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 pharmaceutical field 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 for the drug treatment of hyperuricemia and gout. In the human body, hypoxanthine is metabolized to xanthine, which is further metabolized to produce uric acid, and XO plays a crucial role in the formation of uric acid. When the activity of XO is inhibited, the conversion between hypoxanthine, xanthine and uric acid is inhibited, and the concentration of uric acid in human serum is reduced. Therefore, inhibiting the activity of XO is the key to inhibiting uric acid production.

[0003] Generally, hyperuricemia is defined as blood uric acid levels exceeding 420μmol / L in men and 360μmol / L in women. Currently, hyperuricemia is the second most common metabolic disease after diabetes, and is a serious threat to human health. Hyperuricemia is not only an important biochemical factor in causing gout, but is also closely related to the development of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance. According to the US National Health and Nutrition Examination Survey data, the prevalence of gout among US adults was 3.9% (approximately 8.3 million people) during 2007-2008 (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 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 comorbidities that promote hyperuricemia (hypertension, obesity, metabolic syndrome, type 2 diabetes, chronic kidney disease, etc.) (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 ever-increasing incidence of hyperuricemia and gout is a serious threat to human health, and early intervention and treatment are necessary. However, the currently available uric acid lowering drugs are very limited, and they have obvious toxicity and side effects, leading to poor patient compliance. Currently, the drugs for treating hyperuricemia and gout are mainly divided 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 the reabsorption of uric acid and increase its excretion, thereby lowering the concentration of uric acid in the body. Drugs in this category include benzbromarone, lesinurad, and probenecid. Benzbromarone is an effective uric acid excretion enhancer and has been approved for sale in many countries, but not in the United States. Due to severe liver toxicity, benzbromarone has been withdrawn from the market in some European countries since 2003. Due to racial differences in benzbromarone-related liver-related adverse events, the Chinese Guidelines for Diagnosis and Treatment of Hyperuricemia and Gout (2019) recommends benzbromarone as the first-choice uric acid lowering drug. Lesinurad was approved for sale in the United States in 2015, and its instructions carry a black box warning that it may cause acute renal failure and cardiovascular disease (potentially fatal), and is far less effective than benzbromarone, so it must be used in combination with allopurinol. Probenecid is listed as the first choice uric acid excretion enhancer in monotherapy for uric acid lowering in the US guidelines, but its use is restricted due to several significant interactions with some commonly used medications (nonsteroidal anti-inflammatory agents, β-lactams, heparin, etc.).

[0006] Xanthine oxidase inhibitors mainly include allopurinol and febuxostat. Allopurinol has been widely used clinically since its marketing approval by the US FDA in 1966. Currently, the drug is still recommended as the first-line drug for gout treatment in most countries' gout guidelines. However, allopurinol is poorly effective, only inhibiting reduced XO and not oxidized XO, and related studies have revealed that even when allopurinol is used at the maximum dose, the treatment endpoint achievement 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)).In clinical practice, allopurinol has been reported to cause acute liver failure, so allopurinol should be used with caution when treating patients with hyperuricemia complicated by 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 is a non-purine XO inhibitor created by Teijin Ltd. that can inhibit the oxidized and reduced forms of XO, and is clearly more active than allopurinol. It was launched in Europe in 2008 and in the United States in 2009. As the clinical application of febuxostat continues to expand, cardiovascular adverse events occurring when treating hyperuricemia have been increasingly reported, and due to its cardiovascular toxicity (such as the risk of sudden death), the US Food and Drug Administration required the addition of a black box warning of risks to its instruction manual, and in 2019, the prescription information was adjusted, changing it from a first-line drug to a second-line drug. 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 groups had similar overall risk of adverse cardiovascular events (HR, 1.03; 95% CI, 0.87 to 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 cardiovascular mortality rate (HR, 1.34; 95% CI, 1.03 to 1.73) and a 22% increased all-cause mortality rate (HR, 1.22; 95% CI, 1.01 to 1.47). The most common cause of cardiovascular death was sudden cardiac 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 main urate oxidase drug currently on the market and is administered by intravenous injection. The FDA has 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 reaching the treatment endpoint of <0.36 mmol / L.

