Compounds useful for gout

Abstract

The application discloses a compound capable of treating gout, which is a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof, and the compound can reduce the serum uric acid level of a hyperuricemia rat model, and has potential application values in anti-gout drugs, anti-hyperuricemia drugs and the like.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of compounds that can be used for gout. Background Technology

[0002] Gout is a metabolic disease caused by increased uric acid production and / or decreased uric acid excretion, leading to elevated serum uric acid (SUA) levels. This results in the formation of monosodium urate crystals that deposit in joints, surrounding tissues, and kidneys, causing an inflammatory response and morphological changes in the joints. Gout is the most common inflammatory joint disease in adult men, and its prevalence is on the rise in developed countries, making it a serious metabolic disease threatening human health.

[0003] Currently, there are over 55 million gout patients worldwide, and the number of hyperuricemia patients far exceeds 200 million. In the past two decades, with the improvement of people's living standards and changes in dietary structure, the excessive intake of high-purine foods has led to a significant increase in the number of hyperuricemia and gout patients, and the gout market has shown a trend of substantial growth. Data shows that the global gout drug market was worth 15.65 billion in 2018 and is expected to reach 36.15 billion in 2025. Gout is often associated with a variety of diseases such as hypertension, obesity, cardiovascular disease, diabetes and chronic kidney disease. These comorbidities make the treatment of gout more complicated and increase the risk of premature death (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). Severe gout patients may experience joint disability and kidney failure, which seriously affects their quality of life and health.

[0004] Xanthine oxidase (XO) is an important target for drug treatment of hyperuricemia and gout. It catalyzes the oxidation of hypoxanthine and xanthine to xanthine and uric acid, respectively. Inhibiting XO can reduce uric acid synthesis, thereby lowering serum uric acid concentration. With the application of technologies such as the analysis of xanthine oxidase crystal structure, computer-aided drug design, and high-throughput screening, many XO inhibitors have emerged in recent years. Patent CN102574839A discloses a new class of compounds as xanthine oxidase inhibitors, among which the candidate compound LC350189 is under development and in Phase II clinical trials. Phase II clinical studies have also demonstrated its sufficient efficacy in reducing superalbuminuria (sUA). However, only three drugs (allopurinol, febuxostat, and tobistat) have been approved for marketing so far, and there are still issues regarding the efficacy or safety of drugs in clinical trials.

[0005] Prodrug strategy is an effective drug design method that modifies known biologically active drug molecules with certain drawbacks by adding precursor groups to form chemical substances that can be activated in vivo by enzymes or chemical reactions. Prodrugs typically lack physiological activity or have very low activity, but can be converted into physiologically active drugs through enzymatic or non-enzymatic hydrolysis. Compared to the parent drug, prodrugs not only maintain or enhance the efficacy of the parent drug but also overcome its drawbacks, improving its clinical efficacy. Prodrugs can be used to increase drug solubility, improve bioavailability, and enhance delivery and pharmacokinetic properties. Currently, nearly 10% of drugs on the global market are prodrugs, and in 2008 alone, approximately 30% of small molecule drugs were prodrugs. For example, angiotensin-converting enzyme inhibitors such as enalapril, benazepril, and ramipril are hydrolyzed in vivo to produce their corresponding dicarboxylic acid metabolites, thereby exerting their antihypertensive effects. Some statin lipid-lowering drugs, such as lovastatin and simvastatin, are prodrugs with cyclic structures, which only exhibit hydroxymethylglutaryl-CoA reductase inhibitory activity after undergoing a ring-opening reaction. Proton pump inhibitors such as omeprazole, lansoprazole, and emeprazole all require the acidic environment of the stomach to be activated. The antihistamine loratadine undergoes deformate ethyl esterification in vivo to produce its active metabolite, desloratadine. In addition, many new prodrugs are under development. However, in actual research and development, prodrug compounds still suffer from numerous problems, such as loss of activity or poor activity, and the designed prodrug compounds not matching the designed target effects. Summary of the Invention

[0006] The purpose of this invention is to provide a compound with xanthine oxidase inhibitory activity.

