Substituted heteroaryl carboxylic acid compound as well as preparation method and pharmaceutical application thereof

Abstract

The invention belongs to the field of medicinal chemistry, and discloses a substituted heteroaryl carboxylic acid compound as well as a preparation method and medicinal application thereof. Specifically, the invention discloses a substituted heteroaryl carboxylic acid compound as shown in a formula (I), physiologically acceptable salts of the substituted heteroaryl carboxylic acid compound, a preparation method of the compound, a pharmaceutical composition, application of the substituted heteroaryl carboxylic acid compound in preparation of a urate transporter 1 (URAT1) inhibitor, and application of the substituted heteroaryl carboxylic acid compound in preparation of drugs for preventing and / or treating hyperuricemia and gout. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to substituted heteroaryl carboxylic acid compounds represented by general formula (I) and physiologically acceptable salts thereof, as well as use of these compounds in preparing urate transporter 1 (URAT1) inhibitors and in preparing drugs for preventing or treating URAT1-related diseases, and also relates to preparation methods of these compounds and pharmaceutical compositions containing the compounds. Background Art

[0002] Gout is an inflammatory joint disease caused by the deposition and precipitation of monosodium uric acid in joints and peripheral tissues. Hyperuricemia caused by increased uric acid production or (and) decreased excretion is the direct cause of gout. Gout and hyperuricemia are also closely related to metabolic syndrome, hypertension, diabetes, cardiovascular disease and other diseases.

[0003] Urate-lowering therapy (ULT) is the main strategy for treating hyperuricemia and chronic gout. Currently, urate-lowering therapies are mainly divided into three categories: (1) xanthine oxidase (XO) inhibitors that inhibit uric acid production; (2) urate transporter 1 (URAT1) inhibitors that promote uric acid excretion; and (3) uricases that convert uric acid into water-soluble substances. The pathogenesis of about 90% of hyperuricemia patients is related to reduced uric acid excretion, and URAT1 is an important target that has been clinically verified to regulate uric acid reabsorption and promote uric acid excretion. Therefore, URAT1 inhibitors are important uric acid-lowering therapies. Currently, the main URAT1 inhibitors used in clinical practice are probenecid, benzbromarone, and lesinade. However, probenecid and benzbromarone have problems such as poor tolerability and many toxic and side effects. Lesinade, which was launched in late 2015, is used in combination with the XO inhibitor allopurinol in the clinical treatment of hyperuricemia and chronic gout. However, its inhibitory activity against URAT1 is relatively weak, and a large dose (200 mg / d) is used clinically.

[0004] In recent years, with the change of people's dietary structure and the acceleration of population aging, the incidence of hyperuricemia and gout has continued to rise, and has become a national health problem that cannot be ignored. Currently, there are few clinical treatment drugs, and each has different defects. Therefore, the study of new URAT1 inhibitors has important practical significance and market prospects. Summary of the invention

[0005] The present invention aims to provide a substituted heteroaryl carboxylic acid compound as shown in the general formula (I).

[0006] Another object of the present invention is to provide a method for preparing the substituted heteroaryl carboxylic acid compounds represented by the general formula (I).

[0007] Another object of the present invention is to provide a use of a substituted heteroaryl carboxylic acid compound represented by general formula (I) in the preparation of a urate transporter 1 (URAT1) inhibitor, and in the preparation of a drug for preventing or treating URAT1-related diseases.

[0008] The technical problem solved by the present invention is to provide a substituted heteroaryl carboxylic acid compound represented by formula (I) and a physiologically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition thereof and use thereof in preparing a urate transporter 1 (URAT1) inhibitor, and use thereof in preparing a method for preventing and / or treating hyperuricemia and gout.

[0009] In order to solve the technical problem of the present invention, the present invention adopts the following technical solution:

[0010] The first aspect of the technical solution of the present invention is to provide a substituted heteroaryl carboxylic acid compound represented by the following general formula (I) and a physiologically acceptable salt thereof:

[0011]

[0012] in,

[0013] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro;

[0014] X or Y is independently selected from N or C;

[0015] Z is selected from C 1- C 3 Alkylene,

[0016] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy.

[0017] Another technical solution of the present invention is to provide a compound represented by general formula (IA) or a physiologically acceptable salt thereof:

[0018]

[0019] in,

[0020] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro;

[0021] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy.

[0022] Another technical solution of the present invention is to provide a compound represented by the general formula (IAa) or a physiologically acceptable salt thereof:

[0023]

[0024] in,

[0025] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy;

[0026] R 4 is a monosubstituted or polysubstituted group on the benzene ring selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro.

