Compounds that can be used to lower uric acid

Abstract

The present invention discloses a series of compounds that can be used to lower uric acid, which are compounds represented by general formula (I) or pharmaceutically acceptable salts thereof, and can significantly lower serum uric acid levels in a hyperuricemia rat model, and have potential application value as anti-gout drugs, anti-hyperuricemia drugs, etc. [Formula 1] TIFF2025514336000075.tif1225 (I)

Description

[Technical Field]

[0001] The present invention is in the field of medicine and specifically relates to a series of compounds that can be used to lower uric acid. [Background technology]

[0002] Xanthine oxidase (XO) is an important target in the drug treatment of hyperuricemia and gout. Hypoxanthine in the human body is metabolized to xanthine, which is then further metabolized to produce uric acid. XO plays a crucial role in the formation of uric acid. Inhibition of XO activity inhibits the conversion between hypoxanthine, xanthine, and uric acid, leading to a decrease in the concentration of uric acid in human serum. Therefore, inhibiting XO activity is key to inhibiting uric acid production.

[0003] Generally, hyperuricemia is defined as a blood uric acid level above 420 μmol / L in men and above 360 ​​μmol / L in women. Currently, hyperuricemia is the second most common metabolic disease after diabetes, posing a serious threat to human health. Hyperuricemia is not only an important biochemical factor in the development of gout, but is also closely related to the development of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance. According to data from the US National Health and Nutrition Examination Survey, the prevalence of gout among US adults was 3.9% (approximately 8.3 million people) between 2007 and 2008 (Zhu Y, Pandya BJ, Choi HK. Prevalence of Gout and Hyperuricemia in the US General Population: The National Health and Nutrition Examination Survey 2007-2008 [J]. Arthritis Rheum, 2011, 63(10):3136-3141). A meta-analysis shows that the overall prevalence of hyperuricemia in China is 13.3% and that of gout is 1.1% (Liu R, Han C, Wu D, et al. Prevalence of hyperuricemia and gout in mainland China from 2000 to 2014: A systematic review and meta-analysis[J]. Biomed Research International, 2015:1-12).Over the past few decades, the incidence of gout has gradually increased due to the prevalence of comorbid conditions that promote hyperuricemia (such as hypertension, obesity, metabolic syndrome, type 2 diabetes, and chronic kidney disease) (Khanna D, Fitzgerald JD, Khanna PP, et al. American College of Rheumatology Guidelines for Management of Gout. Part 1: Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia[J]. Arthritis Care & Research, 2012, 64(10):1432-1446).

[0004] The increasing incidence of hyperuricemia and gout poses a serious threat to human health, necessitating early intervention and treatment. However, the currently available uric acid-lowering drugs are very limited, and due to obvious toxicity and side effects, patient compliance is poor. Currently, drugs for treating hyperuricemia and gout mainly fall into three categories: urate / anion transporter 1 (URAT1) inhibitors, xanthine oxidase inhibitors, and urate oxidase inhibitors.

[0005] URAT1 inhibitors primarily act on the urate transporter in the renal proximal tubule to inhibit urate reabsorption and increase its excretion, thereby lowering uric acid levels in the body. Drugs in this category include benzbromarone, lesinurad, and probenecid. Benzbromarone is an effective uricosuric agent approved for sale in many countries, but not in the United States. Due to severe liver toxicity, benzbromarone was withdrawn from the market in some European countries in 2003. Due to racial differences in benzbromarone-related liver-related adverse events, the Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019) recommend benzbromarone as the first-line uric acid-lowering drug. Lesinurad was approved for sale in the United States in 2015, but its package insert carries a black box warning about the risk of acute renal failure and cardiovascular disease (potentially fatal), and its effectiveness is far inferior to that of benzbromarone, requiring its use in combination with allopurinol. Probenecid is listed as the first-choice uricosuric agent for monotherapy in the US guidelines, but its use is limited due to several significant interactions with some commonly used medications (nonsteroidal anti-inflammatory drugs, beta-lactams, heparin, etc.).

[0006] Xanthine oxidase inhibitors primarily include allopurinol and febuxostat. Allopurinol has been widely used clinically since its marketing approval by the US FDA in 1966. Currently, this drug is still recommended as the first-line treatment for gout in most national gout guidelines. However, allopurinol is ineffective, inhibiting only reduced XO but not oxidized XO. Related studies have shown that even at maximum doses, the treatment endpoint rate in subjects is less than 50% (Robert M, Douglas CA, Scott B. Less than half of patients treated with high-dose allopurinol reach serum uric acid target[J]. ACR / ARHP Annual Meeting, 2017, Abstract Number: 1120). It can also cause skin rashes and other rare but fatal side effects, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, with a mortality rate of approximately 10-30% (Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS [J]. Seminars in Cutaneous Medicine and Surgery, 1996, 15(4): 250-257)).Clinically, allopurinol has been reported to cause acute liver failure, so it should be used with caution when treating patients with hyperuricemia and liver disease (Imai H, Kamei H, Onishi Y, et al. Successful living-donor liver transplantation for cholestatic liver failure induced by allopurinol: case report [J]. Transplantation Proceedings, 2015, 47(9):2778-2781). Other side effects of allopurinol include stomach discomfort, nausea, abdominal pain, diarrhea, decreased white blood cells and platelets, headache, fever, loss of appetite, weight loss, painful urination, hematuria, itching, and lethargy.

[0007] Febuxostat, developed by Teijin Limited, is a non-purine XO inhibitor capable of inhibiting both oxidized and reduced forms of XO, with significantly greater activity than allopurinol. It was launched in Europe in 2008 and in the United States in 2009. As febuxostat's clinical application continues to expand, cardiovascular adverse events occurring when treating hyperuricemia have increasingly been reported. Furthermore, due to its cardiovascular toxicity (e.g., risk of sudden death), the US Food and Drug Administration (FDA) required the addition of a black box warning regarding risks to its labeling. In 2019, the prescribing information was adjusted, changing the drug from a first-line to a second-line treatment. In March 2018, the New England Journal of Medicine published the results of a study of 6,190 gout patients. After a mean of 32 months of treatment, the researchers found that the febuxostat and allopurinol treatment groups had similar overall cardiovascular adverse event risks (HR 1.03; 95% CI, 0.87-1.23), but the febuxostat group had higher all-cause and cardiovascular mortality rates than the allopurinol group. Patients in the febuxostat group had a 34% increased risk of cardiovascular mortality (HR 1.34; 95% CI, 1.03-1.73) and a 22% increased risk of all-cause mortality (HR 1.22; 95% CI, 1.01-1.47). Sudden cardiac death was the most common cause of cardiovascular death, occurring in 83 patients (2.7%) in the febuxostat group and 56 patients (1.8%) in the allopurinol group (William B, Kenneth G, Michael A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout [J]. The New England Journal of Medicine, 2018, 378:1200-1210). Febuxostat may also cause severe gastrointestinal side effects, renal side effects, and liver dysfunction.

[0008] Pegloticase is the primary urate oxidase drug currently on the market and is administered intravenously. The FDA has issued multiple black box warnings for this drug, including severe allergic side effects in 20-40% of patients. Its efficacy is mediocre, with only 47% of patients achieving the treatment endpoint of <0.36 mmol / L.

[0009] Over the past few decades, the development of drugs for treating hyperuricemia and gout has progressed slowly, but with the gradual increase in incidence, the development of therapeutic drugs has attracted more and more researchers' attention. The design of new drugs targeting xanthine oxidase has already been widely emphasized, and various compounds have entered clinical trials. However, they still face many problems, such as high toxicity and side effects, and further research is needed. Therefore, effective and low-toxicity XO inhibitors have great potential for development and application value. Summary of the Invention [Problem to be solved by the invention]

[0010] The object of the present invention is to provide compounds that have xanthine oxidase inhibitory activity based on the prior art.

[0011] Another object of the present invention is to provide the use of the above compounds in the pharmaceutical field. [Means for solving the problem]

[0012] The object of the present invention can be achieved by the following solutions. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, [ka] During the ceremony, R is a C1-6 alkyl group, a substituted C1-6 alkyl group, a C3-6 cycloalkyl group, a substituted C3-6 cycloalkyl group, a C3-6 heterocycloalkyl group or a substituted C3-6 heterocycloalkyl group, wherein the substituent of each group associated with R is one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C1-6 alkyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group or a C3-6 heterocycloalkyl group; Ar is substituted or unsubstituted, [ka] and the substituent of the Ar group is one or more selected from deuterium, a hydroxy group, a halogen, a C1-4 alkyl group, and a C1-4 alkoxy group; Y is O or NR 3 and R 1 is a bond, a substituted or unsubstituted C1-6 alkylene group, or a substituted or unsubstituted C2- 12 is an alkenylene group, R 1 the substituent of the group is one or more selected from deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a C1-4 alkyl group, and a C1-4 alkoxy group; R 2 is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one group, C4 to 12 Condensed heteroaromatic ring groups, C4~ 16 Condensed heteroaromatic pyrazolylcarbonyloxy group, C4~ 16 Condensed heteroaromatic ring pyridinylcarbonyloxy group, C4~ 16 Condensed heteroaromatic ring triazolylcarbonyloxy group, C2-6 ester group, pyridyl group, phenyl group, C1-6 alkoxy group, C2- 20 Alkenyl groups, C2~ 20 an alkynyl group, a C2-8 alkylcarbonyloxy group, or a C2-8 alkoxycarbonyloxy group, and R 2the substituent of the group is one or more selected from deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a C1-6 alkyl group, a haloC1-6 alkyl group, a nitrooxy-substituted C1-6 alkyl group, and a C1-6 alkoxy group; R 3 is hydrogen or a C1-6 alkyl group.

