Substituted heteroaryl carboxylic acid compounds, processes for their preparation and pharmaceutical uses thereof

Abstract

The application belongs to the field of pharmaceutical chemistry, and discloses a substituted heteroaryl carboxylic acid compound, a preparation method and pharmaceutical use thereof. Specifically disclosed are a substituted heteroaryl carboxylic acid compound shown in formula (I) and a physiologically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition, and use of the compound in preparation of a urate transporter 1 (URAT1) inhibitor, and application of the compound in preparation of a medicine for preventing and / or treating hyperuricemia and gout.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a substituted heteroaryl carboxylic acid compound represented by general formula (I) and a physiologically acceptable salt thereof, and the use of the compound in preparing a urate transporter 1 (URAT1) inhibitor, the use of the compound in preparing a medicine for preventing or treating a URAT1 related disease, and a preparation method of the compound and a medicine composition containing the compound. BACKGROUND

[0002] Gout is an inflammatory joint disease caused by the deposition and precipitation of monosodium urate in joints and peripheral tissues. Hyperuricemia caused by increased uric acid production or (and) decreased excretion is a direct inducement 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. At present, urate-lowering therapy is mainly divided into three categories: (1) xanthine oxidase (XO) inhibitors for inhibiting uric acid production; (2) urate transporter 1 (URAT1) inhibitors for promoting uric acid excretion; (3) uricase for converting uric acid into water-soluble substances. About 90% of the pathogenesis of hyperuricemia patients is related to decreased uric acid excretion, and URAT1 is an important target for regulating uric acid reabsorption and promoting uric acid excretion, so URAT1 inhibitors are important urate-lowering therapies. The currently used URAT1 inhibitors in clinical practice mainly include probenecid, benzobromarone and lesinurad. However, probenecid and benzobromarone have poor tolerance, many toxic side effects and other problems. Lesinurad, which was marketed at the end of 2015, is used in combination with XO inhibitors allopurinol in clinical practice for the treatment of hyperuricemia and chronic gout, but its inhibitory activity on URAT1 is weak, and the clinical use dose is large (200mg / d).

[0004] In recent years, with the change of people's dietary structure and the acceleration of population aging, the incidence of hyperuricemia and gout is continuously rising, and has become an important public health problem that cannot be ignored. At present, there are few clinical treatment drugs, and each has different defects. Therefore, it is of great practical significance and market prospect to study new URAT1 inhibitors. SUMMARY

[0005] The present application aims to provide a substituted heteroaryl carboxylic acid compound represented by general formula (I).

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

[0007] Still another object of the present application is to provide the use of the substituted heteroaryl carboxylic acid compound represented by the general formula (I) in the preparation of a urate transporter 1 (URAT1) inhibitor, and the use in the preparation of a medicament for preventing or treating a URAT1 related disease.

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

[0009] To solve the technical problem of the present application, the present application adopts the following technical solution:

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

[0011]

[0012] Among them,

[0013] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothiophenyl; the substituent is a single or multiple substituent group, each of which is independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro;

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

[0015] Z is selected from C 1- C3alkylene,

[0016] R1, R2 or R3 is independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0017] Still another technical solution of the present application is to provide a compound represented by the general formula (IA) or its physiologically acceptable salt:

[0018]

[0019] wherein,

[0020] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; said substituents are mono- or poly- substituents each independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro;

[0021] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0022] Yet another aspect of the present application provides a compound represented by the general formula (IAa) or a physiologically acceptable salt thereof:

[0023]

[0024] wherein,

[0025] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0026] R4is a mono- or poly-substituent on the phenyl ring selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

[0027] Yet another aspect of the present application provides a compound represented by the general formula (IAb) or a physiologically acceptable salt thereof:

[0028]

[0029]

[0030] wherein,

[0031] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0032] R5is a mono- or poly-substituent on the pyridyl ring selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

[0033] Still another aspect of the present application provides a compound represented by the general formula (IB) or a physiologically acceptable salt thereof:

[0034]

[0035] wherein,

[0036] Ar is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are mono- or poly-substituents each independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro;

