Novel use of 2,4-disubstituted-5-fluoropyrimidine derivative

Abstract

Provided in the present invention is use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of drugs for lowering uric acid. The 2,4-disubstituted-5-fluoropyrimidine derivative has the following structural formula (I) and provides a new option for drugs for lowering uric acid.

Description

A new use of a 2,4-disubstituted-5-fluoropyrimidine derivative Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a new use of a 2,4-disubstituted-5-fluoropyrimidine derivative. Background Technology

[0002] Hyperuricemia is a metabolic disease caused by purine metabolism disorders. It can be divided into primary hyperuricemia and secondary hyperuricemia. Primary hyperuricemia is generally caused by congenital purine metabolism disorders, while secondary hyperuricemia is mostly caused by systemic diseases or drugs. Clinically, hyperuricemia is defined as a fasting serum uric acid level higher than 420 μmol / L for men and higher than 360 μmol / L for women on two separate occasions.

[0003] Currently, medications for treating hyperuricemia on the market can be divided into two categories: uric acid synthesis inhibitors and uricosuric drugs. A representative uric acid synthesis inhibitor is febuxostat, which inhibits uric acid synthesis by suppressing the activity of xanthine oxidase (XO), thereby lowering uric acid levels. However, its side effects are also significant, including liver failure and tubulointerstitial nephritis. Representative uricosuric drugs are benzbromarone and rasinard. Benzbromarone is an inhibitor of urate transporter 1 (URAT1) and human glucose transporter 9 (GLUT9), while rasinard is an URAT1 inhibitor. Both treat hyperuricemia by inhibiting uric acid reabsorption. The main side effect of benzbromarone is abnormal liver function, and it may also worsen liver disease (cytolytic hepatitis), sometimes with acute exacerbations that are difficult to control. Currently, rasinard has been withdrawn from the FDA due to severe nephrotoxicity.

[0004] CN116514779A discloses a 2,4-disubstituted-5-fluoropyrimidine derivative having the following structure:

[0005] This compound is an inhibitor of homologous domain interacting protein kinase 2 (HIPK2), which is highly expressed in renal interstitial tubular lesions and participates in fibrosis and inflammation by regulating oxidative stress. Inhibiting HIPK2 can suppress fibrosis pathways (TGF-β / Smad3 pathway, Wnt-β-catenin pathway, and Notch pathway) and inflammatory pathways (activating IκB-α to inhibit the NF-κB pathway), thereby achieving the therapeutic goal of renal interstitial fibrosis.

[0006] Recently, compounds of formula II and III have been found to have the potential to inhibit the activity of URAT1 and GLUT9, which may lead to the development of uric acid-lowering drugs with better activity and higher safety. Summary of the Invention

[0007] This invention provides the use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a uric acid-lowering drug, and demonstrates good therapeutic effects; the 2,4-disubstituted-5-fluoropyrimidine derivative has the following structure:

[0008] R3 is selected from:

[0009] R4 is selected from:

[0010] X and Y are each independently selected from nitrogen or carbon atoms; Z is selected from hydrogen, tert-butoxycarbonyl, C1-C5 alkyl, C1-C5 alkyl acyl, C1-C3 alkyl hydroxyl, C1-C3 alkyl sulfonyl, C1-C3 substituted phenyl, and C1-C5 alkyl amide.

[0011] In some embodiments, when the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula II, R4 is... When Z is not tert-butyloxycarbonyl, Z is not a tert-butyloxycarbonyl group.

[0012] In some embodiments, when the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula III, R4 When Z is not tert-butoxycarbonyl, C4-C5 alkyl, C4-C5 alkylacyl, or C4-C5 alkylamide.

[0013] In some embodiments, the C1-C5 alkyl group in the 2,4-disubstituted-5-fluoropyrimidine derivative includes methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopentyl, and isopropyl.

[0014] In some embodiments, the C1-C5 alkyl acyl groups in the 2,4-disubstituted-5-fluoropyrimidine derivative include formyl, acetyl, propionyl, butyryl, valerate, 3,3-dimethyl-1-butyryl, and isovaleryl.

[0015] In some embodiments, the C1-C5 alkylamide groups in the 2,4-disubstituted-5-fluoropyrimidine derivative include formamido, acetamido, propionamido, butamido, valamido, N-tert-butylaminoformyl, and isovaleramido.