[0013] In a preferred embodiment, Ar is a substituted or unsubstituted [ka] where "*" is the bond site to C=O.

[0014] In a preferred embodiment, the compound of the present invention is a compound represented by general formula (II), (III) or (IV): [ka] Selected from.

[0015] In a preferred embodiment, Y is O or NH.

[0016] In a preferred embodiment, R is a C3-6 alkyl group, a substituted C1-6 alkyl group, a C3-6 cycloalkyl group, a substituted C3-6 cycloalkyl group, a C3-6 heterocycloalkyl group or a substituted C3-6 heterocycloalkyl group, wherein the substituent of each group associated with R is one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C1-5 alkyl group, a C1-5 alkoxy group and a C3-6 cycloalkyl group.

[0017] In a preferred embodiment, R is a C3-6 alkyl group, a substituted C1-6 alkyl group, a C3-6 cycloalkyl group, a substituted C3-6 cycloalkyl group, tetrahydrofuran, a substituted tetrahydrofuran, tetrahydrothiophene, a substituted tetrahydrothiophene, pyrrolidine, or a substituted pyrrolidine, and here, the substituents of each group associated with R are one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C1-5 alkyl group, a C1-5 alkoxy group, and a C3-6 cycloalkyl group.

[0018] In a preferred embodiment, R is a C3-6 alkyl group, a substituted C1-3 alkyl group, a C3-6 cycloalkyl group or a substituted C3-6 cycloalkyl group, and the substituents on the R group are selected from deuterium, halogen or a C3-6 cycloalkyl group.

[0019] In a preferred embodiment, R is a C3-6 alkyl group or a C3-6 cycloalkyl group.

[0020] In a preferred embodiment, R is an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.

[0021] In a preferred embodiment, R 1 is a bond, a substituted or unsubstituted C1-4 alkylene group, or a substituted or unsubstituted C4- 12 is an alkenylene group, R 1 The substituent of the group is one or more selected from deuterium, an amino group, a cyano group, a halogen, and a C1-4 alkoxy group.

[0022] In a preferred embodiment, R 2is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one group, an indazolyl group, a quinolinyl group, an isoquinolinyl group, an indolyl group, a benzofuryl group, a purinyl group, an indazolylpyrazolylcarbonyloxy group, a quinolinylpyrazolylcarbonyloxy group, an isoquinolinylpyrazolylcarbonyloxy group, an indolylpyrazolylcarbonyloxy group, a benzofurylpyrazolylcarbonyloxy group, a purinylpyrazolylcarbonyloxy group, an indazolylpyridinylcarbonyloxy group, a quinolinylpyridinylcarbonyloxy group, oxy group, isoquinolinylpyridinylcarbonyloxy group, indolylpyridinylcarbonyloxy group, benzofurylpyridinylcarbonyloxy group, purinylpyridinylcarbonyloxy group, indazolyltriazolylcarbonyloxy group, quinolinyltriazolylcarbonyloxy group, isoquinolinyltriazolylcarbonyloxy group, indolyltriazolylcarbonyloxy group, benzofuryltriazolylcarbonyloxy group, purinyltriazolylcarbonyloxy group, C2-6 ester group, pyridyl group, phenyl group, C1-6 alkoxy group, C6- 20 Alkenyl groups, C6~ 20 an alkynyl group, a C2-8 alkylcarbonyloxy group, or a C2-8 alkoxycarbonyloxy group, and R 2 The substituent of the group is one or more selected from deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a C1-6 alkyl group, a halo C1-6 alkyl group, a nitrooxy-substituted C1-6 alkyl group, and a C1-6 alkoxy group.

[0023] In a preferred embodiment, R 2 is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one group, an indazolylpyrazolylcarbonyloxy group, an indazolylpyridinylcarbonyloxy group, an indazolyltriazolylcarbonyloxy group, an indolylpyrazolylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, an indolyltriazolylcarbonyloxy group, a C2-6 ester group, a pyridyl group, a phenyl group, a C1-6 alkoxy group, a C6- 20alkenyl group, C2-8 alkylcarbonyloxy group, or C2-8 alkoxycarbonyloxy group, and R 2 The substituent of the group is one or more selected from deuterium, a hydroxy group, an amino group, a cyano group, a halogen, a C1-6 alkyl group, a nitrooxy-substituted C1-6 alkyl group, and a C1-6 alkoxy group.

[0024] In a preferred embodiment, R 3 is hydrogen, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a butyl group.

[0025] In preferred embodiments, the compounds of the present invention may be selected from the following: [ka] JPEG0007792730000006.jpg26170

[0026] The present invention also includes pharmaceutical compositions containing the compounds of the present application or pharmaceutically acceptable salts thereof as an active substance, to which pharmaceutically acceptable adjuvants are added.

[0027] The compounds of the present invention or pharmaceutically acceptable salts thereof may be used to produce xanthine oxidase inhibitors, and in particular, may be used to produce antigout drugs or antihyperuricemia drugs.

[0028] Unless otherwise specified, each group referred to in the present invention has the following meaning. "H," or hydrogen, refers to protium (1H), the predominant stable isotope of the element hydrogen.

[0029] "D" or "deuterium" refers to the stable isotope of hydrogen, also known as heavy hydrogen, whose element symbol is D.

[0030] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0031] "Hydroxy group" refers to an --OH group.

[0032] "Amino group" refers to an -NH2 group.

[0033] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group containing 1 to 10 carbon atoms, including straight-chain and branched-chain groups. (A numerical range referred to herein, such as "1 to 10," indicates that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to a maximum of 10 carbon atoms.) An alkyl group containing 1 to 4 carbon atoms is called a lower alkyl group. When a lower alkyl group has no substituent, it is called an unsubstituted lower alkyl group. The alkyl group may be selected from C1-6 alkyl groups, C1-5 alkyl groups, C1-4 alkyl groups, C1-3 alkyl groups, C1-2 alkyl groups, C2-3 alkyl groups, C2-4 alkyl groups, etc. Specific alkyl groups include, but are not limited to, methyl groups, ethyl groups, propyl groups, 2-propyl groups, n-butyl groups, isobutyl groups, and tert-butyl groups. The alkyl group may be substituted or unsubstituted.

[0034] The term "alkenyl group" refers to a hydrocarbon group containing 2 to 30 carbon atoms, including straight-chain and branched-chain groups, having one or more "C=C"s (a numerical range referred to herein, such as "2 to 10", means that the group, in this case the alkenyl group, may contain 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). 20 Alkenyl groups, C2~ 18 Alkenyl groups, C2~ 16 Alkenyl groups, C2~ 14 Alkenyl groups, C2~ 12 Alkenyl groups, C4~ 14 Alkenyl groups, C4~ 12 An alkenyl group, etc. may be selected. Specific alkenyl groups include an ethenyl group, a propenyl group, an allyl group, a butenyl group, an isobutenyl group, a tert-butenyl group, [ka] These include, but are not limited to:

[0035] The term "alkoxy group" refers to an -O-(unsubstituted alkyl) group and an -O-(unsubstituted cycloalkyl) group, and further refers to an -O-(unsubstituted alkyl) group. Among these, the alkyl group may be selected from C1-6 alkyl groups, C1-5 alkyl groups, C1-4 alkyl groups, C1-3 alkyl groups, C1-2 alkyl groups, C2-3 alkyl groups, and C2-4 alkyl groups. Representative examples include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups, and cyclopropoxy groups.

[0036] "Dioxol-2-one group" [ka] It is the base.

[0037] The "pyrazolyl group" is [ka] It refers to one of the following.

[0038] The term "triazolyl group" includes 1,2,3-triazolyl groups, where "1,2,3-triazolyl group" means [ka] Refers to...

[0039] The "pyridyl group" is [ka] It refers to one of the following.

[0040] The term "fused heteroaromatic ring group" refers to an aromatic group containing two or more fused rings and a heteroatom, including, but not limited to, indazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuryl, purinyl, acridinyl, and the like.

[0041] The term "carboxy group" refers to a -COOH group.