[0037] R1, R2or R3are independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0038] Still another aspect of the present application provides a compound represented by the general formula (IC) or a physiologically acceptable salt thereof:

[0039]

[0040] wherein,

[0041] Ar is selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; the substituents are mono- or poly-substituents each independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro;

[0042] R1, R2or R3are independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0043] Still another aspect of the present application provides a compound represented by the general formula (ID) or a physiologically acceptable salt thereof:

[0044]

[0045] wherein,

[0046] Ar is selected from substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted benzofuranyl, substituted or unsubstituted benzothienyl; said substituents are mono or poly substituents each independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro;

[0047] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

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

[0049]

[0050] wherein,

[0051] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0052] R6is a mono or poly substituent on the pyridyl ring selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

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

[0054]

[0055] wherein,

[0056] R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

[0057] R7is a mono or poly substituent on the thienyl ring selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

[0058] Yet another technical solution of the present application is to provide a compound represented by the general formula (IDb) or a physiologically acceptable salt thereof:

[0059]

[0060]

[0061]

[0062]

[0063] The second aspect of the technical scheme of the present application provides a preparation method of the compound shown in general formula (I), characterized in that the method comprises the following steps:

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

[0065]

[0066] Ar, R1, R2, R3, X, Y and Z are as defined in claim 1.

[0067] The third aspect of the technical scheme of the present application provides a pharmaceutical composition, characterized in that the pharmaceutical composition contains an effective dose of any one of the compounds according to 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 drug delivery systems.

[0069] In order to prepare a medicament, the compound of general formula (I) can be mixed with suitable pharmaceutical carrier materials, fragrances, flavorings and pigments in a known manner, and tablets or coated tablets can be prepared therefrom, or they can be suspended or dissolved in water or oil together with other additional substances.

[0070] The present application also relates to a pharmaceutical composition containing a pharmaceutically effective dose of the compound according to general formula (I) and a pharmaceutically acceptable carrier.

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

[0072] The compounds of the present application can be administered orally or parenterally. Oral administration can be in the form of tablets, capsules, and the like. Parental administration can be in the form of injectable solutions or suppositories. These formulations are prepared according to methods known to those skilled in the art. The excipients used in the manufacture of tablets, capsules, and the like are conventional excipients, such as starch, gelatin, acacia, silica, polyethylene glycol, solvents for liquid formulations, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, and the like. The formulations containing the compounds of the present application can also contain other excipients, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, colorants, and the like.

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

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

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

[0076] Beneficial technical effects:

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

[0078] The application is further illustrated by the following examples, which do not limit the scope of the application.

[0079] The reagents and solvents used in the synthesis experiments were purchased through commercial channels and used directly without treatment. The anhydrous solvents were ultra-dry solvents purchased commercially, and the mixing ratio of the solvents was 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 obtained by Varian Mercury 400-MHz nuclear magnetic resonance instrument. The chemical shift (δ) is given in parts per million (ppm), the internal standard is TMS, and the coupling constant is in hertz (Hz).

[0080] Example 1: Preparation of TM-1

[0081]

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

[0083]

[0084] To a solution of 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) in 50 mL of N,N-dimethylformamide, the reaction mixture was heated to 70 °C for 10 h. The reaction was monitored by TLC and the reaction mixture was diluted with water and extracted with ethyl acetate (3x). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate 5:1) to give intermediate IA-1, 1.84 g, yield: 70%. 1 H NMR (400 MHz, DMSO-d6) d 8.31 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 5.3 Hz, 1H), 7.23 (s, 1H), 5.71 (s, 2H).

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

[0086]

[0087] To a solution of intermediate IA-1 (1.05 g, 2 mmol), cesium carbonate (0.997 g, 3 mmol), tris(dibenzylideneacetone)dipalladium (0.092 g, 0.1 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.116 g, 0.2 mmol) in 30 mL of toluene, ethyl mercaptoacetate (0.288 g, 2.4 mmol) was added under nitrogen atmosphere and the reaction mixture was heated to 70 °C for 10 h. The reaction was monitored by TLC and the solid was removed by filtration. The liquid was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether-ethyl acetate 5:1) to give intermediate IA-2, 0.68 g, yield: 65%. 1 H NMR (400 MHz, DMSO-d6) d 8.33 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.37 - 7.32 (m, 2H), 7.08 (s, 1H), 5.70 (s, 2H), 3.85 (q, J = 7.2 Hz, 2H), 3.50 (s, 2H), 0.93 (t, J = 7.2 Hz, 3H).

