A urat1 inhibitor containing an amino pyridine structure and a preparation method and application thereof

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to an URAT1 inhibitor containing an aminopyridine structure, its preparation method, and its application. The URAT1 inhibitor containing an aminopyridine structure has a structure as shown in formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: wherein Ar1 comprises thiophene, thiazole, thiophene substituted with one or more R1s, or thiazole substituted with one or more R1s, wherein R1 comprises C 1‑6 Alkyl, C 1‑6 Alkoxy, halogenated C 1‑6 Alkyl, Halogenated C 1‑6 Alkoxy, C 3‑6 At least one or two of cycloalkyl, halogen, -OH, -COOH and -SH R1 together with the two carbon atoms attached thereto form a C that is optionally substituted with R2. 5‑12 The aromatic ring; the R2 includes H, C 1‑6 Alkyl, C 1‑6 Alkoxy, halogenated C 1‑6 Alkyl, Halogenated C 1‑6 Alkoxy, C 3‑6 At least one of cycloalkyl, halogen, -OH, -COOH, and -SH. It has a certain inhibitory effect on hURAT1 and can be used to prepare uric acid-lowering drugs for the treatment of gout and hyperuricemia.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to an URAT1 inhibitor containing an aminopyridine structure, its preparation method, and its application. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Gout is the most common chronic disease of inflammatory arthritis, and hyperuricemia is a direct trigger for its development. The Chinese guidelines for the diagnosis and treatment of gout define hyperuricemia as two separate fasting serum uric acid levels >0.42 mmol / L (7.0 mg / dL), while the American guidelines define asymptomatic hyperuricemia as serum uric acid >0.408 mmol / L (6.8 mg / dL). With prolonged hyperuricemia, sodium urate slowly deposits as needle-like crystals in soft tissues or joints. These urate crystals activate NLRP3 inflammasomes in macrophages and monocytes, subsequently triggering an inflammatory response and inducing gout.

[0004] The most common clinical treatment method is to use uricosuric drugs and xanthine oxidase inhibitors to lower uric acid levels and address the underlying cause of gout. Xanthine oxidase inhibitors, such as allopurinol or febuxostat, reduce uric acid formation, while uricosuric drugs inhibit the reabsorption of uric acid from the kidneys back into the bloodstream via the URAT1 transporter protein. Urate transporter 1 (URAT1) is an important protein regulating uric acid reabsorption. URAT1 inhibitors increase uric acid excretion by inhibiting uric acid reabsorption, thereby reducing urate levels. Benzbromarone and lesinurad, as marketed URAT1 inhibitors, have limitations due to side effects such as hepatotoxicity and nephrotoxicity, making long-term, high-dose use in clinical practice impossible. They must be used in combination with xanthine oxidase inhibitors to treat hyperuricemia with gout. Furthermore, the efficacy of lesinurad in combination with xanthine oxidase inhibitors is not satisfactory. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a URAT1 inhibitor containing an aminopyridine structure, its preparation method, and its application. The URAT1 inhibitor containing an aminopyridine structure of the present invention has a novel structure and exhibits a certain inhibitory effect on the uric acid transporter hURAT1. It can be used as a candidate compound for the preparation of uric acid-lowering drugs and for the treatment of gout and hyperuricemia.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0007] In a first aspect, the present invention provides a URAT1 inhibitor containing an aminopyridine structure, having a structure as shown in formula (I) or formula (II) or a pharmaceutically acceptable salt thereof:

[0008]

[0009]

[0010] Ar1 includes thiophene, thiazole, thiophene substituted with one or more R1s, or thiazole substituted with one or more R1s, wherein R1 includes C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 At least one or two of cycloalkyl, halogen, -OH, -COOH and -SH, R1 together with the two carbon atoms attached to it forms a C atom optionally substituted with R2. 5-12 The aromatic ring; the R2 includes H, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 At least one of cycloalkyl, halogen, -OH, -COOH, and -SH.

[0011] Preferably, R1 includes C 1-3 At least one of alkyl and methylthio.

[0012] In a second aspect, the present invention provides a method for preparing an URAT1 inhibitor containing an aminopyridine structure as described in the first aspect, comprising the following steps:

[0013] Using DMF as solvent, under the action of potassium iodide and potassium carbonate and under nitrogen protection, the compound shown in formula (III) reacts with N-(3-pyridyl)chloromethanesulfonamide to generate the URAT1 inhibitor containing an aminopyridine structure as described in the first aspect.

[0014]

[0015] Preferably, when the reaction temperature is 70-80℃, the URAT1 inhibitor containing an aminopyridine structure generated by the reaction has the structure shown in formula (I); when the reaction temperature is 90-100℃, the URAT1 inhibitor containing an aminopyridine structure generated by the reaction has the structure shown in formula (II).