[0007] Another object of the present invention is to provide the use of the above-mentioned compounds in the pharmaceutical field.

[0008] The objective of this invention can be achieved through the following measures:

[0009] Compounds of general formula (I) or pharmaceutically acceptable salts thereof,

[0010]

[0011] in,

[0012] R is C 1-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic or substituted C 3-6 Heterocyclic alkyl groups; wherein the substituents in the groups involved in R are selected from deuterium, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl or C 3-6 One or more of heterocyclic alkyl groups;

[0013] Ar can be a substituted or unsubstituted group of the following: The substituents in the Ar group are selected from deuterium, hydroxyl, halogen, and C. 1-4 Alkyl or C 1-4 One or more of the alkoxy groups;

[0014] Y is O or NR 3 ,

[0015] R 1 For connecting bonds, or substitutions or non-substitutions of C 1-6 Alkylene or substituted or unsubstituted C 2-12 Ideonyl, R 1 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl or C 1-4 One or more of the alkoxy groups;

[0016] R 2 It is hydrogen, nitrooxy, carboxyl, or a substituted or unsubstituted group of the following: dioxacyclopenten-2-one, C 4-12 Dense aromatic ring groups, C 4-16 Dense aromatic ring pyrazolyl carbonyloxy group, C 4-16 Dense aromatic ring pyridyl carbonyloxy group, C 4-16 Dense aromatic ring triazolyl carbonyloxy group, C 2-6 Ester group, pyridyl group, phenyl group, C 1-6 Alkoxy, C 2-20 alkenyl, C 2-20 alkynyl group, C 2-8 alkyl carbonyloxy or C 2-8 Alkoxycarbonyloxy, R 2The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 C substituted with alkyl or nitrooxy 1-4 Alkyl or C 1-4 One or more of the alkoxy groups; and R 2 C in the group 4-16 The fused aromatic ring group does not contain an indazole group;

[0017] R 3 It is hydrogen or C 1-6 alkyl.

[0018] In a preferred embodiment, Ar is a substituted or unsubstituted group of the following: The asterisk (*) indicates the connection site with C=O.

[0019] In a preferred embodiment, the compound is selected from compounds represented by general formula (II), (III) or (IV).

[0020]

[0021] In a preferred embodiment, Y is either O or NH.

[0022] In a preferred embodiment, R is C. 3-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic or substituted C 3-6 Heterocyclic alkyl groups; wherein the substituents in the groups involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 Alkyl, C 1-5 Alkoxy or C 3-6 One or more of the cycloalkyl groups.

[0023] In a preferred embodiment, R is C. 3-6 Alkyl, substituted C 1-6 Alkyl, C 3-6 cycloalkyl, substituted C 3-6 Cycloalkyl, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrothiophene, substituted tetrahydrothiophene, tetrahydropyrrole, or substituted tetrahydropyrrole; wherein the substituents in the groups involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 Alkyl, C 1-5 Alkoxy or C 3-6 One or more of the cycloalkyl groups.

[0024] In a preferred embodiment, R is C. 3-6 Alkyl, substituted C 1-3 Alkyl, C3-6 cycloalkyl or substituted C 3-6 The cycloalkyl group, with the substituent in the R group selected from deuterium, halogen, or C... 3-6 Cycloalkyl.

[0025] In a preferred embodiment, R is C. 3-6 Alkyl or C 3-6 Cycloalkyl.

[0026] In a preferred embodiment, R is n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, or cyclopentyl.

[0027] In a preferred embodiment, R 1 For connecting bonds, or substitutions or non-substitutions of C 1-4 Alkylene or substituted or unsubstituted C 2-12 Ideonyl, R 1 The substituents in the group are selected from deuterium, amino, cyano, halogen, or C. 1-4 One or more of the alkoxy groups.

