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

Abstract

The invention belongs to the field of medicines, and particularly relates to a phenyl ether compound containing a hexahydrofuro [3, 2-b] furan structure and application of the phenyl ether compound. The compound is a phenyl ether compound containing a hexahydrofuro [3, 2-b] furan structure as shown in a general formula I and a pharmaceutically acceptable salt thereof, and substituent groups R1, R2 and R3 have meanings given in the specification. The compound disclosed by the invention has obvious inhibitory activity on xanthine oxidase, and the phenyl ether compound containing the hexahydrofuro [3, 2-b] furan structure and the pharmaceutically acceptable salt thereof can be used for preparing medicines for treating hyperuricemia or gout. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure and application thereof. Background Art

[0002] Gout is a chronic arthritis caused by hyperuricemia and urate deposition around joints. When uric acid is overproduced or underexcreted in the body, it will be deposited around 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 patients with hyperuricemia and gout.

[0003] At present, there are three main types of drugs for the treatment of gout, namely 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 can oxidize hypoxanthine into xanthine, and further oxidize xanthine into uric acid. Therefore, xanthine oxidase inhibitors can reduce uric acid levels in the body by inhibiting the production of uric acid, thereby achieving the purpose of treatment. Allopurinol is a purine xanthine oxidase inhibitor launched in 1966 for the treatment of primary and secondary hyperuricemia. Allopurinol and its metabolite oxypurinol can exert their efficacy by inhibiting xanthine oxidase. However, as a purine analog, allopurinol also interferes with normal purine metabolism, which may lead to severe hypersensitivity reactions. In addition, it can also cause side effects such as gastrointestinal discomfort, nephrotoxicity, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Non-purine inhibitors can selectively inhibit xanthine oxidase without affecting other enzymes responsible for purine or pyrimidine metabolism, thereby avoiding the occurrence of hypersensitivity syndrome caused by allopurinol, and have better safety than purine xanthine oxidase inhibitors. Febuxostat is a selective non-purine xanthine oxidase inhibitor developed by Teijin Co., Ltd. of Japan, which was approved by the FDA in 2009. Febuxostat is mainly metabolized by the liver and is suitable for patients with renal insufficiency. However, because febuxostat increases cardiovascular risk, the FDA issued a black box warning for it in 2019. Topiroxostat is a non-purine xanthine oxidase inhibitor developed by Fuji Pharmaceuticals. It was launched in Japan in 2013 for the treatment of hyperuricemia and is not yet available in other countries. Topiroxostat may cause gouty arthritis, and its current application range in the world is small, and its clinical efficacy and adverse reactions have not yet fully emerged. Tigulixostat is a selective xanthine oxidase inhibitor developed by LG Life Sciences of South Korea. The compound has comparable in vitro activity to febuxostat and has significant uric acid-lowering effects in vivo. It is currently in Phase III clinical trials and is a promising clinical drug under development.

[0004] Since the xanthine oxidase inhibitors currently used in clinical practice still have obvious defects and the number of hyperuricemia and gout patients in the world is increasing year by year, the clinical demand for anti-gout drugs has not yet been met. The development of highly effective and low-toxic xanthine oxidase inhibitors has very important clinical value. Summary of the invention

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

[0006] To achieve the above purpose, 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 containing a hexahydrofurano[3,2-b]furan structure as shown in general formula I and a pharmaceutically acceptable salt thereof,

[0008]

[0009] in,

[0010] R1 is selected from

[0011] R2 is selected from cyano or

[0012] R3 is selected from hydrogen, (C1-C6) alkyl, (C2-C4) alkenyl (C1-C6) alkylene, (C2-C4) alkynyl (C1-C6) alkylene; the (C1-C6) alkyl, (C2-C4) alkenyl (C1-C6) alkylene, (C2-C4) alkynyl (C1-C6) alkylene may be optionally substituted by at least one R4;

[0013] R4 is independently selected from hydrogen, halogen, (C1-C6) alkyl.

[0014] Preferably, the compound is a compound represented by general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0015] R1 is selected from

[0016] R2 is selected from cyano or

[0017] R3 is selected from hydrogen, (C1-C6) alkyl, vinyl (C1-C6) alkylene, ethynyl (C1-C6) alkylene; the (C1-C6) alkyl, vinyl (C1-C6) alkylene, ethynyl (C1-C6) alkyl may be optionally substituted by at least one R4;

[0018] R4 is independently selected from hydrogen, halogen, (C1-C6) alkyl.

