Compounds used in gout

Abstract

The present invention discloses a series of compounds for gout, which are represented by general formula (I) or a pharma- ceutically acceptable salt thereof, and can reduce serum uric acid level in a hyperuricemia rat model, and have potential application value as anti-gout drugs, anti-hyperuricemia drugs, etc. [Formula 1] JPEG2025515359000051.jpg1123 (I)

Description

[Technical field]

[0001] The present invention is in the field of medicinal chemistry and specifically relates to a series of compounds used in the treatment of gout. [Background technology]

[0002] Gout is a metabolic disease caused by an increase in serum uric acid (sUA) due to increased production and / or decreased excretion of uric acid in the body, which leads to the formation of monosodium uric acid crystals and their deposition in the joints, surrounding tissues, and kidneys, resulting in autoinflammatory reactions and morphological changes in the joints. Gout is the most common inflammatory joint disease in adult males, and its prevalence is increasing in developed countries, making it a serious metabolic disease that threatens human health.

[0003] At present, there are more than 55 million gout patients worldwide, and the number of hyperuricemia patients is far greater than 200 million. Over the past 20 years, with the improvement of people's living standards and changes in dietary structure, the number of hyperuricemia and gout patients has increased significantly due to excessive intake of high purine foods, and the market size of gout drugs has a tendency to grow significantly. According to relevant data, the global gout drug market size in 2018 was 15.65 billion, and is expected to reach 36.15 billion in 2025. Gout is often associated with various diseases such as hypertension, obesity, cardiovascular disease, diabetes, and chronic kidney disease, and these comorbid diseases make the treatment of gout more complicated and increase the risk of early death (Non-Patent Documents 1 and 2). Patients with severe gout may suffer from joint damage and renal failure, which seriously affects the quality of life and health of patients.

[0004] Xanthine oxidase (XO) is an important target for the drug treatment of hyperuricemia and gout, and it catalyzes the oxidation of hypoxanthine and xanthine to produce xanthine and uric acid, respectively. Therefore, inhibiting XO can reduce the synthesis of uric acid and further lower the serum uric acid concentration. With the application of techniques such as crystal structure analysis of xanthine oxidase, computer-aided drug design, and high-throughput screening, many XO inhibitors have been produced in recent years. Patent Document 1 discloses a series of new compounds as xanthine oxidase inhibitors, among which the candidate compound LC350189 is under development and has progressed to the stage of phase II clinical trials, and the phase II clinical trial research has proven its effect of sufficiently lowering sUA. However, only three drugs (allopurinol, febuxostat, and topiroxostat) are currently approved for commercial sale, and the drugs under development that have entered the clinical stage still have problems regarding efficacy or safety.

[0005] Prodrugs are an effective drug design method that modify and improve drug molecules that have biological activity but also have some drawbacks, by attaching precursor groups to form chemicals that can be activated by enzymes or chemical reactions in the body. Prodrugs generally have no or very low biological activity, but can be converted into biologically active drugs through enzymatic or non-enzymatic degradation. Compared with drug substances, prodrugs not only maintain or enhance the efficacy of the drug substance, but also overcome the drawbacks of the drug substance and improve its clinical efficacy. Prodrugs may be used to increase the solubility of drugs, improve their bioavailability, and improve their delivery properties, pharmacokinetic properties, etc. Currently, nearly 10% of drugs on the world market are prodrugs, and in 2008 alone, about 30% of small molecule drugs are prodrugs. For example, angiotensin converting enzyme inhibitors such as enalapril, benazepril, and ramipril are hydrolyzed in the body to the corresponding dicarboxylic acid metabolites, which exert their antihypertensive effects; some statin lipid lowering drugs such as lovastatin and simvastatin are prodrugs with a cyclic structure, and do not have hydroxymethylglutaryl CoA reductase inhibitory activity unless the ring-opening reaction occurs; proton pump inhibitors such as omeprazole, lansoprazole, and ilaprazole cannot be activated unless they enter the acidic environment of the stomach; and the antihistamine loratadine loses ethyl formate in the body to produce the active metabolite desloratadine. Many new prodrugs have also been developed. However, in actual development, prodrug compounds still have many problems, such as losing activity or poor activity, and designed prodrug compounds do not match the desired target effect. [Prior art documents] [Non-patent literature]

[0006] [Patent Document 1] China Patent Publication No. CN102574839A

[0007] [Non-Patent Document 1] Khanna D, Fitzgerald JD, Khanna PP, et al.American College of Rheumatology Guidelines for Management of Gout.Part 1 [Non-Patent Document 2] Systematic Nonpharmacologic and Pharmacologic Therapeutic Approaches to Hyperuricemia[J].Arthritis Care & Research,2012,64(10):1432-1446 Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide compounds having xanthine oxidase inhibitory activity.