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

[0089]

[0090] Intermediate IA-2 (519 mg, 1 mmol), lithium hydroxide (84 mg, 2 mmol) were added in 30 mL of a mixture of ethanol-water (4:1) and stirred at room temperature for 6 h. TLC monitoring of the reaction was complete, most of the organic solvent was removed under reduced pressure, then diluted with water, slowly adjusted the pH to 4-5 with 1 N aqueous hydrochloric acid solution, the solid was precipitated, suction filtered, column chromatography separation (dichloromethane-methanol 10:1) to obtain the target TM-10. 31 g, yield: 63%, white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 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 TM-1, except that 2,6-dichlorobenzyl bromide is used instead of 2,6-dibromobenzyl bromide in the first step, and the last step has a yield of 62%, white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.33 (m, 2H), 7.16 (s, 1H), 5.69 (s, 2H), 3.48 (s, 2H).

[0094] Example 3: Preparation of TM-3

[0095]

[0096] The synthesis method is similar to TM-2, except that 4-bromo-3-iodo-7- azaindole is used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine in the first step, and the last step has a yield of 55%, white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.18 (d, J = 5.2 Hz, 1H), 7.58 (d, J = 8.1 Hz, 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 was similar to TM-1 except that in the first step 4- (bromomethyl)-3,5-dichloropyridine was used instead of 2,6-dibromobenzyl bromide and the last step gave a 50% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.67 (s, 2H), 8.22 (d, J = 5.2 Hz, 1H), 7.57 (s, 1H), 7.26 (d, J = 5.2 Hz, 1H), 5.69 (s, 2H), 3.49 (s, 2H).

[0100] Example 5: Preparation of TM-5

[0101]

[0102] The synthesis was similar to TM-1 except that in the first step 2-bromo-6- chlorobenzyl bromide was used instead of 2,6-dibromobenzyl bromide and the last step gave a 65% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 7.17 (s, 1H), 5.67 (s, 2H), 3.44 (s, 2H).

[0103] Example 6: Preparation of TM-6

[0104]

[0105] The synthesis was similar to TM-2 except that in the first step 3-iodo-4- methoxy-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine and the last step gave a 52% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.22 (d, J = 5.6 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.77 (d, J = 5.6 Hz, 1H), 5.60 (s, 2H), 3.96 (s, 3H), 3.48 (s, 2H).

[0106] Example 7: Preparation of TM-7

[0107]

[0108] The synthesis procedure was similar to TM-2, except that in the first step 5-bromo-4- chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine, and in the last step the yield was 55% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.56 (s, 1H), 7.58 (d, J = 8.1 Hz, 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 procedure was similar to TM-2, except that in the first step 5-bromo-4- chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine, and in the last step the yield was 55% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 8.1 Hz, 1H), 7.38 (s, 1H), 5.67 (s, 2H), 3.47 (s, 2H).

[0112] Example 9: Preparation of TM-9

[0113]

[0114] The synthesis procedure was similar to TM-2, except that in the first step 5-bromo-4- chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine, and in the last step the yield was 55% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.1 Hz, 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 was similar to TM-2 except that in the first step 5-chloro-3-iodo- 1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine and the last step gave a 56% yield as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.37 (s, 1H), 8.11 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 8.2 Hz, 1H), 7.40 (s, 1H), 5.67 (s, 2H), 3.44 (s, 2H).