[0028] In a preferred embodiment, R 2 The group is hydrogen, nitrooxy, carboxyl, or substituted or unsubstituted of the following groups: dioxacyclopenten-2-one, indazole, quinolinyl, isoquinolinyl, indole, benzofuranyl, purine, quinolinylpyrazolylcarbonyloxy, isoquinolinylpyrazolylcarbonyloxy, indoleylpyrazolylcarbonyloxy, benzofuranylpyrazolylcarbonyloxy, purineylpyrazolylcarbonyloxy, quinolinylpyridinylcarbonyloxy, isoquinolinylpyridinylcarbonyloxy, indoleylpyridinylcarbonyloxy, benzofuranylpyridinylcarbonyloxy, purineylpyridinylcarbonyloxy, quinolinyltriazolylcarbonyloxy, isoquinolinyltriazolylcarbonyloxy, indoleyltriazolylcarbonyloxy, benzofuranyltriazolylcarbonyloxy, purineyltriazolylcarbonyloxy, C 2-6 Ester group, pyridyl group, phenyl group, C 1-6 Alkoxy, C 6-20 alkenyl, C 6-20 alkynyl group, C 2-8 alkyl carbonyloxy or C 2-8 Alkoxycarbonyloxy, R 2 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 C substituted with alkyl or nitrooxy 1-4 Alkyl or C 1-4 One or more of the alkoxy groups.

[0029] In a preferred embodiment, R 2The group is hydrogen, nitrooxy, carboxyl, or substituted or unsubstituted of the following groups: dioxacyclopenten-2-keto, indolepyrazolylcarbonyloxy, indolepyridylcarbonyloxy, indoletriazolylcarbonyloxy, C 2-6 Ester group, pyridyl group, phenyl group, C 1-6 Alkoxy, C 6-20 alkenyl, C 2-8 alkyl carbonyloxy or C 2-8 Alkoxycarbonyloxy, R 2 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 Alkyl, Halogenated C 1-4 C substituted with alkyl or nitrooxy 1-4 Alkyl or C 1-4 One or more of the alkoxy groups.

[0030] In a preferred embodiment, R 2 It is hydrogen, nitrooxy, carboxyl, or a substituted or unsubstituted group of the following: dioxacyclopenten-2-keto, indolylpyrazolylcarbonyloxy, indolylpyridinylcarbonyloxy, C 2-4 Ester group, phenyl group, C 1-4 Alkoxy, C 6-14 alkenyl, C 2-8 alkyl carbonyloxy or C 2-8 Alkoxycarbonyloxy, R 2 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-4 C substituted with alkyl or nitrooxy 1-4 Alkyl or C 1-4 One or more of the alkoxy groups.

[0031] In a preferred embodiment, the compounds of the present invention are selected from:

[0032]

[0033] The present invention also includes a pharmaceutical composition which uses the compound involved in this application or a pharmaceutically acceptable salt thereof as the active substance, supplemented with pharmaceutically acceptable excipients.

[0034] The compounds of the present invention or their pharmaceutically acceptable salts can be used in the preparation of xanthine oxidase inhibitor drugs, particularly in the preparation of anti-gout drugs or anti-hyperuricemia drugs.

[0035] Unless otherwise explicitly defined, all groups referred to in this invention have the following meanings:

[0036] "H" refers to hydrogen, specifically protium (1H), which is the main stable isotope of hydrogen.

[0037] "D", or "deuterium", refers to a stable isotope of hydrogen, also known as heavy hydrogen, and its element symbol is D.

[0038] "Halogen" refers to fluorine, chlorine, bromine, or iodine atoms.

[0039] "Hydroxy group" refers to the -OH group.

[0040] "Amino" refers to the -NH2 group.