[0027] Another technical solution of the present invention is to provide a compound represented by the general formula (IAb) or a physiologically acceptable salt thereof:

[0028]

[0029]

[0030] in,

[0031] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy;

[0032] R 5 is a monosubstituted or polysubstituted group on the pyridine ring selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro.

[0033] Another technical solution of the present invention is to provide a compound represented by the general formula (IB) or a physiologically acceptable salt thereof:

[0034]

[0035] in,

[0036] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro;

[0037] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy.

[0038] Another technical solution of the present invention is to provide a compound represented by the general formula (IC) or a physiologically acceptable salt thereof:

[0039]

[0040] in,

[0041] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro;

[0042] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy.

[0043] Another technical solution of the present invention is to provide a compound represented by the general formula (ID) or a physiologically acceptable salt thereof:

[0044]

[0045] in,

[0046] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro;

[0047] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy.

[0048] Another technical solution of the present invention is to provide a compound represented by the general formula (IDa) or a physiologically acceptable salt thereof:

[0049]

[0050] in,

[0051] R 1 , R 2 or R3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy;

[0052] R 6 is a monosubstituted or polysubstituted group on the pyridine ring selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro.

[0053] Another technical solution of the present invention is to provide a compound represented by the general formula (IDb) or a physiologically acceptable salt thereof:

[0054]

[0055] in,

[0056] R 1 , R 2 or R 3 are independently selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy;

[0057] R 7 is a monosubstituted or polysubstituted group on the thiophene ring selected from hydrogen, halogen, C 1- C 3 Alkyl, C 1- C 3 Alkoxy, trifluoromethyl, cyano, nitro.

[0058] Another technical solution of the present invention is to provide the compound shown or a physiologically acceptable salt thereof, characterized in that the compound is selected from:

[0059]

[0060]

[0061]

[0062]

[0063] The second aspect of the technical solution of the present invention provides a method for preparing the compound represented by general formula (I), characterized in that it comprises the following steps:

[0064] The raw material I-1 undergoes nitrogen alkylation reaction with a halide to obtain an intermediate I-2, and the intermediate I-2 undergoes CS coupling reaction with a thiol compound to obtain an intermediate I-3, and then I-3 is hydrolyzed under alkaline conditions to obtain the target compound I;

[0065]

[0066] Ar, R 1 , R 2 , R 3 The definitions of X, Y, and Z are the same as those in claim 1.

[0067] The third aspect of the technical solution of the present invention provides a pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective dose of any compound as described in the first aspect and a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0068] The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems.

[0069] In order to prepare pharmaceutical preparations, the compounds of general formula (I) can be mixed with suitable pharmaceutical carrier materials, aromatics, flavoring agents and pigments by known methods and made into tablets or coated tablets, or suspended or dissolved in water or oil with other additives.

[0070] The present invention also relates to a pharmaceutical composition comprising a pharmaceutically effective dose of the compound described in the general formula (I) and a pharmaceutically acceptable carrier.

[0071] Pharmacological studies have shown that the compounds of the general formula (I) of the present invention have the activity of inhibiting URAT1 and can be used to treat diseases related to URAT1 activity, such as hyperuricemia and gout.

[0072] The compounds of the present invention can be administered orally or parenterally. Oral administration can be tablets, capsules, coatings, and parenteral administration forms include injections and suppositories. These preparations are prepared according to methods well known to those skilled in the art. The adjuvants used to make tablets, capsules, and coatings are conventional adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, and the solvents used in liquid dosage forms include water, ethanol, propylene glycol, and vegetable oils such as corn oil, peanut oil, olive oil, etc. The preparations containing the compounds of the present invention may also contain other adjuvants, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, pigments, etc.

[0073] The fourth aspect of the technical solution of the present invention provides the use of the compound described in the first aspect and a physiologically acceptable salt thereof in the preparation of a urate transporter 1 inhibitor.

[0074] Also provided is the use of the compound of the first aspect and a physiologically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a URAT1-related disease.

[0075] The disease is selected from hyperuricemia and gout.

[0076] Beneficial technical effects:

[0077] URAT1 inhibitors are important uric acid-lowering drugs used clinically. The compounds involved in the present invention have significant URAT1 inhibitory effects. Among them, some compounds have stronger in vitro URAT1 inhibitory activity than the clinical similar product benzbromarone. DETAILED DESCRIPTION

[0078] The invention will be further described below with reference to the embodiments, but these embodiments do not limit the scope of the invention.