[0009] In 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 drugs for treating hyperuricemia and gout has attracted more and more researchers' attention. The design of new drugs targeting xanthine oxidase has been widely emphasized, and various compounds have entered clinical trials, but they still face many problems, such as high toxicity and side effects, and more 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 which, based on the prior art, have xanthine oxidase inhibitory activity.

[0011] Another object of the present invention is to provide the use of said 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 pharma- ceutically acceptable salt thereof, [ka] During the ceremony, R is C 1~6 Alkyl groups, substituted C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, substituted C 3~6 Cycloalkyl groups, C3~6 Heterocycloalkyl or substituted C 3~6 Heterocycloalkyl groups, where the substituents of each group associated with R are deuterium, cyano, nitro, halogen, C 1~6 Alkyl group, C 1~6 Alkoxy group, C 3~6 Cycloalkyl group or C 3~6 one or more selected from heterocycloalkyl groups; Ar is substituted or unsubstituted, [ka] The Ar group is substituted with deuterium, hydroxyl, halogen, or C. 1~4 Alkyl group or C 1~4 one or more selected from alkoxy groups, Y is O or NR 3 and R 1 is a bond or a substituted or unsubstituted C 1~6 Alkylene group or substituted or unsubstituted C 2~12 alkenylene group, R 1 The substituents of the group are deuterium, hydroxyl group, 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, a carboxy group, or a substituted or unsubstituted dioxol-2-one group; C 4~12 Condensed heteroaromatic ring group, C 4~16 Condensed heteroaromatic pyrazolylcarbonyloxy group, C 4~16 Condensed heteroaromatic pyridinylcarbonyloxy group, C 4~16 Condensed heteroaromatic ring triazolylcarbonyloxy group, C 2~6 Ester group, pyridyl group, phenyl group, C 1~6 Alkoxy group, C 2~20 Alkenyl group, C 2~20 Alkynyl group, C 2~8 Alkylcarbonyloxy group or C 2~8 is an alkoxycarbonyloxy group, R 2The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~6 Alkyl group, haloC 1~6 Alkyl, nitrooxy-substituted C 1~6 Alkyl group or C 1~6 one or more selected from alkoxy groups, R 3 is hydrogen or C 1~6 It is an alkyl group.

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

[0014] In a preferred embodiment, the compound of the present invention is a compound represented by the 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 C 3~6 Alkyl groups, substituted C 1~6 Alkyl group, C 3~6 Cycloalkyl groups, substituted C 3~6 Cycloalkyl groups, C 3~6 Heterocycloalkyl or substituted C 3~6 Heterocycloalkyl groups, where the substituents of each group associated with R are deuterium, cyano, nitro, halogen, C 1~5 Alkyl group, C 1~5 Alkoxy group or C 3~6 The group is one or more selected from cycloalkyl groups.

[0017] In a preferred embodiment, R is C 3~6 Alkyl groups, substituted C 1~6 Alkyl group, C 3~6Cycloalkyl groups, substituted C 3~6 A cycloalkyl group, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrothiophene, substituted tetrahydrothiophene, pyrrolidine or substituted pyrrolidine, where the substituents of each group related to R are deuterium, a cyano group, a nitro group, a halogen, C 1~5 Alkyl group, C 1~5 Alkoxy group or C 3~6 The group is one or more selected from cycloalkyl groups.

[0018] In a preferred embodiment, R is C 3~6 Alkyl groups, substituted C 1~3 Alkyl group, C 3~6 Cycloalkyl or substituted C 3~6 is a cycloalkyl group, and the R group substituents are deuterium, halogen or C 3~6 It is selected from cycloalkyl groups.

