Phenyl ether compound containing hexahydrofuro[3,2-b]furan structure and use thereof

Abstract

The present invention belongs to the field of medicine, and specifically relates to a phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure and use thereof. The compound is a phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure represented by general formula I or a pharmaceutically acceptable salt thereof, wherein substituents R1, R2, and R3 have the meanings given in the description. The compound disclosed in the present invention has significant inhibitory activity against xanthine oxidase, and the phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure and the pharmaceutically acceptable salt thereof can be used for preparing a drug for treating hyperuricemia or gout.

Description

Benzene ether compounds containing hexahydrofurano[3,2-b]furan structure and their applications Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a phenyl ether compound containing a hexahydrofuran[3,2-b]furan structure and its applications. Background Technology

[0002] Gout is a chronic arthritis caused by hyperuricemia and the deposition of urate crystals around the joints. When too much uric acid is produced or not enough is excreted from the body, it deposits in the joints and soft tissues, triggering an inflammatory response. Uric acid levels are related to purine levels in the body. With the continuous improvement of living standards, the intake of purine-rich foods has gradually increased, leading to a significant increase in the number of people with hyperuricemia and gout.

[0003] Currently, there are three main types of drugs for treating gout: drugs that inhibit uric acid production, drugs that promote uric acid excretion, and anti-inflammatory drugs. Uric acid is the final product of purine metabolism in the human body. Xanthine oxidase is a key enzyme in purine metabolism, which oxidizes hypoxanthine to xanthine, and further oxidizes xanthine to uric acid. Therefore, xanthine oxidase inhibitors can lower uric acid levels in the body by inhibiting uric acid production, thereby achieving the therapeutic goal. Allopurinol, a purine-based xanthine oxidase inhibitor marketed in 1966, is used to treat primary and secondary hyperuricemia. Allopurinol and its metabolite oxypurine can both exert their effects by inhibiting xanthine oxidase. However, as a purine analogue, allopurinol can also interfere with normal purine metabolism, potentially leading to severe hypersensitivity reactions. In addition, it can cause side effects such as gastrointestinal discomfort, nephrotoxicity, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Non-purine inhibitors selectively inhibit xanthine oxidase without affecting other enzymes responsible for purine or pyrimidine metabolism, thus avoiding hypersensitivity syndrome caused by allopurinol and exhibiting superior safety compared to purine xanthine oxidase inhibitors. Febuxostat, a selective non-purine xanthine oxidase inhibitor developed by Teijin Pharmaceutical Co., Ltd. of Japan, was approved by the FDA in 2009. Febuxostat is primarily metabolized by the liver and is suitable for patients with renal insufficiency. However, due to its increased cardiovascular risk, the FDA issued a black box warning for it in 2019. Topiroxostat, a non-purine xanthine oxidase inhibitor developed by Fuji Pharmaceutical Co., Ltd., was launched in Japan in 2013 for the treatment of hyperuricemia and is not currently available in other countries. Topiroxostat may cause gouty arthritis, and its global application is currently limited; its clinical efficacy and adverse reactions are not yet fully understood. Tigulixostat is a selective xanthine oxidase inhibitor developed by LG Life Sciences in South Korea. The compound has in vitro activity comparable to febuxostat and significant uric acid-lowering effects in vivo. It is currently in Phase III clinical trials and is a promising clinical investigational drug.

[0004] Because current xanthine oxidase inhibitors used in clinical practice still have significant shortcomings, and the number of patients with hyperuricemia and gout worldwide is increasing year by year, the clinical demand for anti-gout drugs has not yet been met. Therefore, the development of highly effective and low-toxicity xanthine oxidase inhibitors has very important clinical value. Summary of the Invention

[0005] The purpose of this invention is to provide a phenyl ether compound containing a hexahydrofuran[3,2-b]furan structure with xanthine oxidase inhibitory activity, a pharmaceutically acceptable salt thereof, a method for its preparation, and its use in the preparation of a medicament for treating hyperuricemia or gout.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure, wherein the compound is a phenyl ether compound of general formula I containing a hexahydrofurano[3,2-b]furan structure and its pharmaceutically acceptable salt.

[0008] in,

[0009] R1 is selected from

[0010] R2 is selected from cyano or

[0011] R3 is selected from hydrogen, (C1-C6)alkyl, (C2-C4)alkenyl(C1-C6)alkylene, and (C2-C4)ynyl(C1-C6)alkylene; the (C1-C6)alkyl, (C2-C4)alkenyl(C1-C6)alkylene, and (C2-C4)ynyl(C1-C6)alkylene may optionally be substituted by at least one R4;

[0012] R4 is independently selected from hydrogen, halogens, and (C1-C6) alkyl groups.

[0013] Preferably, the compound is a compound of general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0014] R1 is selected from

[0015] R2 is selected from cyano or

[0016] R3 is selected from hydrogen, (C1-C6)alkyl, vinyl(C1-C6)alkylene, and ethynyl(C1-C6)alkylene; the (C1-C6)alkyl, vinyl(C1-C6)alkylene, and ethynyl(C1-C6)alkyl may optionally be substituted by at least one R4;

[0017] R4 is independently selected from hydrogen, halogens, and (C1-C6) alkyl groups.

[0018] Further preferably, the compound is a compound of general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0019] R1 is selected from

[0020] R2 is selected from cyano or

[0021] R3 is selected from hydrogen, (C1-C4)alkyl, vinyl (C1-C3)alkylene, and ethynyl (C1-C3)alkylene; the (C1-C4)alkyl, vinyl (C1-C3)alkylene, and ethynyl (C1-C3)alkylene may optionally be substituted by at least one R4;

[0022] R4 is independently selected from hydrogen, fluorine, and (C1-C3) alkyl groups.

[0023] Further preferably, the compound is a compound of general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0024] R1 is selected from

[0025] R2 is selected from cyano or

[0026] R3 is selected from: hydrogen, methyl, ethyl, isopropyl,

[0027] More preferably, the compound is one of the following specific compounds and its pharmaceutically acceptable salt:

[0028] The pharmaceutically acceptable salt of the compound is a salt formed by the compound and an alkali metal ion, wherein the alkali metal ion is selected from lithium ions, sodium ions, or potassium ions.

[0029] A pharmaceutical composition comprising a phenyl ether compound of general formula I containing a hexahydrofurano[3,2-b]furan structure and its pharmaceutically acceptable salt as an active ingredient, prepared by mixing with a pharmaceutically acceptable carrier or excipient.