[0079] The reagents and solvents used in the synthesis experiments were purchased from commercial sources and used directly without treatment. The anhydrous solvent was a commercially purchased ultra-dry solvent, and the mixing ratio of the solvents was a volume ratio. All reaction monitoring was performed using GF-254 thin layer silica gel plates, and column chromatography separation was performed using 200-300 mesh silica gel. 1 H-NMR was acquired by Varian Mercury 400-MHz NMR spectrometer. Chemical shifts (δ) are given in parts per million (ppm), the internal standard is TMS, and coupling constants are in Hertz (Hz).

[0080] Example 1: Preparation of TM-1

[0081]

[0082] (1) Preparation of intermediate IA-1

[0083]

[0084] 4-Chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine (1.39 g, 5 mmol), 2,6-dibromobenzyl bromide (2.47 g, 7.5 mmol), potassium carbonate (1.38 g, 10 mmol) were added to 50 mL N,N-dimethylformamide in sequence, and the reaction system was heated to 70°C for 10 h. TLC monitored the reaction to be complete, the reaction solution was added with water, extracted with ethyl acetate three times, washed with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography (petroleum ether-ethyl acetate 5:1) was used to obtain intermediate IA-1, 1.84 g, yield: 70%. 1 H NMR (400 MHz, DMSO-d 6)δ8.31(d,J=5.2Hz,1H),7.80(d,J=8.1Hz,2H),7.65(d,J=8.1Hz,1H),7.30(d,J=5.3Hz,1H),7.23(s,1H),5.71(s,2H).

[0085] (2) Preparation of intermediate IA-2

[0086]

[0087] The intermediate IA-1 (1.05 g, 2 mmol), cesium carbonate (0.997 g, 3 mmol), tris(dibenzylideneacetone)palladium (0.092 g, 0.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.116 g, 0.2 mmol) were added to 30 mL of toluene, nitrogen was protected, ethyl mercaptoacetate (0.288 g, 2.4 mmol) was added, and the reaction was carried out at 70°C for 10 h. The reaction was monitored by TLC, the solid was removed by filtration, the liquid was decompressed to remove the solvent, and column chromatography (petroleum ether-ethyl acetate 5:1) was used to obtain 0.68 g of the intermediate IA-2, with a yield of 65%. 1 H NMR (400 MHz, DMSO-d 6 )δ8.33(d,J=5.2Hz,1H),7.81(d,J=8.1Hz,2H),7.37–7.32(m,2H),7.08(s, 1H), 5.70 (s, 2H), 3.85 (q, J = 7.2Hz, 2H), 3.50 (s, 2H), 0.93 (t, J = 7.2Hz, 3H).

[0088] (3) Preparation of target compound TM-1

[0089]

[0090] The intermediate IA-2 (519 mg, 1 mmol) and lithium hydroxide (84 mg, 2 mmol) were added to a 30 mL ethanol-water (4:1) mixed solvent and stirred at room temperature for 6 h. The reaction was monitored by TLC. Most of the organic solvent in the reaction was removed under reduced pressure, and then diluted with water. The pH was slowly adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The solid was precipitated, filtered, and separated by column chromatography (dichloromethane-methanol 10:1) to obtain the target TM-10.31 g, yield: 63%, white solid. 1 H NMR (400 MHz, DMSO-d 6)δ12.53(s,1H),8.31(d,J=5.2Hz,1H),7.80(d,J=8.1Hz,2H),7.33(m,2H),7.16(s,1H),5.69(s,2H),3.48(s,2H).

[0091] Example 2: Preparation of TM-2

[0092]

[0093] The synthesis method is similar to that of TM-1, except that 2,6-dichlorobenzyl bromide is used instead of 2,6-dibromobenzyl bromide in the first step, and the yield of the last step is 62%, and the product is a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ12.53(s,1H),8.29(d,J=5.2Hz,1H),7.59(s,1H),7.57(s,1H),7.48(m,1H),7.29(d,J=4.3Hz,2H)5.68(s,2H),3.48(s,2H).

[0094] Example 3: Preparation of TM-3

[0095]

[0096] The synthesis method is similar to that of TM-2, except that 4-bromo-3-iodo-7-azaindole is used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield of the last step is 55%, as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ12.54(s,1H),8.18(d,J=5.2Hz,1H),7.58(d,J=8.1Hz,2H),7.51–7.43(m,2H),7.32(s,1H),5.67(s,2H),3.49(s,2H).