[0042] The term "ester group" refers to a "-C(=O)-O-alkyl" group, in which the alkyl group may be selected from C1-6 alkyl groups, C1-5 alkyl groups, C1-4 alkyl groups, C1-3 alkyl groups, C1-2 alkyl groups, C2-3 alkyl groups, and C2-4 alkyl groups. Representative examples include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, and isopropyl formate. A substituted ester group refers to an ester group in which a hydrogen atom of the ester group has been replaced with a substituent, or in which multiple hydrogen atoms of the ester group have been replaced with the same or different substituents.

[0043] A "heterocycloalkyl group" refers to a saturated cyclic group containing 3 to 10 ring atoms, which includes one or more heteroatoms selected from N, O, and S. A numerical range referred to herein, such as "3 to 6," means that the heterocycloalkyl group may contain 3, 4, or 5 carbon atoms, up to a maximum of 6 carbon atoms as ring atoms. Examples of heterocycloalkyl groups that may be selected include C3-8 heterocycloalkyl groups, C3-6 heterocycloalkyl groups, C3-5 heterocycloalkyl groups, C3-4 heterocycloalkyl groups, C3-9 heterocycloalkyl groups, and C4-6 heterocycloalkyl groups. Specific alkyl groups include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, 1,4-dioxane, oxospiro[3,3]heptyl, oxospiro[4,4]nonyl, oxospiro[5,5]undecyl, oxospiro[6,6]tridecyl, oxobicyclo[1,1,1]pentyl, oxobicyclo[2,2,2]octyl, oxobicyclo[3,2,1]octyl, azospiro[3,3]heptyl, azospiro[4,4]nonyl, azospiro[5,5]undecyl, azospiro[6,6]tridecyl, azobicyclo[1,1,1]pentyl, azobicyclo[2,2,2]octyl, or azobicyclo[3,2,1]octyl. A heterocycloalkyl group can be substituted or unsubstituted.

[0044] "C4~ 16 The term "fused heteroaromatic ring pyrazolylcarbonyloxy group" refers to an -OC(=O)-pyrazolyl-fused heteroaromatic ring group containing 4 to 16 carbon atoms, and a specific example thereof is an indazolylpyrazolylcarbonyloxy group. [ka] , indolylpyrazolylcarbonyloxy group [ka] Including, but not limited to:

[0045] The term "C2-8 alkoxycarbonyloxy group" refers to an -OC(=O)-O-alkyl group containing 2 to 8 carbon atoms.

[0046] The term "C2-8 alkylcarbonyloxy group" refers to an -OC(=O)-alkyl group containing 2 to 8 carbon atoms.

[0047] "C4~ 16 The term "fused heteroaromatic ring pyridinylcarbonyloxy group" refers to an -OC(=O)-pyridinyl-fused heteroaromatic ring group containing 4 to 16 carbon atoms, and a specific example thereof is an indazolylpyridinylcarbonyloxy group. [ka] , indolylpyridinylcarbonyloxy group [ka] Including, but not limited to:

[0048] "C4~ 16 The term "fused heteroaromatic ring triazolylcarbonyloxy group" refers to an -OC(=O)-triazolyl-fused heteroaromatic ring group containing 4 to 16 carbon atoms, and a specific example thereof is an indazolyltriazolylcarbonyloxy group. [ka] , indolyltriazolylcarbonyloxy group [ka] Including, but not limited to:

[0049] A "bond" refers to a bond in which the groups on both ends are directly connected by a covalent bond. 1 -R 2 For example, R 1When is a bond, the fragment of the group is YR 2 becomes.

[0050] "Nitrooxy group" refers to the -ONO2 group.

[0051] "Pharmaceutically acceptable salts" includes salts of compounds of general formula (I) formed with organic or inorganic acids, and refers to those salts that retain the bioavailability and properties of the parent compound. Such salts include, but are not limited to: (1) Salts formed with acids, obtained by reacting the free base of the parent compound with an inorganic or organic acid, such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, and the like; and organic acids, such as, but not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, or malonic acid.

[0052] (2) Salts formed by replacing an acidic proton in the parent compound with a metal ion or coordinating with an organic base, where the metal ion is, for example, an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, and the organic base is, for example, ethanolamine, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-methylglucamine, etc.

[0053] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or pharmaceutically acceptable salts and prodrugs thereof, with other chemical components (e.g., pharmaceutically acceptable carriers and excipients) to facilitate administration of the compounds to an organism.

[0054] The present invention further claims protection for a pharmaceutical composition comprising any of the compounds described above, a pharmaceutically acceptable salt thereof, or a readily hydrolyzable prodrug thereof, and another active pharmaceutical ingredient.

[0055] The present invention also includes any of the above compounds and pharmaceutically acceptable salts thereof, which may be formulated into any clinically or pharmaceutically acceptable dosage form by methods known in the art. For oral administration, they may be formulated into conventional solid preparations, such as tablets, capsules, pills, and granules, or into oral liquid preparations, such as oral solutions, oral suspensions, and syrups. When formulated as oral preparations, appropriate fillers, binders, disintegrants, lubricants, and the like may be added. For parenteral administration, they may be formulated into injections, such as injection solutions, sterile powders for injections, and concentrated injection solutions. When formulated as injections, they may be produced using conventional methods in the pharmaceutical field, and when formulated as injections, additives may not be added, or appropriate additives may be added based on the properties of the drug. [Effects of the Invention]

[0056] The compounds provided by the present invention can significantly reduce serum uric acid levels in a hyperuricemia rat model, and have potential application value as anti-gout drugs, anti-hyperuricemia drugs, etc. Febuxostat has the risk of serious sudden cardiac death, severe nephrotoxicity and hepatotoxicity, and the compounds provided by the present invention may have some advantages in reducing drug toxicity, and are therefore expected to be developed as drugs. DETAILED DESCRIPTION OF THE INVENTION

[0057] The present invention will be further explained below using examples, but the scope of protection of the present invention is not limited to the following examples.

[0058] Example 1: Synthesis of ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (2) [ka] In Step A, a mixture containing 5-bromo-1H-indazole-3-carbonitrile (3.0 g, 13.5 mmol), isopropyl iodide (9.19 g, 54.1 mmol), dicesium carbonate (8.80 g, 27.0 mmol), and DMF (50 mL) was stirred at 80 °C for 1.5 h. The mixture was cooled to room temperature and filtered to remove insoluble materials. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with water (50 mL × 2), then saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 1:50 to 1:30) to give 5-bromo-1-isopropyl-1H-indazole-3-carbonitrile (1) (2.10 g). The yield was 58.9%. 1 H NMR(CDCl3,400MHz)δ 7.95(d,J=1.2Hz,1H),7.55(dd,J=1.2,8.8Hz,1H),7.45(d,J=8.8Hz,1H),4.93-4.87(m,1H),1.61(d,J=6.4Hz,6H).

[0059] In Step B, a mixture containing ethyl 1H-pyrazole-4-carboxylate (1.06 g, 7.56 mmol), compound 1 (1.0 g, 3.79 mmol), potassium carbonate (833 mg, 6.04 mmol), cuprous iodide (1.05 g, 5.51 mmol), (1S,2S)-1,2-diaminocyclohexane (432 mg, 3.78 mmol), and DMF (20 mL) was stirred overnight at 110° C. under a nitrogen atmosphere. After cooling to room temperature, water (80 mL) was added, followed by extraction with ethyl acetate (40 mL×3). The combined organic phase was washed with saturated brine (30 mL×3) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, elution with ethyl acetate:petroleum ether = 1:15 to 1:4) to give ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (2) (500 mg) in 40.8% yield. 1 H NMR(DMSO-d6,400MHz)δ 9.31(s,1H),8.47(d,J=1.2Hz,1H),8.23-8.16(m,3H),5.29-5.22(m,1H),4.29(q,J=7.2Hz,2H),1.54(d,J=7.2Hz,6H),1.33(t,J=7.2Hz,3H). MS(ESI,m / z):324.1[M+H] + .

[0060] Example 2: Synthesis of methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (5) [ka] In Step A, a mixture containing compound 2 (500 mg, 1.55 mmol), lithium hydroxide hydrate (623 mg, 14.8 mmol), water (1.5 mL), methanol (1.5 mL), and THF (1.5 mL) was stirred at 20 °C for 2 h. Some of the solvent was removed by distillation under reduced pressure, and water (8 mL) was added. The pH was adjusted to 1-2 with 6 M hydrochloric acid. After filtration, the filter cake was recrystallized from acetonitrile to give 1-(3-carbamoyl-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (3) (300 mg). The yield was 61.8%. MS (ESI, m / z): 313.9 [M+H] + .