[0030] The carrier or excipient includes diluents, binders, wetting agents, disintegrants, lubricants, and flow aids known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, and dicalcium phosphate; wetting agents include, but are not limited to, water, ethanol, and isopropanol; binders include, but are not limited to, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, and polyethylene glycol; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, sodium carboxymethyl starch, and sodium dodecyl sulfonate; lubricants and flow aids include, but are not limited to, talc, silica, and polyethylene glycol.

[0031] The pharmaceutical composition of the present invention can be formulated into several dosage forms, including but not limited to injections, tablets, capsules, etc.

[0032] The use of a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure and pharmaceutical compositions thereof, wherein the phenyl ether compound of general formula I containing a hexahydrofurano[3,2-b]furan structure, its pharmaceutically acceptable salt, or the pharmaceutical composition thereof, can be used to prepare a medicament for the prevention and / or treatment of diseases related to xanthine oxidase. The diseases related to xanthine oxidase are selected from gout or hyperuricemia.

[0033] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodide; "alkyl" refers to a straight-chain or branched alkyl group. This represents the junction of substituents.

[0034] The phenyl ether compounds of the present invention containing the hexahydrofurano[3,2-b]furan structure shown in general formula I, and their pharmaceutically acceptable salts, can be used in combination with other active ingredients to achieve better therapeutic effects. Attached Figure Description

[0035] Figure 1 shows the effect of the compound provided in the embodiments of the present invention on the serum uric acid level in mice with acute hyperuricemia. ### indicates comparison with the control group, P<0.001; **** indicates comparison with the model group, P<0.0001.

[0036] Figure 2 shows the effect of the compound provided in the embodiments of the present invention on the serum uric acid level in mice with acute hyperuricemia. #### indicates comparison with the control group, P<0.0001; **** indicates comparison with the model group, P<0.0001; * indicates comparison with the febuxostat group, P<0.05. Detailed Implementation

[0037] The phenyl ether compounds of general formula I containing hexahydrofurano[3,2-b]furan structures of the present invention can be prepared by the method described below or a similar method.

[0038] All starting materials used in the following synthetic routes are prepared or are commercially available by means well known to those skilled in the art of organic chemistry, as described in these procedures. The derivatives of this invention are prepared by means of the methods described in these procedures or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these procedures are as defined in the claims.

[0039] The synthetic routes for phenyl ether compounds containing the hexahydrofuran[3,2-b]furan structure are as follows, depending on the different substituents.

[0040] Route 1, when R1 is The synthetic route when R2 is a cyano group is as follows:

[0041] (a) Using ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazol-5-carboxylate as a starting material, intermediate 2 was prepared by reacting isosorbide with Mitsunobu reaction;

[0042] (b) Using intermediate 2 as a raw material, intermediate 3 was prepared by substitution reaction with the corresponding halohydrocarbon;

[0043] (c) Using intermediate 3 as a raw material, the target compound was prepared by ester hydrolysis under alkaline conditions.

[0044] Route 2, when R1 is R2 is The synthesis route is as follows:

[0045] (d) Intermediate 5 was prepared from 4-hydroxy-3-nitrobenzene as a raw material by cyano hydrolysis reaction;

[0046] (e) Using intermediate 5 as a raw material, intermediate 6 was prepared by thiolation reaction with Lawesson reagent;

[0047] (f) Using intermediate 6 as a raw material, intermediate 7 was prepared by cyclization reaction with ethyl 2-chloroacetoacetate;

[0048] (g) Using intermediate 7 as a raw material, intermediate 8 was prepared by reacting isosorbide with Mitsunobu;

[0049] (h) Using intermediate 8 as a raw material, intermediate 9 is prepared by substitution reaction with the corresponding halohydrocarbon;

[0050] (i) Using intermediate 9 as a raw material, intermediate 10 was prepared by nitro reduction reaction;

[0051] (j) Intermediate 11 was prepared by reacting intermediate 10 with triethyl orthoformate and sodium azide.

[0052] (k) The target compound was prepared by ester hydrolysis under alkaline conditions using intermediate 11 as a raw material.

[0053] Route 3, when R1 is R2 is The synthesis route is as follows:

[0054] (l) Using 4-methoxyphenylhydrazine hydrochloride as a raw material, intermediate 13 was prepared by ring-closing reaction under the action of (E)-2-cyano-3-ethoxy ethyl acrylate;

[0055] (m) Intermediate 14 is prepared by deamination reaction using intermediate 13 as raw material;

[0056] (n) Using intermediate 14 as raw material, intermediate 15 is prepared by nitration under the conditions of concentrated nitric acid and glacial acetic acid;

[0057] (o) Using intermediate 15 as a raw material, intermediate 16 was prepared by demethylation reaction in the presence of AlCl3;

[0058] (p) Intermediate 17 was prepared by reacting intermediate 16 with isosorbide via Mitsunobu reaction.

[0059] (q) Using intermediate 17 as a raw material, intermediate 18 is prepared by substitution reaction with the corresponding halohydrocarbon;

[0060] (r) Intermediate 19 was prepared from intermediate 18 by nitro reduction reaction;

[0061] (s) Intermediate 20 was prepared by reacting intermediate 19 with triethyl orthoformate and sodium azide.

[0062] (t) The target compound was prepared by ester hydrolysis under alkaline conditions using intermediate 20 as a raw material.

[0063] The examples provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the present invention in any way.

[0064] Example 1: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-1)

[0065] Step 1: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid ethyl ester

[0066] Under nitrogen protection, triphenylphosphine (6.8 g, 26.0 mmol) was dissolved in tetrahydrofuran (50 mL), and diisopropyl azodicarbonate (5.3 g, 26.0 mmol) was added under ice bath conditions. After stirring for 10 min, a tetrahydrofuran (50 mL) solution of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazolyl-5-carboxylate (5.0 g, 17.3 mmol) was added. The reaction solution was cooled to room temperature, and a tetrahydrofuran (50 mL) solution of isosorbide (3.0 g, 20.8 mmol) was added, followed by N,N-diisopropylethylamine (3.4 g, 26.0 mmol). After the addition was complete, the reaction was carried out at 60 °C for 12 h. After the reaction was complete, the reaction solution was evaporated to dryness, poured into water (150 mL), extracted with ethyl acetate (100 mL × 3), the organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 5.94 g of a pale yellow solid, with a yield of 82.3%. ESI-MS m / z: 417.12 [M+H] + .