[0009] Another object of the present invention is to provide the use of said compounds in the pharmaceutical field. [Means for solving the problem]

[0010] 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, 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 1~6 Alkyl group, C 1~6 Alkoxy group, C3~6 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 2 The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~4 Alkyl group, haloC 1~4 Alkyl, nitrooxy-substituted C 1~4 Alkyl group or C1~4 alkoxy groups, and R 2 Group C 4~16 The condensed heteroaromatic ring group does not include an indazolyl group. R 3 is hydrogen or C 1~6 It is an alkyl group.

[0011] In a preferred embodiment, Ar is a substituted or unsubstituted [ka] where "*" is the site of attachment to C=O.

[0012] In a preferred embodiment, the compound is a compound of general formula (II), (III) or (IV) [ka] Selected from.

[0013] In a preferred embodiment, Y is O or NH.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] In a preferred embodiment, R is C 3~6 Alkyl group or C 3~6 It is a cycloalkyl group.

[0018] 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.

[0019] In a preferred embodiment, R 1 is a bond or a substituted or unsubstituted C 1~4 Alkylene group or substituted or unsubstituted C 2~12 alkenylene group, R 1 The substituent of the group is deuterium, amino group, cyano group, halogen or C 1~4 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

[0020] 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, a quinolinylpyrazolylcarbonyloxy group, an isoquinolinylpyrazolylcarbonyloxy group, an indolylpyrazolylcarbonyloxy group, a benzofurylpyrazolylcarbonyloxy group, a purinylpyrazolylcarbonyloxy group, a quinolinylpyridinylcarbonyloxy group, an isoquinolinylpyridinylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, a benzofurylpyridinylcarbonyloxy group, a purinylpyridinylcarbonyloxy 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 substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~4 Alkyl group, haloC 1~4 Alkyl, nitrooxy-substituted C 1~4 Alkyl group or C 1~4 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

[0021] In a preferred embodiment, R 2 is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one 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 C2~8 is an alkoxycarbonyloxy group, R 2 The substituents of the group are deuterium, hydroxyl group, amino group, cyano group, halogen, C 1~4 Alkyl group, haloC 1~4 Alkyl, nitrooxy-substituted C 1~4 Alkyl group 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 2 is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one group, an indolylpyrazolylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, C 2~4 Ester group, phenyl group, C 1~4 Alkoxy group, C 6~14 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 1~4 Alkyl, nitrooxy-substituted C 1~4 Alkyl group or C 1~4 The alkoxy group is one or more groups selected from the group consisting of alkoxy groups.

[0023] In a preferred embodiment, the compound of the invention is selected from: [ka]

[0024] 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 pharma- ceutically acceptable auxiliaries are added.

[0025] 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.

[0026] 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.

[0027] "D" or "deuterium" refers to the stable isotope of hydrogen, also called heavy hydrogen, whose atomic symbol is D.

[0028] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0029] "Hydroxy" refers to an -OH group.

[0030] An "amino group" refers to an -NH2 group.

[0031] "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.

[0032] "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:

[0033] 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.

[0034] The "dioxol-2-one group" is [ka] It is based on

[0035] The term "pyrazolyl group" refers to [ka] It refers to one of the following.

[0036] The term "triazolyl group" includes 1,2,3-triazolyl groups, where "1,2,3-triazolyl group" means [ka] Refers to...

[0037] 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.

[0038] The term "carboxy group" refers to a -COOH group.

[0039] 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.

[0040] 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.

[0041] "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 thereof is an indolylpyrazolylcarbonyloxy group. [ka] Includes.

[0042] "C 2~8 The term "alkoxycarbonyloxy group" refers to an -OC(=O)-O-alkyl group containing 2 to 8 carbon atoms.