[0061] In Step B, trifluoroacetic anhydride (906 mg, 4.31 mmol) and triethylamine (873 mg, 8.63 mmol) were added to a solution of compound 3 (300 mg, 0.958 mmol) in dichloromethane (5 mL) under ice-water bath. Upon completion, the resulting mixture was stirred overnight at room temperature. Saturated brine (20 mL) was added, followed by extraction with dichloromethane (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, followed by purification by preparative HPLC to give 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (4). 1 H NMR (DMSO-d6,400MHz)δ 9.10(s,1H),8.39(d,J=1.6Hz,1H),8.21-8.12(m,2H),8.05(s,1H),5.22(q,J=6.4Hz,1H),1.53(d,J=6.4Hz,6H). MS(ESI,m / z):296.2[M+H] + .

[0062] In Step C, a mixture containing compound 4 (250 mg, 0.847 mmol), iodomethane (192 mg, 1.35 mmol), potassium carbonate (235 mg, 1.70 mmol), and DMF (5 mL) was stirred at room temperature overnight. Water (20 mL) was added and the mixture was filtered. The filter cake was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:petroleum ether = 1:1) to give methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (5). 1 H NMR (DMSO-d6,400MHz)δ 9.34(s,1H),8.46(d,J=1.6Hz,1H),8.23-8.16(m,3H),5.28-5.22(m,1H),3.83(s,3H),1.54(d,J=7.2Hz,6H). MS(ESI,m / z):310.1[M+H] + .

[0063] Example 3: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (6) [ka] A mixture containing compound 4 (150 mg, 0.508 mmol), 4-chloromethyl-5-methyl-1,3-dioxol-2-one (91 mg, 0.613 mmol), potassium carbonate (140 mg, 1.01 mmol), potassium iodide (110 mg, 0.663 mmol), and DMF (5 mL) was stirred at room temperature for 3 hours. Water (20 mL) was added and the mixture was filtered. The filter cake was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane) to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (6). 1H NMR(DMSO-d6,400MHz)δ 9.47(s,1H),8.58(d,J=1.2Hz,1H),8.34-8.25(m,3H),5.38-5.31(m,1H),5.29(s,2H),2.33(s,3H),1.63(d,J=6.8Hz,6H). MS(ESI,m / z):408.1[M+H] + .

[0064] Example 4: Synthesis of isopropyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (7) [ka] A mixture containing compound 4 (250 mg, 0.847 mmol), isopropyl bromide (325 mg, 2.64 mmol), potassium carbonate (235 mg, 1.70 mmol), potassium iodide (190 mg, 1.14 mmol), and DMF (5 mL) was stirred at 30 °C for 48 h. Water (20 mL) was added and the mixture was filtered. The filter cake was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:petroleum ether = 1:1) to give isopropyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (7) (190 mg). The yield was 66.5%. 1 H NMR(DMSO-d6,400MHz)δ 9.28(s,1H),8.47(d,J=1.2Hz,1H),8.24-8.16(m,3H),5.29-5.22(m,1H),5.16-5.10(m,1H),1.54(d,J=6.4Hz,6H),1.32(d,J=6.4Hz,6H). MS(ESI,m / z):338.1[M+H] + .

[0065] Example 5: Synthesis of bis[1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid]propane-1,3-diester (8) [ka] A mixture containing compound 4 (200 mg, 0.677 mmol), 1,3-dibromopropane (68 mg, 0.337 mmol), potassium carbonate (187 mg, 1.35 mmol), potassium iodide (146 mg, 0.880 mmol), and DMF (5 mL) was stirred at 30 °C for 48 h. Water (20 mL) was added and the mixture was filtered. The filter cake was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:petroleum ether = 1:1) to give bis[1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid]propane-1,3-diester (8) (146 mg). The yield was 68.4%. 1 H NMR(DMSO-d6,400MHz)δ 9.20(s,2H),8.24(s,2H),8.12-8.05(m,6H),5.23-5.16(m,2H),4.45(t,J=6.0Hz,4H),2.18(t,J=6.0Hz,2H),1.53(d,J=6.4Hz,12H). MS(ESI,m / z):631.1[M+H] + .

[0066] Example 6: Synthesis of [1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl ester (9) [ka] A mixture containing compound 4 (200 mg, 0.677 mmol), L-valine methyl ester hydrochloride (136 mg, 0.811 mmol), diisopropylethylamine (219 mg, 1.69 mmol), HBTU (385 mg, 1.02 mmol), and DMF (5 mL) was stirred overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated brine (15 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether:ethyl acetate:triethylamine = 100:10:1) to give [1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl ester (9) (268 mg). The yield was 96.9%. 1 H NMR(DMSO-d6,400MHz)δ 9.23(s,1H),8.34-8.29(m,3H),8.20-8.14(m,2H),5.27-5.24(m,1H),4.38-4.34(m,1H),3.67 (s,3H),2.18-2.13(m,1H),1.55(d,J=6.8Hz,6H),0.99(d,J=6.8Hz,3H),0.94(d,J=6.4Hz,3H). MS(ESI,m / z):409.2[M+H] + .

[0067] Example 7: Synthesis of 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-amino-4-methoxy-4-oxobutan-2-yl] ester (11) [ka] In Step A, a mixture containing compound 4 (200 mg, 0.677 mmol), Boc-L-threonine methyl ester (189 mg, 0.810 mmol), DCC (210 mg, 1.02 mmol), and dichloromethane (5 mL) was stirred overnight at room temperature. The insoluble material was removed by filtration, and the filter cake was eluted with dichloromethane (5 mL). The solvent was removed by vacuum distillation, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether:ethyl acetate:triethylamine=100:4:1) to give 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-(Boc-amino)-4-methoxy-4-oxobutan-2-yl] ester (10) (340 mg). The yield was 99.8%.

[0068] In Step B, a solution of compound 10 (340 mg, 0.666 mmol) and trifluoroacetic acid (0.3 mL) in dichloromethane (5 mL) was stirred overnight at room temperature. Water (20 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (20 mL × 2), and the combined organic phase was washed with saturated brine (10 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting product was recrystallized from ethyl acetate / petroleum ether to give 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-amino-4-methoxy-4-oxobutan-2-yl] ester (11). 1 H NMR(DMSO-d6,400MHz)δ 9.32(s,1H),8.44(s,1H),8.23-8.18(m,3H),5.32-5.23(m,2H),3.61(s,3 H),3.55(s,1H),2.06(s,2H),1.54(d,J=6.4Hz,6H),1.35(d,J=6.4Hz,3H). MS(ESI,m / z):411.1[M+H] + .

[0069] Example 8: Synthesis of (pyridin-2-yl)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (12) [ka] A mixture containing compound 4 (190 mg, 0.643 mmol), pyridine-2-methanol (84 mg, 0.770 mmol), DCC (210 mg, 0.969 mmol), DMAP (2 mg, 0.0163 mmol), and dichloromethane (5 mL) was stirred at room temperature overnight. Insoluble materials were removed by filtration, and the filter cake was eluted with dichloromethane (5 mL). The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:triethylamine = 100:1) to give (pyridin-2-yl)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (12) (75 mg). The yield was 30.2%. 1 H NMR(DMSO-d6,400MHz)δ 9.42(s,1H),8.58(d,J=4.4Hz,1H),8.50(d,J=1.6Hz,1H),8.30(s,1H),8.23(d,J=1.6Hz,1H),8.20(s,1H),7.8 8-7.85(m,1H),7.56(d,J=8.0Hz,1H),7.39-7.36(m,1H),5.40(s,2H),5.29-5.23(m,1H),1.54(d,J=6.4Hz,6H). MS(ESI,m / z):387.1[M+H] + .

[0070] Example 9: Synthesis of 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (3,7,11-trimethyldodecyl-2,6,10-trien-1-yl) ester (13) [ka] The procedure for synthesizing compound 13 using compound 4 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as starting materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 9.29(s,1H),8.47(s,1H),8.23-8.15(m,3H),5.44-5.40(m,1H),5.29-5.22(m,1H),5.10- 5.00(m,2H),4.79-4.74(m,2H),2.11-1.89(m,8H),1.83-1.74(m,6H),1.58-1.52(m,12H). MS(ESI,m / z):500.3[M+H] + .

[0071] Example 10: Synthesis of 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (3,7-dimethyloctane-2,6-dien-1-yl) ester (14) [ka] The procedure for synthesizing compound 14 using compound 4 and 3,7-dimethyloctane-2,6-dien-1-ol as starting materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 9.31(s,1H),8.47(d,J=1.6Hz,1H),8.23-8.16(m,3H),5.44-5.41(m,1H),5.28-5.23(m,1H),5.22-5.07(m,1H) ),4.78(d,J=6.8Hz,2H),2.10-2.03(m,4H),1.74(s,3H),1.63(s,3H),1.57(s,3H),1.55(s,3H),1.53(s,3H). MS(ESI,m / z):432.2[M+H] + .