[0097] Example 4: Preparation of TM-4

[0098]

[0099] The synthesis method is similar to that of TM-1, except that 4-(bromomethyl)-3,5-dichloropyridine is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 50%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ12.59(s,1H),8.67(s,2H),8.22(d,J=5.2Hz,1H),7.57(s,1H),7.26(d,J=5.2Hz,1H),5.69(s,2H),3.49(s,2H).

[0100] Example 5: Preparation of TM-5

[0101]

[0102] The synthesis method is similar to that of TM-1, except that 2-bromo-6-chlorobenzyl bromide is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 65%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.28(d,J=5.2Hz,1H),7.74(d,J=8.1Hz,1H),7.61(d,J=8.1Hz,1H),7.39(t ,J=8.1Hz,1H),7.28(d,J=5.2Hz,1H),7.17(s,1H),5.67(s,2H),3.44(s,2H).

[0103] Example 6: Preparation of TM-6

[0104]

[0105] The synthesis method is similar to that of TM-2, except that 3-iodo-4-methoxy-1H-pyrrolo[2,3-B]pyridine is used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield of the last step is 52%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.44(s,1H),8.22(d,J=5.6Hz,1H),7.58(d,J=8.1Hz,2H),7.47(t,J=8.1Hz, 1H), 6.89 (s, 1H), 6.77 (d, J = 5.6Hz, 1H), 5.60 (s, 2H), 3.96 (s, 3H), 3.48 (s, 2H).

[0106] Example 7: Preparation of TM-7

[0107]

[0108] The synthesis method is similar to that of TM-2, except that 5-bromo-4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine is used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the last step has a yield of 55% as a white solid.1 H NMR (400 MHz, DMSO-d 6 )δ12.55(s,1H),8.56(s,1H),7.58(d,J=8.1Hz,2H),7.52–7.43(m,1H),7.37(s,1H),5.67(s,2H),3.49(s,2H).

[0109] Example 8: Preparation of TM-8

[0110]

[0111] The synthesis method is similar to that of TM-2, except that 4,5-dichloro-3-iodo-1H-pyrrolo[2,3-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step, and the yield in the last step is 54%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.49(s,1H),7.58(d,J=8.1Hz,2H),7.47(t,J=8.1Hz,1H),7.38(s,1H),5.67(s,2H),3.47(s,2H).

[0112] Example 9: Preparation of TM-9

[0113]

[0114] The synthesis method is similar to that of TM-2, except that 4,6-dichloro-3-iodo-1H-pyrrolo[2,3-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step and the yield of the last step is 55%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ7.56(d,J=8.1Hz,2H),7.49–7.42(m,1H),7.40(s,1H),7.26(s,1H),5.60(s,2H),3.45(s,2H).

[0115] Example 10: Preparation of TM-10

[0116]

[0117] The synthesis method is similar to that of TM-2, except that 5-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step and the yield in the last step is 56%, as a white solid. 1 HNMR (400 MHz, DMSO-d6 )δ12.55(s,1H),8.37(s,1H),8.11(s,1H),7.58(d,J=8.2Hz,2H),7.47(t,J=8.2Hz,1H),7.40(s,1H),5.67(s,2H),3.44(s,2H).

[0118] Example 11: Preparation of TM-11

[0119]

[0120] The synthesis method is similar to that of TM-2, except that 6-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step, and the yield of the last step is 65%, as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ8.08(d,J=8.1Hz,1H),7.58(d,J=8.1Hz,2H),7.48(t,J=8.1Hz,1H),7.31–7.13(m,2H),5.61(s,2H),3.39(s,2H).

[0121] Example 12: Preparation of TM-12

[0122]

[0123] The synthesis method is similar to that of TM-1, except that 1-bromo-3-(bromomethyl)-2,4-dimethoxybenzene is used in the first step to replace 2,6-dibromobenzyl bromide, and the yield of the last step is 52%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.51(s,1H),8.32(d,J=5.2Hz,1H),7.66(d,J=9.1Hz,1H),7.43–7.34(m,1H),7.30(d, J=5.2Hz,1H),6.93(d,J=9.1Hz,1H),5.47(s,2H),3.82(s,3H),3.62(s,3H),3.49(s,2H).

[0124] Example 13: Preparation of TM-13

[0125]

[0126] The synthesis method is similar to that of TM-1, except that 2,3,5-tribromo-4-(bromomethyl)thiophene is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 45%, and the product is a white solid.1 H NMR (400 MHz, DMSO-d 6 )δ8.24(d,J=5.2Hz,1H),7.44(s,1H),7.25(d,J=5.2Hz,1H),5.41(s,2H),3.45(s,2H).