[0019] In a preferred embodiment, R is C 3~6 Alkyl group or C 3~6 It is a 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 or a substituted or unsubstituted C 1~4 Alkylene group or substituted or unsubstituted C 4~12 alkenylene group, R 1 The substituent of the group is deuterium, an amino group, a cyano group, a halogen or C 1~4 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

[0022] In a preferred embodiment, R 2is a hydrogen atom, 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, group, quinolinylpyridinylcarbonyloxy group, isoquinolinylpyridinylcarbonyloxy group, indolylpyridinylcarbonyloxy group, benzofurylpyridinylcarbonyloxy group, purinylpyridinylcarbonyloxy group, indazolyltriazolylcarbonyloxy group, quinolinyltriazolylcarbonyloxy group, isoquinolinyltriazolylcarbonyloxy group, indolyltriazolylcarbonyloxy group, benzofuryltriazolylcarbonyloxy group, purinyltriazolylcarbonyloxy group, C 2~6 Ester group, pyridyl group, phenyl group, C 1~6 Alkoxy group, C 6~20 Alkenyl group, C 6~20 Alkynyl group, C 2~8 Alkylcarbonyloxy group or C 2~8 is an alkoxycarbonyloxy group, R 2 The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~6 Alkyl group, haloC 1~6 Alkyl, nitrooxy-substituted C 1~6 Alkyl group or C 1~6 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

[0023] In a preferred embodiment, R 2is 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, C 2~6 Ester group, pyridyl group, phenyl group, C 1~6 Alkoxy group, C 6~20 Alkenyl group, C 2~8 Alkylcarbonyloxy group or C 2~8 is an alkoxycarbonyloxy group, R 2 The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~6 Alkyl, nitrooxy-substituted C 1~6 Alkyl group or C 1~6 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

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

[0025] In a preferred embodiment, the compound of the present invention may be selected from: [ka] TIFF2025514336000007.tif28112

[0026] The present invention also includes pharmaceutical compositions comprising the compound according to the present application or a pharma- ceutically acceptable salt thereof as an active substance, to which a pharma- ceutically acceptable auxiliary is added.

[0027] The compounds of the present invention or pharma- ceutically acceptable salts thereof may be used to produce xanthine oxidase inhibitors, in particular, to produce anti-gout or anti-hyperuricemia 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 primary stable isotope of the element hydrogen.

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

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

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

[0032] An "amino group" refers to an -NH2 group.

[0033] "Alkyl group" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups, containing 1 to 10 carbon atoms (numerical ranges referred to herein, e.g., "1 to 10," refer to the group, in which case the alkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). Alkyl groups containing 1 to 4 carbon atoms are referred to as lower alkyl groups. When the lower alkyl group has no substituents, it is referred to as an unsubstituted lower alkyl group. As an alkyl group, C 1~6 Alkyl group, C 1~5 Alkyl group, C 1~4 Alkyl group, C 1~3 Alkyl group, C 1~2 Alkyl group, C 2~3 Alkyl group, C 2~4 Alkyl groups, etc. may be selected. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl groups, etc. The alkyl groups may be substituted or unsubstituted.

[0034] "Alkenyl group" refers to a hydrocarbon group containing 2 to 30 carbon atoms, including straight and branched chain groups having one or more "C=C"s (numerical ranges referred to herein, such as "2 to 10", mean that the group, in this case the alkenyl group, may contain 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). 2~20 Alkenyl group, C 2~18 Alkenyl group, C 2~16 Alkenyl group, C 2~14 Alkenyl group, C 2~12 Alkenyl group, C 4~14 Alkenyl group, C 4~12 Alkenyl groups, etc. may be selected. Specific alkenyl groups include ethenyl, propenyl, allyl, butenyl, isobutenyl, tert-butenyl, [ka] These include, but are not limited to, the following:

[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. 1~6 Alkyl group, C 1~5 Alkyl group, C 1~4 Alkyl group, C 1~3 Alkyl group, C 1~2 Alkyl group, C 2~3 Alkyl group, C 2~4 Alkyl groups and the like may be selected. Representative examples include, but are not limited to, methoxy groups, ethoxy groups, propoxy groups, cyclopropoxy groups, and the like.