[0067] Step 2: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-1)

[0068] At room temperature, ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylate (0.15 g, 0.36 mmol) and sodium hydroxide (0.06 g, 1.44 mmol) were added sequentially to a mixed solution of methanol (1.5 mL) and water (0.5 mL), and the reaction was carried out at 50 °C for 1 h. After the reaction was completed, water was added, the pH was adjusted to 2 with 2N HCl aqueous solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and separated by column chromatography to obtain 0.059 g of white solid, with a yield of 42.3%. 1H NMR(600MHz,DMSO-d6)δ8.30(d,J=2.1Hz,1H),8.23(dd,J=8.9,2.1Hz,1H),7. 45(d,J=9.0Hz,1H),5.15(d,J=2.8Hz,1H),4.66(d,J=3.7Hz,1H),4.49(d,J=3. 7Hz,1H),4.16(d,J=2.5Hz,1H),4.01(dd,J=10.8,3.8Hz,1H),3.93(d,J=10.6H z,1H),3.81(dd,J=9.5,3.5Hz,1H),3.74(d,J=9.5Hz,1H),2.66(s,3H).ESI-MS m / z:388.9[M+H] + 386.9 [MH] - .

[0069] Example 2: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-2)

[0070] Preparation Method 1:

[0071] At room temperature, the intermediate 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) obtained in step one of Example 1 was dissolved in N,N-dimethylformamide (1.5 mL). Sodium hydrogen (0.03 g, 0.36 mmol) was slowly added, and the mixture was stirred for 1 min. Then, iodomethane (0.08 g, 0.54 mmol) was added dropwise, and the reaction was continued at room temperature for 10 min. After the reaction was completed, the reaction solution was slowly added to water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with water (10 mL), washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a white solid, which was directly added to the next step according to the theoretical yield. The obtained white solid was dissolved in methanol (3 mL), followed by the addition of sodium hydroxide (0.06 g, 1.44 mmol) and water (1 mL). The mixture was heated to 50 °C and reacted for 1 h. After the reaction was complete, water was added, and the pH was adjusted to 2 with 2N HCl aqueous solution. The mixture was extracted with dichloromethane (10 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The resulting white solid was separated by column chromatography, yielding 0.048 g, with a yield of 33.2%. 1H NMR(600MHz,DMSO-d6)δ8.32(d,J=2.0Hz,1H),8.25(dd,J=8.8,1.6Hz,1H),7.44(d ,J=9.0Hz,1H),5.15(d,J=3.2Hz,1H),4.65(d,J=3.9Hz,1H),4.63(d,J=3.9Hz,1H) ,4.05(dd,J=10.8,3.8Hz,1H),3.95(d,J=10.6Hz,1H),3.91(d,J=3.1Hz,1H),3.88 (d,J=10.0Hz,1H),3.83(dd,J=10.0,3.8Hz,1H),3.31(s,3H),2.66(s,3H).ESI-MS m / z: 402.7 [M+H] + 400.9 [MH] - .

[0072] Example 3: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-ethoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (compound I-3)

[0073] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylate (0.15 g, 0.36 mmol) and iodoethane (0.08 g, 0.54 mmol) as raw materials, 0.045 g of a white solid was obtained by general preparation method 1, with a yield of 29.8%. 1 H NMR (600MHz, DMSO-d6) δ8.31(d,J=2.0Hz,1H),8.24(dd,J=8.9,2.0Hz,1H),7.44(d,J=9.0Hz,1H),5.15(d,J=2.6Hz,1H),4.63(s,2H),4.04(dd,J= 10.8,3.9Hz,1H),4.00(s,1H),3.95(dd,J=10.6,1.0Hz,1H),3.84(d,J=2.6Hz,2H),3.55–3.50(m,2H),2.66(s,3H),1.11(t,J=7.0Hz,3H).ESI-MS m / z:417.1[M+H] + 414.9 [MH] - .

[0074] Example 4: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-isopropoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (compound I-4)

[0075] Preparation Method 2:

[0076] Under light-protected conditions at room temperature, the intermediate 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) obtained in step one of Example 1 was dissolved in 1,2-dichloroethane (2 mL), silver oxide (0.17 g, 0.72 mmol) was added, the mixture was stirred for 30 min, and iodoisopropane (0.12 g, 0.72 mmol) was added dropwise. The mixture was heated to 60 °C and reacted for 24 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through a diatomaceous earth sieve, the filter cake was washed with dichloromethane (10 mL), and the filtrate was concentrated to obtain a white solid, which was directly added to the next step according to the theoretical yield. The obtained white solid was dissolved in methanol (3 mL), and sodium hydroxide (0.06 g, 1.44 mmol) and water (1 mL) were added sequentially. The mixture was heated to 50 °C and reacted for 1 h. After the reaction was complete, water (5 mL) was added, the pH was adjusted to 2 with 2N HCl aqueous solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The resulting white solid was separated by column chromatography, yielding 0.025 g, with a yield of 16.2%. 1 H NMR (600MHz, DMSO-d6) δ8.24(d,J=1.4Hz,1H),8.18(dd,J=8.9,1.5Hz,1H),7.42(d,J=9. 0Hz,1H),5.12(d,J=2.4Hz,1H),4.62(d,J=3.9Hz,1H),4.56(d,J=3.9Hz,1H),4.08(d,J=2 .8Hz,1H),4.04(dd,J=10.7,3.7Hz,1H),3.95(d,J=10.6Hz,1H),3.86(dd,J=9.7,4.0Hz, 1H),3.76–3.71(m,2H),2.64(s,3H),1.11(d,J=6.1Hz,3H),1.09(d,J=6.1Hz,3H).ESI-MS m / z:431.1[M+H] + 429.0 [MH] - .

[0077] Example 5: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-isobutoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (compound I-5)

[0078] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylic acid (0.15 g, 0.36 mmol) and isobutane iodide (0.13 g, 0.72 mmol) as raw materials, 0.024 g of a white solid was obtained by general preparation method II, with a yield of 15.1%. 1 H NMR (600MHz, DMSO-d6) δ8.22(s,1H),8.16(d,J=8.4Hz,1H),7.41(d,J=8.9Hz,1H),5.12(d,J=2.2Hz,1H),4.63(s,2H),4.04(dd,J=10.7,3.6H z,1H),3.98–3.94(m,2H),3.84(d,J=2.3Hz,2H),3.28–3.22(m,2H),2.64(s,3H),1.76(dt,J=13.3,6.6Hz,1H),0.85(d,J=6.6Hz,6H).ESI-MS m / z:445.1[M+H] + 443.1 [MH] - .