[0127] Example 14: Preparation of TM-14

[0128]

[0129] The synthesis method is similar to that of TM-1, except that 2-bromo-3-(bromomethyl)benzothiophene is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 52%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.55(s,1H),8.33(d,J=5.1Hz,1H),7.97(d,J=7.5Hz,1H),7.86(d,J=7.5Hz,1H), 7.63(s,1H),7.36(t,J=6.3Hz,2H),7.31(d,J=5.1Hz,1H),5.70(s,2H),3.50(s,2H).

[0130] Example 15: Preparation of TM-15

[0131]

[0132] The synthesis method is similar to that of TM-1, except that 2-bromo-3-(bromomethyl)benzofuran is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 45%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.54(s,1H),8.29(d,J=5.3Hz,1H),7.87(s,1H),7.57(d,J=7.9Hz,1H),7.44(d,J =7.9Hz, 1H), 7.29 (t, J = 7.7Hz, 2H), 7.21 (t, J = 7.7Hz, 1H), 5.57 (s, 2H), 3.52 (s, 2H).

[0133] Example 16: Preparation of TM-16

[0134]

[0135] The synthesis method is similar to that of TM-1, except that 3-bromo-2-(bromomethyl)benzothiophene is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield of the last step is 54%, and the product is a white solid.1 H NMR (400 MHz, DMSO-d 6 )δ8.26(d,J=5.3Hz,1H),7.92(d,J=8.1Hz,1H),7.84(s,1H),7.74(d,J=8.1Hz,1H),7.5 0(t,J=7.6Hz,1H),7.42(t,J=7.6Hz,1H),7.32–7.16(m,1H),5.80(s,2H),3.52(s,2H).

[0136] Example 17: Preparation of TM-17

[0137]

[0138] The synthesis method is similar to that of TM-1, except that 2-(bromomethyl)biphenyl is used in the first step instead of 2,6-dibromobenzyl bromide, and the yield in the last step is 42%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.13(d,J=5.1Hz,1H),7.49–7.32(m,7H),7.29–7.20(m,3H),6.83(d,J=7.6Hz,1H),5.43(s,2H),3.48(s,2H).

[0139] Example 18: Preparation of TM-18

[0140]

[0141] The synthesis method was similar to that of TM-4, except that 3-iodo-7-azaindole was used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield in the last step was 62%, resulting in a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.51(s,1H),8.68(s,2H),8.30(dd,J=4.7,1.6Hz,1H),8.04(dd,J=7.9,1. 6Hz, 1H), 7.55 (s, 1H), 7.21 (dd, J = 7.9, 4.7Hz, 1H), 5.69 (s, 2H), 3.43 (s, 2H).

[0142] Example 19: Preparation of TM-19

[0143]

[0144] The synthesis method is similar to that of TM-20, except that 4-(bromomethyl)-3,5-dibromopyridine is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the first step, and the yield in the last step is 48%, and the product is a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ12.45(s,1H),8.81(d,J=1.9Hz,2H),8.32(d,J=4.9Hz,1H),8.05(d,J=8.0 Hz, 1H), 7.42 (s, 1H), 7.23 (dd, J = 8.0, 4.9Hz, 1H), 5.67 (s, 2H), 3.43 (s, 2H).

[0145] Example 20: Preparation of TM-20

[0146]

[0147] The synthesis method was similar to that of TM-1, except that 3-iodo-7-azaindole was used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield in the last step was 51%, resulting in a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.49(s,1H),8.38(dd,J=4.7,1.6Hz,1H),8.05(dd,J=8.1,1.6Hz,1H),7.80(d,J=8.1Hz,2 H), 7.32 (t, J = 8.1Hz, 1H), 7.24 (dd, J = 7.8, 4.7Hz, 1H), 7.13 (s, 1H), 5.69 (s, 2H), 3.40 (s, 2H).

[0148] Example 21: Preparation of TM-21

[0149]

[0150] The synthesis method is similar to that of TM-2, except that 3-iodo-7-azaindole is used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield of the last step is 55%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.49(s,1H),8.36(dd,J=4.6,1.6Hz,1H),8.04(dd,J=7.9,1.6Hz,1H),7.58(d,J=8.1 Hz, 2H), 7.48 (m, 1H), 7.27 (s, 1H), 7.23 (dd, J = 7.9, 4.6Hz, 1H), 5.68 (s, 2H), 3.41 (s, 2H).