[0016] Preferably, the molar ratio of the compound shown in formula (III), N-(3-pyridyl)chloromethanesulfonamide, potassium iodide and potassium carbonate is 1:(1-1.1):(0.9-1.1):(2.9-3.1).

[0017] Preferably, it also includes a synthetic step of a compound as shown in formula (III):

[0018] S1. The compound shown in formula (IV) was dissolved in dichloromethane. After cooling to 0°C, sulfur phosgene was added dropwise and stirred. Then, triethylamine was added dropwise. After the addition was completed, the temperature was restored to room temperature and the reaction was carried out. After the reaction was complete, the reaction system was poured into water. After extraction, washing, separation, drying, and filtration, the filtrate was concentrated under reduced pressure and then subjected to column chromatography to obtain the compound shown in formula (V).

[0019] S2. Dissolve the compound shown in formula (V) in tetrahydrofuran, add 2-thiophene methylamine and triethylamine in sequence, react at room temperature, evaporate the tetrahydrofuran after the reaction is complete, add ethanol to dissolve and add KOH to react, pour the reaction system into water after the reaction is complete, and obtain the compound shown in formula (III) after extraction, washing, drying, filtration and recrystallization.

[0020]

[0021] More preferably, in step S1, the molar ratio of the compound as shown in formula (IV), phosgene, and triethylamine is 1:(1.1-1.3):(1.9-2.1).

[0022] More preferably, in step S2, the molar ratio of the compound as shown in formula (V), 2-thiophene methylamine and triethylamine is 1:(1.1-1.3):(1.9-2.1).

[0023] Thirdly, the present invention provides the use of URAT1 inhibitors containing an aminopyridine structure as described in the first aspect in the preparation of uric acid-lowering drugs.

[0024] Fourthly, the present invention provides a pharmaceutical composition comprising an URAT1 inhibitor containing an aminopyridine structure as described in the first aspect and a pharmaceutically acceptable excipient.

[0025] The beneficial effects achieved by one or more technical solutions of the present invention are as follows:

[0026] This invention provides URAT1 inhibitors containing an aminopyridine structure whose inhibitory activity is comparable to Lesinurad, with three URAT1 inhibitors showing superior activity compared to the positive control Lesinurad. A single-concentration inhibitor of URAT1 with strong inhibitory activity was tested for inhibitory activity at an IC50 concentration. 50 The inhibitory effect IC50 of URAT1 inhibitor 1 was measured.50 The concentration was 4.199 μmol / L, and the in vitro inhibitory activity of URAT1 inhibitor 1 was superior to that of the positive control Lesinurad (IC50). 50 =7.3 μmol / L). Attached Figure Description

[0027] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0028] Figure 1 The inhibitory effect of URAT1 inhibitor 1-11 on hURAT1 at a concentration of 1 μmol / L was investigated, with Lesinurad as a positive control.

[0029] Figure 2 The curve shows the inhibition of hURAT1 by URAT1 inhibitor 1. Detailed Implementation

[0030] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0031] Example 1

[0032] Preparation of compound 1-M1:

[0033]

[0034] Methyl 4-amino-5-methylthiophene-3-carboxylate (2.57 g, 15 mmol) was dissolved in 30 mL of dichloromethane in a 100 mL round-bottom flask. The solution was cooled to 0 °C, and phosgene (2.07 g, 18 mmol) was added dropwise. After stirring at this temperature for 10 min, triethylamine (3.04 g, 30 mmol) was added dropwise. After the addition was complete, the solution was gradually restored to room temperature, and the reaction was analyzed by TLC after 1 h. After the reaction was complete, the reaction system was poured into 100 mL of water and extracted three times with dichloromethane (60 mL). The combined organic phases were washed with saturated NaCl aqueous solution (100 mL), separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and subjected to column chromatography (EA:PE = 1:20) to give intermediate compound 1-M1 (3.04 g), with a yield of 95.0%.

