 g, prepared according to the method in 8.2 above) and dichloromethane (18 mL) were added to a reaction flask. Phosphorus tribromide (2.70 g) was added at -15°C and stirred until the starting material reacted completely. The reaction was quenched by adding water. The aqueous and organic phases were separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with semi-saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the product F2003 (1.56 g).

[0185] 8.4 Preparation of F2004:

[0186] 3-Cyano-7-azaindole (0.678 g), F2003 (1.56 g, prepared according to the method in 8.3 above), and dimethylformamide (6 mL) were added to a reaction flask. The temperature was maintained at approximately 50°C. Sodium hydroxide (0.227 g) was added and the reaction was stirred for 1 hour. Water was added to quench the reaction. Citric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to yield the crude product F2004 (2.20 g).

[0187] 8.5 Preparation of F-20:

[0188] F2004 (2.20 g, prepared according to the method in 8.4 above), methanol (2 mL), tetrahydrofuran (4 mL), and water (2 mL) were added to a reaction flask. Lithium hydroxide was added to adjust the pH of the system to approximately 14, and the reaction was stirred at 50°C for 1 hour. The reaction solution was concentrated to dryness, extracted with water and ethyl acetate, and the aqueous phase was collected. The pH was adjusted to 5-6 with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was collected, concentrated, and purified by column chromatography to obtain the product F-20 (0.854 g). Mass spectrum: [M+H] + :364.14; NMR: 1 HNMR(400MHz,DMSO-d6)δ12.90(br,1H),8.48(s,1H),8.45(dd,J=4.8,1.6Hz,1H),8.21(dd,J=8.0Hz,1.6Hz,1H),7.38-7.36(m,2H),7.28(td,J =7.6Hz,1.6Hz,1H),7.20(td,J=7.6Hz,1.6Hz,1H),6.77(d,J=8.0Hz,1H ),5.68(s,2H),2.69-2.61(m,2H),2.20-2.13(m,3H),1.92-1.82(m,1H).

[0189] Example 9: Preparation of Compound F-26

[0190] 9.1 Preparation of F2601:

[0191] 2-Bromo-5-fluorobenzaldehyde (24.7 g), sodium hydrosulfide (10.3 g), potassium carbonate (25 g) and dimethylformamide (250 mL) were added to a reaction flask and reacted at 70°C for 30 minutes. Cooled to room temperature. Ethyl 1-bromocyclobutanecarboxylate (27.56 g) was added and reacted for 30 minutes. The system changed from brown-black to red. After the raw materials were basically reacted, copper acetate aqueous solution was added to quench the reaction. Ethyl acetate was added for extraction, washed with half-saturated brine, dried over anhydrous sodium sulfate, and the organic phase was collected. After concentration and column chromatography purification, the product F2601 (18 g) was obtained.

[0192] 9.2 Preparation of F2602:

[0193] F2601 (18 g, prepared according to the method in 9.1 above) and methanol (40 ml) were added to a reaction flask, stirred below 0°C, and sodium borohydride (1.69 g) was added and allowed to react for 2 hours. The reaction was quenched by adding water. The methanol was removed by concentration under reduced pressure, and the residual solution was adjusted to a pH of approximately 6 with citric acid. The solution was then extracted with aqueous copper acetate and ethyl acetate. The solution was washed with semi-saturated brine and dried over anhydrous sodium sulfate. The organic phase was collected and concentrated to yield the product F2602 (13.21 g).

[0194] 9.3 Preparation of F2603:

[0195] F2602 (10.80 g, prepared according to the method in 9.2 above) and dichloromethane (55 mL) were added to a reaction flask. Phosphorus tribromide (10.28 g) was added at -15°C and stirred until the starting material was completely consumed. The reaction was quenched by adding water. The organic and aqueous phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with semi-saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the product F2603 (6.15 g).

[0196] 9.4 Preparation of F2604:

[0197] 3-Cyano-7-azaindole (0.716 g), F2603 (1.606 g, prepared according to the method in 9.3 above), and dimethylformamide (5 mL) were added to a reaction flask. The temperature was maintained at approximately 50°C. Sodium hydride (0.300 g) was added and the reaction was stirred for 1 hour. The reaction mixture was quenched with water. Citric acid was added to adjust the pH to 4, and ethyl acetate was added for extraction. The mixture was dried over anhydrous sodium sulfate, and the organic phase was collected and concentrated to yield the crude product F2604 (2.87 g).

[0198] 9.5 Preparation of F-26:

[0199] F2604 (2.87 g, prepared according to the method in 9.4 above), ethanol (3 mL), tetrahydrofuran (6 mL), and water (3 mL) were added to a reaction flask. Lithium hydroxide was added to adjust the pH of the system to 14, and the reaction was stirred at 50°C for 1 hour. The reaction solution was concentrated to dryness, extracted with water and ethyl acetate, and the aqueous phase was collected. The pH was adjusted to 5-6 with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was collected, concentrated, and purified by column chromatography to obtain the product F-26 (0.497 g). Mass spectrum: [M+H] + :382.15, NMR: 1HNMR(400MHz,DMSO-d6)δ12.91(br,1H),8.49(s,1H),8.46(dd,J=4.4Hz,1.2Hz,1H),8.21(dd,J=8.0Hz,1.2Hz,1H),7.52-7.48(m,1H),7.41-7. 36(m,1H),7.21(td,J=8.4Hz,2.8Hz,1H),6.68(dd,J=10.0Hz,2.4Hz,1H ),5.71(s,2H),2.65-2.58(m,2H),2.21-2.09(m,3H),1.89-1.84(m,1H).