[0019] Further preferably, the compound is a compound represented by general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0020] R1 is selected from

[0021] R2 is selected from cyano or

[0022] R3 is selected from hydrogen, (C1-C4) alkyl, vinyl (C1-C3) alkylene, ethynyl (C1-C3) alkylene; the (C1-C4) alkyl, vinyl (C1-C3) alkylene, ethynyl (C1-C3) alkylene may be optionally substituted by at least one R4;

[0023] R4 is independently selected from hydrogen, fluorine, (C1-C3) alkyl.

[0024] Still more preferably, the compound is a compound represented by general formula I and a pharmaceutically acceptable salt thereof, wherein:

[0025] R1 is selected from

[0026] R2 is selected from cyano or

[0027] R3 is selected from: hydrogen, methyl, ethyl, isopropyl,

[0028] More preferably, the compound is the following specific compound and a pharmaceutically acceptable salt thereof:

[0029]

[0030] 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 ion, sodium ion or potassium ion.

[0031] A pharmaceutical composition, comprising a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as shown in general formula I and a pharmaceutically acceptable salt thereof as an active ingredient, which is mixed with a pharmaceutically acceptable carrier or excipient to prepare the composition.

[0032] The carrier or excipient includes diluents, binders, wetting agents, disintegrants, lubricants, glidants, etc. known in the art. Diluents include but are not limited to starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, calcium hydrogen phosphate, etc.; wetting agents include but are not limited to water, ethanol, isopropanol, etc.; binders include but are not limited to starch slurry, dextrin, syrup, honey, glucose solution, acacia glue slurry, gelatin slurry, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene glycol, etc.; disintegrants include but are not limited to dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium dodecyl sulfate, etc.; lubricants and glidants include but are not limited to talc, silicon dioxide, polyethylene glycol, etc.

[0033] The pharmaceutical composition of the present invention can be formulated into several dosage forms, including but not limited to injections, tablets, capsules, and the like.

[0034] A phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure and its pharmaceutical composition use, wherein the phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure shown in general formula I and its pharmaceutically acceptable salt or the pharmaceutical composition can be used to prepare a drug for preventing and / or treating diseases related to xanthine oxidase. The diseases related to xanthine oxidase are selected from gout or hyperuricemia.

[0035] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine; "alkyl" refers to a straight chain or branched chain alkyl; Represents the place where substituents are attached.

[0036] The phenyl ether compounds containing a hexahydrofurano[3,2-b]furan structure represented by general formula I and pharmaceutically acceptable salts thereof of the present invention can be used in combination with other active ingredients to achieve a better therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Effects of the example compounds provided in the examples of the present invention on the serum uric acid level in mice with acute hyperuricemia. ### indicates that compared with the control group, P < 0.001; **** indicates that compared with the model group, P < 0.0001.

[0038] Figure 2 Effects of the example compounds provided in the examples of the present invention on the serum uric acid level in mice with acute hyperuricemia#### indicates that compared with the control group, P < 0.0001; **** indicates that compared with the model group, P < 0.0001; * indicates that compared with the febuxostat group, P < 0.05. DETAILED DESCRIPTION

[0039] The phenyl ether compounds containing a hexahydrofurano[3,2-b]furan structure having the general formula I of the present invention can be prepared by the method described in the following reaction scheme or a similar method.

[0040] All starting materials for the following synthetic routes are prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry, or are commercially available. The derivatives of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those skilled in the art of organic chemistry. All variables used in these schemes are as defined in the claims.

[0041] Depending on the substituents, the synthetic routes of phenyl ether compounds containing hexahydrofurano[3,2-b]furan structures are as follows.

[0042] Route 1, when R1 is When R2 is cyano, the synthetic route is as follows:

[0043]

[0044] (a) ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate was used as a raw material and reacted with isosorbide to obtain intermediate 2 through Mitsunobu reaction;

[0045] (b) intermediate 2 is used as a raw material, and reacted with the corresponding halogenated hydrocarbon to obtain intermediate 3 through substitution reaction;

[0046] (c) Using intermediate 3 as the starting material, the target compound was prepared by ester hydrolysis under alkaline conditions.