[0151] Example 22: Preparation of TM-22

[0152]

[0153] The synthesis method is similar to that of TM-2, except that 3-iodo-5-methyl-1H-pyrrolo[2,3-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step and the yield in the last step is 51%, as a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ8.20(s,1H),7.84(s,1H),7.62–7.54(m,2H),7.47(dd,J=9.2,7.2Hz,1H),7. 20(d,J=1.7Hz,1H), 5.64(d,J=1.7Hz,2H), 3.38(d,J=1.7Hz,2H), 2.42(s,3H).

[0154] Example 23: Preparation of TM-23

[0155]

[0156] The synthesis method is similar to that of TM-2, except that 3-iodo-1H-pyrazolo[3,4-B]pyridine is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step and the yield in the last step is 60%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.70(s,1H),8.64(d,J=4.5Hz,1H),8.22(d,J=8.1Hz,1H),7.54(s,1H),7.52(s ,1H),7.43(t,J=8.1Hz,1H),7.28(dd,J=8.1,4.5Hz,1H),5.82(s,2H),3.81(s,2H).

[0157] Example 24: Preparation of TM-24

[0158]

[0159] The synthesis method is similar to that of TM-2, except that 3-iodoindazole is used in the first step instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine, and the yield of the last step is 59%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ12.65(s,1H),7.71(dd,J=14.8,8.3Hz,2H),7.54(d,J=8.3Hz,2H),7.50–7.39(m,2H),7.19(t,J=7.5Hz,1H),5.76(s,2H),3.77(s,2H).

[0160] Example 25: Preparation of TM-25

[0161]

[0162] The synthesis method is similar to that of TM-24, except that ethyl 3-mercaptopropionate is used instead of ethyl mercaptoacetate in the second step, and the yield of the last step is 55%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.25(s,1H),7.74(d,J=8.5Hz,1H),7.64(d,J=8.1Hz,1H),7.54(d,J=8.1Hz,2H),7 .50–7.40(m,2H),7.19(t,J=7.5Hz,1H),3.08(t,J=7.0Hz,2H),2.53(t,J=7.0Hz,2H).

[0163] Example 26: Preparation of TM-26

[0164]

[0165] (1) Preparation of intermediate IA-3

[0166]

[0167] 3-Mercaptoindole (746 mg, 5 mmol), ethyl bromoacetate (877 mg, 5.25 mmol), and potassium carbonate (1.38 g, 10 mmol) were added to 50 mL of acetonitrile and reacted at 70 °C for 12 h. The reaction was completed after monitoring by TLC. After the solvent was removed under reduced pressure, column chromatography (petroleum ether-ethyl acetate 5:1) was used to obtain 1.05 g of intermediate IA-3 in a yield of 89%.

[0168] (2) Preparation of intermediate IA-4

[0169]

[0170] The intermediate IA-3 (471 mg, 2 mmol), 4-(bromomethyl)-3,5-dichloropyridine (723 mg, 3 mmol), and potassium carbonate (552 mg, 4 mmol) were added to 50 mL of N,N-dimethylformamide in sequence, and the reaction system was heated to 70°C for 10 h. The reaction was complete when monitored by TLC. The reaction solution was added with water, extracted with ethyl acetate three times, washed with saturated sodium chloride solution, and the organic phase was dried with anhydrous sodium sulfate. After removing the solvent under reduced pressure, column chromatography (petroleum ether-ethyl acetate 5:1) was used to obtain the intermediate IA-4, 0.45 g, yield: 57%.

[0171] (2) Preparation of target compound TM-26

[0172]

[0173] The intermediate IA-4 (395 mg, 1 mmol) and lithium hydroxide (84 mg, 2 mmol) were added to a 30 mL ethanol-water (4:1) mixed solvent and stirred at room temperature for 6 h. The reaction was monitored by TLC. Most of the organic solvent in the reaction was removed under reduced pressure, and then diluted with water. The pH was slowly adjusted to 4-5 with 1N hydrochloric acid aqueous solution. The solid was precipitated, filtered, and separated by column chromatography (dichloromethane-methanol 10:1) to obtain 0.195 g of the target product, with a yield of 53%, as a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.46(s,1H),8.72(d,J=1.5Hz,2H),7.64(d,J=8.2Hz,1H),7.49(d,J=8.2Hz,1H), 7.38(s,1H),7.23(t,J=7.5Hz,1H),7.15(t,J=7.5Hz,1H),5.62(s,2H),3.38(s,2H).