[0072] Example 11: Synthesis of (pivaloyloxy)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (15) [ka] A mixture containing compound 4 (120 mg, 0.406 mmol), chloromethyl pivalate (74 mg, 0.491 mmol), potassium carbonate (113 mg, 0.818 mmol), potassium iodide (88 mg, 0.530 mmol), and DMF (5 mL) was stirred at room temperature for 48 h. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (20 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:petroleum ether = 1:1) to give (pivaloyloxy)methyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (15). 1 H NMR(DMSO-d6,400MHz)δ 9.41(s,1H),8.50(d,J=1.2Hz,1H),8.26-8.17(m,3H),5.94(s,2H),5.29-5.22(m,1H),1.54(d,J=6.4Hz,6H),1.17(s,9H). MS(ESI,m / z):410.1[M+H] + .

[0073] Example 12: Synthesis of methyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (19) [ka] In Step A, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.20 g, 1.47 mmol) was added to a mixture containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (8.40 g, 34.4 mmol), methyl 2-bromopyridine-4-carboxylate (9.0 g, 41.7 mmol), potassium carbonate (12.0 g, 87.0 mmol), dioxane (100 mL), and water (20 mL). Upon completion, the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature, filtered, and the filter cake was eluted with a small amount of ethyl acetate. Most of the solvent was removed by distillation under reduced pressure, and ethyl acetate (500 mL) was added. The mixture was washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, elution with ethyl acetate:dichloromethane=1:15) to give methyl 2-(1H-indazol-5-yl)isonicotinate (16). 1 H NMR(DMSO-d6,400MHz)δ 13.25(s,1H),8.90(d,J=4.8Hz,1H),8.61(s,1H),8.40(s,1H),8.23-8.1 9(m,2H),7.79(dd,J=1.2,4.8Hz,1H),7.69(d,J=8.8Hz,1H),3.99(s,3H). MS(ESI,m / z):254.1[M+H] + .

[0074] In Step B, dicesium carbonate (7.08 g, 21.7 mmol) and iodine (5.50 g, 21.7 mmol) were added to a solution of compound 16 (2.75 g, 10.9 mmol) in DMF (30 mL). Upon completion, the resulting mixture was stirred at room temperature for 2 hours. Water (120 mL) and 2 M sodium thiosulfate solution (20 mL) were added. After filtration, the filter cake was dissolved in ethyl acetate (300 mL), filtered to remove insoluble material, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give methyl 2-(3-iodo-1H-indazol-5-yl)isonicotinate (17) (3.90 g). The yield was 94.5%.

[0075] In Step C, a mixture containing compound 17 (3.90 g, 10.3 mmol), potassium carbonate (1.70 g, 12.3 mmol), isopropyl bromide (1.90 g, 15.4 mmol), potassium iodide (340 mg, 2.05 mmol), and DMF (40 mL) was stirred at 60 °C overnight. After cooling to room temperature, water (160 mL) was added and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with water (40 mL × 2), then with saturated brine (40 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 1:10) to give methyl 2-(3-iodo-1-isopropyl-1H-indazol-5-yl)isonicotinate (18) (3.81 g). The yield was 87.8%.

[0076] In Step D, a mixture containing compound 18 (3.81 g, 9.04 mmol), cuprous cyanide (1.14 g, 12.7 mmol), and DMF (30 mL) was stirred at 120 °C overnight. After cooling to room temperature, ethyl acetate (100 mL) and water (100 mL) were added, and the mixture was filtered to remove insoluble materials. After layering, the aqueous layer was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with water (40 mL × 2), followed by saturated brine (40 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 1:12 to 1:2) to give methyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (19) (1.0 g). The yield was 34.5%. 1H NMR(DMSO-d6,400MHz)δ 8.92(d,J=4.8Hz,1H),8.67(s,1H),8.53(s,1H),8.41(d,J=8.8Hz,1H),8.12(d,J=8.8 Hz,1H),7.83(d,J=4.8Hz,1H),5.29-5.22(m,1H),3.97(s,3H),1.55(d,J=6.8Hz,6H). MS(ESI,m / z):321.1[M+H] + .

[0077] Example 13: Synthesis of isopropyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (21) [ka] In Step A, a mixture containing compound 19 (1.0 g, 3.12 mmol), 2 M sodium hydroxide solution (15 mL), methanol (5 mL), and THF (5 mL) was stirred at room temperature for 30 min. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL). The product was in the aqueous phase. The pH of the aqueous phase was adjusted to 5-6 with 2 M citric acid solution. Filtration afforded 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (20) (688 mg). The yield was 72.0%. 1 H NMR(DMSO-d6,400MHz)δ 8.88(d,J=4.8Hz,1H),8.65(s,1H),8.50(s,1H),8.40(dd,J=1.6,9.2Hz,1H),8.13 (d,J=8.8Hz,1H),7.82(d,J=8.8Hz,1H),5.30-5.23(m,1H),1.58(d,J=6.8Hz,6H). MS(ESI,m / z):307.3[M+H] + .

[0078] The procedure for Step B was the same as in Example 4, and isopropyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (21) was obtained. 1H NMR(DMSO-d6,400MHz)δ 8.91(dd,J=0.8,4.8Hz,1H),8.64(d,J=0.8Hz,1H),8.48(s,1H),8.41(dd,J=1.6,8.8Hz,1H),8.12(d,J= 8.8Hz,1H),7.81(dd,J=1.6,4.8Hz,1H),5.29-5.20(m,2H),1.56(d,J=6.4Hz,6H),1.39(d,J=6.4Hz,6H). MS(ESI,m / z):349.1[M+H] + .

[0079] Example 14: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (22) [ka] The procedure for synthesizing compound 22 using compound 20 and 4-chloromethyl-5-methyl-1,3-dioxol-2-one as starting materials was as described in Example 3. 1 H NMR(DMSO-d6,400MHz)δ 8.93(d,J=5.2Hz,1H),8.67(s,1H),8.53(s,1H),8.40(dd,J=1.6,9.2Hz,1H),8.12(d,J=9.2Hz,1H ),7.85(dd,J=1.6,9.2Hz,1H),5.33(s,2H),5.29-5.22(m,1H),2.26(s,3H),1.55(d,J=6.8Hz,6H). MS(ESI,m / z):419.1[M+H] + .

[0080] Example 15: Synthesis of [2-(3-cyano-1-isopropyl-1H-indazol-5-yl)pyridine-4-carbonyl]-L-valine methyl ester (23) [ka] The procedure for synthesizing compound 23 using compound 20 and L-valine methyl hydrochloride as starting materials was as described in Example 6. 1H NMR(DMSO-d6,400MHz)δ 9.10(d,J=7.6Hz,1H),8.85(d,J=4.8Hz,1H),8.65(s,1H),8.48(s,1H),8.42(d,J=8.8Hz,1H),8.15(d,J=8.8Hz,1H),7.77(d,J=5.2Hz,1H) ,5.28-5.23(m,1H),4.42-4.38(m,1H),3.70(s,3H),2.26-2.21(m,1H),1.56(d,J=6.8Hz,6H),1.03(d,J=6.8Hz,3H),0.98(d,J=6.8Hz,3H). MS(ESI,m / z):539.0[M+DMSO+ACN+H] + .

[0081] Example 16: Synthesis of 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (3,7,11-trimethyldodecyl-2,6,10-trien-1-yl) ester (24) [ka] The procedure for synthesizing compound 24 using compound 20 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as starting materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 8.90(d,J=4.8Hz,1H),8.63(s,1H),8.48(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.80(dd,J=1.6,5.2Hz,1H),5. 49-5.46(m,1H),5.29-5.22(m,1H),5.11-5.07(m,2H),4.92-4.87(m,2H),2.12-1.88(m,8H),1.89-1.77(m,6H),1.64-1.52(m,12H). MS(ESI,m / z):511.3[M+H] + .

[0082] Example 17: Synthesis of 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (3,7-dimethyloctane-2,6-dien-1-yl) ester (25) [ka] The procedure for synthesizing compound 25 using compound 20 and 3,7-dimethyloctane-2,6-dien-1-ol as starting materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 8.90(d,J=4.8Hz,1H),8.64(s,1H),8.48(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.81(dd,J=1.6,5.2H z,1H),5.49-5.47(m,1H),5.26-5.24(m,1H),5.08-5.07(m,1H),4.92-4.90(m,2H),2.09-2.04(m,4H),1.77-1.57(m,15H). MS(ESI,m / z):443.2[M+H] + .

[0083] Example 18: Synthesis of {1-[(ethoxycarbonyl)oxy]}ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (26) [ka] A mixture containing compound 20 (100 mg, 0.326 mmol), potassium carbonate (90 mg, 0.651 mmol), 1-chloroethyl ethyl carbonate (75 mg, 0.492 mmol), potassium iodide (70 mg, 0.422 mmol), and DMF (3 mL) was stirred at 40 °C overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with water (15 mL × 2), then with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether:dichloromethane:triethylamine = 400:100:1) to give {1-[(ethoxycarbonyl)oxy]}ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (26). 1H NMR(DMSO-d6,400MHz)δ 8.94(d,J=5.2Hz,1H),8.67(s,1H),8.52(s,1H),8.40(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.84(dd,J=1.6,5.2Hz,1H),6 .96(q,J=5.2Hz,1H),5.29-5.22(m,1H),4.19(q,J=6.8Hz,2H),1.65(d,J=5.2Hz,3H),1.56(d,J=6.8Hz,6H),1.24(d,J=6.8Hz,3H). MS(ESI,m / z):423.1[M+H] + .