[0036] The "dioxol-2-one group" is [ka] It is based on

[0037] The term "pyrazolyl group" means [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] An "ester group" refers to a "-C(=O)-O-alkyl" group, in which the alkyl group is C 1~6 Alkyl group, C 1~5 Alkyl group, C 1~4 Alkyl group, C 1~3 Alkyl group, C 1~2 Alkyl group, C 2~3 Alkyl group, C 2~4 alkyl groups, etc. Representative examples include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, etc. A substituted ester group refers to an ester group in which a hydrogen atom of the ester group is replaced by one substituent, or in which multiple hydrogen atoms of the ester group are each replaced by the same or different substituents.

[0043] The term "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. In this specification, a numerical range such as "3 to 6" means that the group, which is a heterocycloalkyl group, may contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., and contains up to 6 carbon atoms as ring atoms. Heterocycloalkyl groups include C 3~8 Heterocycloalkyl groups, C 3~6 Heterocycloalkyl groups, C 3~5 Heterocycloalkyl groups, C 3~4 Heterocycloalkyl groups, C 3~9 Heterocycloalkyl groups, C 4~6 Heterocycloalkyl groups and the like may be selected. 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] "C 4~16 The term "condensed heteroaromatic ring pyrazolylcarbonyloxy group" refers to an -OC(=O)-pyrazolyl-condensed heteroaromatic ring group containing 4 to 16 carbon atoms, and a specific example is an indazolylpyrazolylcarbonyloxy group. [ka] , indolylpyrazolylcarbonyloxy group [ka] This includes, but is not limited to:

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

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

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

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

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

[0050] A "nitrooxy group" refers to the -ONO2 group.

[0051] "Pharmaceutically acceptable salts" refers to salts formed by the compounds of general formula (I) with organic or inorganic acids, which retain the bioavailability and properties of the parent compound. Such salts include, but are not limited to, the following: (1) Salts formed with acids, which result from the reaction of 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, and the like.

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

[0053] A "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or pharma- ceutically acceptable salts and prodrugs thereof, with other chemical components, such as pharma- ceutically 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 pharma- ceutically acceptable salt thereof, or a readily hydrolyzable prodrug thereof, and another pharma- ceutical active ingredient.

[0055] The present invention also includes any of the above compounds and their pharma- ceutically acceptable salts, which may be formulated into any clinically or pharma- ceutical acceptable dosage form in a manner known in the art. For oral administration, they may be formulated into a conventional solid preparation, such as tablets, capsules, pills, and granules, or into an oral liquid preparation, such as oral liquid, oral suspension, syrup, etc. For oral administration, they may be formulated into an appropriate filler, binder, disintegrant, lubricant, etc. For parenteral administration, they may be formulated into an injection, such as an injection solution, a sterile powder for injection, or a concentrated solution for injection. For injection, they may be produced by a conventional method in the pharmaceutical field, and for injection, they may not need to add additives, or may add appropriate additives based on the properties of the drug. Effect of the Invention