[0047] Route 2, when R1 is R2 is The synthetic route is as follows:

[0048]

[0049] (d) Using 4-hydroxy-3-nitrobenzonitrile as a raw material, intermediate 5 is prepared by cyano hydrolysis reaction;

[0050] (e) intermediate 5 is used as a raw material, and intermediate 6 is prepared by thiolation reaction with Lawesson's reagent;

[0051] (f) intermediate 6 is used as a raw material, and intermediate 7 is prepared by cyclization reaction with ethyl 2-chloroacetoacetate;

[0052] (g) intermediate 7 is used as a raw material, and isosorbide is reacted with intermediate 8 by Mitsunobu reaction;

[0053] (h) intermediate 8 is used as a raw material, and reacted with the corresponding halogenated hydrocarbon to obtain intermediate 9 through substitution reaction;

[0054] (i) intermediate 9 is used as a raw material to prepare intermediate 10 by nitro reduction reaction;

[0055] (j) intermediate 10 is used as a raw material, reacted with triethyl orthoformate and sodium azide to obtain intermediate 11;

[0056] (k) Using intermediate 11 as a starting material, the target compound was prepared by ester hydrolysis under alkaline conditions.

[0057] Route 3, when R1 is R2 is The synthetic route is as follows:

[0058]

[0059] (l) Using 4-methoxyphenylhydrazine hydrochloride as a raw material, in the presence of (E)-2-cyano-3-ethoxyethyl acrylate, intermediate 13 was prepared by a cyclization reaction;

[0060] (m) using intermediate 13 as a raw material, preparing intermediate 14 through deamination reaction;

[0061] (n) Using intermediate 14 as a raw material, intermediate 15 is prepared by nitration reaction in concentrated nitric acid and glacial acetic acid;

[0062] (o) intermediate 15 is used as a raw material, and intermediate 16 is prepared by demethylation reaction in the presence of AlCl3;

[0063] (p) intermediate 16 is used as a raw material and reacted with isosorbide to obtain intermediate 17 by Mitsunobu reaction;

[0064] (q) using intermediate 17 as a raw material, and reacting it with the corresponding halogenated hydrocarbon to obtain intermediate 18;

[0065] (r) Using intermediate 18 as a raw material, intermediate 19 is prepared by nitro reduction reaction;

[0066] (s) intermediate 19 is used as a raw material, reacted with triethyl orthoformate and sodium azide to obtain intermediate 20;

[0067] (t) Using intermediate 20 as the starting material, the target compound was prepared by ester hydrolysis under alkaline conditions.

[0068] The examples provided below further illustrate and illustrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparations does not limit the scope of the present invention in any way.

[0069] Example 1: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-1)

[0070]

[0071] Step 1: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0072]

[0073] Under N2 protection, triphenylphosphine (6.8 g, 26.0 mmol) was dissolved in tetrahydrofuran (50 mL), and diisopropyl azodicarboxylate (5.3 g, 26.0 mmol) was added in an ice bath. After stirring for 10 min, a solution of ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methylthiazole-5-carboxylate (5.0 g, 17.3 mmol) in tetrahydrofuran (50 mL) was added. The reaction solution was cooled to room temperature, a solution of isosorbide (3.0 g, 20.8 mmol) in tetrahydrofuran (50 mL) was added, and then N,N-diisopropylethylamine (3.4 g, 26.0 mmol) was added. After the addition was complete, the reaction was carried out at 60°C for 12 h. After the reaction was completed, 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, the organic phase was concentrated and purified by column chromatography to obtain 5.94 g of a light yellow solid with a yield of 82.3%. ESI-MS m / z: 417.12 [M+H] + .

[0074] Step 2: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-1)

[0075]

[0076] At room temperature, ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylate (0.15 g, 0.36 mmol) and sodium hydroxide (0.06 g, 1.44 mmol) were added to a mixed solution of methanol (1.5 mL) and water (0.5 mL) in sequence, and reacted at 50°C for 1 h. After the reaction was completed, water was added, and the pH was adjusted to 2 with a 2N HCl aqueous solution, and 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. 0.059 g of a white solid was obtained by column chromatography, and the yield was 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] - .

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

[0078]

[0079] Preparation method 1:

[0080] At room temperature, the intermediate 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuran[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) obtained in step 1 of Example 1 was dissolved in N,N-dimethylformamide (1.5 mL), sodium hydrogen (0.03 g, 0.36 mmol) was slowly added, and after stirring for 1 min, 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 with anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain a white solid, which was directly put into 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 in turn. The temperature was raised to 50°C for 1 h. After the reaction was completed, water was added, and the pH was adjusted to 2 with 2N HCl aqueous solution. The mixture was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 0.048 g of white solid was obtained by column chromatography, and the yield was 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(d d,J=10.8,3.8Hz,1H),3.95(d,J=10.6Hz,1H),3.91(d,J=3.1Hz,1H),3.88(d,J=10.0H z,1H),3.83(dd,J=10.0,3.8Hz,1H),3.31(s,3H),2.66(s,3H).ESI-MSm / z:402.7[M+H] + ,400.9[MH] - .