[0084] Example 19: Synthesis of (2-acetoxy)ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (27) [ka] The procedure for synthesizing compound 27 using compound 4 and ethylene glycol monoacetate as raw materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 9.34(s,1H),8.48(d,J=1.6Hz,1H),8.24-8.16(m,3H),5.29-5.23(m,1H), 4.47-4.45(m,2H),4.35-4.33(m,2H),2.06(s,3H),1.55(d,J=6.4Hz,6H). MS(ESI,m / z):382.5[M+H] + .

[0085] Example 20: Synthesis of (2-acetoxy)ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (28) [ka] The procedure for synthesizing compound 28 using compound 20 and ethylene glycol monoacetate as starting materials was as described in Example 8. 1H NMR(DMSO-d6,400MHz)δ 8.93(d,J=5.2Hz,1H),8.64(s,1H),8.50(s,1H),8.38(dd,J=1.6,8.8Hz,1H),8.13(d,J=8.8Hz,1H),7.83(dd,J =1.6,5.2Hz,1H),5.29-5.22(m,1H),4.59-4.56(m,2H),4.44-4.41(m,2H),2.07(s,3H),1.56(d,J=6.8Hz,6H). MS(ESI,m / z):393.1[M+H] + .

[0086] Example 21: Synthesis of (2-methoxy)ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (29) [ka] The procedure for synthesizing compound 29 using compound 4 and ethylene glycol monomethyl ether as raw materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 9.33(s,1H),8.49(d,J=1.6Hz,1H),8.24-8.16(m,3H),5.29-5.22(m,1H),4.3 8(t,J=4.4Hz,2H),3.65(t,J=4.4Hz,2H),3.32(s,3H),1.54(d,J=6.8Hz,6H). MS(ESI,m / z):354.1[M+H] + .

[0087] Example 22: Synthesis of (2-methoxy)ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (30) and (2-methoxy)ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate hydrobromide (31) [ka] In Step A, the procedure for synthesizing compound 30 using compound 20 and ethylene glycol monomethyl ether as raw materials was as described in Example 8. 1H NMR(DMSO-d6,400MHz)δ 8.93(d,J=4.8Hz,1H),8.66(s,1H),8.51(s,1H),8.39(dd,J=1.6,9.2Hz,1H),8.13(d,J=9.2Hz,1H),7.83(dd,J=1. 6,5.2Hz,1H),5.29-5.23(m,1H),4.51(t,J=4.4Hz,2H),3.72(t,J=4.4Hz,2H),3.33(s,3H),1.55(d,J=6.4Hz,6H). MS(ESI,m / z):365.1[M+H] + .

[0088] In Step B, hydrogen bromide was poured into a solution of compound 30 (48 mg, 0.132 mmol) in dichloromethane (10 mL) to make the solution strongly acidic, followed by distillation to remove the dichloromethane and recrystallization from ethyl acetate / petroleum ether to give 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (2-methoxy)ethyl hydrobromide (31). 1 H NMR(DMSO-d6,400MHz)δ 8.93(d,J=4.8Hz,1H),8.65(s,1H),8.51(s,1H),8.39(dd,J=1.6,8.8Hz,1H),8.13(d,J=8.8Hz,1H),7.83(dd,J =1.6,5.2Hz,1H),5.29-5.23(m,1H),4.52-4.50(m,2H),3.74-3.71(m,2H),3.33(s,3H),1.55(d,J=6.4Hz,6H). MS(ESI,m / z):365.1[M+H] + .

[0089] Example 23: Synthesis of cinnamyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (32) [ka] The procedure for synthesizing compound 32 using compound 4 and cinnamyl alcohol as starting materials was as described in Example 8. 1H NMR(DMSO-d6,400MHz)δ 9.38(s,1H),8.49(d,J=1.6Hz,1H),8.26-8.17(m,3H),7.52-7.50(m,2H),7.39-7.29(m,3H),6.81(d ,J=16.0Hz,1H),6.54-6.46(m,1H),5.29-5.22(m,1H),4.95(d,J=5.6Hz,2H),1.54(d,J=6.8Hz,6H). MS(ESI,m / z):412.1[M+H] + .

[0090] Example 24: Synthesis of cinnamyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (33) [ka] The procedure for synthesizing compound 33 using compound 20 and cinnamyl alcohol as starting materials was as described in Example 8. 1 H NMR(DMSO-d6,400MHz)δ 8.93(d,J=4.8Hz,1H),8.68(s,1H),8.56(s,1H),8.39(dd,J=1.6,8.8Hz,1H),8.12(d,J=8.8Hz,1H),7.84(dd,J=1.6,4.8Hz,1H),7.54-7. 52(m,2H),7.39-7.30(m,3H),6.86(d,J=16.4Hz,1H),6.60-6.52(m,1H),5.29-5.22(m,1H),5.08(d,J=5.6Hz,2H),1.55(d,J=6.8Hz,6H). MS(ESI,m / z):423.1[M+H] + .

[0091] Example 25: Synthesis of (1-isobutyloxy)ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (34) [ka] The procedure for synthesizing compound 34 using compound 4 and 1-chloroethyl isobutyrate as starting materials was as described in Example 18. 1H NMR(DMSO-d6,400MHz)δ 9.36(s,1H),8.48(s,1H),8.23-8.16(m,3H),6.98(q,J=5.6Hz,1H),5.2 9-5.22 (m, 1H), 2.62-2.55 (m, 1H), 1.57-1.54 (m, 9H), 1.12-1.10 (m, 6H). MS(ESI,m / z):410.1[M+H] + .

[0092] Example 26: Synthesis of (1-isobutyloxy)ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (35) [ka] The procedure for synthesizing compound 35 using compound 20 and 1-chloroethyl isobutyrate as starting materials was as described in Example 18. 1 H NMR(DMSO-d6,400MHz)δ 8.94(d,J=4.8Hz,1H),8.66(s,1H),8.50(s,1H),8.39(dd,J=1.6,9.2Hz,1H),8.12(d,J=9.2Hz,1H),7.83(dd,J=1.2,4.8Hz,1H), 7.04(q,J=5.2Hz,1H),5.29-5.22(m,1H),2.65-2.58(m,1H),1.63(d,J=5.2Hz,3H),1.56(d,J=6.4Hz,6H),1.12(d,J=6.8Hz,6H). MS(ESI,m / z):421.2[M+H] + .

[0093] Example 27: Synthesis of bis[2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid]propane-1,3-diester (36) [ka] The procedure for synthesizing compound 36 using compound 20 and 1,3-dibromopropane as starting materials was as described in Example 5. 1H NMR(DMSO-d6,400MHz)δ 8.72(d,J=4.8Hz,2H),8.32-8.31(m,4H),8.17(dd,J=1.2,8.8Hz,2H),7.98(d,J=8.8Hz,2H),7.71(d, J=4.8Hz,2H),5.22-5.15(m,2H),4.62(t,J=6.0Hz,4H),2.33(t,J=6.0Hz,2H),1.53(d,J=6.4Hz,12H). MS(ESI,m / z):653.2[M+H] + .

[0094] Example 28: Synthesis of [4-(nitrooxy)]butyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (38) [ka] In Step A, a mixture containing 4-bromobutyl acetate (1.0 g, 5.13 mmol), silver nitrate (1.30 g, 7.65 mmol), and acetonitrile (15 mL) was stirred overnight at reflux in the dark. It was cooled to room temperature and filtered to remove insoluble material. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then 2 M sodium hydroxide solution (2.5 mL) and methanol (5 mL) were added to the residue. Upon completion, the resulting mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether:ethyl acetate = 5:1) to give 4-hydroxybutyl nitrate (37) (400 mg) in 57.5% yield.

[0095] In Step B, a mixture containing compound 4 (80 mg, 0.272 mmol), compound 37 (40 mg, 0.296 mmol), DCC (84 mg, 0.407 mmol), DMAP (4 mg, 0.0327 mmol), and dichloromethane (5 mL) was stirred overnight at room temperature. Insoluble materials were removed by filtration. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluting with petroleum ether:ethyl acetate = 10:1 to 10:3) to give [4-(nitrooxy)]butyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (38). 1 H NMR(DMSO-d6,400MHz)δ 9.31(s,1H),8.46(s,1H),8.23-8.16(m,3H),5.29-5.22(m,1H),4.61(t,J= 6.0Hz, 2H), 4.29 (t, J = 6.0Hz, 2H), 1.87-1.80 (m, 4H), 1.54 (d, J = 6.4Hz, 6H). MS(ESI,m / z):413.3[M+H] + .