[0056] The compound provided by the present invention can significantly reduce the serum uric acid level in a hyperuricemia rat model, and has potential application value as an anti-gout drug, anti-hyperuricemia drug, etc. Febuxostat has the risk of serious sudden cardiac death, severe renal toxicity and hepatic toxicity, and the compound provided by the present invention may have some advantages in reducing drug toxicity, and therefore has the potential to be developed as a drug. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0057] The present invention will be further described below with reference to 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] 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. It was cooled to room temperature and filtered to remove insoluble materials. Water (200 mL) was added and extracted with ethyl acetate (80 mL×3), and the combined organic phase was washed with water (50 mL×2), then with 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, eluted with ethyl acetate:petroleum ether=1:50-1:30) 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] 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 nitrogen atmosphere. It was cooled to room temperature, water (80 mL) was added, extracted with ethyl acetate (40 mL×3), and 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=1:15-1:4) to give ethyl 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (2) (500 mg), yield 40.8%. 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] 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. Part of the solvent was removed by distillation under reduced pressure, water (8 mL) was added, and the pH was adjusted to 1-2 with 6 M hydrochloric acid. After filtration, the filter cake was recrystallized with 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), 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, and upon completion, the resulting mixture was stirred at room temperature overnight. Saturated saline (20 mL) was added, extracted with dichloromethane (20 mL x 2), and the combined organic phase was washed with saturated saline (20 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and then purified by preparative HPLC to obtain 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] 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 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 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (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 h. Water (20 mL) was added and 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 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 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 hydrochloride (136 mg, 0.811 mmol), diisopropylethylamine (219 mg, 1.69 mmol), HBTU (385 mg, 1.02 mmol) and DMF (5 mL) was stirred at room temperature overnight. Water (20 mL) was added, extracted with ethyl acetate (30 mL x 2), and the combined organic phase was washed with saturated brine (15 mL x 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, eluted 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 (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] Step A: A mixture containing compound 4 (200 mg, 0.677 mmol), Boc-L-threonine methyl (189 mg, 0.810 mmol), DCC (210 mg, 1.02 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 vacuum distillation and the product was purified by column chromatography (200-300 mesh silica gel, elution 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 at room temperature overnight. 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 x 2), and the combined organic phase was washed with saturated brine (10 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting product was recrystallized with 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 vacuum distillation 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 raw 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 raw 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 extracted with ethyl acetate (20 mL x 2), and the combined organic phase was washed with saturated brine (20 mL x 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 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (pivaloyloxy)methyl (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] Step A: 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), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.20 g, 1.47 mmol) was added, and upon completion, the resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 hours. It 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, 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, eluted 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] Step B: To a solution of compound 16 (2.75 g, 10.9 mmol) in DMF (30 mL), dicesium carbonate (7.08 g, 21.7 mmol), iodine (5.50 g, 21.7 mmol) were added, and upon completion, the resulting mixture was stirred at room temperature for 2 hours. Water (120 mL) and 2M sodium thiosulfate solution (20 mL) were added. After filtration, the filter cake was dissolved in ethyl acetate (300 mL), filtered to remove insolubles, 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] 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. It was cooled to room temperature, water (160 mL) was added, extracted with ethyl acetate (100 mL×2), and 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, eluted 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. It was cooled to room temperature, and ethyl acetate (100 mL) and water (100 mL) were added, followed by filtration to remove insoluble materials. After layering, the aqueous layer was extracted with ethyl acetate (100 mL×2), and 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 vacuum distillation, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with ethyl acetate:petroleum ether=1:12-1:2) 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] 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 extracted with ethyl acetate (50 mL), the product being in the aqueous phase. The pH of the aqueous phase was adjusted to 5-6 with 2 M citric acid solution. Filtration gave 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 of Step B was the same as in Example 4 to give isopropyl 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (21). 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 raw 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 raw 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 extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with water (15 mL x 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, eluted with petroleum ether: dichloromethane: triethylamine = 400: 100: 1) to give 2-(3-cyano-1-isopropyl-1H-indazol-5-yl) isonicotinic acid {1-[(ethoxycarbonyl)oxy]}ethyl ester (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 raw 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-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester (30) and 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester hydrobromide (31) [ka] In Step A, the procedure for synthesizing compound 30 using compound 20 and ethylene glycol monomethyl ether as raw materials was the same as 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 dichloromethane and recrystallization from ethyl acetate / petroleum ether to give 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (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 raw 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 raw 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 raw 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 raw 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 raw 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] 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 at reflux overnight in the dark. It was cooled to room temperature and filtered to remove insolubles. Water (60 mL) was added, 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, 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 a yield of 57.5%.