[0043] "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 thereof is an indolylpyridinylcarbonyloxy group. [ka] Includes.

[0044] "C 4~16 The term "condensed heteroaromatic ring triazolylcarbonyloxy group" refers to an -OC(=O)-triazolyl-condensed heteroaromatic ring group containing 4 to 16 carbon atoms, and a specific example is an indolyltriazolylcarbonyloxy group. [ka] Includes.

[0045] 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.

[0046] A "nitrooxy group" refers to the -ONO2 group.

[0047] "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.

[0048] (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.

[0049] 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.

[0050] 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.

[0051] 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

[0052] 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

[0053] 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.

[0054] Example 1: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (4) [ka] Step A: A mixture containing 5-bromo-1H-indole-3-carbonitrile (10.0 g, 45.2 mmol), isopropyl iodide (30.8 g, 181 mmol), dicesium carbonate (29.5 g, 90.5 mmol) and acetonitrile (100 mL) was stirred at 80° C. for 3 h. It was cooled to room temperature and filtered to remove insoluble materials. The filter cake was eluted with ethyl acetate (200 mL). The solvent was removed by vacuum distillation and the product was purified by column chromatography (200-300 mesh silica gel, elution with ethyl acetate:petroleum ether=1:15-1:3) to give 5-bromo-1-isopropyl-1H-indole-3-carbonitrile (1) (11.6 g). The yield was 97.5%.

[0055] Step B: A mixture containing ethyl 1H-pyrazole-4-carboxylate (3.20 g, 22.8 mmol), compound 1 (3.03 g, 11.5 mmol), potassium carbonate (3.15 g, 22.8 mmol), cuprous iodide (2.17 g, 11.4 mmol), (1S,2S)-1,2-diaminocyclohexane (1.01 g, 11.4 mmol) and DMF (50 mL) was stirred overnight at 110° C. under nitrogen atmosphere. The mixture was cooled to room temperature, and ethyl acetate (100 mL) was added, washed with saturated saline (50 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=1:30-1:4) to give ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (2) (3.10 g), yield 83.6%.

[0056] In step C, a mixture containing compound 2 (600 mg, 1.86 mmol), 2 M sodium hydroxide solution (12 mL), methanol (4 mL) and THF (4 mL) was stirred at 30° C. for 1 h. Some of the solvent was removed by distillation under reduced pressure, water (10 mL) was added, and the product was extracted with ethyl acetate (10 mL) in the aqueous phase. The pH of the aqueous phase was adjusted to 4-5 with 2 M citric acid solution. After filtration, the filter cake was recrystallized with methanol to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (3) (400 mg). The yield was 73.1%.

[0057] Step D: A mixture containing compound 3 (150 mg, 0.510 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 overnight. 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-indol-5-yl)-1H-pyrazole-4-carboxylate (4). 1 H NMR(DMSO-d6,400MHz)δ 9.30(s,1H),8.58(s,1H),8.23(s,1H),8.21(s,1H),7.96-7.90(m,2H),5.19(s,2H),4.96-4.89(m,1H),2.23(s,3H),1.51(d,J=6.4Hz,6H). MS(ESI,m / z):407.1[M+H] + .

[0058] Example 2: Synthesis of bis[1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid]propane-1,3-diester (5) [ka] A mixture containing compound 3 (150 mg, 0.510 mmol), 1,3-dibromopropane (51 mg, 0.253 mmol), potassium carbonate (141 mg, 1.02 mmol), potassium iodide (110 mg, 0.663 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-indol-5-yl)-1H-pyrazole-4-carboxylic acid]propane-1,3-diester (5) (59.4 mg). The yield was 37.1%. 1 H NMR(DMSO-d6,400MHz)δ 9.19(s,2H),8.55(s,2H),8.14-8.12(m,4H),7.86-7.84(m,4H),4.93-4.86( m,2H),4.43(t,J=6.0Hz,4H),2.16(t,J=6.0Hz,2H),1.49(d,J=6.4Hz,12H). MS(ESI,m / z):629.2[M+H] + .