[0035] Preparation of compound 1-M2:

[0036]

[0037] Intermediate compound 1-M1 (0.75 g, 3.5 mmol) was dissolved in tetrahydrofuran (30 mL) in a 100 mL round-bottom flask. 2-Thiophene methylamine (0.48 g, 4.2 mmol) and triethylamine (0.71 g, 7 mmol) were added sequentially, and the mixture was stirred at room temperature. After 30 min, the reaction was confirmed by TLC to be complete. The tetrahydrofuran was then evaporated, and the mixture was dissolved in methanol (30 mL). KOH (0.30 g, 5.3 mmol) was added, and the mixture was stirred at room temperature again. After 30 min, the reaction was confirmed by TLC to be complete. The reaction mixture was poured into 100 mL of water, and extracted three times with ethyl acetate (50 mL). The organic phases were combined, washed with saturated NaCl solution (50 mL), dried over anhydrous sodium sulfate, and filtered. Recrystallization from ethyl acetate yielded intermediate compound 1-M2 (0.88 g), with a yield of 85.5%. Spectroscopic data of compound 1-M2 are as follows: 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),8.30(s,1H),7.38(dd,J=5.2,1.2Hz,1H) ,7.20(d,J=2.8Hz,1H),6.94(dd,J=4.8,3.2Hz,1H),5.76(s,2H),2.51(s,3H).

[0038] Preparation of N-(3-pyridyl)chloromethanesulfonamide:

[0039]

[0040] Compound 3-aminopyridine (0.94 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) were dissolved in dichloromethane (20 mL), cooled to 0 °C, and chloromethanesulfonyl chloride (3.28 g, 22 mmol) was added dropwise. The mixture was then gradually brought back to room temperature and stirred at room temperature for 2 h. The solvent was evaporated using a rotary evaporator, and the residue obtained was the crude N-(3-pyridyl)-N-(chloromethanesulfonyl)chloromethanesulfonamide, which was directly used in the next reaction. A 10% NaOH solution was added to the crude N-(3-pyridyl)-N-(chloromethanesulfonyl)chloromethanesulfonamide, and the mixture was stirred in an ice-water bath for 30 min, then gradually brought back to room temperature until the reaction was complete as detected by TLC. After the reaction was complete, the reaction system was poured into ice water (50 mL), and the pH was adjusted to 7 with 2 M hydrochloric acid. Extraction was performed with dichloromethane (20 mL × 6). The combined organic phases were washed with 5% saline (20 mL), dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain the crude intermediate N-(3-pyridyl)chloromethanesulfonamide. Purification by column chromatography (EtOAc / n-hexane) yielded 1.34 g of N-(3-pyridyl)chloromethanesulfonamide, with a yield of 65.8%. Spectroscopic data of N-(3-pyridyl)chloromethanesulfonamide: 1HNMR(400MHz,DMSO-d6)δ8.45(d,J=2.4Hz,1H),8.35(dd,J=4.8,1.2Hz,1H),7.6 5(ddd,J=7.6,3.6,1.6Hz,1H),7.39(ddd,,J=8.0,5.2,0.8Hz,1H),5.12(s,2H).

[0041] Preparation of URAT1 inhibitor 1:

[0042]

[0043] Compound 1-M2 (0.88 g, 3 mmol), N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) were dissolved in DMF and heated to 70 °C under nitrogen protection until the reaction was complete as detected by TLC. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to 7 with dilute hydrochloric acid. The mixture was extracted with dichloromethane (50 ml × 6), and the combined organic phases were washed with 5% saline (50 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated by rotary evaporation. The resulting product was purified by column chromatography (EtOAc / n-hexane) to obtain URAT1 inhibitor 1 (0.95 g), with a yield of 68.5%. Spectroscopic data of URAT1 inhibitor 1: 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 8.28 (s, 1H), 8.26 (d, J = 2.4Hz, 1H), 8.10-8.09 (m, 1H), 7.51 -7.49(m,1H),7.47(dd,J=4.2,1.2Hz,1H),7.14-7.12(m,2H),6.99(dd,J=5.2,3.6Hz,1H),5.39(s,1H),5.30(s,1H),2.35(s,3H). 13 C NMR(100MHz,DMSO-d6)δ157.12,149.12,144.55,141.14,140.68,137.91,134.58,13 0.02,127.73,126.78,126.60,126.09,124.74,123.57,122.84,50.63,41.33,10.97.

[0044] Example 2

[0045] Preparation of compound 2-M1:

[0046]

[0047] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 2-amino-4-ethyl-5-methylthiophene-3-carboxylic acid (2.99 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and the intermediate compound 2-M1 (3.15 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 87.1%.

[0048] Preparation of compound 2-M2:

[0049]

[0050] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 2-M1 (0.84 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 2-M2 (0.86 g), with a yield of 78.5%. Spectroscopic data of compound 2-M2: 1 H NMR (400MHz, DMSO-d6) δ13.67(s,1H),7.38(dd,J=5.2,1.2Hz,1H),7.23(d,J=2.4Hz,1H),6.95 (dd,J=5.2,3.2Hz,1H),5.73(s,2H),2.77(q,J=7.2Hz,2H),2.30(s,3H),1.05(t,J=7.2Hz,3H).