[0095] 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 at room temperature overnight. 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, eluted with petroleum ether:ethyl acetate=10:1-10:3) to give 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate [4-(nitrooxy)]butyl (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 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate [3-(nitrooxy)methyl]phenyl (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 the dark under ice-water bath for 5 h. Insoluble materials were removed by filtration. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 2), and 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 Example 28, Step B, to give 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate [3-(nitrooxy)methyl]phenyl (42). 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 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid [3-(nitrooxy)methyl]phenyl (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 raw materials was 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 from 3-bromo-1-propanol and compound 20 was the same as 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, which was ground with 0.5% CMC-Na immediately before use to prepare a suspension of the corresponding concentration for intragastric administration.

[0103] Febuxostat was purchased from Sigma and 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 their care a. Animal species and source Thirty-six SPF male SD rats weighing 180-200 g were purchased from Shanghai SCXK 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 an individually ventilated cage system with air cleanliness class 10,000. The laboratory temperature was 26 ± 2°C, the relative humidity was 60-80%, the hourly ventilation rate was 10-15 times / h, the photoperiod was 12 (day) / 12 (night), and there were three rats per cage.

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

[0107] The bedding material was sterilized granular bedding material and was purchased from Jiangsu Cooperative Pharmaceutical Bio-Engineering Co., Ltd.

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

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

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

[0111] 2. Experimental Method (1) Grouping Thirty-six male SD rats were acclimated for one week, and their body weight was approximately 200–230 g. Based on body weight, they were randomly stratified into six groups, six rats per group, and were administered (1) normal group (0.5% CMC-Na), (2) model group (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, dosing schedule and measurement index After purchasing, each group of rats was kept and adapted, then fasted for 12 hours, and modeled with 300mg / kg of potassium oxonate ip, and 0.5 hours after modeling, each test drug group was intragastrically administered once. Blood was collected from the retroorbital venous plexus before potassium oxonate injection and 1 hour, 3 hours, and 5 hours after potassium oxonate injection, and centrifuged at 3500rpm for 10 minutes, and 30μL of serum was collected to measure uric acid levels at each time point.

[0113] (3) Data processing and statistical methods All measurement data from each experiment are reported as mean ± standard deviation (s). For intergroup comparisons, significance was examined using one-way analysis of variance with 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 solvent group, the serum uric acid level in the potassium oxonate model group increased significantly at 1 hour, 3 hours, and 5 hours after modeling (P<0.05). Compared with the model group at the same time point, both febuxostat 1 mg / kg and 2 mg / kg were able to significantly lower the serum uric acid level at 1 hour, 3 hours, and 5 hours after modeling (P<0.01). Compared with the model group at the same time point, the compound 22 1.45 mg / kg group was able to significantly lower the serum uric acid level at 1 hour after modeling (P<0.05). The compound 22 2.9 mg / kg group was able to significantly lower the serum uric acid level at 1 hour 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 their care a. Animal species and source Thirty-six SPF male SD rats weighing 180-200 g were purchased from Shanghai SCXK 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 an individually ventilated cage system with air cleanliness class 10,000. The laboratory temperature was 26 ± 2°C, the relative humidity was 60-80%, the hourly ventilation rate was 10-15 times / h, the photoperiod was 12 (day) / 12 (night), and there were three rats per cage.

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

[0120] The bedding material was sterilized granular bedding material and was purchased from Jiangsu Cooperative Pharmaceutical Bio-Engineering Co., Ltd.