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

[0082]

[0083] Using 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) and iodoethane (0.08 g, 0.54 mmol) as raw materials, according to the preparation method 1, 0.045 g of a white solid was obtained, and the yield was 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] - .

[0084] Example 4: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-isopropoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-4)

[0085]

[0086] Preparation method 2:

[0087] At room temperature and in the dark, the intermediate 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuran[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) obtained in step 1 of Example 1 was dissolved in 1,2-dichloroethane (2 mL), silver oxide (0.17 g, 0.72 mmol) was added, stirred for 30 min, iodoisopropyl ether (0.12 g, 0.72 mmol) was added dropwise, and the temperature was raised to 60° C. for 24 h. After the reaction was completed, the reaction solution was cooled to room temperature, filtered with diatomaceous earth, the filter cake was washed with dichloromethane (10 mL), and the filtrate was concentrated to obtain a white solid, which was directly put into 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 in sequence. The temperature was raised to 50 °C for 1 h. After the reaction was completed, water (5 mL) was added, and the pH was adjusted to 2 with 2N HCl aqueous solution. The mixture was extracted with dichloromethane (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 0.025 g of white solid was obtained by column chromatography, and the yield was 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] - .

[0088] Example 5: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-isobutoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-5)

[0089]

[0090] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylate (0.15 g, 0.36 mmol) and isobutyl iodide (0.13 g, 0.72 mmol) as raw materials, according to the general preparation method 2, 0.024 g of a white solid was obtained, and the yield was 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] - .

[0091] Example 6: 2-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-cyanophenyl)-4-methylthiazole-5-carboxylic acid (Compound I-6)

[0092]

[0093] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylate (0.15 g, 0.36 mmol) and allyl bromide (0.07 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.027 g of a white solid was obtained, and the yield was 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] - .

[0094] Example 7: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-[(2-methylallyl)oxy]hexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-7)

[0095]

[0096] Using 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) and 3-bromo-2-methylpropene (0.07 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.030 g of a white solid was obtained, and the yield was 18.6%. 1H 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] - .

[0097] Example 8: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-[(3-methylbut-2-en-1-yl)oxy]hexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-8)

[0098]

[0099] Using 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) and 1-bromo-3-methyl-2-butene (0.08 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.032 g of a white solid was obtained, and the yield was 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] - .

[0100] Example 9: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-9)

[0101]

[0102] Using 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) and propargyl bromide (0.06 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.028 g of a white solid was obtained, and the yield was 18.2%. 1 H 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] - .

[0103] Example 10: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(2,2-difluoroethoxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-10)

[0104]

[0105] Using 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.15 g, 0.36 mmol) and 1,1-difluoro-2-iodoethane (0.1 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.037 g of a white solid was obtained, and the yield was 22.7%. 1H 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] - .

[0106] Example 11: 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-(2,2,2-trifluoroethoxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-11)

[0107]

[0108] Using ethyl 2-(3-cyano-4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylate (0.15 g, 0.36 mmol) and 2-iodo-1,1,1-trifluoroethane (0.11 g, 0.54 mmol) as raw materials, according to the general preparation method 1, 0.044 g of a white solid was obtained 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] - .

[0109] Example 12: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-12)

[0110]

[0111] Step 1: 4-Hydroxy-3-nitrobenzamide

[0112]

[0113] At room temperature, 4-hydroxy-3-nitrobenzonitrile (5g, 30.47mmol) was dissolved in dimethyl sulfoxide (75mL), potassium carbonate (12.63g, 91.4mmol) was added, and hydrogen peroxide solution (15mL) was added in batches. The reaction was allowed to react at room temperature for 40min. After the reaction was completed, the reaction solution was added to water (200mL), and the pH was adjusted to 1 with 2N HCl aqueous solution. A large amount of solid was precipitated, which was filtered and dried to obtain 4.98g of light yellow solid, with a yield of 89.7%. ESI-MS m / z: 183.24 [M+H] + .