[0016] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative is specifically the following compound: tert-butyl-4-(4-((5-fluoro-2-((4-(methoxyformyl)phenyl)amino)pyridin-4-yl)amino)phenyl)piperazine-1-carboxylic acid ester (6e compound);

[0017] 1-(5-fluoro-4-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (6f compound);

[0018] 1-(4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (6g compound);

[0019] 1-(5-fluoro-4-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (compound 7a / compound I);

[0020] 1-(5-fluoro-4-((4-(4-isopentylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (compound 8a);

[0021] 1-(5-fluoro-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine (12h compound);

[0022] The pharmaceutically acceptable salts are hydrochloride, sulfate, phosphate, perchlorate, methanesulfonate, trifluoromethanesulfonate, formate, acetate, propionate, butyrate, maleate, succinate, trifluoroacetate, succinate, salicylate, DL-aspartate, D-aspartate, L-aspartate, DL-glutamate, D-glutamate, L-glutamate, glycerolate, stearate, DL-tartrate, D-tartrate, L- Tartrate, (±)mandelate, (R)-(-)mandelate, (S)-(+)mandelate, citrate, mucilage, malonate, benzoate, DL-malate, (±) lactate, L-(+)-lactate, D-(+)-lactate, pyrate, D-α-galacturonate, glycerate, DL-cysteine, D-cysteine, L-cysteine, (4S)-hydroxy-L-proline, cyclopropane-1, 1-Dicarboxylate, 2,2-Methylmalonate, Tyrosine salt, Proline salt, Fumarate, 1-Hydroxy-2-naphthylcarboxate, Phosphonoacetate, Carbonate, Bicarbonate, 3-Phosphoglutamate, DL-Pyroglutamate, D-Pyroglutamate, L-Pyroglutamate, p-Toluenesulfonate, Benzenesulfonate, Ethylsulfonate, (±) Camphorsulfonate, Naphthalenesulfonate, 1R-(-)-Camphorsulfonate, 1S-(+)-Camphorsulfonate, 1,5-Naphthalene Disulfonates, 1,2-ethanedisulfonates, 1,3-propanedisulfonates, 3-(N-morpholino)propanesulfonates, biphenylsulfonates, hydroxyethylsulfonates, 1-hydroxy-2-naphthalenesulfonates, dihydrogen phosphates, potassium hydrogen phosphates, dipotassium phosphates, potassium phosphates, sodium hydrogen phosphates, disodium phosphates, sodium phosphates, sodium dihydrogen phosphates, calcium phosphates, third-generation calcium phosphates, hexafluorophosphates, vinyl phosphates, 2-hydroxyethyl phosphates, and phenyl phosphates.

[0023] In some embodiments, the drug is used to inhibit uric acid transporter 1 (URAT1).

[0024] In some embodiments, the drug is used to inhibit glucose transporter 9 (GLUT9).

[0025] In some embodiments, the drug has inhibitory activity against OAT4 and agonistic activity against OAT1 / OAT3.

[0026] In some embodiments, the drug is used to prevent or treat hyperuricemia, gout, gouty arthritis, and kidney disorders associated with hyperuricemia.

[0027] In some embodiments, the dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is 5-100 mg / day.

[0028] In some embodiments, the amount of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof is selected from 10-80 mg, preferably 20-70 mg, more preferably 30-60 mg, and most preferably about 35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 58 mg.

[0029] In some embodiments, the drug may be formulated as tablets, capsules, granules, powders, oral liquids, injections, or topical preparations.

[0030] In some embodiments, the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof may be administered once daily, twice daily, once every two days, or once every three days.

[0031] In some embodiments, the drug can be administered by any suitable means, and the compounds and pharmaceutically acceptable compositions described above can be given to humans or other animals orally, topically, or otherwise, depending on the severity of the disease.

[0032] The term "pharmaceutically acceptable salt" refers to both organic and inorganic salts of the compounds of the present invention. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and / or toxicologically compatible with other components comprising the formulation and / or the mammals treated with it.

[0033] As used herein, the term "treatment" for any disease or condition refers to anything that can slow, interrupt, prevent, control, or stop the progression of the disease or condition, but does not necessarily mean the complete disappearance of all symptoms of the disease or condition. It also includes preventative treatment of said symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, "treatment" refers to improving the disease or condition (i.e., slowing, preventing, or alleviating the development of the disease or at least one of its clinical symptoms). In other embodiments, "treatment" refers to alleviating or improving at least one bodily parameter, including bodily parameters that may not be perceptible to the patient. In still other embodiments, "treatment" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing bodily parameters), or both. In still other embodiments, "treatment" refers to preventing or delaying the onset, occurrence, or worsening of the disease or condition.