[0059] Example 3: Synthesis of [1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl ester (6) [ka] A mixture containing compound 3 (70 mg, 0.238 mmol), L-valine methyl hydrochloride (47.8 mg, 0.285 mmol), diisopropylethylamine (77 mg, 0.596 mmol), HBTU (135 mg, 0.356 mmol) and DMF (5 mL) was stirred at room temperature overnight. Water (20 mL) was added and 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: dichloromethane: triethylamine = 200: 100: 1) to give [1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl (6) (78.5 mg). The yield was 80.9%. 1 H NMR(DMSO-d6,400MHz)δ 9.16(s,1H),8.57(s,1H),8.29(d,J=8.0Hz,1H),8.22(s,1H),8.06(s,1H),7.94-7.86(m,2H),4.95-4.89(m,1H),4. 38-4.34(m,1H),3.67(s,3H),2.18-2.12(m,1H),1.51(d,J=6.4Hz,6H),0.99(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H). MS(ESI,m / z):408.2[M+H] + .

[0060] Example 4: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (3,7-dimethyloctane-2,6-dien-1-yl) ester (7) [ka] A mixture containing compound 3 (70 mg, 0.238 mmol), 3,7-dimethyloctane-2,6-dien-1-ol (44 mg, 0.285 mmol), DCC (74 mg, 0.359 mmol), DMAP (3 mg, 0.0246 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 petroleum ether:dichloromethane:triethylamine=300:100:1) to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (3,7-dimethyloctane-2,6-dien-1-yl) ester (7) (53 mg). The yield was 51.7%. 1 H NMR(DMSO-d6,400MHz)δ 9.22(s,1H),8.57(s,1H),8.22(d,J=1.6Hz,1H),8.14(s,1H),7.95-7.89(m,2H),5.44-5.41(m,1H),5.08-5.06(m,1H),4.9 5-4.89(m,1H),4.77(d,J=7.2Hz,2H),2.10-2.05(m,4H),1.74(s,3H),1.63(s,3H),1.57(s,3H),1.51(s,3H),1.50(s,3H). MS(ESI,m / z):431.2[M+H] + .

[0061] Example 5: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (3,7,11-trimethyldodecyl-2,6,10-trien-1-yl) ester (8) [ka] The procedure for synthesizing compound 8 using compound 3 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as raw materials was as described in Example 4. 1H NMR(DMSO-d6,400MHz)δ 9.20(s,1H),8.57(s,1H),8.21(s,1H),8.13(d,J=2.4Hz,1H),7.95-7.89(m,2H),5.43-5.40(m,1H),5.10 -5.02(m,2H),4.95-4.89(m,1H),4.78-4.73(m,2H),2.11-1.91(m,8H),1.74(s,3H),1.64-1.50(m,15H). MS(ESI,m / z):499.2[M+H] + .

[0062] Example 6: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-amino-4-methoxy-4-oxobutan-2-yl] ester (10) [ka] Step A: A mixture containing compound 3 (120 mg, 0.408 mmol), Boc-L-threonine methyl (114 mg, 0.489 mmol), DCC (168 mg, 0.814 mmol) and dichloromethane (4 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 petroleum ether:dichloromethane:triethylamine=300:100:1) to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-(Boc-amino)-4-methoxy-4-oxobutan-2-yl] ester (9) (218 mg). The yield was 100%.

[0063] In step B, a solution of compound 9 (218 mg, 0.427 mmol) and trifluoroacetic acid (0.4 mL) in dichloromethane (4 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-indol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-amino-4-methoxy-4-oxobutan-2-yl] ester (10). 1 H NMR(DMSO-d6,400MHz)δ 9.23(s,1H),8.58(s,1H),8.18-8.16(m,2H),7.93-7.92(m,2H),5.32-5.30(m,1H), 4.94-4.91(m,1H),3.61-3.58(m,4H),1.51(d,J=6.4Hz,6H),1.35(d,J=6.4Hz,3H). MS(ESI,m / z):410.1[M+H] + .