[0114] Step 2: 4-Hydroxy-3-nitrobenzamide

[0115]

[0116] At room temperature, the intermediate 4-hydroxy-3-nitrobenzamide (4 g, 21.96 mmol) obtained in step 1 was dissolved in tetrahydrofuran (60 mL), and Lawesson reagent (10.66 g, 26.35 mmol) was added. The mixture was heated to 60°C under N2 protection for 1 h. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the concentrated filtrate was subjected to column chromatography to obtain 3.64 g of a yellow solid with a yield of 83.7%. ESI-MS m / z: 199.16 [M+H] + .

[0117] Step 3: 2-(4-hydroxy-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0118]

[0119] At room temperature, the intermediate 4-hydroxy-3-nitrobenzamide (5 g, 25.23 mmol) obtained in step 2 was dissolved in ethanol (15 mL), ethyl 2-chloroacetoacetate (8.3 g, 50.45 mmol) was added, and the temperature was raised to 80°C for 6 h. A large amount of yellow solid precipitated. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filter cake was washed with ether and dried to obtain 5.9 g of yellow solid, with a yield of 75.9%. ESI-MS m / z: 309.26 [M+H] + .

[0120] Step 4: 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0121]

[0122] Under N2 protection, triphenylphosphine (2.55 g, 9.73 mmol) was dissolved in tetrahydrofuran (20 mL), and diisopropyl azodicarboxylate (1.97 g, 9.73 mmol) was added in an ice bath. After stirring for 10 min, a solution of ethyl 2-(4-hydroxy-3-nitrophenyl)-4-methylthiazole-5-carboxylate (2 g, 6.49 mmol) in tetrahydrofuran (20 mL) was added. After the reaction solution was cooled to room temperature, a solution of isosorbide (1.14 g, 7.78 mmol) in tetrahydrofuran (10 mL) 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 completed, 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, the organic phase was concentrated and purified by column chromatography to obtain 2.02 g of a light yellow solid, with a yield of 71.2%. ESI-MS m / z: 437.29 [M+H] + .

[0123] Step 5: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0124]

[0125] At room temperature, the intermediate 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuran[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.3g, 0.69mmol) obtained in step 4 was dissolved in N,N-dimethylformamide (3mL), sodium hydrogen (0.05g, 1.37mmol) was slowly added, and after stirring for 1min, iodomethane (0.15g, 1.03mmol) was added dropwise, and the reaction was continued at room temperature for 10min. After the reaction was completed, the reaction solution was slowly added to water (10mL), extracted with ethyl acetate (10mL×3), the organic phases were combined, washed with water (10mL), washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to obtain 0.28g of a yellow solid with a yield of 90.7%. ESI-MS m / z:451.31[M+H] + .

[0126] Step 6: 2-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0127]

[0128] Dissolve NH4Cl (0.17 g, 3.11 mmol) in water (1.5 mL) and add reduced iron powder (0.17 g, 3.11 mmol). Heat to 80°C to activate the iron powder for 30 min. Then add the intermediate 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuran[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.28 g, 0.62 mmol) and ethanol (4.5 mL) obtained in step 5, and continue the reaction for 1 h. After the reaction was completed, ethyl acetate (10 mL) and water (10 mL) were added, diatomaceous earth was used for suction filtration, and the filtrate was extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL), dried with anhydrous sodium sulfate, suction filtered, and the organic phase was concentrated. 0.24 g of yellow solid was obtained by column chromatography, and the yield was 92.5%. ESI-MS m / z: 421.27 [M+H] + .

[0129] Step 7: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester

[0130]

[0131] The intermediate 2-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.24 g, 0.57 mmol) obtained in step 6 was dissolved in glacial acetic acid (3 mL), triethyl orthoformate (0.17 g, 1.14 mmol) and sodium azide (0.07 g, 1.14 mmol) were added in sequence, and heated to 60°C under N2 protection for 3 h. After the reaction was completed, the mixture was cooled to room temperature, water (10 mL) was added, the pH was adjusted to 13 with 2N NaOH aqueous solution, and extracted with ethyl acetate (15 mL×3), the organic phases were combined, washed with saturated sodium chloride (15 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 0.17 g of a yellow solid was obtained by column chromatography, and the yield was 63.2%. ESI-MS m / z:474.35[M+H] + .

[0132] Step 8: 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-12)

[0133]

[0134] The intermediate 2-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofurano[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazolyl-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.17 g, 0.36 mmol) obtained in step 7 was dissolved in methanol (3 mL), and sodium hydroxide (0.06 g, 1.44 mmol) and water (1 mL) were added in sequence. The temperature was raised to 50°C for reaction 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. 0.068 g of a white solid was obtained by column chromatography, and the yield was 42.5%. 1H 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] - .