[0200] Example 10: Preparation of other compounds

[0201] Referring to the methods of Examples 1-9, some compounds of the present application were obtained, as shown in Table 1.

[0202] Table 1 Some examples of compounds in this application

[0203] Example 11: Efficacy Test

[0204] The inhibitory effects of each compound on uric acid transporter URAT1 were tested.

[0205] 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).

[0206] 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).

[0207] 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 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: A: <100 nmol / L; B: 100-500 nmol / L; C: 500-1000 nmol / L; D: >1000 nmol / L. The results are shown in Table 2.

[0208] Table 2: Inhibitory effects of some compounds of this application on uric acid transporter (IC 50 )

[0209] This experiment shows that compared with similar compounds, the compounds of the present application have stronger inhibitory activity against URAT1.

[0210] Example 12: Toxicology Test

[0211] Each compound was tested for toxicity in mice by repeated 28-day dosing.

[0212] 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 removed 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.

[0213] Results: After repeated administration of compounds F-02, F-05, F-07, F-08, F-09, F-10, F-11, F-12, F-13, F-14, F-16, F-17, F-20, F-26, F-27, F-28, and F-30 for 28 days, histopathological examination of the mice showed no liver or kidney toxicity. After repeated administration of verinurad for 28 days, histopathological examination of three out of eight mice showed kidney toxicity.

[0214] This experiment shows that the compound of the present application has better safety than similar compounds.

[0215] 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 is a six-membered ring, ring Y is a five-membered ring, ring Z is 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, R2 and R3 are each independently selected from -CH2- or -S-; a, b and q are each independently selected from 0, 1, 2 or 3, and a, b and q are not all 0; R4 and R5 are each independently selected from alkyl or alkoxy, and R4 and R5 are optionally cyclic or not cyclic 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 at least one of ring G and ring Y is a heterocyclic ring.

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.

5. The compound according to claim 1, wherein at least one of ring G and ring Y is an unsaturated ring.

6. 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, R5, a, b and q are as defined in claim 1; R6, R7 and R 12 are each independently selected from -C- or -N-; R8, R9, R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 20 Each is independently selected from -C-, -N-, -S- or -O-.

7. The compound according to claim 6, wherein R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 and R 14 At least one of them is -N-.

8. The compound according to claim 6, wherein R6 is -N-.

9. The compound according to claim 6, wherein ring Y is an unsaturated ring.

10. The compound according to claim 1, wherein the compound of formula I is as shown in formula I-II: in, Ring G, Ring Z, R1, R2, R3, R4, R5, R7, R8, R9, R 10 , R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , a, b and q are as defined in claim 6; Ring G, Ring Y or Ring Z is optionally further substituted; R 13 and R 14 Each is independently selected from -C- or -N-.

11. The compound according to claim 10, wherein R 13 , R 14 , R7 and R 12 There are 0 to 2 -N- in it.

12. The compound according to claim 10, wherein ring Y is selected from pyrrole, imidazole, pyrazole or triazole. The compound according to claim 1 , wherein ring G is an unsaturated six-membered ring.

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

15. The compound according to claim 14, wherein R8, R9, R 10 and R 11 There are 0 to 3 -N- in it.

16. The compound according to claim 14, wherein ring G is selected from benzene, pyridine, pyridazine, pyrimidine, pyrazine or triazine. The compound according to claim 1 , wherein ring Z is an unsaturated six-membered ring.

18. The compound according to claim 1, wherein the compound of formula I is as shown in formula I-IV: in, R1, R2, R3, R4, R5, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , a, b and q are as defined in claim 14, 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-.

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

20. The compound according to claim 18, wherein ring Z is benzene, pyridine, pyridazine, pyrimidine, pyrazine or triazine.

21. The compound according to claim 1, wherein R1 is -CH2-, R2 is -S-, R3 is -CH2-, a and q are independently selected from 0, 1, 2 or 3, and b is 1.

22. The compound according to claim 1, wherein R2 is -CH2-, b is selected from 1, 2 or 3, a is 0, and q is 0.

23. The compound according to claim 1, wherein the compound of formula I is as shown in formula IV: in, R4, R5, 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 18, ring G, ring Y or ring Z is optionally further substituted; b is selected from 1, 2 or 3.

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 as shown in formula I-VI: in, R4, R5, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 and b as defined in claim 23; 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 or 2, and m and n are each independently selected from 0, 1, 2, 3 or 4.

27. The compound according to claim 1, wherein R4 and R5 do not form a ring together, and R4 and R5 are each independently selected from C1-C5 alkyl.

28. The compound according to claim 1, wherein R4 and R5 are taken together to form a ring, and R4 and R5 together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

29. The compound represented by formula II: in, Ring Y, Ring G, Ring Z, R1, R2, R3, R4, R5, a, b and q are as defined 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 drug for reducing uric acid levels in the body or a drug for treating a disease 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.