[0064] Example 7: Synthesis of {1-[(ethoxycarbonyl)oxy]}ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (11) [ka] A mixture containing compound 3 (100 mg, 0.340 mmol), potassium carbonate (93 mg, 0.673 mmol), 1-chloroethyl ethyl carbonate (78 mg, 0.511 mmol), potassium iodide (73 mg, 0.440 mmol) and DMF (2 mL) was stirred at 40 °C 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 water (10 mL x 2), then 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 ethyl acetate:petroleum ether = 1:10) to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate {1-[(ethoxycarbonyl)oxy]}ethyl (11) (51 mg). The yield was 36.5%. 1 H NMR(DMSO-d6,400MHz)δ 9.31(s,1H),8.58(s,1H),8.23(d,J=1.6Hz,1H),8.21(s,1H),7.96-7.90(m,2H),6.87(q,J=5.6Hz,1H),4. 96-4.89(m,1H),4.17(q,J=7.2Hz,2H),1.58(d,J=5.2Hz,3H),1.51(d,J=6.4Hz,6H),1.23(t,J=6.8Hz,3H). MS(ESI,m / z):411.1[M+H] + .

[0065] Example 8: Synthesis of (2-acetoxy)ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (12) [ka] The procedure for synthesizing compound 12 using compound 3 and ethylene glycol monoacetate as raw materials was as described in Example 4. 1H NMR(DMSO-d6,400MHz)δ 9.25(s,1H),8.58(s,1H),8.22(d,J=1.6Hz,1H),8.16(s,1H),7.96-7.90(m,2H),4.96- 4.89(m,1H),4.46-4.44(m,2H),4.34-4.32(m,2H),2.05(s,3H),1.51(d,J=6.8Hz,6H). MS(ESI,m / z):381.1[M+H] + .

[0066] Example 9: Synthesis of (2-methoxy)ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (13) [ka] The procedure for synthesizing compound 13 using compound 3 and ethylene glycol monomethyl ether as raw materials was as described in Example 4. 1 H NMR(DMSO-d6,400MHz)δ 9.23(s,1H),8.58(s,1H),8.22(d,J=2.0Hz,1H),8.15(s,1H),7.96-7.89(m,2H),4.96-4.8 9(m,1H),4.38(t,J=4.8Hz,2H),3.65(t,J=4.8Hz,2H),3.32(s,3H),1.51(d,J=6.8Hz,6H). MS(ESI,m / z):353.1[M+H] + .

[0067] Example 10: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-cinnamyl carboxylate (14) [ka] The procedure for synthesizing compound 14 using compound 3 and cinnamyl alcohol as raw materials was as described in Example 4. 1H NMR(DMSO-d6,400MHz)δ 9.29(s,1H),8.57(s,1H),8.23-8.21(m,2H),7.97-7.90(m,2H),7.52-7.50(m,2H),7.38-7.2 9(m,3H),6.81(d,J=16.0Hz,1H),6.53-6.48(m,1H),4.95-4.91(m,3H),1.49(d,J=6.4Hz,6H). MS(ESI,m / z):411.1[M+H] + .

[0068] Example 11: Synthesis of (1-isobutyloxy)ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (15) [ka] The procedure for synthesizing compound 15 using compound 3 and 1-chloroethyl isobutyrate as raw materials was as described in Example 7. 1 H NMR(DMSO-d6,400MHz)δ 9.28(s,1H),8.57(s,1H),8.22(d,J=1.6Hz,1H),8.19(s,1H),7.96-7.90(m,2H),6.97(q,J=5.6Hz,1H) ,4.96-4.89(m,1H),2.61-2.54(m,1H),1.55(d,J=5.6Hz,3H),1.51(d,J=6.8Hz,6H),1.12-1.09(m,6H). MS(ESI,m / z):409.2[M+H] + .

[0069] Example 12: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (17) [ka] Starting from 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (16) (the procedure for synthesizing compound 16 is referred to Examples 2 and 3 of Patent CN115160299) and 4-chloromethyl-5-methyl-1,3-dioxol-2-one, the procedure for synthesizing compound 17 is referred to Step D of Example 1. 1 H NMR(CDCl3,400MHz)δ 8.56(d,J=2.0Hz,1H),8.29(s,1H),8.17(dd,J=2.0,8.8Hz,1H),7.82(s,1H),7.56( d,J=8.8Hz,1H),5.18(s,2H),4.79-4.73(m,1H),2.29(s,3H),1.62(d,J=6.4Hz,6H). MS(ESI,m / z):408.0[M+H] + .