[0034] As used in this invention, the terms "therapeutic effective amount" or "therapeutic effective dose" refer to the amount of the compound of this invention that can elicit a biological or medical response in an individual (e.g., reduce or inhibit enzyme or protein activity, or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc.).

[0035] The compounds of formula II and formula III provided by this invention have strong inhibitory activity against URAT1 and GLUT9, and can reduce blood uric acid by inhibiting uric acid reabsorption, providing a new option for uric acid-lowering drugs. Since compounds of formula II and formula III can treat not only hyperuricemia but also renal interstitial fibrosis, they also reduce the side effects of renal interstitial nephritis compared to febuxostat. Attached Figure Description

[0036] Figure 1 is a statistical graph showing the effect of compound I in Example 3 on adenine-induced serum uric acid levels in mice;

[0037] Figure 2 is an HE staining image (200X) showing the effect of compound I in Example 3 on adenine-induced kidney pathological changes in mice.

[0038] Figure 3 is a statistical graph of HE staining scores showing the effect of compound I in Example 3 on adenine-induced renal pathological changes in mice.

[0039] Figure 4 is a Masson staining diagram (200X) showing the effect of compound I in Example 3 on the collagen fiber content in the kidneys of mice induced by adenine diet.

[0040] Figure 5 is a statistical chart of Masson staining scores showing the effect of compound I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet.

[0041] Figure 6 shows the Sirius red staining (200X) of the effect of compound I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet.

[0042] Figure 7 is a statistical graph of Sirius red staining scores showing the effect of compound I in Example 3 on the content of collagen fibers in the kidneys of mice induced by adenine diet.

[0043] Figure labels: (1) group: normal diet group; (2) group: 0.2% adenine diet group; (3) group: 0.2% adenine diet + compound of formula I (25 mg / kg) group; (4) group: 0.2% adenine diet + compound of formula I (50 mg / kg) group; (5) group: 0.2% adenine diet + compound of formula I (100 mg / kg) group; (6) group: 0.2% adenine diet + dapagliflozin (10 mg / kg) group. Detailed Implementation

[0044] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0045] Example 1: Activity assay of compound I against URAT1 target

[0046] Experimental Methods: First, prepared HEK293T cells were seeded into 96-well plates. When the cells reached 70-90% confluence, a mixture of Lipofectamine 3000 transfection reagent and URAT1 recombinant plasmid (100 ng / well) was transferred to the 96-well plate and incubated at 37°C in a 5% CO2 incubator for 24 h. The expression of green fluorescent protein (EGFP) was observed using an inverted fluorescence microscope to verify successful transfection. After successful transfection, the culture medium was removed from the plate, and the cells were washed twice with phosphate-buffered saline (PBS). The remaining waste liquid in the wells was aspirated and discarded. 50 μl of solutions containing various specific concentrations of Formula I compound or Resinard (40 μM, 20 μM, 10 μM, 5 μM, 2.5 μM) were added to each well. Formula I compound or Resinard was not added to the blank group and model group. After incubation for 30 minutes, 50 μM [14C]-uric acid solution (diluted with prepared buffer) was added to each well and incubated for 15 minutes. The experiment was terminated with PBS, and the cells were washed three times. Then, 40 μL of 0.1M NaOH aqueous solution was added to each well and incubated for 30 min. After complete cell lysis, 0.2 mL of scintillation buffer was added to each well, and the cells were shaken at 260 rpm for 15 min on a shaker. The intracellular fluid radioactivity (CPM) was measured using a Micro Beta2 liquid scintillation detector. All tests were repeated three times, and the average value was taken.

[0047] Experimental Results: Under the experimental conditions, the results show that both Resinard and Compound I exhibit inhibitory activity against URAT1. Among them, the IC50 of the Resinard sample was [missing value]. 50 = 6.03 ± 1.06 μM, IC50 of compound I as test sample 50 =10.91±1.23μM, exhibiting strong URAT1 inhibitory activity, indicating that compound I can lower blood uric acid levels by inhibiting uric acid reabsorption.

[0048] In another embodiment, at a concentration of 10 μm of compound I, the inhibition rate of GLUT9 was 21.45%, slightly lower than the 30.12% of the positive control (benzbromarone), indicating that compound I also has inhibitory activity against GLUT9.