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

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

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

[0124] 2. Experimental Method (1) Grouping Thirty-six male SD rats were acclimated for one week, and their body weight was approximately 220–240 g. Based on body weight, they were randomly stratified into six groups, six rats per group, and were administered (1) normal group (0.5% CMC-Na), (2) model group (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, dosing schedule and measurement index After purchasing, each group of rats was kept and adapted, then fasted for 12 hours, and modeled with 300mg / kg of potassium oxonate ip. 0.5 hours after modeling, each test drug group was intragastrically administered once. The administration was continued for 3 days, and on the third day, blood was collected from the retroorbital venous plexus before potassium oxonate injection and 1 hour, 3 hours, and 5 hours after potassium oxonate injection, and centrifuged at 3500rpm for 10 minutes, and 30μL of serum was collected to measure uric acid levels at each time point.

[0126] (3) Data processing and statistical methods All measurement data from each experiment are reported as mean ± standard deviation (s). For intergroup comparisons, significance was examined using one-way analysis of variance with 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 solvent group, the potassium oxonate model group showed a significant increase in serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.05). Compared with the model group at the same time point, the febuxostat group was able to significantly lower serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01). Compared with the model group at the same time point, compound 13 was able to significantly lower serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01 or P<0.05). Compound 38 was able to significantly lower serum uric acid levels at 1, 3, and 5 hours after modeling (P<0.01 or P<0.05). Compound 41 was able to significantly lower serum uric acid levels at 3 and 5 hours after modeling (P<0.01). [Table 2]

[0128] Example 36: In vivo pharmacokinetic 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 out, a predetermined amount of DMSO was added, and the mixture was vortexed under ultrasonication to obtain a 10 mg / mL stock solution.

[0129] Preparation of test compounds for intragastric administration: Transfer an appropriate amount of compound stock solution, add a specified amount of Solutol HS15 solution, vortex for 1 minute, add a specified amount of saline, and mix thoroughly to homogenize, to obtain a 1 mg / mL solution.

[0130] Preparation of test compounds for intravenous injection: Transfer an appropriate amount of compound stock solution, add a specified amount of Solutol HS15 solution, vortex for 1 minute, add a specified amount of saline, and mix thoroughly to homogenize, to obtain 0.5 mg / mL solutions.

[0131] (2) Laboratory animals The 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, and 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, SD rats were sampled from the jugular vein (150 μL / sample), added to a centrifuge tube containing the anticoagulant sodium heparin, and 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 concentration 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 the general formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (I) During the ceremony, R is C １～６ Alkyl group, substituted C １～６ Alkyl group, C ３～６ Cycloalkyl group, substituted C ３～６ Cycloalkyl group, C ３～６ Heterocycloalkyl group or substituted C ３～６ Heterocycloalkyl groups, where the substituents of each group associated with R are deuterium, cyano, nitro, halogen, C １～６ Alkyl group, C １～６ Alkoxy group, C ３～６ Cycloalkyl group or C ３～６ heterocycloalkyl groups, Ar is substituted or unsubstituted, 【Chemistry 2】 The Ar group is substituted with deuterium, a hydroxyl group, a halogen, or C. １～４ Alkyl group or C １～４ one or more selected from alkoxy groups, Y is O or NR ３ and R １ is a bond or a substituted or unsubstituted C １～６ Alkylene group or substituted or unsubstituted C ２～１２ alkenylene group, R １ The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C １～４ Alkyl group or C １～４ one or more selected from alkoxy groups, R ２ is a hydrogen atom, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one group; C ４～１２ Condensed heteroaromatic ring group, C ４～１６ Condensed heteroaromatic pyrazolylcarbonyloxy group, C ４～１６ Condensed heteroaromatic ring pyridinylcarbonyloxy group, C ４～１６ Condensed heteroaromatic ring triazolylcarbonyloxy group, C ２～６ Ester group, pyridyl group, phenyl group, C １～６ Alkoxy group, C ２～２０ Alkenyl group, C ２～２０ Alkynyl group, C ２～８ Alkylcarbonyloxy group or C ２～８ is an alkoxycarbonyloxy group, R ２ The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C １～６ Alkyl group, haloC １～６ Alkyl group, nitrooxy-substituted C １～６ Alkyl group or C １～６ one or more selected from alkoxy groups, R ３ is hydrogen or C １～６ It is an alkyl group.