[0070] Example 13: Synthesis of bis[2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid]propane-1,3-diester (18) [ka] The procedure for synthesizing compound 18 using compound 16 and 1,3-dibromopropane as raw materials was as described in Example 2. 1 H NMR(CDCl3,400MHz)δ 8.44(d,J=2.0Hz,2H),8.25(s,2H),8.10(dd,J=2.0,8.8Hz,2H),7.79(s,2H),7.53(d,J=8.8Hz ,2H),4.79-4.72(m,2H),4.65(t,J=6.0Hz,4H),2.39(t,J=6.0Hz,2H),1.61(d,J=6.8Hz,12H). MS(ESI,m / z):631.2[M+H] + .

[0071] Example 14: Synthesis of {1-[(ethoxycarbonyl)oxy]}ethyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (19) [ka] The procedure for synthesizing compound 19 using compound 16 and 1-chloroethyl ethyl carbonate as raw materials was as described in Example 7. 1 H NMR(CDCl3,400MHz)δ 8.56(d,J=2.0Hz,1H),8.28(s,1H),8.17(dd,J=2.0,8.8Hz,1H),7.81(s,1H),7.55(d,J=8.8Hz,1H),7.10(q,J=5.2H) z,1H),4.79-4.72(m,1H),4.26(q,J=7.2Hz,2H),1.72(d,J=5.6Hz,3H),1.61(d,J=6.8Hz,6H),1.34(t,J=6.8Hz,3H). MS(ESI,m / z):412.1[M+H] + .

[0072] Example 15: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (3,7,11-trimethyldodecyl-2,6,10-trien-1-yl) ester (20) [ka] The procedure for synthesizing compound 20 using compound 16 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as raw materials was as described in Example 4. 1H NMR(DMSO-d6,400MHz)δ 8.65(s,1H),8.61-8.60(m,1H),8.24(s,1H),8.06(dd,J=2.0,8.8Hz,1H),8.00(d,J=8.8Hz,1H),5.50- 5.43(m,1H),5.09-4.84(m,5H),2.10-1.87(m,8H),1.76(s,3H),1.63-1.61(m,2H),1.56-1.49(m,13H). MS(ESI,m / z):544.3[M+HCO2] - .

[0073] Example 16: Synthesis of (pyridin-2-yl)methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (21) [ka] A mixture containing compound 16 (80 mg, 0.271 mmol), pyridine-2-methanol (36 mg, 0.330 mmol), DCC (84 mg, 0.407 mmol), DMAP (3 mg, 0.0246 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 dichloromethane) to give (pyridin-2-yl)methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (21) (69 mg). The yield was 65.9%. 1H NMR(CDCl3,400MHz)δ 8.65-8.64(m,1H),8.57(d,J=2.0Hz,1H),8.32(s,1H),8.18(dd,J=2.0,8.8Hz,1H),7.81(s,1H),7.78-7 .74(m,1H),7.57-7.50(m,2H),7.30-7.28(m,1H),5.58(s,2H),4.79-4.72(m,1H),1.61(d,J=6.8Hz,6H). MS(ESI,m / z):387.4[M+H] + .

[0074] Example 17: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinate (27) [ka] Step A: To a mixture containing 5-indole boronic acid pinacol ester (7.29 g, 30.0 mmol), 2-bromopyridine-4-methyl carboxylate (7.78 g, 36.0 mmol), potassium carbonate (10.4 g, 75.2 mmol), dioxane (100 mL) and water (20 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.09 g, 1.50 mmol) was added, and upon completion, the resulting mixture was stirred under nitrogen atmosphere at 80° C. for 3 hours. Most of the solvent was removed by distillation under reduced pressure, water (100 mL) was added, extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed 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=1:5) to give methyl 2-(1H-indol-5-yl)isonicotinate (22) (1.30 g) in a yield of 17.2%.

[0075] Step B: To a solution of compound 22 (1.30 g, 5.15 mmol) in DMF (25 mL) was added dicesium carbonate (3.35 g, 10.3 mmol), iodine (2.62 g, 10.3 mmol), and upon completion, the resulting mixture was stirred at room temperature overnight. Water (60 mL) and 2M sodium thiosulfate solution (20 mL) were added. After filtration, the filter cake was dissolved in ethyl acetate (200 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-indol-5-yl)isonicotinate (23) (1.10 g). The yield was 51.4%. MS (ESI, m / z): 379.1 [M+H] + .