[0174] Example 27: Preparation of TM-27

[0175]

[0176] The synthesis method is similar to that of TM-26, except that 4-(bromomethyl)-3,5-dibromopyridine is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 52%, and the product is a white solid. 1 HNMR (400 MHz, DMSO-d 6)δ12.45(s,1H),8.84(s,2H),7.64(d,J=7.5Hz,1H),7.52(d,J=8.2Hz,1H ),7.24(d,J=3.6Hz,2H),7.17(t,J=7.5Hz,1H),5.59(s,2H),3.38(s,2H).

[0177] Example 28: Preparation of TM-28

[0178]

[0179] The synthesis method is similar to that of TM-26, except that 3-(bromomethyl)-2,4-dichloropyridine is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 55%, and the product is a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ12.44(s,1H),8.44(d,J=5.3Hz,1H),7.74(d,J=5.3Hz,1H),7.64(d,J=7.7Hz,1H),7.55(d,J= 8.3Hz, 1H), 7.33 (s, 1H), 7.24 (t, J = 7.7Hz, 1H), 7.16 (t, J = 7.7Hz, 1H), 5.60 (s, 2H), 3.38 (s, 2H).

[0180] Example 29: Preparation of TM-29

[0181]

[0182] The synthesis method is similar to that of TM-26, except that 2-(bromomethyl)-3-chloropyridine is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 58%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.46(s,1H),8.43(dd,J=4.7,1.4Hz,1H),7.97(dd,J=8.1,1.4Hz,1H),7.62(q,J=2.6Hz,2H ),7.46–7.42(m,1H),7.38(dd,J=8.1,4.7Hz,1H),7.18–7.04(m,2H),5.64(s,2H),3.40(s,2H).

[0183] Example 30: Preparation of TM-30

[0184]

[0185] The synthesis method is similar to that of TM-26, except that 2-bromomethyl-6-methylpyridine is used in the second step instead of 4-(bromomethyl)-3,5-dichloropyridine, and the yield of the last step is 54%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.45(s,1H),7.71(s,1H),7.65(dd,J=6.9,1.8Hz,1H),7.56(t,J=7.7Hz,1H),7.43(d,J=8.0H z, 1H), 7.14 (dq, J = 7.7, 5.7Hz, 3H), 6.65 (d, J = 7.7Hz, 1H), 5.46 (s, 2H), 3.40 (s, 2H), 2.46 (s, 3H).

[0186] Example 31: Preparation of TM-31

[0187]

[0188] The synthesis method is similar to that of TM-26, except that 4,6-dimethoxy-2-bromomethylpyrimidine is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 49%, and the product is a white solid. 1 HNMR (400 MHz, DMSO-d 6 )δ12.42(s,1H),7.66(s,1H),7.63(d,J=7.7Hz,1H),7.43(d,J=8.0Hz,1H),7. 20–7.08(m,2H),6.11(s,1H),5.43(s,2H),3.73(d,J=0.9Hz,6H),3.39(s,2H).

[0189] Example 32: Preparation of TM-32

[0190]

[0191] The synthesis method is similar to that of TM-26, except that 2-bromo-3-bromomethylthiophene is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 55%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6)δ12.44(s,1H),7.68(s,1H),7.64(d,J=7.7Hz,1H),7.52(d,J=5.6Hz,1H),7.47(d,J=8.1Hz,1H ), 7.20 (t, J = 7.4Hz, 1H), 7.13 (t, J = 7.4Hz, 1H), 6.73 (d, J = 5.6Hz, 1H), 5.32 (s, 2H), 3.39 (s, 2H).

[0192] Example 33: Preparation of TM-33

[0193]

[0194] The synthesis method is similar to that of TM-26, except that ethyl 1-bromocyclobutanecarboxylate is used instead of ethyl bromoacetate in the first step, 2,6-dichlorobenzyl bromide is used instead of 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step is 45%, and the product is a white solid. 1 H NMR (400 MHz, DMSO-d 6 )δ12.45(s,1H),7.67–7.58(m,3H),7.55(d,J=8.2Hz,1H),7.52–7.46(m,1H),7.26–7.18(m,2 H),7.14(t,J=7.5Hz,1H),5.62(s,2H),2.42–2.30(m,2H),1.99(d,J=9.8Hz,3H),1.70(s,1H).