[0135] Example 13: 2-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-13)

[0136]

[0137] Using 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.3 g, 0.69 mmol) and allyl bromide (0.12 g, 1.03 mmol) as raw materials, according to the preparation method of steps 5 to 8 of Example 12, 0.084 g of a white solid was obtained, and the yield was 52.6%. 1 H 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] - .

[0138] Example 14: 4-methyl-2-(4-{[(3S,3aR,6S,6aR)-6-[(2-methylallyl)oxy]hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)thiazole-5-carboxylic acid (Compound I-14)

[0139]

[0140] Using 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.3 g, 0.69 mmol) and 3-bromo-2-methylpropene (0.15 g, 1.03 mmol) as raw materials, according to the preparation method of steps 5 to 8 of Example 12, 0.078 g of a white solid was obtained, and the yield was 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] - .

[0141] Example 15: 4-methyl-2-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)thiazole-5-carboxylic acid (Compound I-15)

[0142]

[0143] Using 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.3 g, 0.69 mmol) and propargyl bromide (0.12 g, 1.03 mmol) as raw materials, according to the preparation method of steps 5 to 8 of Example 12, 0.062 g of a white solid was obtained, and the yield was 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] - .

[0144] Example 16: 2-(4-{[(3S,3aR,6S,6aR)-6-(but-2-yn-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-4-methylthiazole-5-carboxylic acid (Compound I-16)

[0145]

[0146] Using 2-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-4-methylthiazole-5-carboxylic acid ethyl ester (0.3 g, 0.69 mmol) and 1-bromo-2-butyne (0.14 g, 1.03 mmol) as raw materials, according to the preparation method of steps 5 to 8 of Example 12, 0.052 g of a white solid was obtained, and the yield was 32.2%. 1HNMR(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] + .

[0147] Example 17: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-17)

[0148]

[0149] Step 1: 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0150]

[0151] At room temperature, 4-methoxyphenylhydrazine hydrochloride (5g, 28.6mmol) and (E)-2-cyano-3-ethoxy ethyl acrylate (4.8g, 28.6mmol) were added to ethanol (50mL), and sodium acetate (2.4g, 28.6mmol) was added, and the mixture was reacted at 78℃ for 1h. After the reaction was completed, the mixture was cooled to room temperature, and water (200mL) was added to precipitate a large amount of solid, which was filtered and dried to obtain 6.9g of khaki solid, with a yield of 92.3%. ESI-MS m / z: 262.3[M+H] + .

[0152] Step 2: 1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0153]

[0154] At room temperature, the intermediate 5-amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5g, 19.1mmol) obtained in step 1 was dissolved in tetrahydrofuran (50mL), and isoamyl nitrite (2.2g, 19.1mmol) was added, and the mixture was reacted at 65°C for 1h. After the reaction was completed, water (100mL) was added, and ethyl acetate was extracted (100mL×3). The organic phases were combined, washed with saturated sodium chloride (100mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 4.3g of yellow solid was separated by column chromatography, and the yield was 90.3%. ESI-MSm / z: 247.1[M+H] + .

[0155] Step 3: 1-(4-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0156]

[0157] At room temperature, the intermediate 1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5g, 20.3mmol) obtained in step 2 was dissolved in glacial acetic acid (50mL), and concentrated nitric acid (15mL) was slowly added dropwise, and the reaction was carried out at room temperature for 30min. After the reaction was completed, water (200mL) was added to precipitate a yellow solid, which was filtered by suction. The filter cake was dissolved in dichloromethane (50mL), and after stirring with saturated sodium bicarbonate solution (50mL), the organic phase was separated and concentrated to obtain 5.4g of off-white solid, with a yield of 91.1%. ESI-MS m / z: 292.3[M+H] + .

[0158] Step 4: 1-(4-Hydroxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0159]

[0160] At room temperature, the intermediate 1-(4-methoxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (3g, 10.3mmol) obtained in step 3 was dissolved in 1,2-dichloroethane (30mL), AlCl3 (6.9g, 51.5mmol) was added, and the reaction solution was heated to 60°C for 1h under N2 protection. After the reaction was completed, the reaction solution was evaporated to dryness and water (100mL) was added to precipitate a green solid, which was filtered and dried. After the filter cake was slurried with ethanol, filtered and dried to obtain 1.9g of gray-green solid, with a yield of 65.5%. ESI-MS m / z: 277.9[M+H] + .