[0118] Example 11: Preparation of TM-11

[0119]

[0120] The synthesis was similar to TM-2 except that in the first step 5-chloro-3-iodo- 1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H-pyrrolo[2,3-B]pyridine and the last step gave a 56% yield as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 8.08 (d, J = 8.1 Hz, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 8.1 Hz, 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 was similar to TM-1 except that in the first step 1-bromo-3- (bromomethyl)-2,4-dimethoxybenzene was used instead of 2,6-dibromobenzyl bromide and the last step gave a 52% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.30 (d, J = 5.2 Hz, 1H), 6.93 (d, J = 9.1 Hz, 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 was similar to TM-1 except that in the first step 2,3,5-tribromo-4- (bromomethyl)thiophene was used instead of 2,6-dibromobenzyl bromide and the last step gave a 45% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 5.2 Hz, 1H), 7.44 (s, 1H), 7.25 (d, J = 5.2 Hz, 1H), 5.41 (s, 2H), 3.45 (s, 2H).

[0127] Example 14: Preparation of TM-14

[0128]

[0129] The synthesis was similar to TM-1 except that in the first step 2-bromo-3- (bromomethyl)benzothiophene was used instead of 2,6-dibromobenzyl bromide and the last step gave a 52% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 8.33 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.63 (s, 1H), 7.36 (t, J = 6.3 Hz, 2H), 7.31 (d, J = 5.1 Hz, 1H), 5.70 (s, 2H), 3.50 (s, 2H).

[0130] Example 15: Preparation of TM-15

[0131]

[0132] The synthesis was similar to TM-1 except that in the first step 2-bromo-3- (bromomethyl)benzothiophene was used instead of 2,6-dibromobenzyl bromide and the last step gave a 52% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.29 (d, J = 5.3 Hz, 1H), 7.87 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.29 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H), 5.57 (s, 2H), 3.52 (s, 2H).

[0133] Example 16: Preparation of TM-16

[0134]

[0135] The synthesis was similar to TM-1 except that in the first step 2-(bromomethyl)biphenyl was used instead of 2,6-dibromobenzyl bromide and in the last step the yield was 54% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 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 was similar to TM-1 except that in the first step 2-(bromomethyl)biphenyl was used instead of 2,6-dibromobenzyl bromide and in the last step the yield was 54% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.32 - 7.16 (m, 1H), 5.80 (s, 2H), 3.52 (s, 2H).

[0139] Example 18: Preparation of TM-18

[0140]

[0141] The synthesis was similar to TM-4 except that in the first step 3-iodo-7- azaindole was used instead of 4-chloro-3-iodo-lH-pyrrolo[2,3-B]pyridine and in the last step the yield was 62% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J = 5.3 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.32 - 7.16 (m, 1H), 5.80 (s, 2H), 3.52 (s, 2H).

[0142] Example 19: Preparation of TM-19

[0143]

[0144] Synthetic procedure similar to TM-20 except that in the first step 4- (bromomethyl)-3,5-dibromopyridine was used instead of 4-(bromomethyl)-3,5- dichloropyridine and in the last step the yield was 48% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.81 (d, J = 1.9 Hz, 2H), 8.32 (d, J = 4.9 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.23 (dd, J = 8.0, 4.9 Hz, 1H), 5.67 (s, 2H), 3.43 (s, 2H).

[0145] Example 20: Preparation of TM-20

[0146]

[0147] Synthetic procedure similar to TM-1 except that in the first step 3-iodo-7- azaindole was used instead of 4-chloro-3-iodo-lH-pyrrolo[2,3-B]pyridine and in the last step the yield was 51% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.38 (dd, J = 4.7, 1.6 Hz, 1H), 8.05 (dd, J = 8.1, 1.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.24 (dd, J = 7.8, 4.7 Hz, 1H), 7.13 (s, 1H), 5.69 (s, 2H), 3.40 (s, 2H).

[0148] Example 21: Preparation of TM-21

[0149]

[0150] Synthetic procedure similar to TM-2 except that in the first step 3-iodo-7- azaindole was used instead of 4-chloro-3-iodo-lH-pyrrolo[2,3-B]pyridine and in the last step the yield was 55% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.38 (dd, J = 4.7, 1.6 Hz, 1H), 8.05 (dd, J = 8.1, 1.6 Hz, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 8.1 Hz, 1H), 7.24 (dd, J = 7.8, 4.7 Hz, 1H), 7.13 (s, 1H), 5.69 (s, 2H), 3.40 (s, 2H).