[0049] Example 2: Effect of Compound I of Formula I on a Rat Model of Hyperuricemia Induced by Potassium Oxygenate

[0050] Experimental Methods: Fifty-six qualified SPF-grade male SD rats were randomly divided into seven groups according to body weight: a normal control group, a model control group, a febuxostat group (2 mg / kg; febuxostat efficacy data shows that 1 mg / kg can significantly reduce serum uric acid levels in mice with potassium oxonate-induced hyperuricemia), and groups with compound I dosages of 1, 2, 3, and 4 (6.3 mg / kg, 12.5 mg / kg, 25 mg / kg, and 50 mg / kg, respectively), with eight animals in each group. Before administration, animals were fasted for at least 12 hours but allowed free access to water. A hyperuricemia model was established by a single intraperitoneal injection of 300 mg / kg potassium oxonate (OAPS) at 10 mL / kg. The normal control group received an equal volume of 0.9% sodium chloride injection. Administration of the drug was administered immediately after model establishment. Animals in each group were orally administered the corresponding concentration of the drug at 10 mL / kg via gavage, while the normal control and model control groups received an equal volume of pure water via gavage. Administration was once daily. Blood samples were collected from the jugular vein before modeling and at 2, 3, 4, 5, 6, and 8 hours after modeling. Serum uric acid levels were measured using an automated biochemical analyzer.

[0051] Experimental Results: Compared with the normal control group, the serum uric acid level of rats in the model control group was significantly increased after modeling (P≤0.01); compared with the model control group, the serum uric acid level of rats with hyperuricemia induced by potassium oxonate was significantly increased 3 h after administration of compound I dose 1 (6.3 mg / kg) (P≤0.05); the serum uric acid level of rats with hyperuricemia induced by potassium oxonate was significantly decreased 5 h and 6 h after administration of compound I dose 2 (12.5 mg / kg) (P≤0.05); the serum uric acid level of rats with hyperuricemia induced by potassium oxonate was significantly decreased in compound I dose 3 group (25 mg / kg). At 4, 5, and 6 hours after administration of potassium oxonate-induced hyperuricemia, serum uric acid levels in rats were significantly reduced (P≤0.05 or P≤0.01). In the four groups (50 mg / kg) of Formula I, serum uric acid levels were significantly reduced at 4, 5, and 6 hours after administration of potassium oxonate-induced hyperuricemia (P≤0.05 or P≤0.01). In the febuxostat group (2 mg / kg), serum uric acid levels were significantly reduced at 2, 4, 5, 6, and 8 hours after administration of potassium oxonate-induced hyperuricemia (P≤0.05 or P≤0.01). In conclusion, Formula I compounds (12.5 mg / kg, 25 mg / kg, and 50 mg / kg) can all reduce serum uric acid levels in potassium oxonate-induced hyperuricemia rats.

[0052] Table 1. Effects of Compound I of Formula 1 on serum uric acid levels in a rat model of potassium oxonate-induced hyperuricemia ( n=8) Note: Compared with the normal control group, ++P≤0.01; compared with the model control group, *P≤0.05, **P≤0.01.

[0053] Example 3: Effect of Compound I on Serum Uric Acid in Mice with Adenine-Induced Chronic Hyperuricemia

[0054] Eight-week-old male C57-BL6 mice were housed in an SPF-grade animal facility in the animal laboratory, with a light pattern of 12 hours of daylight / 12 hours of darkness. After one week of acclimatization, the mice were randomly divided into: (1) normal diet group (n=6); (2) 0.2% adenine diet group (n=8); (3) 0.2% adenine diet + compound I (25 mg / kg) (n=8); (4) 0.2% adenine diet + compound I (50 mg / kg) (n=8); (5) 0.2% adenine diet + compound I (100 mg / kg) (n=8); (6) 0.2% adenine diet + dapagliflozin (10 mg / kg) (n=5). The normal diet group was fed a normal control diet (Terlotinib, Jiangsu Nantong, LAD 3001), while the other five groups were fed a diet containing 0.2% adenine (Terlotinib, Jiangsu Nantong, TP 1S002) to establish a renal fibrosis model. The four treatment groups were fed a diet containing 0.2% adenine and simultaneously administered the corresponding concentration of Formula I compound and 10 mg / kg / day of dapagliflozin via gavage, respectively. The normal control group and the 0.2% adenine diet group were administered an equal volume of pure water via gavage, once daily. On day 21, all mice were euthanized, blood samples were collected to measure uric acid levels, and kidney tissue was collected for HE staining, Masson staining, and Sirius red staining.