[0161] Step 5: 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0162]

[0163] Using 1-(4-hydroxy-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (5 g, 18.0 mmol) as the raw material, according to the preparation method of step 4 of Example 12, 5.0 g of light yellow solid was obtained with a yield of 68.6%. ESI-MS m / z: 406.1 [M+H] + .

[0164] Step 6: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0165]

[0166] 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 iodomethane (0.52 g, 3.7 mmol) as raw materials, according to the preparation method of step 5 of Example 12, 1 g of light yellow solid was obtained with a yield of 92.2%. ESI-MS m / z: 420.0[M+H] + .

[0167] Step 7: 1-(3-amino-4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0168]

[0169] 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, according to the preparation method of step 6 of Example 12, 0.8 g of a light yellow solid was obtained with a yield of 89.7%. ESI-MS m / z: 389.8 [M+H] + .

[0170] Step 8: 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0171]

[0172] Using 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 (0.5 g, 1.3 mmol) as the starting material, according to the preparation method of step 7 of Example 12, 0.35 g of a light yellow solid was obtained with a yield of 61.8%. ESI-MS m / z: 442.9 [M+H] + .

[0173] Step 9: 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)

[0174]

[0175] Using 1-(4-{[(3S,3aR,6S,6aR)-6-methoxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.15 g, 0.34 mmol) as starting material and following the preparation method of step eight in 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] + .

[0176] Example 18: 1-(4-{[(3S,3aR,6S,6aR)-6-(allyloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-18)

[0177]

[0178] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and allyl bromide (0.45 g, 3.7 mmol) as raw materials, according to the preparation method of steps 6 to 9 of Example 17, 0.053 g of a white solid was obtained, and the yield was 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] + .

[0179] Example 19: 1-(4-{[(3S,3aR,6S,6aR)-6-((2-methylallyl)oxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-19)

[0180]

[0181] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[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, according to the preparation method of steps 6 to 9 of Example 17, 0.045 g of a white solid was obtained, and the yield was 31.7%. 1 H 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] + .

[0182] Example 20: 1-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-20)

[0183]

[0184] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl]oxy}-3-nitrophenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 2.5 mmol) and propargyl bromide (0.44 g, 3.7 mmol) as raw materials, according to the preparation method of steps 6 to 9 of Example 17, 0.052 g of a white solid was obtained, and the yield was 36.6%. 1H 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] + .

[0185] Example 21: 1-(4-{[(3S,3aR,6S,6aR)-6-(prop-2-yn-1-yloxy)hexahydrofuro[3,2-b]furan-3-yl]oxy}-3-(1H-tetrazol-1-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Compound I-21)

[0186]

[0187] Using 1-(4-{[(3S,3aR,6S,6aR)-6-hydroxyhexahydrofuro[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, according to the preparation method of steps 6 to 9 of Example 17, 0.051 g of a white solid was obtained, and the yield was 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]+ .

[0188] Study on the pharmacological activity of the compounds of the present invention

[0189] 1. Evaluation of the Inhibition of Xanthine Oxidase Activity by the Example Compounds

[0190] The inhibitory activity of the example compounds on xanthine oxidase in vitro was investigated by 295 nm spectrophotometry. The inhibition rates of some compounds on xanthine oxidase at 50 nM were evaluated. The IC values ​​of some compounds for inhibiting xanthine oxidase were evaluated. 50 Xanthine and xanthine oxidase were purchased from Sigma-Aldrich.

[0191] Experimental steps:

[0192] (1) First, dilute the compound to be tested to 10 mM with DMSO to obtain a stock solution, and then continue to dilute the compound stock solution with buffer to the required concentration.

[0193] (2) Xanthine oxidase and test compound solution were added to a 96-well plate in sequence, mixed thoroughly, and incubated at room temperature for a period of time. Then, xanthine solution (8 μM) was added and incubated at room temperature for a period of time. The absorbance at 295 nm was measured using a Bio Tek microplate reader.

[0194] (3) All data were analyzed using computer software Graphpad Prism.

[0195] The results of the inhibitory activity of the example compounds on xanthine oxidase are shown in Table 1.

[0196] Table 1: Inhibitory activity results of the example compounds on xanthine oxidase

[0197] Example Inhibition rate % (50nM) <![CDATA[IC 50 (nM) a ]]> 1 63.7 - 2 76.9 4.8±1.8 3 56.6 - 4 74.8 19.5±6.7 5 72.4 23.3±6.2 6 93.9 4.1±1.3 7 85.0 7.2±3.2 8 64.7 - 9 88.2 9.7±3.5 10 73.4 19.6±5.4 11 59.7 - 12 - 3.7±1.3 13 - 0.9±0.3 14 - 1.6±0.6 15 - 0.5±0.2 16 - 1.1±0.4 17 - 11.5±3.9 18 - 1.6±0.6 19 - 1.7±0.8 20 - 2.2±1.0 21 - 4.1±1.6 febuxostat - 0.8±0.3 tigulixostat - 1.0±0.4

[0198] Note: a The results were expressed as mean ± standard deviation (Mean ± SD), and “-” means not measured.