[0041] "Alkyl" refers to a saturated aliphatic hydrocarbon group containing 1-10 carbon atoms, including straight-chain and branched groups (the numerical range mentioned in this application, such as "1-10," refers to the group, which is an alkyl group and can contain 1, 2, 3, etc., up to 10 carbon atoms). Alkyl groups containing 1-4 carbon atoms are called lower alkyl groups. When a lower alkyl group has no substituents, it is called an unsubstituted lower alkyl group. The alkyl group can be C10 or C20. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-3 Alkyl, C 2-4 Alkyl groups, etc. Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl. Alkyl groups can be substituted or unsubstituted.

[0042] "Alkenyl" refers to a hydrocarbon group containing 2-30 carbon atoms and having one or more "C=C" chains, including straight-chain and branched groups (the numerical range mentioned in this application, such as "2-10", refers to the group, which is an alkenyl group and can contain 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). The alkenyl group can be C... 2-20 alkenyl, C 2-18 alkenyl, C 2-16 alkenyl, C 2-14 alkenyl, C 2-12 alkenyl, C 4-14 alkenyl, C 412 Alkenyl groups, etc. Specific alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutylenyl, tert-butylenyl, etc. wait.

[0043] "Alkoxy" represents both -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, and further represents -O- (unsubstituted alkyl). The alkyl group can be C10 or C20. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C2-3 Alkyl, C 2-4 Alkyl groups, etc. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, etc.

[0044] "Dioxacyclopenten-2-one" is Group.

[0045] "Pyrazolyl" refers to Any one of them.

[0046] "Triazolyl" includes 1,2,3-triazolyl, where "1,2,3-triazolyl" refers to...

[0047] "Fused aromatic ring group" refers to an aromatic group containing two or more fused rings and heteroatoms, including but not limited to indazolyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl, purinyl, acridineyl, etc.

[0048] "Carboxyl group" refers to the -COOH group.

[0049] "Ester group" refers to the "-C(=O)-O-alkyl" group, where the alkyl group can be C. 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C 2-3 Alkyl, 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 is replaced by one substituent, or in which multiple hydrogen atoms in an ester group are replaced by the same or different substituents.

[0050] "Heterocyclic alkyl" refers to a saturated cyclic group containing 3-10 ring atoms, wherein the ring atoms contain one or more heteroatoms selected from N, O, and S. The numerical range mentioned in this application, such as "3-6," means that the group, in this case, is a heterocyclic alkyl group and can contain 3, 4, 5, or even 6 carbon atoms as ring atoms. The heterocyclic alkyl group can be C... 3-8 Heterocyclic alkyl, C 3-6 Heterocyclic alkyl, C 3-5 Heterocyclic alkyl, C 3-4 Heterocyclic alkyl, C 3-9 Heterocyclic alkyl, C 4-6Heterocyclic alkyl groups, etc. Specific alkyl groups include, but are not limited to, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, 1,4-dioxane, oxospiro[3,3]heptyl, oxospiro[4,4]nonyl, oxospiro[5,5]undecyl, oxospiro[6,6]trideyl, oxobicyclo[1,1,1]pentyl, oxobicyclo[2,2,2]octyl, oxobicyclo[3,2,1]octyl, azeospiro[3,3]heptyl, azeospiro[4,4]nonyl, azeospiro[5,5]undecyl, azeospiro[6,6]trideyl, azeobicyclo[1,1,1]pentyl, azeobicyclo[2,2,2]octyl, or azeobicyclo[3,2,1]octyl, etc. Heterocyclic alkyl groups can be substituted or unsubstituted.

[0051] “C 4-16 "Dysfunctional aromatic ring pyrazolyl carbonyloxy group" refers to a -OC(=O)-pyrazolyl-dysfunctional aromatic ring group containing 4-16 carbon atoms. A specific example includes indolepyrazolyl carbonyloxy group.

[0052] “C 2-8 "Alkoxycarbonyloxy" refers to an -OC(=O)-O-alkyl group containing 2-8 carbon atoms.