[0151] Example 22: Preparation of TM-22

[0152]

[0153] The synthesis was similar to TM-2 except that in the first step 3-iodo-5- methyl-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine and the last step gave a 51% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.84 (s, 1H), 7.62 - 7.54 (m, 2H), 7.47 (dd, J = 9.2, 7.2 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 5.64 (d, J = 1.7 Hz, 2H), 3.38 (d, J = 1.7 Hz, 2H), 2.42 (s, 3H).

[0154] Example 23: Preparation of TM-23

[0155]

[0156] The synthesis was similar to TM-2 except that in the first step 3-iodo-5- methyl-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine and the last step gave a 51% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.84 (s, 1H), 7.62 - 7.54 (m, 2H), 7.47 (dd, J = 9.2, 7.2 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 5.64 (d, J = 1.7 Hz, 2H), 3.38 (d, J = 1.7 Hz, 2H), 2.42 (s, 3H).

[0157] Example 24: Preparation of TM-24

[0158]

[0159] The synthesis was similar to TM-2 except that in the first step 3-iodo-5- methyl-1H-pyrrolo[2,3-B]pyridine was used instead of 4-chloro-3-iodo-1H- pyrrolo[2,3-B]pyridine and the last step gave a 51% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.84 (s, 1H), 7.62 - 7.54 (m, 2H), 7.47 (dd, J = 9.2, 7.2 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 5.64 (d, J = 1.7 Hz, 2H), 3.38 (d, J = 1.7 Hz, 2H), 2.42 (s, 3H).

[0160] Example 25: Preparation of TM-25

[0161]

[0162] The synthesis was similar to TM-24 except that in the second step ethyl 3- mercaptopropionate was used instead of ethyl mercaptoacetate. The final step gave a yield of 55% as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.50 - 7.40 (m, 2H), 7.19 (t, J = 7.5 Hz, 1H), 3.08 (t, J = 7.0 Hz, 2H), 2.53 (t, J = 7.0 Hz, 2H).

[0163] Example 26: Preparation of TM-26

[0164]

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

[0166]

[0167] To a solution of 3-mercaptoindole (746 mg, 5 mmol), ethyl bromoacetate (877 mg, 5.25 mmol), potassium carbonate (1.38 g, 10 mmol) in 50 mL of acetonitrile was added and the reaction mixture was heated to 70 °C for 12 h. The reaction was monitored by TLC. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was purified by column chromatography (petroleum ether-ethyl acetate 5:1) to give intermediate IA-3, 1.05 g, yield: 89%.

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

[0169]

[0170] To a solution of intermediate IA-3 (471 mg, 2 mmol), 4-(bromomethyl)-3,5- dichloropyridine (723 mg, 3 mmol), potassium carbonate (552 mg, 4 mmol) in 50 mL of N,N-dimethylformamide was added and the reaction mixture was heated to 70 °C for 10 h. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3x10 mL). The combined organic extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether-ethyl acetate 5:1) to give intermediate IA-4, 0.45 g, yield: 57%.

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

[0172]

[0173] Intermediate IA-4 (395 mg, 1 mmol), lithium hydroxide (84 mg, 2 mmol) were added into 30 mL of a mixture of ethanol-water (4:1) and stirred at room temperature for 6 h. TLC monitoring showed the reaction was complete. Most of the organic solvent was removed under reduced pressure, then diluted with water and slowly adjusted the pH to 4-5 with 1 N aqueous hydrochloric acid solution. The solid was precipitated, suction filtered, and column chromatography (dichloromethane-methanol 10:1) to give the target product 0.195 g, yield 53%, white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.72 (d, J = 1.5 Hz, 2H), 7.64 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.38 (s, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 5.62 (s, 2H), 3.38 (s, 2H).

[0174] Example 27: Preparation of TM-27

[0175]

[0176] The synthesis method was similar to TM-26, except that 4-(bromomethyl)-3,5- dibromopyridine was used to replace 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step was 52%, white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 8.84 (s, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 3.6 Hz, 2H), 7.17 (t, J = 7.5 Hz, 1H), 5.59 (s, 2H), 3.38 (s, 2H).