[0079] Example 6: 2-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-cyanophenyl)-4-methylthiazol-5-carboxylic acid (compound I-6)

[0080] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylic acid (0.15 g, 0.36 mmol) and allyl bromo (0.07 g, 0.54 mmol) as raw materials, 0.027 g of a white solid was obtained by general preparation method 1, with a yield of 17.8%. 1H NMR (600MHz, DMSO-d6) δ8.22(d,J=1.2Hz,1H),8.16(dd,J=8.5,0.9Hz,1H),7.41(d,J=9.0 Hz,1H),5.92–5.86(m,1H),5.28(dd,J=17.3,1.5Hz,1H),5.16(dd,J=10.6,1.1Hz,1H),5.1 3(d,J=2.4Hz,1H),4.67(d,J=4.1Hz,1H),4.65(d,J=4.0Hz,1H),4.06–4.03(m,4H),3.95( d,J=10.6Hz,1H),3.88(d,J=9.8Hz,1H),3.85(dd,J=10.0,3.7Hz,1H),2.64(s,3H).ESI-MS m / z:428.9[M+H] + 427.0 [MH] - .

[0081] Example 7: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-[(2-methylallyl)oxy]hexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-7)

[0082] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylate (0.15 g, 0.36 mmol) and 3-bromo-2-methylpropene (0.07 g, 0.54 mmol) as raw materials, 0.030 g of a white solid was obtained by general preparation method one, with a yield of 18.6%. 1 H NMR (600MHz, DMSO-d6) δ8.27(d,J=1.0Hz,1H),8.21(dd,J=8.6,1.0Hz,1H),7.43(d,J=8 .9Hz,1H),5.15(d,J=2.2Hz,1H),4.95(s,1H),4.87(s,1H),4.68–4.65(m,2H),4.04(dd ,J=10.8,3.6Hz,1H),4.02(d,J=2.6Hz,1H),3.97(d,J=3.7Hz,2H),3.94(d,J=6.6Hz,2H ),3.89(d,J=9.9Hz,1H),3.85(dd,J=10.0,3.5Hz,1H),2.66(s,3H),1.68(s,3H).ESI-MS m / z:464.6[M+Na] +441.1 [MH] - .

[0083] Example 8: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-[(3-methylbut-2-en-1-yl)oxy]hexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylic acid (Compound I-8)

[0084] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylate (0.15 g, 0.36 mmol) and 1-bromo-3-methyl-2-butene (0.08 g, 0.54 mmol) as raw materials, 0.032 g of a white solid was obtained according to general preparation method one, with a yield of 19.7%. 1 H NMR (600MHz, DMSO-d6) δ8.20(s,1H),8.15(d,J=8.5Hz,1H),7.40(d,J=8.9Hz,1H),5.26(t,J=6.4Hz,1H),5.12(d,J=2.5Hz,1H),4.65(d,J=3. 9Hz,1H),4.62(d,J=3.8Hz,1H),4.05–4.00(m,4H),3.95(d,J=10.6Hz,1H),3.86–3.83(m,2H),2.63(s,3H),1.70(s,3H),1.64(s,3H).ESI-MS m / z:457.2[M+H] + 455.1 [MH] - .

[0085] Example 9: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-9)

[0086] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylate (0.15 g, 0.36 mmol) and bromopropyne (0.06 g, 0.54 mmol) as raw materials, 0.028 g of a white solid was obtained according to the general preparation method, with a yield of 18.2%. 1H NMR(600MHz,DMSO-d6)δ8.21(s,1H),8.16(d,J=8.2Hz,1H),7.41(d,J=8.7Hz ,1H),5.13(s,1H),4.71(d,J=3.4Hz,2H),4.64(d,J=3.4Hz,2H),4.27(s,2H) ,4.18(s,1H),4.05(dd,J=11.0,3.5Hz,3H),3.96(d,J=10.5Hz,1H),3.91(d, J=10.1Hz,1H),3.86(dd,J=9.7,2.6Hz,1H),3.50(s,1H),2.64(s,3H).ESI-MS m / z:449.1[M+Na] + 425.0 [MH] - .

[0087] Example 10: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(2,2-difluoroethoxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-10)

[0088] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylate (0.15 g, 0.36 mmol) and 1,1-difluoro-2-iodoethane (0.1 g, 0.54 mmol) as raw materials, 0.037 g of a white solid was obtained according to general preparation method one, with a yield of 22.7%. 1 H NMR(600MHz,DMSO-d6)δ8.20(d,J=1.6Hz,1H),8.15(dd,J=8.8,1.7Hz,1H),7.41(d, J=9.0Hz,1H),6.15(tt,J=54.9,3.6Hz,1H),5.14(d,J=2.7Hz,1H),4.70(d,J=4.0Hz ,1H),4.65(d,J=4.0Hz,1H),4.17(d,J=2.6Hz,1H),4.04(dd,J=10.8,3.8Hz,1H),3. 96(d,J=10.6Hz,1H),3.92(d,J=10.3Hz,1H),3.86–3.80(m,3H),2.63(s,3H).ESI-MS m / z:453.2[M+H] + 475.3 [M+Na] + 451.0 [MH] - .

[0089] Example 11: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(2,2,2-trifluoroethoxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-11)

[0090] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazolyl-5-carboxylate (0.15 g, 0.36 mmol) and 2-iodo-1,1,1-trifluoroethane (0.11 g, 0.54 mmol) as raw materials, 0.044 g of a white solid was obtained according to general preparation method one, with a yield of 25.7%. 1 H NMR (600MHz, DMSO-d6) δ8.20(s,1H),8.15(d,J=6.6Hz,1H),7.44(d,J=8.9Hz,1H),5.36(d,J=3.8H z,1H),5.22(s,1H),4.90(s,1H),4.82(s,1H),4.79(s,1H),4.07–3.99(m,5H),2.63(s,3H).ESI-MS m / z:470.8[M+H] + 493.0 [M+Na] + 468.9 [MH] - .

[0091] Example 12: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-12)

[0092] Step 1: 4-Hydroxy-3-nitrobenzamide

[0093] At room temperature, 5 g (30.47 mmol) of 4-hydroxy-3-nitrobenzonitrile was dissolved in 75 mL of dimethyl sulfoxide, and 12.63 g (91.4 mmol) of potassium carbonate was added. Hydrogen peroxide solution was added in portions (15 mL), and the reaction was allowed to proceed for 40 min at room temperature. After the reaction was complete, the reaction solution was added to 200 mL of water, and the pH was adjusted to 1 with 2N HCl aqueous solution. A large amount of solid precipitated, which was filtered and dried to obtain 4.98 g of a pale yellow solid, with a yield of 89.7%. ESI-MS m / z: 183.24 [M+H] + .