[0051] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0052] Preparation of URAT1 inhibitor 2

[0053]

[0054] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 2-M2 (0.97 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) to obtain URAT1 inhibitor 2 (0.68 g), with a yield of 45.8%. Spectroscopic data of URAT1 inhibitor 2: 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.30(d,J=2.4Hz,1H),8.22(dd,J=4.8,1 .2Hz,1H),7.57(ddd,J=8.4,1.6,0.6Hz,1H),7.48(dd,J=2.6,0.6Hz,1H),7.25 (dd,J=4.4,2.4Hz,1H),7.17(d,J=1.2Hz,1H),6.99(dd,J=2.5,1.6Hz,1H),5.3 9(s,2H),5.23(s,2H),2.84(q,J=7.2Hz,2H),2.36(s,3H),1.09(t,J=8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ159.88,156.71,152.14,144.50,140.62,137.02,135.05,134.83,1 29.23,128.27,126.94,126.67,125.83,123.70,118.63,50.41,42.13,19.87,14.96,12.29.

[0055] Example 3

[0056] Preparation of compound 3-M1:

[0057]

[0058] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 2-amino-5-ethylthiophene-3-carboxylate (2.78 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and the intermediate compound 3-M1 (2.33 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 68.4%.

[0059] Preparation of compound 3-M2

[0060]

[0061] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 3-M1 (0.80 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 3-M2 (0.86 g), with a yield of 82.0%. Spectroscopic data of compound 3-M2: 1H NMR (400MHz, DMSO-d6) δ13.74(s,1H),7.39(dd,J=5.2,1.2Hz,1H),7.21(d,J=2.8Hz,1H),6.98(s, 1H), 6.95 (dd, J=5.2, 3.6Hz, 1H), 5.73 (s, 2H), 2.77 (qd, J=7.6, 0.8Hz, 2H), 1..22 (t, J=7.6Hz, 3H).

[0062] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0063] Preparation of URAT1 inhibitor 3

[0064]

[0065] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 3-M2 (0.93 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) to obtain URAT1 inhibitor 3 (0.76 g), with a yield of 52.6%. Spectroscopic data of URAT1 inhibitor 3: 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.28(d,J=4Hz,1H),8.20(d,J=4Hz,1H),7.56(d,J=8Hz,1H),7.48(dd,J=4,2Hz,1H),,7.25(dd,J= 8,4Hz,1H),7.17(d,J=4Hz,1H),7.08(s,1H),6.99(dd,,J=4,2Hz,1H),5.41(s,2H),5.23(s,2H),2.83(q,J=8Hz,2H),1.26(t,J=8Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ160.39,156.47,152.59,144.48,144.42,140.51,136.88,12 8.28,126.94,126.72,125.76,123.75,120.38,117.35,50.46,42.33,23.12,15.32.

[0066] Example 4

[0067] Preparation of compound 4-M1:

[0068]

[0069] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 2-amino-4-isopropylthiophene-3-carboxylate (2.99 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and the intermediate compound 4-M1 (2.39 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 66%.

[0070] Preparation of compound 4-M2

[0071]

[0072] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 4-M1 (0.84 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 4-M2 (0.78 g), with a yield of 69.4%. Spectroscopic data of compound 4-M2: 1 H NMR (400MHz, DMSO-d6) δ13.77(s,1H),7.39(dd,J=5.2,1.2Hz,1H),7.23(d,J=2.4Hz,1H),6.95(dd ,J=5.2,3.6Hz,1H),6.92(d,J=0.8Hz,1H),5.74(s,2H),3.53-3.46(m,1H),1.20(d,J=6.8Hz,6H).

[0073] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0074] Preparation of URAT1 inhibitor 4

[0075]

[0076] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 4-M2 (0.97 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) to obtain URAT1 inhibitor 4 (0.72 g), with a yield of 48.8%. Spectroscopic data of URAT1 inhibitor 4: 1H NMR (400MHz, CDCl3) δ8.33 (s, 1H), 8.13 (s, 1H), 7.65 (d, J = 7.6Hz, 1H), 7.26-7.21 (m, 3H), 6. 94(s,1H),6.69(s,1H),5.36(s,2H),5.07(s,2H),3.65-3.62(m,1H),1.25(d,J=5.2Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ162.82,156.99,153.00,145.24,144.46,140.59,136.93,134.8 4,128.35,126.98,126.67,125.81,123.69,117.71,115.52,50.45,42.15,28.28,22.80.

[0077] Example 5

[0078] The preparation of compound 1-M1, compound 1-M2 and N-(3-pyridyl)chloromethanesulfonamide were the same as in Example 1.