[0177] Example 28: Preparation of TM-28

[0178]

[0179] The synthesis method was similar to TM-26, except that 3-(bromomethyl)-2,4- dichloropyridine was used to replace 4-(bromomethyl)-3,5-dichloropyridine in the second step, and the yield of the last step was 55%, white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.44 (d, J = 5.3 Hz, 1H), 7.74 (d, J = 5.3 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 7.24 (t, J = 7.7 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 5.60 (s, 2H), 3.38 (s, 2H).

[0180] Example 29: Preparation of TM-29

[0181]

[0182] The synthesis was similar to TM-26 except that in the second step 2- (bromomethyl)-3-chloropyridine was used instead of 4-(bromomethyl)-3,5- dichloropyridine and the last step gave a 58% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.43 (dd, J = 4.7, 1.4 Hz, 1H), 7.97 (dd, J = 8.1, 1.4 Hz, 1H), 7.62 (q, J = 2.6 Hz, 2H), 7.46 - 7.42 (m, 1H), 7.38 (dd, J = 8.1, 4.7 Hz, 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 was similar to TM-26 except that in the second step 2- (bromomethyl)-3-chloropyridine was used instead of 4-(bromomethyl)-3,5- dichloropyridine and the last step gave a 58% yield as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.71 (s, 1H), 7.65 (dd, J = 6.9, 1.8 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.14 (dq, J = 7.7, 5.7 Hz, 3H), 6.65 (d, J = 7.7 Hz, 1H), 5.46 (s, 2H), 3.40 (s, 2H), 2.46 (s, 3H).

[0186] Example 31: Preparation of TM-31

[0187]

[0188] The synthesis was similar to TM-26 except that in the second step 4,6-dimethoxy- 2-bromomethylpyrimidine was used instead of 4-(bromomethyl)-3,5-dichloropyridine and the last step gave a 49% yield of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.66 (s, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.11 (s, 1H), 5.43 (s, 2H), 3.73 (d, J = 0.9 Hz, 6H), 3.39 (s, 2H).

[0189] Example 32: Preparation of TM-32

[0190]

[0191] The synthesis was similar to TM-26 except that in the second step 2-bromo-3- bromomethylthiophene was used instead of 4-(bromomethyl)-3,5-dichloropyridine and the last step gave a 55% yield of a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.68 (s, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 5.32 (s, 2H), 3.39 (s, 2H).

[0192] Example 33: Preparation of TM-33

[0193]

[0194] The synthesis was similar to TM-26 except that in the first step ethyl 1- bromocyclobutane carboxylate was used instead of ethyl bromoacetate and in the second step 2,6-dichlorobenzyl bromide was used instead of 4-(bromomethyl)-3,5- dichloropyridine and the last step gave a 45% yield of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.67 - 7.58 (m, 3H), 7.55 (d, J = 8.2 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.26 - 7.18 (m, 2H), 7.14 (t, J = 7.5 Hz, 1H), 5.62 (s, 2H), 2.42 - 2.30 (m, 2H), 1.99 (d, J = 9.8 Hz, 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 cell strain stably expressing hURAT1 (DMEM medium + 10% fetal bovine serum + 500 μg / mL G418 + 1% P / S) was cultured and inoculated into 96-well cell culture plates for 12-24 hours. The compound was prepared into a 10 mM stock solution with DMSO, then diluted into 1 mM with buffer, and further diluted by 4 times. After the cells in the 96-well plate were cultured and adhered, the 14 C-uric acid absorption test in hURAT1 stably expressing cells. 50 μL of the corresponding compound and 0.1 Ci / mL C-uric acid solution were added to each well, and incubated in a 37°C incubator for 5 minutes. Then, 150 μL of ice-cold buffer was immediately added to terminate the absorption. 50 μL / well of lysis solution was added to all wells, and placed on a shaker at 900 rpm for 5 minutes. 150 μL / well of scintillation solution Microsint40 was added, and shaken at 900 rpm for 5 minutes. The radioactivity was measured using a MicroBetaTrilux (produced by PerkinElmer) instrument, and the data was analyzed by XL-fit software. 14 C-uric acid solution, and incubated in a 37°C incubator for 5 minutes. Then, 150 μL of ice-cold buffer was immediately added to terminate the absorption. 50 μL / well of lysis solution was added to all wells, and placed on a shaker at 900 rpm for 5 minutes. 150 μL / well of scintillation solution Microsint40 was added, and shaken at 900 rpm for 5 minutes. The radioactivity was measured using a MicroBetaTrilux (produced by PerkinElmer) instrument, and the data was analyzed by XL-fit software.