[0094] Step 2: 4-Hydroxy-3-nitrothiobenzamide

[0095] At room temperature, the intermediate 4-hydroxy-3-nitrobenzamide (4 g, 21.96 mmol) obtained in step one was dissolved in tetrahydrofuran (60 mL), and Lawesson's reagent (10.66 g, 26.35 mmol) was added. The mixture was heated to 60 °C for 1 h under N2 protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the concentrated filtrate was subjected to column chromatography to give 3.64 g of a yellow solid, with a yield of 83.7%. ESI-MS m / z: 199.16 [M+H] + .

[0096] Step 3: Ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid

[0097] At room temperature, the intermediate 4-hydroxy-3-nitrothiobenzamide (5 g, 25.23 mmol) obtained in step two was dissolved in ethanol (15 mL), and ethyl 2-chloroacetoacetate (8.3 g, 50.45 mmol) was added. The mixture was heated to 80 °C and reacted for 6 h, resulting in the precipitation of a large amount of yellow solid. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with diethyl ether and dried to give 5.9 g of yellow solid, with a yield of 75.9%. ESI-MS m / z: 309.26 [M+H] + .

[0098] Step 4: 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazol-5-carboxylic acid ethyl ester

[0099] Under nitrogen protection, triphenylphosphine (2.55 g, 9.73 mmol) was dissolved in tetrahydrofuran (20 mL), and diisopropyl azodicarbonate (1.97 g, 9.73 mmol) was added under ice bath conditions. After stirring for 10 min, a tetrahydrofuran (20 mL) solution of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methylthiazolyl-5-carboxylate (2 g, 6.49 mmol) was added. After cooling the reaction solution to room temperature, a tetrahydrofuran (10 mL) solution of isosorbide (1.14 g, 7.78 mmol) was added, followed by N,N-diisopropylethylamine (1.26 g, 9.73 mmol). After the addition was complete, the reaction was carried out at 60 °C for 12 h. After the reaction was complete, the reaction solution was evaporated to dryness, poured into water (60 mL), extracted with ethyl acetate (60 mL × 3), the organic phases were combined, washed with saturated sodium chloride (60 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 2.02 g of a pale yellow solid, with a yield of 71.2%. ESI-MS m / z: 437.29 [M+H] + .

[0100] Step 5: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylic acid ethyl ester

[0101] At room temperature, the intermediate 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylic acid ethyl ester (0.3 g, 0.69 mmol) obtained in step four was dissolved in N,N-dimethylformamide (3 mL). Sodium hydrogen (0.05 g, 1.37 mmol) was slowly added, and the mixture was stirred for 1 min. Then, iodomethane (0.15 g, 1.03 mmol) was added dropwise, and the reaction was continued at room temperature for 10 min. After the reaction was complete, the reaction solution was slowly added to water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with water (10 mL), washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to give 0.28 g of yellow solid, with a yield of 90.7%. ESI-MS m / z: 451.31 [M+H] + .

[0102] Step Six: Ethyl 2-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid ester

[0103] Dissolve NH4Cl (0.17 g, 3.11 mmol) in water (1.5 mL), and add reduced iron powder (0.17 g, 3.11 mmol). Activate the iron powder at 80 °C for 30 min. Then, add the intermediate obtained in step five, ethyl 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylate (0.28 g, 0.62 mmol), and ethanol (4.5 mL), and continue the reaction for 1 h. After the reaction was complete, ethyl acetate (10 mL) and water (10 mL) were added. The mixture was filtered through a diatomaceous earth filter. The filtrate was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 0.24 g of a yellow solid was obtained by column chromatography, with a yield of 92.5%. ESI-MS m / z: 421.27 [M+H] + .

[0104] Step 7: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid ethyl ester

[0105] The intermediate 2-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazol-5-carboxylic acid ethyl ester (0.24 g, 0.57 mmol) obtained in step six was dissolved in glacial acetic acid (3 mL), followed by the addition of triethyl orthoformate (0.17 g, 1.14 mmol) and sodium azide (0.07 g, 1.14 mmol). The reaction was carried out under N2 protection at 60 °C for 3 h. After the reaction was completed, the mixture was cooled to room temperature, and water (10 mL) was added. The pH was adjusted to 13 with 2N NaOH aqueous solution. The mixture was extracted with ethyl acetate (15 mL × 3), and the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The resulting product was separated by column chromatography to obtain 0.17 g of a yellow solid, with a yield of 63.2%. ESI-MS m / z: 474.35 [M+H] + .

[0106] Step 8: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid (compound I-12)

[0107] The intermediate 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid ethyl ester (0.17 g, 0.36 mmol) obtained in step seven was dissolved in methanol (3 mL), and sodium hydroxide (0.06 g, 1.44 mmol) and water (1 mL) were added sequentially. The mixture was heated to 50 °C and reacted for 1 h. After the reaction was completed, the mixture was cooled to room temperature, water (5 mL) was added, the pH was adjusted to 2 with 2N HCl aqueous solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. The resulting product was separated by column chromatography to obtain 0.068 g of white solid, with a yield of 42.5%. 1 H NMR (600MHz, DMSO-d6) δ9.80 (s, 1H), 8.32 (d, J = 1.6 Hz, 1H), 8.18 (dd, J = 8.5, 1. 3Hz,1H),7.57(d,J=8.8Hz,1H),5.16(d,J=2.1Hz,1H),4.62(d,J=3.5Hz,1H),4. 50(d,J=3.5Hz,1H),3.98(dd,J=10.7,3.5Hz,1H),3.88(d,J=11.4Hz,1H),3.85 (d,J=9.5Hz,2H),3.80(dd,J=9.8,3.4Hz,1H),3.28(s,3H),2.67(s,3H).ESI-MS m / z:444.1[MH] - .

[0108] Example 13: 2-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-13)

[0109] Using ethyl 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylic acid (0.3 g, 0.69 mmol) and allyl bromide (0.12 g, 1.03 mmol) as raw materials, and following steps five to eight of Example 12, a white solid of 0.084 g was obtained, with a yield of 52.6%. 1H NMR (600MHz, DMSO-d6) δ9.80(s,1H),8.32(s,1H),8.18(d,J=8.6Hz,1H),7.57(d,J=8.8Hz,1 H),5.87(ddt,J=16.1,10.4,5.2Hz,1H),5.26(d,J=17.2Hz,1H),5.15(d,J=10.5Hz,2H),4.65 (d,J=3.3Hz,1H),4.52(d,J=3.4Hz,1H),4.03–3.99(m,3H),3.98(dd,J=11.0,3.4Hz,1H),3.8 9(d,J=11.1Hz,1H),3.86(d,J=11.0Hz,1H),3.82(dd,J=9.9,3.2Hz,1H),2.67(s,3H).ESI-MS m / z:470.1[MH] - .