[0096] Example 29: Synthesis of [4-(nitrooxy)]butyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (39) [ka] The procedure for synthesizing compound 39 using compound 20 and compound 37 as starting materials was as described in Step B of Example 28. 1 H NMR(DMSO-d6,400MHz)δ 8.91(d,J=4.8Hz,1H),8.63(s,1H),8.49(s,1H),8.38(dd,J=1.6,9.2Hz,1H),8.11(d,J=9.2Hz,1H),7.83(dd,J=1.2, 4.8Hz,1H),5.29-5.22(m,1H),4.62(t,J=6.0Hz,2H),4.42(t,J=6.0Hz,2H),1.89-1.86(m,4H),1.56(d,J=6.4Hz,6H). MS(ESI,m / z):424.0[M+H] + .

[0097] Example 30: Synthesis of [3-(nitrooxy)methyl]phenyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (41) [ka] In Step A, a mixture containing 3-(bromomethyl)phenol (500 mg, 2.67 mmol), silver nitrate (500 mg, 2.94 mmol), and acetonitrile (5 mL) was stirred in an ice-water bath in the dark for 5 h. The mixture was filtered to remove insoluble materials. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether:ethyl acetate = 35:1) to give 3-hydroxybenzyl nitrate (40) (230 mg). The yield was 50.9%.

[0098] The procedure for Step B was the same as in Step B of Example 28, and 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate [3-(nitrooxy)methyl]phenyl (42) was obtained. 1 H NMR(DMSO-d6,400MHz)δ 9.58(s,1H),8.53(d,J=1.6Hz,1H),8.40(s,1H),8.28-8.19(m,2H),7.57-7.53(m,1H),7. 44-7.42(m,2H),7.37-7.35(m,1H),5.64(s,2H),5.30-5.23(m,1H),1.55(d,J=6.4Hz,6H). MS(ESI,m / z):447.0[M+H] + .

[0099] Example 31: Synthesis of [3-(nitrooxy)methyl]phenyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (42) [ka] The procedure for synthesizing compound 42 using compound 20 and compound 40 as starting materials was as described in Step B of Example 28. 1 H NMR(DMSO-d6,400MHz)δ 9.00(d,J=5.2Hz,1H),8.73(s,2H),8.46(dd,J=1.6,8.8Hz,1H),8.14(d,J=8.8Hz,1H),8.01(dd,J=1.6,5.2Hz,1H ),7.61-7.57(m,1H),7.53-7.52(m,1H),7.48-7.45(m,2H),5.66(s,2H),5.30-5.23(m,1H),1.56(d,J=6.8Hz,6H). MS(ESI,m / z):457.9[M+H] + .

[0100] Example 32: Synthesis of [2-(nitrooxy)]ethyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (44) [ka] The procedure for synthesizing compound 44 using 2-iodoethanol and compound 20 as starting materials was as described in Example 28. 1 H NMR(DMSO-d6,400MHz)δ 8.91(d,J=4.8Hz,1H),8.63(s,1H),8.50(s,1H),8.37(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.8 1(dd,J=1.2,4.8Hz,1H),5.27-5.20(m,1H),4.94-4.92(m,2H),4.69-4.67(m,2H),1.53(d,J=6.8Hz,6H). MS(ESI,m / z):396.0[M+H] + .

[0101] Example 33: Synthesis of [3-(nitrooxy)]propyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (46) [ka] The procedure for synthesizing compound 46 using 3-bromo-1-propanol and compound 20 as starting materials was as described in Example 28. 1 H NMR(DMSO-d6,400MHz)δ 8.91(d,J=5.2Hz,1H),8.63(s,1H),8.49(s,1H),8.38(dd,J=1.6,8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.83(dd,J=1.2, 4.8Hz,1H),5.28-5.18(m,1H),4.56(t,J=6.4Hz,2H),4.43(t,J=6.4Hz,2H),1.91-1.87(m,2H),1.54(d,J=6.8Hz,6H). MS(ESI,m / z):468.5[M+ACN+Na] + .

[0102] Example 34: Experimental study on the treatment of hyperuricemia in rats with compound 22 1. Experimental Materials (1) Test drug Compound 22 was a pale yellow powder and was ground with 0.5% CMC-Na immediately before use to prepare a suspension of the corresponding concentration for intragastric administration.

[0103] Febuxostat, purchased from Sigma, was ground with 0.5% CMC-Na immediately before use to prepare a suspension of the corresponding concentration for intragastric administration.

[0104] (2) Animals and care a. Animal species and source Thirty-six SPF male SD rats weighing 180–200 g were purchased from Shanghai Slice Laboratory Animal Co., Ltd., with production permit number SCXK(Kyoto)2019-0010 and quality certificate number 110324221100913432.

[0105] b. Rearing conditions All rats were housed in individually ventilated cage systems with air cleanliness class 10,000. The laboratory temperature was 26±2°C, the relative humidity was 60-80%, the air change rate was 10-15 times per hour, and the photoperiod was 12 (day) / 12 (night). Rats were housed three per cage.

[0106] The feed was a granular complete feed for mice, purchased from Jiangsu Cooperative Pharmaceutical and Biotechnology Co., Ltd., and its quality complies with GB14924.1-2001 "General quality standard for compound feed for laboratory animals."

[0107] The bedding was sterilized granular bedding and was purchased from Jiangsu Cooperative Pharmaceutical and Bioengineering Co., Ltd.

[0108] Drinking water was provided by drinking purified water, which was acidified and then allowed to drink ad libitum.

[0109] (3) Main equipment and devices The Varioskan LUX multimode microreader was purchased from Thermo, USA; the BS210S precision electronic balance (0.1 mg–10 g) was purchased from Sartorius, Germany; the FEJ-200 electronic balance (0.1–200 g) was purchased from Fuzhou Fu Riheng Zhibao Electronics Co., Ltd.; and the Pacific TII+Genpure XCAD PLUS UV / TOC / UF pure and ultrapure water system was purchased from Thermo, USA.

[0110] (4) Main reagents The uric acid detection kit (phosphotungstic acid reduction method) was purchased from Nanjing Jiancheng Institute of Biological Engineering with lot number 20220305, potassium oxonate with product number 00164 and lot number GR4VI-RK was purchased from Tokyo Chemical Industry Co., Ltd. (TCI), and carboxymethylcellulose sodium (CMC-Na) with lot number 20170810 was chemically pure and purchased from Sinopharm Group Chemical Reagents Co., Ltd.

[0111] 2. Experimental Method (1) Grouping Thirty-six male SD rats were acclimated for one week, weighing approximately 200–230 g. Based on body weight, they were randomly stratified into six groups, each with six rats. These groups were administered: (1) normal (0.5% CMC-Na), (2) model (0.5% CMC-Na), (3) febuxostat 1 mg / kg, (4) febuxostat 2 mg / kg, (5) compound 22 1.45 mg / kg, and (6) compound 22 2.9 mg / kg. The drugs in each group were prepared as suspensions of the corresponding concentrations, and the dose was 0.5 mL / 100 g.

[0112] (2) Model establishment, dosage regimen, and measurement index After purchasing, rats in each group were housed and adapted, then fasted for 12 hours. They were then subjected to modeling with 300 mg / kg of potassium oxonate (ip). 0.5 hours after modeling, each test drug group received a single intragastric administration. Blood samples were collected from the retroorbital venous plexus before and 1, 3, and 5 hours after potassium oxonate injection. The samples were centrifuged at 3500 rpm for 10 minutes, and 30 μL of serum was collected to measure uric acid levels at each time point.

[0113] (3) Data processing and statistical methods All measurement data for each experiment are reported as mean ± standard deviation (s). For intergroup comparisons, significance was examined using one-way analysis of variance Dunnett's test (ANOVA-Dunnett T), with P<0.05 as an indicator of significance and P<0.01 as an indicator of high significance.

[0114] 3. Experimental Results The results are shown in Table 1. Compared with the vehicle group, the potassium oxonate model group showed significantly elevated serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.05). Compared with the model group at the same time points, febuxostat at 1 mg / kg and 2 mg / kg significantly reduced serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01). Compared with the model group at the same time points, the compound 22 1.45 mg / kg group significantly reduced serum uric acid levels at 1 hour after modeling (P<0.05). The compound 22 2.9 mg / kg group significantly reduced serum uric acid levels at 1 and 5 hours after modeling (P<0.05). [Table 1]

[0115] Example 35: Experimental study on the treatment of hyperuricemia in rats with compounds 13, 38 and 41 1. Experimental Materials (1) Test drug Compound 13 was a pale yellow powder, and compounds 38 and 41 were almost white powders. Immediately before use, they were ground with 0.5% CMC-Na to prepare a 0.4 mg / mL suspension for intragastric administration.