[0199] Results:

[0200] The inhibitory rate of the above compounds on hURAT1 was measured at a concentration of 0.625 μM or 10 μM, respectively. The IC 50 values of the compounds with better inhibitory activity were determined and calculated, and the results are shown in Table 1.

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

[0202]

[0203] a: Inhibition of hURAT1 at a concentration of 0.625 μM. b: Inhibition of 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, ###0001### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IA) and a physiologically acceptable salt thereof: ###0002### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IAa) and a physiologically acceptable salt thereof: ###0003### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IAb) and a physiologically acceptable salt thereof: ###0004### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IB) and a physiologically acceptable salt thereof: ###0005### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBa) and a physiologically acceptable salt thereof: ###0006### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBb) and a physiologically acceptable salt thereof: ###0007### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBc) and a physiologically acceptable salt thereof: ###0008### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBd) and a physiologically acceptable salt thereof: ###0009### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBe) and a physiologically acceptable salt thereof: ###0010### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBf) and a physiologically acceptable salt thereof: ###0011### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBg) and a physiologically acceptable salt thereof: ###0012### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBh) and a physiologically acceptable salt thereof: ###0013### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBi) and a physiologically acceptable salt thereof: ###0014### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBj) and a physiologically acceptable salt thereof: ###0015### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBk) and a physiologically acceptable salt thereof: ###0016### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IB1) and a physiologically acceptable salt thereof: ###0017### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBm) and a physiologically acceptable salt thereof: ###0018### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBn) and a physiologically acceptable salt thereof: ###0019### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBo) and a physiologically acceptable salt thereof: ###0020### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBp) and a physiologically acceptable salt thereof: ###0021### wherein, X is selected from N, Y is selected from N or C; and the compound is a compound represented by the following general formula (IBq) and a physiologically acceptable salt thereof: ###0022### wherein, X is selected from N, Y is selected from N or C; and the ​ 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; said substituents are mono- or poly- substituents each independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro; ​ Z is selected from C 1- C3alkylene, R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

2. The compound according to claim 1, and physiologically acceptable salts thereof, characterized by ​ ​ 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; said substituents are mono- or poly- substituents each independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro; R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy.

3. The compound according to claim 2, and physiologically acceptable salts thereof, characterized by ​ ​ R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy; R4is a mono- or polysubstituted radical on the phenyl ring, selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

4. The compound and physiologically acceptable salts thereof according to claim 2, characterized by ​ ​ R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy; R5is a mono- or polysubstituted radical on the pyridine ring, selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

5. The compound according to claim 1, and physiologically acceptable salts thereof, characterized by ​ ​ 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; said substituents are mono- or poly- substituents each independently selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro; R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy. ​ ​ R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy; R6is a mono- or polysubstituted radical on the pyridine ring, selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro. ​ ​ R1, R2or R3are independently selected from hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy; R7is a mono- or polysubstituted radical on the thiophene ring selected from the group consisting of hydrogen, halogen, C 1- C3alkyl, C 1- C3alkoxy, trifluoromethyl, cyano, nitro.

8. The compound according to claim 1, and physiologically acceptable salts thereof, characterized by ​ 9. Process for the preparation of a compound according to any one of claims 1 to 5, characterized in that, ​ ​ Ar, R1, R2, R3, X, Y, Z are defined as in claim 1.

10. A pharmaceutical composition, characterized by, ​ 11. The pharmaceutical composition of claim 10, wherein, ​ ​ ​

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