[0110] Example 14: 4-Methyl-2-(4-{[(3S,3aR,6S,6aR)-6-[(2-methylallyl)oxy]hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)thiazol-5-carboxylic acid (Compound I-14)

[0111] Using ethyl 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylate (0.3 g, 0.69 mmol) and 3-bromo-2-methylpropene (0.15 g, 1.03 mmol) as raw materials, and following steps five to eight of Example 12, a white solid of 0.078 g was obtained, with a yield of 48.5%. 1 H NMR (600MHz, DMSO-d6) δ13.50(s,1H),9.81(s,1H),8.32(s,1H),8.18(d,J=8. 3Hz,1H),7.57(d,J=8.8Hz,1H),5.16(s,1H),4.93(s,1H),4.86(s,1H),4.66(d ,J=3.0Hz,1H),4.52(d,J=2.9Hz,1H),3.97(s,2H),3.92–3.89(m,3H),3.87(d ,J=11.2Hz,1H),3.82(dd,J=9.7,3.0Hz,1H),2.68(s,3H),1.67(s,3H).ESI-MS m / z: 508.0 [M+Na] + 484.1 [MH] -.

[0112] Example 15: 4-Methyl-2-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)thiazol-5-carboxylic acid (Compound I-15)

[0113] Using ethyl 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylic acid (0.3 g, 0.69 mmol) and bromopropyne (0.12 g, 1.03 mmol) as raw materials, and following steps five to eight of Example 12, a white solid of 0.062 g was obtained, with a yield of 38.9%. 1 H NMR (600MHz, DMSO-d6) δ13.55(s,1H),9.80(s,1H),8.31(d,J=1.4Hz,1H),8.17(dd,J=8. 5,1.1Hz,1H),7.57(d,J=8.8Hz,1H),5.17(d,J=2.4Hz,1H),4.65(d,J=3.7Hz,1H),4.56( d,J=3.7Hz,1H),4.23(d,J=1.7Hz,2H),4.13(d,J=2.1Hz,1H),3.98(dd,J=10.7,3.6Hz,1 H),3.89(d,J=9.1Hz,2H),3.83(dd,J=10.2,3.6Hz,1H),3.47(s,1H),2.67(s,3H).ESI-MS m / z:470.1[M+H] + 492.1 [M+Na] + 468.1 [MH] - .

[0114] Example 16: 2-(4-{[(3S,3aR,6S,6aR)-6-(but-2-yn-1-yloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazol-5-carboxylic acid (Compound I-16)

[0115] Using ethyl 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazolyl-5-carboxylic acid (0.3 g, 0.69 mmol) and 1-bromo-2-butyne (0.14 g, 1.03 mmol) as raw materials, and following steps five to eight of Example 12, a white solid of 0.052 g was obtained, with a yield of 32.2%. 1 H NMR(600MHz,DMSO-d6)δ13.66(s,1H),9.79(s,1H),8.30(s,1H),8.17(d,J=8 .2Hz,1H),7.56(d,J=8.8Hz,1H),5.16(s,1H),4.63(d,J=3.3Hz,1H),4.54(d ,J=3.3Hz,1H),4.17(s,2H),4.11(s,1H),3.97(dd,J=10.6,3.2Hz,1H),3.90 –3.85(m,2H),3.81(dd,J=10.0,3.4Hz,1H),2.67(s,3H),1.83(s,3H).ESI-MS m / z:484.4[M+H] + .

[0116] Example 17: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-17)

[0117] Step 1: Ethyl 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

[0118] At room temperature, 4-methoxyphenylhydrazine hydrochloride (5 g, 28.6 mmol) and (E)-2-cyano-3-ethoxyacrylate (4.8 g, 28.6 mmol) were added to ethanol (50 mL), followed by sodium acetate (2.4 g, 28.6 mmol). The reaction was carried out at 78 °C for 1 h. After the reaction was complete, the mixture was cooled to room temperature, and water (200 mL) was added. A large amount of solid precipitated, which was filtered and dried to give 6.9 g of a light yellow solid, with a yield of 92.3%. ESI-MS m / z: 262.3 [M+H] + .

[0119] Step 2: 1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0120] At room temperature, the intermediate ethyl 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (5 g, 19.1 mmol) obtained in step one was dissolved in tetrahydrofuran (50 mL), and isoamyl nitrite (2.2 g, 19.1 mmol) was added. The reaction was carried out at 65 °C for 1 h. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. Column chromatography was used to separate the solid into 4.3 g of yellow solid, with a yield of 90.3%. ESI-MS m / z: 247.1 [M+H] + .

[0121] Step 3: 1-(4-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0122] At room temperature, the intermediate 1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 20.3 mmol) obtained in step two was dissolved in glacial acetic acid (50 mL), and concentrated nitric acid (15 mL) was slowly added dropwise. The reaction was carried out at room temperature for 30 min. After the reaction was completed, water (200 mL) was added, and a yellow solid precipitated. The solid was filtered, and the filter cake was dissolved in dichloromethane (50 mL). After stirring with saturated sodium bicarbonate solution (50 mL), the organic phase was separated. The organic phase was concentrated to give 5.4 g of off-white solid, with a yield of 91.1%. ESI-MS m / z: 292.3 [M+H] + .

[0123] Step 4: Ethyl 1-(4-hydroxy-3-nitrophenyl)-1H-pyrazole-4-carboxylate

[0124] At room temperature, the intermediate 1-(4-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (3 g, 10.3 mmol) obtained in step three was dissolved in 1,2-dichloroethane (30 mL), and AlCl3 (6.9 g, 51.5 mmol) was added. Under N2 protection, the reaction solution was heated to 60 °C and reacted for 1 h. After the reaction was completed, the reaction solution was evaporated to dryness, and water (100 mL) was added, precipitating a green solid. The solid was filtered, the filter cake was dried, and then slurried with ethanol, filtered, and dried to obtain 1.9 g of a gray-green solid, with a yield of 65.5%. ESI-MS m / z: 277.9 [M+H] + .