[0053] “C 4-16 "Dysfunctional aromatic ring pyridyl carbonyloxy group" refers to a -OC(=O)-pyridyl-dysyl-dysyl group containing 4-16 carbon atoms. A specific example is indolepyridyl carbonyloxy group.

[0054] “C 4-16 "Dysfunctional aromatic ring triazole carbonyloxy group" refers to a -OC(=O)-triazole-dysfunctional aromatic ring group containing 4-16 carbon atoms. A specific example is indole-triazole carbonyloxy group.

[0055] A "linking bond" refers to a group whose two ends are directly connected by a covalent bond. Taking the group fragment YR as an example... 1 -R 2 For example, when R 1 When it is a linker bond, the fragment of this group is YR. 2 .

[0056] "Nitrooxy group" refers to the -ONO2 group.

[0057] "Pharmaceutically acceptable salts" are salts formed from compounds of general formula (I) and organic or inorganic acids, representing those salts that retain the bioavailability and properties of the parent compound. These salts include, but are not limited to:

[0058] (1) It forms salts with acids by reacting the free base of the parent compound with inorganic or organic acids. Inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc., and organic acids include (but are not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-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, etc.

[0059] (2) Salts formed by replacing acidic protons in the parent compound with metal ions or by coordination with organic bases. Metal ions include alkali metal ions, alkaline earth metal ions or aluminum ions, and organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.

[0060] "Pharmaceutical composition" refers to one or more compounds described herein, or pharmaceutically acceptable salts and prodrugs thereof, mixed with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0061] The present invention further claims protection for pharmaceutical compositions comprising any of the compounds described above, their pharmaceutically acceptable salts or their readily hydrolyzable prodrugs, and other pharmaceutically active ingredients.

[0062] This invention also includes any of the aforementioned compounds and their pharmaceutically acceptable salts, which can be formulated into any clinically or pharmaceutically acceptable dosage form using methods known in the art. For oral administration, they can be formulated into conventional solid dosage forms, such as tablets, capsules, pills, granules, etc.; or into oral liquid dosage forms, such as oral solutions, oral suspensions, syrups, etc. When formulating oral dosage forms, suitable fillers, binders, disintegrants, lubricants, etc., can be added. For parenteral administration, they can be formulated into injectable preparations, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When formulating injectable preparations, conventional methods in the existing pharmaceutical field can be used. When formulating injectable preparations, excipients may not be added, or suitable excipients may be added depending on the properties of the drug.

[0063] The compounds provided by this invention can significantly reduce serum uric acid levels in a rat model of hyperuricemia, and have potential application value in anti-gout drugs and anti-hyperuricemia drugs. Because febuxostat is associated with severe sudden cardiac death, severe nephrotoxicity, and hepatotoxicity, the compounds provided by this invention may have certain advantages in reducing drug toxicity and possess good prospects for drug development. Detailed Implementation

[0064] The present invention will be further described below with reference to the embodiments, but the scope of protection of the present invention is not limited to the following embodiments.

[0065] Example 1: Synthesis of methyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl) ester (4)

[0066]

[0067] Step A: A mixture containing 5-bromo-1H-indole-3-carboxynitrile (10.0 g, 45.2 mmol), isopropane iodoformane (30.8 g, 181 mmol), cesium carbonate (29.5 g, 90.5 mmol), and acetonitrile (100 mL) was stirred at 80 °C for 3 hours. After cooling to room temperature, insoluble matter was removed by filtration. The filter cake was washed with ethyl acetate (200 mL). The solvent was removed under reduced pressure, and the product was purified by column chromatography (200–300 mesh silica gel, elution with ethyl acetate:petroleum ether = 1:15–1:3) to give 5-bromo-1-isopropyl-1H-indole-3-carboxynitrile (1) (11.6 g). The yield was 97.5%.

[0068] 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. After cooling to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed 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). The yield was 83.6%.