[0079] Preparation of URAT1 inhibitor 5

[0080]

[0081] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 1-M2 (0.88 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 5 (0.38 g), with a yield of 35.6%. Spectroscopic data of URAT1 inhibitor 5: 1 HNMR(400MHz,DMSO-d6)δ8..85(d,J=2.8Hz,1H),8.83(s,1H),8.25(dd,J=4.6,1.6Hz,1H),8.19(s,1H),8.14- 8.14(m,1H),7.40-7.36(m,2H),7.18(d,J=3.6Hz,1H),6.95(dd,J=5.0,3.6Hz,1H),5.67(s,2H),2.43(s,3H). 13C NMR(100MHz,DMSO-d6)δ158.15,144.94,143.51,142.64,142.03,138.74,136.58 ,128.07,127.12,126.71,126.08,124.88,123.93,123.25,123.11,38.39,11.00.

[0082] Example 6

[0083] The preparation of compound 2-M1, compound 2-M2, and N-(3-pyridyl)chloromethanesulfonamide were the same as in Example 2.

[0084] Preparation of URAT1 inhibitor 6

[0085]

[0086] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 2-M2 (0.94 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 6 (0.74 g), with a yield of 64.5%. Spectroscopic data of URAT1 inhibitor 6: 1 HNMR(400MHz, DMSO-d6)δ9..15(s,1H),8.66(d,J=2.4Hz,1H),8.31(dd,J=4.8,1.6Hz,1H),7.91-7.88(m,1H),7.43-7.38(m,2H),7.2 3(d,J=3.2Hz,1H),6.97(dd,J=5.2,3.6Hz,1H),5.66(s,2H),3.32(s,2H),2.82(q,J=7.2Hz,2H),2.29(s,3H),1.09(t,J=7.2Hz,3H). 13 CNMR(100MHz,DMSO-d6)δ162.45,157.19,148.11,144.56,144.05,138.10,135.65,134.9 1,129.95,127.48,126.64,126.24,124.50,123.46,115.39,38.37,19.96,15.02,12.07.

[0087] Example 7

[0088] The preparation of compound 3-M1, compound 3-M2, and N-(3-pyridyl)chloromethanesulfonamide were the same as in Example 3.

[0089] Preparation of URAT1 inhibitor 7

[0090]

[0091] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 3-M2 (0.93 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 7 (0.55 g), with a yield of 49.5%. Spectroscopic data of URAT1 inhibitor 7: 1 HNMR (400MHz, DMSO-d6) δ9..19(s,1H),8.66(d,J=2.4Hz,1H),8.32(dd,J=4.4,1.2Hz,1H),7.90(dd,J=8.4,,1.6Hz,1H),7 .43-7.39(m,2H),7.23(d,J=3.2Hz,1H),6.96(t,J=5.6Hz,2H),5.67(s,2H),2.76(q,J=7.2Hz,2H),1.23(t,J=7.2Hz,3H). 13 C NMR(100MHz,DMSO-d6)δ162.98,156.99,148.37,144.75,144.19,139.86,137.91,13 5.58,130.03,127.54,126.69,126.27,123.48,117.31,116.88,38.89,23.06,15.29.

[0092] Example 8

[0093] The preparation of compound 4-M1, compound 4-M2, and N-(3-pyridyl)chloromethanesulfonamide were the same as in Example 4.

[0094] Preparation of URAT1 inhibitor 8

[0095]

[0096] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 4-M2 (0.97 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 8 (0.49 g), with a yield of 42.7%. Spectroscopic data of URAT1 inhibitor 8: 1 HNMR(400MHz, DMSO-d6)δ9..22(s,1H),8.67(d,J=2.4Hz,1H),8.33(dd,J=4.8,1.2Hz,1H),7.93-7.90(m,1H),7.43-7.39(m,2H), 7.25(d,J=3.6Hz,1H),6.97(dd,J=5.2,3.6Hz,1H),6.82(s,1H),5.67(s,2H),3.56(dt,J=13.7,6.9Hz,1H),1.22(d,J=6.8Hz,6H). 13 C NMR(100MHz,DMSO-d6)δ165.43,157.50,148.48,145.40,144.75,144.27,138.01,13 5.54,130.22,127.55,126.64,126.27,123.47,114.57,111.11,38.38,28.32,22.80.

[0097] Example 9

[0098] Preparation of compound 5-M1:

[0099]

[0100] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 4-amino-2-(methylthio)thiazole-5-carboxylic acid (3.06 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and after 2 h of reaction, phosgene (1.04 g, 9 mmol) was added. The intermediate compound 5-M1 (1.38 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 37.3%.