[0195] Pharmacological experiments:

[0196] Experimental Example 1: In vitro inhibitory activity of target compounds on hURAT1

[0197] method:

[0198] HEK-293T cells stably expressing hURAT1 were cultured (DMEM medium + 10% fetal bovine serum + 500 μg / mL G418 + 1% P / S), and the cells were inoculated into 96-well cell culture plates and cultured for 12 to 24 hours. The compound was prepared into a 10 mM concentration mother solution with DMSO, and then diluted to 1 mM with buffer, and further diluted 4 times in equal proportions. After the cells in the 96-well plate adhered to the wall, the 14 C-uric acid uptake test in cells stably expressing hURAT1. 50 μL of the corresponding compound and 0.1 Ci / mL were added to each well. 14C-uric acid solution, incubated in a 37°C incubator for 5 minutes, immediately added 150 μl of ice-cold buffer to terminate absorption. Add 50 μl / well of lysis solution to all wells, place on an oscillator at 900 rpm for 5 minutes; add 150 μl / well of scintillation liquid Microsint40, oscillate at 900 rpm for 5 minutes; use MicroBetaTrilux (PerkinElmer) instrument to measure radioactivity, and analyze data using XL-fit software.

[0199] result:

[0200] The inhibition rates of the above compounds on hURAT1 at concentrations of 0.625 μM or 10 μM were determined respectively; the IC values ​​of the compounds with better inhibitory activity were determined and calculated. 50 The results are shown in Table 1.

[0201] Table 1. Inhibitory effects of compounds on hURAT1

[0202]

[0203] a: The inhibition rate of the compound on hURAT1 at a concentration of 0.625 μM. b: The inhibition rate of the compound on hURAT1 at a concentration of 10 μM. ND: Not Determined, not tested.

Claims

1. A substituted heteroaryl carboxylic acid compound represented by the following general formula (I) and a physiologically acceptable salt thereof, in, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro; X or Y is independently selected from N or C; Z is selected from C 1- C3 alkylene, R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy.

2. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IA) and a physiologically acceptable salt thereof: in, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro; R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy.

3. The compound according to claim 2 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IAa) and a physiologically acceptable salt thereof: in, R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy; R4 is a monosubstituted or polysubstituted group on the benzene ring selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro.

4. The compound according to claim 2 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IAb) and a physiologically acceptable salt thereof: in, R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy; R5 is a monosubstituted or polysubstituted group on the pyridine ring selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro.

5. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IB) and a physiologically acceptable salt thereof: in, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro; R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy.

6. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IC) and a physiologically acceptable salt thereof: in, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro; R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy.

7. The compound according to claim 1 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (ID) and a physiologically acceptable salt thereof: in, Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are monosubstituted or polysubstituted groups, each of which is independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro; R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy.

8. The compound according to claim 7 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IDa) and a physiologically acceptable salt thereof: in, R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy; R6 is a monosubstituted or polysubstituted group on the pyridine ring selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro.

9. The compound according to claim 7 and its physiologically acceptable salt, characterized in that The compound is a compound represented by the general formula (IDb) and a physiologically acceptable salt thereof: in, R1, R2 or R3 are independently selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy; R7 is a monosubstituted or polysubstituted group on the thiophene ring selected from hydrogen, halogen, C 1- C3 alkyl, C 1- C3 alkoxy, trifluoromethyl, cyano, nitro.

10. The compound according to claim 1 and its physiologically acceptable salts, characterized in that The compound is selected from:

11. A method for preparing the compound according to any one of claims 1 to 10, characterized in that: The following steps are involved: The raw material I-1 undergoes nitrogen alkylation reaction with a halide to obtain an intermediate I-2, and the intermediate I-2 undergoes CS coupling reaction with a thiol compound to obtain an intermediate I-3, and then I-3 is hydrolyzed under alkaline conditions to obtain the target compound I; Ar, R1, R2, R3, X, Y, and Z are as defined in claim 1.

12. A pharmaceutical composition, characterized in that The pharmaceutical composition contains an effective dose of any compound according to any one of claims 1 to 10 and a physiologically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, characterized in that The pharmaceutical composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various microparticle delivery systems.

14. Use of the compound according to any one of claims 1 to 10 and a physiologically acceptable salt thereof in the preparation of a urate transporter 1 inhibitor.

15. Use of the compound according to any one of claims 1 to 10 or a physiologically acceptable salt thereof in the preparation of a medicament for preventing and / or treating a URAT1-related disease.

16. The use according to claim 15, wherein the disease is selected from hyperuricemia and gout.

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