[0076] Step C: A mixture containing compound 23 (1.10 g, 2.91 mmol), potassium carbonate (480 mg, 3.47 mmol), isopropyl bromide (530 mg, 4.31 mmol), potassium iodide (100 mg, 0.602 mmol) and DMF (20 mL) was stirred at 60° C. overnight. 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 water (30 mL×2), then with saturated brine (30 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-indol-5-yl)isonicotinate (24) (600 mg). The yield was 49.1%.

[0077] Step D: A mixture containing compound 24 (600 mg, 1.43 mmol), cuprous cyanide (200 mg, 2.33 mmol) and DMF (6 mL) was stirred at 120° C. overnight. It was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added, followed by filtration to remove insoluble materials. After layering, the aqueous layer was extracted with ethyl acetate (20 mL×3), and the combined organic layers were washed with water (15 mL×2), followed by saturated brine (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to give methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinate (25) (267 mg). The yield was 58.5%.

[0078] Step E: A mixture containing compound 25 (267 mg, 0.836 mmol), 2 M sodium hydroxide solution (4 mL), methanol (1.3 mL) and THF (1.3 mL) was stirred at room temperature for 30 min. Water (15 mL) was added and extracted with ethyl acetate (10 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-indol-5-yl)isonicotinic acid (26) (255 mg). The yield was 99.9%.

[0079] The procedure of Step F was the same as that of Step D in Example 1, and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinate (27) was obtained. 1 H NMR(CDCl3,400MHz)δ 8.88(d,J=5.2Hz,1H),8.44(d,J=1.6Hz,1H),8.36(s,1H),8.11(dd,J=1.6,8.8Hz,1H),7.78-7.77 (m,2H),7.57(d,J=8.8Hz,1H),5.19(s,2H),4.80-4.73(m,1H),2.30(s,3H),1.61(d,J=6.4Hz,6H). MS(ESI,m / z):418.2[M+H] + .

[0080] Example 18: Synthesis of {1-[(ethoxycarbonyl)oxy]}ethyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinate (28) [ka] The procedure for synthesizing compound 28 using compound 26 and 1-chloroethyl ethyl carbonate as raw materials was as described in Example 7. 1 H NMR(CDCl3,400MHz)δ 8.86(d,J=4.8Hz,1H),8.44(d,J=1.6Hz,1H),8.36(s,1H),8.09(dd,J=1.6,8.8Hz,1H),7.80-7.78(m,2H),7.56(d,J=8.8Hz,1H),7 .09(q,J=5.2Hz,1H),4.80-4.73(m,1H),4.26(q,J=7.2Hz,2H),1.72(d,J=5.6Hz,3H),1.61(d,J=6.8Hz,6H),1.34(t,J=7.2Hz,3H). MS(ESI,m / z):422.4[M+H] + .

[0081] Example 19: Synthesis of [4-(nitrooxy)]butyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate (30) [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-hydroxy)butyl nitrate (29) (400 mg) in a yield of 57.5%.

[0082] The procedure of Step B was the same as in Example 4, and 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate [4-(nitrooxy)]butyl ester (30) was obtained. 1 H NMR(DMSO-d6,400MHz)δ 9.22(s,1H),8.57(s,1H),8.20(d,J=1.6Hz,1H),8.16(s,1H),7.95-7.89(m,2H),4.96-4.89( m,1H),4.61(t,J=6.0Hz,2H),4.28(t,J=6.0Hz,2H),1.87-1.78(m,4H),1.51(d,J=6.8Hz,6H). MS(ESI,m / z):412.5[M+H] + .

[0083] Example 20: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate [3-(nitrooxy)methyl]phenyl (32) [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, 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-hydroxy)benzyl nitrate (31) (230 mg). The yield was 50.9%.

[0084] The procedure of Step B was the same as in Example 4 to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylate [3-(nitrooxy)methyl]phenyl (32). 1 H NMR(DMSO-d6,400MHz)δ 9.49(s,1H),8.58(s,1H),8.36(s,1H),8.27(s,1H),7.98-7.94(m,2H),7.57-7.53 (m,1H),7.44-7.35(m,3H),5.64(s,2H),4.97-4.90(m,1H),1.52(d,J=6.4Hz,6H). MS(ESI,m / z):446.1[M+H] + .