[0125] Step 5: 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0126] Using ethyl 1-(4-hydroxy-3-nitrophenyl)-1H-pyrazole-4-carboxylate (5 g, 18.0 mmol) as the starting material, and following the preparation method in step four of Example 12, 5.0 g of a pale yellow solid was obtained, with a yield of 68.6%. ESI-MS m / z: 406.1 [M+H] + .

[0127] Step Six: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0128] Using ethyl 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylate (1 g, 2.5 mmol) and methyl iodide (0.52 g, 3.7 mmol) as starting materials, and following the preparation method in step five of Example 12, 1 g of a pale yellow solid was obtained, with a yield of 92.2%. ESI-MS m / z: 420.0 [M+H] + .

[0129] Step 7: 1-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0130] Using 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.4 mmol) as the starting material, 0.8 g of a pale yellow solid was obtained according to step six of Example 12, with a yield of 89.7%. ESI-MS m / z: 389.8 [M+H] + .

[0131] Step 8: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0132] Using ethyl 1-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-1H-pyrazole-4-carboxylate (0.5 g, 1.3 mmol) as a starting material, 0.35 g of a pale yellow solid was obtained according to step seven of Example 12, with a yield of 61.8%. ESI-MS m / z: 442.9 [M+H] + .

[0133] Step Nine: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-17)

[0134] Using ethyl 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylate (0.15 g, 0.34 mmol) as the starting material, and following the preparation method in step eight of Example 12, 0.060 g of a white solid was obtained, with a yield of 42.5%. 1 H NMR (600MHz, DMSO-d6) δ12.69(s,1H),9.83(s,1H),9.11(s,1H),8.34(d,J=2.6Hz, 1H),8.17(dd,J=9.1,2.6Hz,1H),8.12(s,1H),7.61(d,J=9.2Hz,1H),5.13(s,1H), 4.60(d,J=4.0Hz,1H),4.47(d,J=4.0Hz,1H),3.95(dd,J=10.7,3.8Hz,1H),3.88(s ,1H),3.86(s,1H),3.84(s,1H),3.78(dd,J=10.3,3.9Hz,1H),3.28(s,3H).ESI-MS m / z: 415.3 [M+H] + .

[0135] Example 18: 1-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-18)

[0136] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and bromopropene (0.45 g, 3.7 mmol) as raw materials, and following steps six to nine of Example 17, a white solid of 0.053 g was obtained, with a yield of 37.6%. 1 H NMR (600MHz, DMSO-d6) δ12.70(s,1H),9.83(s,1H),9.11(s,1H),8.34(s,1H),8.17(d,J=9.0Hz,1H),8. 12(s,1H),7.61(d,J=9.1Hz,1H),5.87(ddt,J=16.5,10.6,5.4Hz,1H),5.26(d,J=17.2Hz,1H),5.16(s,1 H),5.14(s,1H),4.63(d,J=3.5Hz,1H),4.49(d,J=3.4Hz,1H),4.03–4.00(m,2H),3.99(s,1H),3.95(dd ,J=10.8,3.4Hz,1H),3.87(d,J=7.4Hz,1H),3.85(d,J=6.2Hz,1H),3.80(dd,J=10.0,3.4Hz,1H).ESI-MS m / z:441.2[M+H] + .

[0137] Example 19: 1-(4-{[(3S,3aR,6S,6aR)-6-((2-methylallyl)oxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-19)

[0138] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and 3-bromo-2-methylpropene (0.5 g, 3.7 mmol) as raw materials, and following steps six to nine of Example 17, a white solid of 0.045 g was obtained, with a yield of 31.7%. 1H NMR(600MHz,DMSO-d6)δ12.61(s,1H),9.83(s,1H),9.09(s,1H),8.34(s,1H), 8.17(d,J=8.1Hz,1H),8.10(s,1H),7.61(d,J=8.8Hz,1H),5.14(s,1H),4.93(s ,1H),4.86(s,1H),4.65–4.61(m,1H),4.49(s,1H),3.96(s,1H),3.93(s,1H),3 .91(s,2H),3.87(d,J=13.6Hz,2H),3.80(d,J=8.3Hz,1H),1.66(s,3H).ESI-MS m / z: 455.4 [M+H] + .

[0139] Example 20: 1-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-20)

[0140] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and bromopropyne (0.44 g, 3.7 mmol) as raw materials, and following steps six to nine of Example 17, a white solid of 0.052 g was obtained, with a yield of 36.6%. 1 H NMR(600MHz,DMSO-d6)δ12.63(s,1H),9.81(s,1H),9.10(s,1H),8.33(d,J=2.6Hz,1H), 8.16(dd,J=9.1,2.7Hz,1H),8.11(s,1H),7.61(d,J=9.2Hz,1H),5.14(s,1H),4.62(d,J =3.9Hz,1H),4.53(d,J=3.9Hz,1H),4.23(d,J=2.3Hz,2H),4.13–4.12(m,1H),3.96(dd, J=10.7,3.7Hz,1H),3.90–3.86(m,2H),3.83–3.80(m,1H),3.48(t,J=2.2Hz,1H).ESI-MS m / z:439.1[M+H] + .

[0141] Example 21: 1-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-21)

[0142] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and 1-bromo-2-butyne (0.49 g, 3.7 mmol) as raw materials, and following steps six to nine of Example 17, a white solid of 0.051 g was obtained, with a yield of 35.8%. 1 H NMR(600MHz,DMSO-d6)δ12.73(s,1H),9.80(s,1H),9.07(s,1H),8.33(d,J=2.5Hz,1H),8 .16(dd,J=9.1,2.5Hz,1H),8.09(s,1H),7.60(d,J=9.2Hz,1H),5.14(s,1H),4.61(d,J=4. 0Hz,1H),4.51(d,J=4.0Hz,1H),4.18–4.16(m,2H),4.10(d,J=2.9Hz,1H),3.94(dd,J=10 .7,3.7Hz,1H),3.86(d,J=10.7Hz,2H),3.80(dd,J=10.2,3.7Hz,1H),1.83(s,3H).ESI-MS m / z:453.2[M+H] + .

[0143] Pharmacological activity study of the compounds of this invention

[0144] 1. Evaluation of the inhibitory activity of the compounds on xanthine oxidase in the examples

[0145] The inhibitory activity of the compounds in the examples against xanthine oxidase in vitro was investigated using a 295 nm spectrophotometric method. The inhibition rates of some compounds against xanthine oxidase at 50 nM were evaluated, and the IC50 of some compounds against xanthine oxidase was also evaluated. 50 Xanthine and xanthine oxidase were purchased from Sigma-Aldrich.