[0116] Febuxostat was purchased from Sigma and crushed with 0.5% CMC-Na immediately before use to prepare a 0.4 mg / mL suspension for intragastric administration.

[0117] (2) Animals and care a. Animal species and source Thirty-six SPF male SD rats weighing 180–200 g were purchased from Shanghai Slice Laboratory Animal Co., Ltd., with production permit number SCXK(Kyoto)2019-0010 and quality certificate number 110324221100913432.

[0118] b. Rearing conditions All rats were housed in individually ventilated cage systems with air cleanliness class 10,000. The laboratory temperature was 26±2°C, the relative humidity was 60-80%, the air change rate was 10-15 times per hour, and the photoperiod was 12 (day) / 12 (night). Rats were housed three per cage.

[0119] The feed was a granular complete feed for mice, purchased from Jiangsu Cooperative Pharmaceutical and Biotechnology Co., Ltd., and its quality complies with GB14924.1-2001 "General quality standard for compound feed for laboratory animals."

[0120] The bedding was sterilized granular bedding and was purchased from Jiangsu Cooperative Pharmaceutical and Bioengineering Co., Ltd.

[0121] Drinking water was provided by drinking purified water, which was acidified and then allowed to drink ad libitum.

[0122] (3) Main equipment and devices The Varioskan LUX multimode microreader was purchased from Thermo, USA; the BS210S precision electronic balance (0.1 mg–10 g) was purchased from Sartorius, Germany; the FEJ-200 electronic balance (0.1–200 g) was purchased from Fuzhou Fu Riheng Zhibao Electronics Co., Ltd.; and the Pacific TII+Genpure XCAD PLUS UV / TOC / UF pure and ultrapure water system was purchased from Thermo, USA.

[0123] (4) Main reagents The uric acid detection kit (phosphotungstic acid reduction method) was purchased from Nanjing Jiancheng Institute of Biological Engineering with lot number 20230224, potassium oxonate with product number 00164 and lot number T6GKM-TA was purchased from Tokyo Chemical Industry Co., Ltd. (TCI), and carboxymethylcellulose sodium (CMC-Na) with lot number 20170810 was chemically pure and purchased from Sinopharm Group Chemical Reagents Co., Ltd.

[0124] 2. Experimental Method (1) Grouping Thirty-six male SD rats were acclimated for one week, weighing approximately 220–240 g. Based on body weight, they were randomly stratified into six groups, each with six rats. Each group received: (1) normal (0.5% CMC-Na), (2) model (0.5% CMC-Na), (3) febuxostat 2 mg / kg, (4) compound 13 2 mg / kg, (5) compound 38 2 mg / kg, and (6) compound 41 2 mg / kg. The drugs in each group were prepared as suspensions of the corresponding concentrations, and the dose was 0.5 mL / 100 g.

[0125] (2) Model establishment, dosage regimen, and measurement index After purchasing, each group of rats was housed and adapted, then fasted for 12 hours. They were then administered ip with 300 mg / kg of potassium oxonate. 0.5 hours after administration, each test drug group received a single intragastric administration. Administration was continued for three consecutive days. On the third day, blood samples were collected from the retroorbital venous plexus before the potassium oxonate injection and 1, 3, and 5 hours after the potassium oxonate injection. The samples were centrifuged at 3500 rpm for 10 minutes, and 30 μL of serum was collected. Uric acid levels were measured at each time point.

[0126] (3) Data processing and statistical methods All measurement data for each experiment are reported as mean ± standard deviation (s). For intergroup comparisons, significance was examined using one-way analysis of variance Dunnett's test (ANOVA-Dunnett T), with P<0.05 as an indicator of significance and P<0.01 as an indicator of high significance.

[0127] 3. Experimental Results The results are shown in Table 2. Compared with the vehicle group, the potassium oxonate model group showed significantly elevated serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.05). Compared with the model group at the same time points, the febuxostat group significantly reduced serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01). Compared with the model group at the same time points, compound 13 significantly reduced serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01 or P<0.05). Compound 38 significantly reduced serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01 or P<0.05). Compound 41 significantly reduced serum uric acid levels at 3 and 5 hours after modeling (P<0.01). [Table 2]

[0128] Example 36: In vivo pharmacokinetics study of compounds in SD rats 1. Experimental Materials (1) Test drug Preparation of compound stock solutions: An appropriate amount of solid powder of each compound was weighed, a predetermined amount of DMSO was added, and the mixture was vortexed under ultrasonication to obtain a 10 mg / mL stock solution.

[0129] To prepare test compounds for intragastric administration, an appropriate amount of the compound stock solution was transferred to each tube, a predetermined amount of Solutol HS15 solution was added, and the mixture was vortexed for 1 minute. A predetermined amount of saline was then added and the mixture was thoroughly mixed to obtain a 1 mg / mL solution.

[0130] To prepare the test compound for intravenous injection, an appropriate amount of the compound stock solution was transferred to each well, a predetermined amount of Solutol HS15 solution was added, and the mixture was vortexed for 1 minute. A predetermined amount of saline was then added and the mixture was thoroughly mixed to obtain a 0.5 mg / mL solution.

[0131] (2) Experimental animals The SD rats were SPF males, 6 to 8 weeks old, purchased from JH Laboratory Animal Co., Ltd. with permit numbers SCXK(SH)2017-0012 and SCXK(SH)2022-0009, and passport numbers 20170012022154 and 20220009005149.

[0132] 2. Experimental Method (1) Dosage and method of administration The experimental animals were fasted overnight before intragastric administration, fed 4 hours after administration, and allowed to drink water ad libitum during the experiment. Each test compound was divided into two groups: an intravenous administration group and an oral administration group. The specific administration doses and methods are shown in Table 3 below. [Table 3]

[0133] (2) Operation procedure Before administration and 5 minutes (intravenous administration group only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration, jugular blood samples (150 μL / sample) were collected from SD rats and added to centrifuge tubes containing the anticoagulant sodium heparin. The samples were centrifuged at 2000 g for 5 minutes at 4°C to separate plasma. The plasma samples were analyzed using LC / MS / MS to measure the concentrations of each test compound in the plasma samples.

[0134] (3) Pharmacokinetic analysis Non-compartmental model-related parameters were calculated with the software WinNonlin® Professional.

[0135] 3. Experimental Results The pharmacokinetic parameters of each test compound in SD rats obtained by the above method are shown in Table 4. Each compound of the present invention has good pharmacokinetic parameters and high bioavailability. [Table 4]

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony, R is C 1 ~ 6 Alkyl group or substituted C 1 ~ 6 an alkyl group, wherein the substituents of each group represented by R are one or more selected from the group consisting of deuterium, a cyano group, a nitro group, and a halogen; Ar is substituted or unsubstituted, 【Chemistry 2】 The substituents of the Ar group are deuterium, hydroxyl, halogen, C 1 ~ 4 Alkyl group or C 1 ~ 4 one or more selected from alkoxy groups, Y is O; R 1 is a bond or a substituted or unsubstituted C 1 ~ 6 Alkylene group or substituted or unsubstituted C 2 ~ 12 is an alkenylene group, and R 1 The substituents of the group are deuterium, amino group, cyano group, halogen, C 1 ~ 4 Alkyl group or C 1 ~ 4 one or more selected from alkoxy groups, R 2 is hydrogen, a nitrooxy group, or a substituted or unsubstituted dioxol-2-one group, an indazolylpyrazolylcarbonyloxy group, an indazolylpyridinylcarbonyloxy group, an indolylpyrazolylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, a pyridyl group, a phenyl group, a C 1-6 alkoxy group, a C 6-20 alkenyl group, a C 2-8 alkylcarbonyloxy group, or a C 2-8 alkoxycarbonyloxy group, and the substituent of the R 2 group is one or more selected from deuterium, a hydroxy group, an amino group, a cyano group, a halogen atom, a C 1-6 alkyl group, a nitrooxy-substituted C 1-6 alkyl group, and a C 1-6 alkoxy group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound selected from compounds represented by general formula (II) or (III): 【Transformation 3】

3. R is C 3 ~ 6 Alkyl group or substituted C 1 ~ 6 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl group, and R has one or more substituents selected from the group consisting of deuterium, a cyano group, a nitro group, and a halogen atom.

4. R 1 is a bond or a substituted or unsubstituted C 1 ~ 4 Alkylene group or substituted or unsubstituted C 4 ~ 12 is an alkenylene group, and R 1 The substituent of the group is deuterium, an amino group, a cyano group, a halogen, or C 1 ~ 4 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the aryl group is one or more selected from the group consisting of alkoxy groups.

5. A compound selected from the following or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 【change】

6. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active substance, and a pharmaceutically acceptable auxiliary agent added thereto.

7. 10. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of an antigout drug or an antihyperuricemia drug.

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