[0085] Example 21: Experimental study on the treatment of hyperuricemia in rats with compounds 1. Experimental Materials (1) Test drug Both compounds 30 and 32 were almost white powders, and were ground with 0.5% CMC-Na immediately before use to prepare a 0.4 mg / mL suspension for intragastric administration.

[0086] 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.

[0087] (2) Animals and their care a. Animal species and source Thirty Sprague Dawley (SD) rats, SPF males, weighing 230-250 g, were purchased from Shanghai SCXK Laboratory Animal Co., Ltd., with production permit number SCXK(Hu)2022-0004 and quality certificate number 20220004017238.

[0088] 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.

[0089] 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".

[0090] The bedding material was sterilized granular bedding material and was purchased from Jiangsu Cooperative Pharmaceutical Bio-Engineering Co., Ltd.

[0091] Drinking water was provided by drinking purified water, which was then acidified and then allowed to be drunk ad libitum.

[0092] (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.

[0093] (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.

[0094] 2. Experimental Method (1) Grouping Thirty 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 five groups, with six rats per group: (1) normal group (0.5% CMC-Na), (2) model group (0.5% CMC-Na), (3) febuxostat 2 mg / kg, (4) compound 30 2 mg / kg, and (5) compound 32 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.

[0095] (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.

[0096] (3) Data processing and statistical methods All measurement data from each experiment are reported as (mean value) ± 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 being an indicator of significance and P<0.01 being an indicator of high significance.

[0097] 3. Experimental Results 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<0.01). Compared with the model group at the same time point, febuxostat was able to significantly lower the serum uric acid level after modeling (P<0.01). Compared with the model group at the same time point, compound 30 and compound 32 were able to significantly lower the serum uric acid level after modeling (P<0.01 or P<0.05). The results are shown in Table 1. [Table 1]

[0098] Example 22: In vivo pharmacokinetic study of compound 11 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.

[0099] 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.

[0100] 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.

[0101] (2) Laboratory animals The rats were SPF males, 6 to 8 weeks old, purchased from JH Laboratory Animal Co.LTD with permit number SCXK(SH)2022-0009 and pass certificate number 20220009004139.

[0102] 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 2 below. [Table 2]

[0103] (2) Operation procedure Before administration and 5 minutes (intravenous administration group only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 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.

[0104] (3) Pharmacokinetic analysis Non-compartmental model related parameters were calculated with the software WinNonlin® Professional.

[0105] 3. Experimental Results The pharmacokinetic parameters of the test compounds obtained by the above method in SD rats are shown in Table 3. The compounds of the examples of the present invention have good pharmacokinetic parameters and high bioavailability. [Table 3]

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 １～４ Alkyl group, haloC １～４ Alkyl group, nitrooxy-substituted C １～４ Alkyl group or C １～４ alkoxy groups, and R ２ Group C ４～１６ The condensed heteroaromatic ring group does not include an indazolyl group. R ３ is hydrogen or C １～６ It is an alkyl group.

2. 2. The compound according to claim 1, which is a compound selected from the group consisting of compounds represented by 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 is a heterocycloalkyl group, Here, 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 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; Here, 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 compound according to claim 3, 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 ２～１２ 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, a quinolinylpyrazolylcarbonyloxy group, an isoquinolinylpyrazolylcarbonyloxy group, an indolylpyrazolylcarbonyloxy group, a benzofurylpyrazolylcarbonyloxy group, a purinylpyrazolylcarbonyloxy group, a quinolinylpyridinylcarbonyloxy group, an isoquinolinylpyridinylcarbonyloxy group, an indolylpyridinylcarbonyloxy group, a benzofurylpyridinylcarbonyloxy group, a purinylpyridinylcarbonyloxy 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 １～４ Alkyl group, haloC １～４ Alkyl group, nitrooxy-substituted C １～４ Alkyl group 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.

7. R ２ is hydrogen, a nitrooxy group, a carboxy group, or a substituted or unsubstituted dioxol-2-one 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 １～４ Alkyl group, nitrooxy-substituted C １～４ Alkyl group or C １～４ 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】

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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