[0101] Preparation of compound 5-M2

[0102]

[0103] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 5-M1 (0.86 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 5-M2 (0.90 g), with a yield of 78.5%. Spectroscopic data of compound 5-M2: 1 H NMR (400MHz, DMSO-d6) δ14.20(s,1H),7.40(dd,J=5.2,1.2Hz,1H),7.22-7.21(m,1H),6.95(dd,J=5.2,3.6Hz,1H),5.73(s,2H),2.79(s,3H).

[0104] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0105] Preparation of URAT1 inhibitor 9

[0106]

[0107] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 5-M2 (0.98 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 9 (0.46 g), with a yield of 39.5%. Spectroscopic data of URAT1 inhibitor 9: 1 HNMR(400MHz,DMSO-d6)δ9.34(s,1H),8.69(d,J=2.4Hz,1H),8.37(dd,J=4.6,1.6Hz,1H),7.96-7.93(m ,1H),7.46-7.42(m,2H),7.26(d,J=3.2Hz,1H),6.98(dd,J=4.8,3.6Hz,1H),5.67(s,2H),2.74(s,3H). 13 C NMR(100MHz,DMSO-d6)δ176.67,165.99,156.83,151.99,145.71,145.36,137 .95,135.76,131.41,128.16,127.23,126.88,123.96,106.65,39.51,16.31.

[0108] Example 10

[0109] Preparation of compound 6-M1:

[0110]

[0111] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 4-amino-5-thiazocarboxylate (2.37 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and after 2 h of reaction, phosgene (1.04 g, 9 mmol) was added. The intermediate compound 6-M1 (1.09 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 36.3%.

[0112] Preparation of compound 6-M2

[0113]

[0114] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 6-M1 (0.70 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 6-M2 (0.79 g), with a yield of 80.4%. Spectroscopic data of compound 6-M2: 1 H NMR (400MHz, DMSO-d6) δ14.36(s,1H),9.54(s,1H),7.40(dd,J=4.8,1.2Hz,1H),7.23(d,J=2.4Hz,1H),6.95(dd,J=4.8,3.2Hz,1H),5.77(s,2H).

[0115] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0116] Preparation of URAT1 inhibitor 10

[0117]

[0118] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 6-M2 (0.84 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) at 100 °C to obtain URAT1 inhibitor 10 (0.57 g), with a yield of 55.7%. Spectroscopic data of URAT1 inhibitor 10: 1HNMR(400MHz,DMSO-d6)δ9.50(s,1H),9.34(s,1H),8.72(d,J=2.4Hz,1H),8.37(dd,J=4.4,1.2Hz,1H),7.98 (dd,J=8.4,6.8Hz,1H),7.45-7.43(m,2H),7.27(d,J=3.2Hz,1H),6.98(dd,J=5.2,3.6Hz,1H),5.71(s,2H). 13 C NMR(100MHz,DMSO-d6)δ166.00,162.28,157.69,151.24,145.16,144.75, 137.44,135.41,130.74,127.77,126.77,126.43,123.48,107.39,54.92.

[0119] Example 11

[0120] Preparation of compound 7-M1:

[0121]

[0122] The procedure was the same as that for the preparation of compound 1-M1 in Example 1, except that methyl 3-amino-4-methylthiophene-2-carboxylate (2.57 g, 15 mmol) was reacted with phosgene (2.07 g, 18 mmol), and the intermediate compound 7-M1 (2.87 g) was obtained by column chromatography (EA:PE = 1:50), with a yield of 89.5%.

[0123] Preparation of compound 7-M2:

[0124]

[0125] The procedure was the same as for the preparation of compound 1-M2 in Example 1, except that intermediate compound 7-M1 (0.74 g, 3.5 mmol) was reacted with 2-thiophene methylamine (0.48 g, 4.2 mmol), and recrystallized from ethyl acetate to give intermediate compound 7-M2 (0.9 g), with a yield of 87.2%. Spectroscopic data of compound 7-M2: 1 H NMR (400MHz, DMSO-d6) δ13..26(s,1H),7.82(d,J=0.8Hz,1H),7.39(dd,J=5.2,1.2H z,1H),7.23(d,J=2.8Hz,1H),6.95(dd,J=5.2,3.6Hz,1H),5.79(s,2H),2.29(s,3H).

[0126] The preparation of N-(3-pyridyl)chloromethanesulfonamide was the same as in Example 1.