[0199] The results of in vitro enzyme tests showed that the example compounds could significantly inhibit xanthine oxidase, and the activities of many example compounds were comparable to those of febuxostat and tigulixostat.

[0200] 2. Evaluation of uric acid-lowering activity of the example compounds in an acute hyperuricemia mouse model

[0201] An acute hyperuricemia animal model was constructed using ICR mice, and tigulixostat and febuxostat were used as positive controls to evaluate the in vivo uric acid-lowering activity of Examples 13, 14, 15, 16 and 19.

[0202] 2.1 Test materials

[0203] Potassium oxonate (Shanghai Yuanye), hypoxanthine (Solarbio), sodium carboxymethyl cellulose (Shanghai Yuanye), PEG300 (Solarbio), Tween-80 (Solarbio), uric acid assay kit (Nanjing Jiancheng Biology), ICR mice (Liaoning Changsheng Biotechnology Co., Ltd.)

[0204] 2.2 Experimental steps

[0205] (1) SPF ICR male mice were randomly divided into groups of 8 per group and fasted for 12 h with free access to water. Subsequently, except for the control group, mice in other groups were gavaged with hypoxanthine (400 mg / kg) and potassium oxonate (300 mg / kg) to induce acute hyperuricemia in mice, and the control group was given a solvent control.

[0206] (2) One hour later, the model group was given a solvent control by oral gavage, and the other groups were given the test compound (all at a dose of 5 mg / kg). Two hours after administration, 500 μL of blood was collected from the venous plexus of the fundus of the eye.

[0207] (3) After the collected blood was coagulated at room temperature for 1 hour, all blood samples were centrifuged (3500 rpm min -1 , 10 min, 4°C), and the absorbance at a wavelength of 510 nm was measured using a uric acid detection kit.

[0208] (4) All data were analyzed and graphed using Graphpad Prism software.

[0209] The results of uric acid lowering activity of Examples 13, 14, and 15 in the acute hyperuricemia mouse model are shown in Figure 1 The results of uric acid lowering activity of Examples 15, 16, and 19 in the acute hyperuricemia mouse model are shown in Figure 2 .

[0210] The experimental results are as follows Figure 1 and Figure 2 As shown, at a dose of 5 mg / kg, Examples 13, 14, 15, 16 and 19 can significantly reduce the serum uric acid level of acute hyperuricemia model mice, and the activities of Examples 14, 15 and 19 are better than tigulixostat and febuxostat, indicating 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 compound is a phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as shown in general formula I and a pharmaceutically acceptable salt thereof. 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, (C2-C4) alkynyl (C1-C6) alkylene; the (C1-C6) alkyl, (C2-C4) alkenyl (C1-C6) alkylene, (C2-C4) alkynyl (C1-C6) alkylene may be optionally substituted by at least one R4; R4 is independently selected from hydrogen, halogen, (C1-C6) alkyl.

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

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

4. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure as claimed in claim 3, characterized in that: The compound is a compound represented by general formula I and a pharmaceutically acceptable salt thereof, 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 claimed in claim 4, characterized in that: The compound is the following specific compound and a pharmaceutically acceptable salt thereof:

6. The phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure according to any one of claims 1 to 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 ion, sodium ion or potassium ion.

7. A pharmaceutical composition, characterized in that The composition comprises the phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure and a pharmaceutically acceptable salt thereof as claimed in claim 1 as an active ingredient, which is mixed with a pharmaceutically acceptable carrier or excipient to obtain the composition.

8. A phenyl ether compound containing a hexahydrofurano[3,2-b]furan structure and its pharmaceutical composition, characterized in that: Use of the phenyl ether compound containing a hexahydrofuro[3,2-b]furan structure and its pharmaceutically acceptable salt as described in claim 1 or the pharmaceutical composition as described in claim 7 in the preparation of a drug for preventing and / or treating diseases related to xanthine oxidase.

9. The use according to claim 8, characterized in that: The disease associated with xanthine oxidase is selected from gout or hyperuricemia.

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