[0055] 1. Blood uric acid level

[0056] Figure 1 shows that compared with the normal diet group, the serum uric acid level of mice in the 0.2% adenine diet group was significantly increased (p < 0.05); while compared with the 0.2% adenine diet group, the serum uric acid level of mice in the 0.2% adenine diet + compound I (25 mg / kg, 50 mg / kg and 100 mg / kg) group was significantly decreased (p < 0.05), and the uric acid level of mice in the 0.2% adenine diet + dapagliflozin (10 mg / kg) group showed no significant change.

[0057] In Figure 1, * indicates that the normal diet group was significantly different from the 0.2% adenine diet group (P < 0.05); # indicates that the treatment group was significantly different from the 0.2% adenine diet group (P < 0.05).

[0058] 2. HE staining

[0059] Figure 2 shows that, compared with the normal diet group, the 0.2% adenine diet group showed significantly increased inflammatory cell infiltration, renal tubular dilation, and atrophy in the kidneys of mice, with significantly higher HE staining pathological scores. Compared with the 0.2% adenine diet group, the 0.2% adenine diet + compound I (50 mg / kg) and 0.2% adenine diet + compound I (100 mg / kg) groups showed reduced inflammatory cell infiltration, renal tubular dilation, and atrophy in the kidneys of mice. Figure 3 and Table 2 show that the renal tissue pathological scores of the 0.2% adenine diet + compound I (50 mg / kg) and 0.2% adenine diet + compound I (100 mg / kg) groups were statistically significant compared with the 0.2% adenine diet group, and the 0.2% adenine diet + compound I (100 mg / kg) group had a better effect on improving the pathological changes in the model mice than the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0060] Table 2. Pathological scores of mice in each group

[0061] In Figure 3 and Table 2, *** indicates that the normal diet group was compared with the 0.2% adenine diet group (P < 0.001); ### indicates that the treatment group was compared with the 0.2% adenine diet group (P < 0.001); @ indicates that the treatment group was compared with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group (P < 0.05).

[0062] 3. Masson staining

[0063] Figure 4 shows that, compared with the normal diet group, mice in the 0.2% adenine diet group showed significant collagen deposition in the renal interstitium. Compared with the 0.2% adenine diet group, mice in the 0.2% adenine diet + compound I (50, 100 mg / kg) treatment group showed a reduction in renal interstitial collagen deposition area, with the 0.2% adenine diet + compound I (100 mg / kg) group showing the most significant therapeutic effect. Figure 5 and Table 3 show that the renal interstitial collagen area in the 0.2% adenine diet + compound I (50 and 100 mg / kg) groups was statistically significant compared with the 0.2% adenine diet group, and the improvement in renal interstitial collagen deposition in the 0.2% adenine diet + compound I (100 mg / kg) group was better than that in the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0064] Table 3. Collagen area represented by Masson staining in each group of mice.

[0065] In Figure 5 and Table 3, *** indicates that the normal diet group is compared with the 0.2% adenine diet group (P < 0.001); # indicates that the treatment group is compared with the 0.2% adenine diet group (P < 0.05); ## indicates that the treatment group is compared with the 0.2% adenine diet group (P < 0.01); ### indicates that the treatment group is compared with the 0.2% adenine diet group (P < 0.001); @ indicates that the treatment group is compared with the 0.2% adenine diet + dapagliflozin (10 mg / kg) group (P < 0.05).

[0066] 4. Sirius red staining

[0067] Figure 6 shows that, compared with the normal diet group, mice in the 0.2% adenine diet group showed significant collagen deposition in the renal interstitium. Compared with the 0.2% adenine diet group, mice in the 0.2% adenine diet + compound I (50, 100 mg / kg) group showed a reduction in collagen deposition in the renal interstitium, i.e., the area of ​​the red region, with the 0.2% adenine diet + compound I (100 mg / kg) group showing the most significant therapeutic effect. Figure 7 and Table 4 show that the collagen area in the renal interstitium of mice in the 0.2% adenine diet + compound I (50 and 100 mg / kg) group was statistically significant compared with the 0.2% adenine diet group, and the improvement in renal interstitial collagen deposition in the 0.2% adenine diet + compound I (100 mg / kg) group was better than that in the 0.2% adenine diet + dapagliflozin (10 mg / kg) group.