[0127] Preparation of URAT1 inhibitor 11

[0128]

[0129] The procedure was the same as for the preparation of URAT1 inhibitor 1 in Example 1, except that compound 7-M2 (0.88 g, 3 mmol) was reacted with N-(3-pyridyl)chloromethanesulfonamide (0.68 g, 3.3 mmol), KI (0.50 g, 3 mmol), and K2CO3 (1.24 g, 9 mmol) to obtain URAT1 inhibitor 11 (0.63 g), with a yield of 45.4%. Spectroscopic data of URAT1 inhibitor 11: 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.24(d,J=2.8Hz,1H),8.10(dd,J=4.4,1.2Hz,1H),7.81(d,J=0.8Hz,1H),7.49-7.46(m ,2H),7.18(d,J=2.8Hz,1H),7.13(dd,J=8.4,4.8Hz,1H),7.00(dd,J=4.8,3.6Hz,1H),5.48(s,2H),5.35(s,2H),2.06(s,3H). 13 C NMR(100MHz,DMSO-d6)δ156.93,153.88,153.47,144.64,140.68,136.94,134.48,13 2.76,131.23,128.25,126.93,126.79,126.15,123.56,118.80,50.73,42.21,12.03.

[0130] Example 12

[0131] Screening test for the inhibitory effect of URAT1 inhibitor 1-11 on the uric acid transporter hURAT1. Materials and methods:

[0132] (1) Cell line: Human uric acid transporter (hURAT1) high expression cell line (HEK293-URAT1).

[0133] (2) Experimental conditions:

[0134] The transporter was URAT1, and the substrate was 5 μmol / L. 14 C-Uric acid, administration time 2 min.

[0135] (3) Preparation of test drug:

[0136] 1) Preparation of 20 mmol / L stock solution

[0137] Using DMSO as the solvent, each compound was prepared into a 20 mmol / L stock solution.

[0138] 2) Preparation of working fluid

[0139] ① Single concentration: (1μmol / L): Using DMSO as the solvent, dilute stock solutions 1-11 to 200 times the dosing concentration, i.e., 200μmol / L, and dilute Lesinurad (Les, positive control) stock solution to 200μmol / L.

[0140] ②IC 50 Using DMSO as the solvent, stock solution No. 1 was diluted to 200 times the working solution of each drug concentration, namely 6000, 2000, 600, 200, 60, and 20 μmol / L.

[0141] ③ Use HBSS (without Cl) - Using a buffer solution as a solvent, the 200-fold working solutions in 1) and 2) were diluted by 100-fold to obtain 2-fold working solutions for each dosage concentration.

[0142] ④ Use HBSS (without Cl) - ) Preparation of buffer solution for standard substrate 14 The working solution of C-Uric acid is prepared by mixing twice the volume of the working solution in step 3) with an equal volume of the working solution in step 3.

[0143] (4) Administration method

[0144] After resuscitation and passage, hURAT1-expressing cell line (HEK293-URAT1) was used to select well-grown adherent cells for trypsin digestion into a single-cell suspension. The cell density was then adjusted to approximately 1.5 × 10⁻⁶ cells in the culture medium. 5 Cells / mL were seeded at 1 mL / well into 24-well cell culture plates and cultured for 2–3 days in an incubator at 37°C, 5% CO2, and saturated humidity.

[0145] After the cells had filled all the wells, the culture medium was removed, and the cells were washed twice with HBSS preheated to 37°C. Then, 1 mL of HBSS buffer at 37°C was added to each well and the cells were incubated for 10 min. Next, HBSS was replaced with 500 μL of working solution containing the radiolabeled probe substrate. After 2 min, the reaction was terminated with cold HBSS buffer, and 300 μL of 0.1 mol / L NaOH was added to each well to lyse the cells. The cell lysate was collected in a scintillation bottle, 1.5 mL of scintillation fluid was added, and the radioactivity intensity in the sample was measured using a Tri-Carb 2910TR liquid scintillation analyzer. Two replicates (n=2) were set up for each compound, positive control, and blank control.

[0146] (5) Data processing

[0147] The transport value Uc of the control group containing only the analyte was defined as 100%. Using this as a standard, the percentage (In) of the transport value U to Uc in each control group after the addition of the test compound was calculated; this percentage is the transport ratio. The transport ratio characterizes the strength of the compound's inhibitory effect on the transporter (a lower transport ratio In indicates stronger activity). The formula is as follows:

[0148]

[0149] Each group was configured with 2 replicates (n=2). Mean ± standard error (SD) was calculated using Excel statistical formulas, and IC was calculated using GraphPad Prism software. 50 .

[0150] Experimental results:

[0151] (1) Single concentration activity inhibition

[0152] like Figure 1 As shown, the positive control 1 μmol / L Lesinurad inhibited hURAT1 activity to 69.98%, indicating successful establishment of the cell model. Under single concentrations of 1 μmol / L, URAT1 inhibitors 1-11 exhibited different inhibitory effects on hURAT1, inhibiting hURAT1 activity to 58.46%, 73.09%, 78.78%, 67.02%, 81.19%, 67.33%, 76.09%, 70.31%, 81.42%, 82.56%, and 76.77%, respectively. Compared with the positive control drug Lesinurad at the same concentration (1 μmol / L), three of the URAT1 inhibitors showed superior inhibitory activity, while the inhibitory activity of the other compounds was comparable to that of Lesinurad.