[0146] Experimental steps:

[0147] (1) First, dilute the compound to be tested to 10 mM with DMSO to obtain a stock solution, and then continue to dilute the stock solution of the compound to the required concentration with buffer solution.

[0148] (2) Add xanthine oxidase and test compound solution to the 96-well plate in sequence, mix thoroughly, incubate at room temperature for a period of time, add xanthine solution (8 μM), continue to incubate at room temperature for a period of time, and detect absorbance at 295 nm using Bio Tek microplate reader.

[0149] (3) All data were analyzed using the computer software GraphpadPrism.

[0150] The results of the inhibitory activity of the compounds in the examples against xanthine oxidase are shown in Table 1.

[0151] Table 1: Results of the inhibitory activity of the compounds in the examples on xanthine oxidase

[0152] Note: a Results are expressed as mean ± standard deviation (Mean ± SD), with "-" indicating unmeasured.

[0153] In vitro enzyme assays showed that the compounds in the examples significantly inhibited xanthine oxidase, and the activities of several of the compounds in the examples were comparable to febuxostat and tigulixostat.

[0154] 2. Evaluation of the uric acid-lowering activity of the compounds in a mouse model of acute hyperuricemia.

[0155] An acute hyperuricemia animal model was established using ICR mice. Tigulixostat and febuxostat were used as positive controls. The in vivo uric acid-lowering activity of Examples 13, 14, 15, 16 and 19 was evaluated.

[0156] 2.1 Test Materials

[0157] Potassium oxonate (Shanghai Yuanye), hypoxanthine (Solarbio), sodium carboxymethyl cellulose (Shanghai Yuanye), PEG300 (Solarbio), Tween-80 (Solarbio), uric acid assay kit (Nanjing Jiancheng Biotechnology), ICR mice (Liaoning Changsheng Biotechnology Co., Ltd.)

[0158] 2.2 Test Procedure

[0159] (1) SPF-grade ICR male mice were randomly divided into groups of 8 mice each. They were fasted and allowed free access to water for 12 hours. Subsequently, except for the control group, the mice in the other groups were administered hypoxanthine (400 mg / kg) and potassium oxonate (300 mg / kg) by gavage to induce an acute hyperuricemia model in mice. The control group was given a solvent control.

[0160] (2) One hour later, the model group was given the solvent control by gavage, while the other groups were given the test compound (at a dose of 5 mg / kg). Two hours after administration, 500 μL of blood was collected from the fundus venous plexus of each group.

[0161] (3) After the collected blood coagulated at room temperature for 1 hour, all blood samples were centrifuged (3500 rpm·min). -1 The absorbance at 510 nm was measured using a uric acid assay kit (10 min, 4℃).

[0162] (4) All data were analyzed and plotted using GraphpadPrism software.

[0163] The uric acid-lowering activity results of Examples 13, 14, and 15 in the mouse model of acute hyperuricemia are shown in Figure 1; the uric acid-lowering activity results of Examples 15, 16, and 19 in the mouse model of acute hyperuricemia are shown in Figure 2.

[0164] The experimental results are shown in Figures 1 and 2. At a dose of 5 mg / kg, Examples 13, 14, 15, 16 and 19 can significantly reduce serum uric acid levels in mice with acute hyperuricemia. The activities of Examples 14, 15 and 19 are superior to tigulixostat and febuxostat, showing that they have significant uric acid-lowering activity in animal models.

Claims

1. A phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure, characterized in that: The compounds are phenyl ethers containing a hexahydrofurano[3,2-b]furan structure, as shown in general formula I, and their pharmaceutically acceptable salts. in, R1 is selected from R2 is selected from cyano or R3 is selected from hydrogen, (C1-C6)alkyl, (C2-C4)alkenyl(C1-C6)alkylene, and (C2-C4)ynyl(C1-C6)alkylene; the (C1-C6)alkyl, (C2-C4)alkenyl(C1-C6)alkylene, and (C2-C4)ynyl(C1-C6)alkylene may optionally be substituted by at least one R4; R4 is independently selected from hydrogen, halogens, and (C1-C6) alkyl groups.

2. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in claim 1, characterized in that: The compound is a compound of general formula I and its pharmaceutically acceptable salt, wherein: R1 is selected from R2 is selected from cyano or R3 is selected from hydrogen, (C1-C6)alkyl, vinyl(C1-C6)alkylene, and ethynyl(C1-C6)alkylene; the (C1-C6)alkyl, vinyl(C1-C6)alkylene, and ethynyl(C1-C6)alkylene may optionally be substituted by at least one R4; R4 is independently selected from hydrogen, halogens, and (C1-C6) alkyl groups.

3. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in claim 2, characterized in that: The compound is a compound of general formula I and its pharmaceutically acceptable salt, wherein: R1 is selected from R2 is selected from cyano or R3 is selected from hydrogen, (C1-C4)alkyl, vinyl (C1-C3)alkylene, and ethynyl (C1-C3)alkylene; the (C1-C4)alkyl, vinyl (C1-C3)alkylene, and ethynyl (C1-C3)alkylene may optionally be substituted by at least one R4; R4 is independently selected from hydrogen, fluorine, and (C1-C3) alkyl groups.

4. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in claim 3, characterized in that: The compound is a compound of general formula I and its pharmaceutically acceptable salt, wherein: R1 is selected from R2 is selected from cyano or R3 is selected from: hydrogen, methyl, ethyl, isopropyl, 5. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in claim 4, characterized in that: The compounds are the following specific compounds and their pharmaceutically acceptable salts:

6. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in any one of claims 1-5, characterized in that: The pharmaceutically acceptable salt of the compound is a salt formed by the compound and an alkali metal ion, wherein the alkali metal ion is selected from lithium ions, sodium ions, or potassium ions.

7. A pharmaceutical composition, characterized in that, The composition is prepared by mixing a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as described in claim 1 and its pharmaceutically acceptable salt as the active ingredient with a pharmaceutically acceptable carrier or excipient.

8. The application of a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure and its pharmaceutical composition thereof, characterized in that: The use of the phenyl ether compound containing the hexahydrofurano[3,2-b]furan structure of claim 1 and its pharmaceutically acceptable salt, or the pharmaceutical composition of claim 7, in the preparation of a medicament for the prevention and / or treatment of diseases related to xanthine oxidase.

9. The application according to claim 8, characterized in that: The diseases associated with xanthine oxidase are selected from gout or hyperuricemia.

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