2. The compound according to claim 1, which is a compound selected from the group consisting of compounds represented by general formula (II), (III) and (IV) or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】

3. Y is O or NH and R is C ３～６ Alkyl group, substituted C １～６ Alkyl group, C ３～６ Cycloalkyl group, substituted C ３～６ Cycloalkyl group, C ３～６ Heterocycloalkyl group or substituted C ３～６ Heterocycloalkyl groups, where the substituents of each group related to R are deuterium, cyano, nitro, halogen, C １～５ Alkyl group, C １～５ Alkoxy group or C ３～６ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the cycloalkyl group is one or more selected from the group consisting of cycloalkyl groups.

4. R is C ３～６ Alkyl group, substituted C １～６ Alkyl group, C ３～６ Cycloalkyl group, substituted C ３～６ a cycloalkyl group, tetrahydrofuran, a substituted tetrahydrofuran, tetrahydrothiophene, a substituted tetrahydrothiophene, pyrrolidine, or a substituted pyrrolidine, wherein the substituent of each group related to R is deuterium, a cyano group, a nitro group, a halogen, C １～５ Alkyl group, C １～５ Alkoxy group or C ３～６ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the cycloalkyl group is one or more selected from the group consisting of cycloalkyl groups.

5. R １ is a bond or a substituted or unsubstituted C １～４ Alkylene group or substituted or unsubstituted C ４～１２ alkenylene group, 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 pharma- ceutically acceptable salt thereof, wherein the aryl group is one or more selected from the group consisting of alkoxy groups.

6. R ２ is 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, or an indazolylpyridinylcarbonyloxy group. group, a quinolinylpyridinylcarbonyloxy group, an isoquinolinylpyridinylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, a benzofurylpyridinylcarbonyloxy group, a purinylpyridinylcarbonyloxy group, an indazolyltriazolylcarbonyloxy group, a quinolinyltriazolylcarbonyloxy group, an isoquinolinyltriazolylcarbonyloxy group, an indolyltriazolylcarbonyloxy group, a benzofuryltriazolylcarbonyloxy group, a purinyltriazolylcarbonyloxy group, C ２～６ Ester group, pyridyl group, phenyl group, C １～６ Alkoxy group, C ６～２０ Alkenyl group, C ６～２０ Alkynyl group, C ２～８ Alkylcarbonyloxy group or C ２～８ is an alkoxycarbonyloxy group, R ２ The substituent of the group is deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, C １～６ Alkyl group, haloC １～６ Alkyl group, nitrooxy-substituted C １～６ Alkyl group or C １～６ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein the aryl group is one or more selected from the group consisting of alkoxy groups.

7. 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, C ２～６ Ester group, pyridyl group, phenyl group, C １～６ Alkoxy group, C ６～２０ Alkenyl group, C ２～８ Alkylcarbonyloxy group or C ２～８ is an alkoxycarbonyloxy group, R ２ The substituent of the group is deuterium, a hydroxyl group, an amino group, a cyano group, a halogen, C １～６ Alkyl group, nitrooxy-substituted C １～６ Alkyl group or C １～６ 6. The compound according to claim 5, or a pharma- ceutically acceptable salt thereof, wherein the aryl group is one or more selected from the group consisting of alkoxy groups.

8. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, which is a compound selected from the following: 【Chemistry 4】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

9. A pharmaceutical composition comprising the compound according to claim 1 or a pharma- ceutically acceptable salt thereof as an active substance, to which a pharma- ceutically acceptable auxiliary agent is added.

10. 13. Use of the compound according to claim 1 or a pharma- ceutically acceptable salt thereof in the manufacture of an anti-gout drug or an anti-hyperuricemia drug.

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