[0153] (2)IC 50 Test Results

[0154] URAT1 inhibitor 1 showed strong inhibitory activity against hURAT1. An IC50 assay was performed on this URAT1 inhibitor. 50 Test. (e.g.) Figure 2 As shown, the IC50 of URAT1 inhibitor 1 on hURAT1 inhibition is... 50 It is 4.199 μmol / L.

[0155] Conclusion: Single-concentration activity inhibition assays showed that URAT1 inhibitors 1-11 all exhibited varying degrees of inhibition against hURAT1, with three compounds showing superior inhibitory activity compared to Lesinurad; URAT1 inhibitor 1 showed the strongest inhibitory activity, with an IC50 value of [missing information - likely an IC50 value] for its inhibitory effect on hURAT1. 50 The concentration was 4.199 μmol / L, and the activity was significantly better than the positive control Lesinurad (IC50). 50 =7.3 μmol / L), which can be used as a candidate drug for the treatment of gout and hyperuricemia.

[0156] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A URAT1 inhibitor containing an aminopyridine structure, characterized in that, Having a structure as shown in formula (I) or formula (II) or a pharmaceutically acceptable salt thereof: Formula (I); Formula (II); Wherein, Ar1 is thiophene, thiazole, thiophene substituted with one or more R1s, or thiazole substituted with one or more R1s, wherein R1 is C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, C 3-6 At least one of cycloalkyl, halogen, -OH, and -SH.

2. The URAT1 inhibitor containing an aminopyridine structure as described in claim 1, characterized in that, R1 is C 1-3 alkyl.

3. A method for preparing a URAT1 inhibitor containing an aminopyridine structure as described in claim 1 or 2, characterized in that, Includes the following steps: Using DMF as solvent, under the action of potassium iodide and potassium carbonate and under nitrogen protection, the compound shown in formula (III) reacts with N-(3-pyridyl)chloromethanesulfonamide to generate the URAT1 inhibitor containing an aminopyridine structure as described in claim 1 or 2. Formula (III).

4. The preparation method according to claim 3, characterized in that, When the reaction temperature is 70-80℃, the URAT1 inhibitor containing an aminopyridine structure generated by the reaction has the structure shown in formula (I); when the reaction temperature is 90-100℃, the URAT1 inhibitor containing an aminopyridine structure generated by the reaction has the structure shown in formula (II).

5. The preparation method according to claim 3, characterized in that, The molar ratio of the compound shown in formula (III), N-(3-pyridyl)chloromethanesulfonamide, potassium iodide and potassium carbonate is 1:(1-1.1):(0.9-1.1):(2.9-3.1).

6. The preparation method according to claim 3, characterized in that, It also includes the synthetic steps of compounds as shown in formula (III): S1. The compound shown in formula (IV) was dissolved in dichloromethane. After cooling to 0°C, sulfur phosgene was added dropwise and stirred. Then, triethylamine was added dropwise. After the addition was completed, the temperature was restored to room temperature and the reaction was carried out. After the reaction was complete, the reaction system was poured into water. After extraction, washing, separation, drying, and filtration, the filtrate was concentrated under reduced pressure and then subjected to column chromatography to obtain the compound shown in formula (V). S2. Dissolve the compound shown in formula (V) in tetrahydrofuran, add 2-thiophene methylamine and triethylamine in sequence, react at room temperature, evaporate the tetrahydrofuran after the reaction is complete, add ethanol to dissolve and add KOH to react, pour the reaction system into water after the reaction is complete, and obtain the compound shown in formula (III) after extraction, washing, drying, filtration and recrystallization. Formula (IV); Formula (V).

7. The preparation method according to claim 6, characterized in that, In step S1, the molar ratio of the compound shown in formula (IV), phosgene, and triethylamine is 1:(1.1-1.3):(1.9-2.1).

8. The preparation method according to claim 6, characterized in that, In step S2, the molar ratio of the compound shown in formula (V), 2-thiophene methylamine and triethylamine is 1:(1.1-1.3):(1.9-2.1).

9. The use of the URAT1 inhibitor containing an aminopyridine structure as described in claim 1 or 2 in the preparation of uric acid-lowering drugs.

10. A pharmaceutical composition, characterized in that, This includes URAT1 inhibitors containing an aminopyridine structure as described in claim 1 or 2, and pharmaceutically acceptable excipients.

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