[0068] Table 4. Collagen area represented by Sirius red staining in each group of mice.

[0069] In Figure 7 and Table 4, *** indicates that the normal diet group was compared with the 0.2% adenine diet group (P < 0.001); ### indicates that the treatment group was compared with the 0.2% adenine diet group (P < 0.001); @@@ indicates that the treatment group was compared with the 0.2% adenine diet group + dapagliflozin (10 mg / kg) group (P < 0.001).

Claims

1. Use of a 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a uric acid-lowering medicament, said 2,4-disubstituted-5-fluoropyrimidine derivative having the following structure: in, R3 is selected from: R4 is selected from: X and Y are each independently selected from nitrogen or carbon atoms; Z is selected from hydrogen, tert-butoxycarbonyl, C1-C5 alkyl, C1-C5 alkyl acyl, C1-C3 alkyl hydroxyl, C1-C3 alkyl sulfonyl, C1-C3 substituted phenyl, and C1-C5 alkyl amide.

2. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of uric acid-lowering drugs, characterized in that, When the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula II, R4 is... When Z is not tert-butyloxycarbonyl, Z is not a tert-butyloxycarbonyl group.

3. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of uric acid-lowering drugs, characterized in that, When the 2,4-disubstituted-5-fluoropyrimidine derivative is a compound of formula III, R4 is... When Z is not tert-butoxycarbonyl, C4-C5 alkyl, C4-C5 alkylacyl, or C4-C5 alkylamide.

4. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a uric acid-lowering medicament, characterized in that, The C1-C5 alkyl groups in the 2,4-disubstituted-5-fluoropyrimidine derivatives include methyl, ethyl, propyl, butyl, pentyl, isobutyl, isopentyl, and isopropyl.

5. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a uric acid-lowering medicament, characterized in that, The C1-C5 alkyl acyl groups in the 2,4-disubstituted-5-fluoropyrimidine derivatives include formyl, acetyl, propionyl, butyryl, valeryl, 3,3-dimethyl-1-butyryl, and isovaleryl.

6. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-3 in the preparation of a uric acid-lowering medicament, characterized in that, The C1-C5 alkylamide groups in the 2,4-disubstituted-5-fluoropyrimidine derivatives include formamido, acetamido, propionamido, butyramido, pentamido, N-tert-butylaminoformyl, and isovaleramido.

7. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of uric acid-lowering drugs, characterized in that, The 2,4-disubstituted-5-fluoropyrimidine derivatives specifically include the following compounds: tert-butyl-4-(4-((5-fluoro-2-((4-(methoxycarboxyl)phenyl)amino)pyridin-4-yl)amino)phenyl)piperazine-1-carboxylic acid ester; 1-(5-fluoro-4-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(4-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-fluoropyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-fluoro-4-((4-(piperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-fluoro-4-((4-(4-isopentylpiperazin-1-yl)phenyl)amino)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine; 1-(5-Fluoro-4-(6-(piperazin-1-yl)pyridin-3-yl)pyrimidin-2-yl)-1H-benzo[d]imidazol-2-amine.

8. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the preparation of a uric acid-lowering medicament, characterized in that, The drug is used to inhibit uric acid transporter 1.

9. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the preparation of a uric acid-lowering medicament, characterized in that, The drug is used to inhibit glucose transporter 9.

10. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the preparation of a uric acid-lowering medicament, characterized in that, The drug is used to prevent or treat hyperuricemia, gout, gouty arthritis, and kidney disorders associated with hyperuricemia.

11. The use of the 2,4-disubstituted 5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-7 in the preparation of a uric acid-lowering medicament, characterized in that, The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or its pharmaceutically acceptable salt is 5-100 mg / day.

12. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 11 in the preparation of a uric acid-lowering medicament, characterized in that, The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or its pharmaceutically acceptable salt is 10-80 mg / day.

13. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 12 in the preparation of a uric acid-lowering medicament, characterized in that, The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or its pharmaceutically acceptable salt is 20-70 mg / day.

14. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 13 in the preparation of a uric acid-lowering medicament, characterized in that, The dosage of the 2,4-disubstituted-5-fluoropyrimidine derivative or its pharmaceutically acceptable salt is 30-60 mg / day.

15. The use of the 2,4-disubstituted-5-fluoropyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-14 in the preparation of a uric acid-lowering medicament, characterized in that, The drug can be formulated into tablets, capsules, granules, powders, oral liquids, injections, and topical preparations.

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