[0069] Step C: A mixture containing compound 2 (600 mg, 1.86 mmol), 2M sodium hydroxide solution (12 mL), methanol (4 mL), and THF (4 mL) was stirred at 30 °C for 1 hour. Part of the solvent was removed by vacuum distillation, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The product was in the aqueous phase. The pH of the aqueous phase was adjusted to 4–5 with 2M citric acid solution. The mixture was filtered, and the filter cake was recrystallized from 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%.

[0070] Step D: A mixture containing compound 3 (150 mg, 0.510 mmol), 4-chloromethyl-5-methyl-1,3-dioxacyclopenten-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 overnight at room temperature. Water (20 mL) was added, and the mixture was filtered. The filter cake was purified by column chromatography (200–300 mesh silica gel, eluted with dichloromethane) to give methyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl) ester (4). 1 HNMR (DMSO-d6, 400MHz) δ9.30 (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] + .

[0071] Example 2: Synthesis of bis[1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid]prop-1,3-diester (5)

[0072]

[0073] 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 hours. Water (20 mL) was added, and the mixture was filtered. The filter cake was purified by column chromatography (200–300 mesh silica gel, dichloromethane:petroleum ether = 1:1 elution) to give bis[1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid]prop-1,3-diester (5) (59.4 mg). The yield was 37.1%. 1H NMR (DMSO-d6, 400MHz) δ9.19 (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] + .

[0074] Example 3: Synthesis of [1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl ester (6)

[0075]

[0076] A mixture containing compound 3 (70 mg, 0.238 mmol), L-valine methyl ester 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 overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated brine (15 mL × 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200–300 mesh silica gel, petroleum ether:dichloromethane:triethylamine = 200:100:1 elution) to give [1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carbonyl]-L-valine methyl ester (6) (78.5 mg). The yield was 80.9%. 1 H NMR (DMSO-d6, 400MHz) δ9.16 (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), 4.95-4.8 9 (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] + .

[0077] 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)

[0078]

[0079] 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 overnight at room temperature. Insoluble matter was removed by filtration, and the filter cake was washed with dichloromethane (5 mL). The solvent was removed under reduced pressure, and the product was purified by column chromatography (200–300 mesh silica gel, petroleum ether:dichloromethane:triethylamine = 300:100:1 elution) 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) δ9.22 (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), 4.95 -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] + .

[0080] 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)

[0081]

[0082] The experimental procedure for synthesizing compound 8 using compound 3 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as raw materials is described in Example 4. 1H NMR (DMSO-d6, 400MHz) δ9.20 (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] + .

[0083] 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-oxobut-2-yl] ester (10)

[0084]

[0085] Step A: A mixture containing compound 3 (120 mg, 0.408 mmol), Boc-L-threonine methyl ester (114 mg, 0.489 mmol), DCC (168 mg, 0.814 mmol), and dichloromethane (4 mL) was stirred overnight at room temperature. Insoluble matter was removed by filtration, and the filter cake was washed with dichloromethane (5 mL). The solvent was removed under reduced pressure, and the product was purified by column chromatography (200–300 mesh silica gel, petroleum ether:dichloromethane:triethylamine = 300:100:1 elution) to give 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [(2R,3S)-3-(Boc-amino)-4-methoxy-4-oxobut-2-yl] ester (9) (218 mg). The yield was 100%.

[0086] Step B: A solution of compound 9 (218 mg, 0.427 mmol) and trifluoroacetic acid (0.4 mL) in dichloromethane (4 mL) was stirred overnight at room temperature. Water (20 mL) was added, and the pH was adjusted to 7–8 with saturated sodium bicarbonate solution. Extraction was performed with dichloromethane (20 mL × 2), and the combined organic phases were washed with saturated brine (10 mL × 2) and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the product was recrystallized from 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-oxobut-2-yl] ester (10). 1H NMR (DMSO-d6, 400MHz) δ9.23 (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] + .

[0087] Example 7: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid {1-[(ethoxycarbonyl)oxy]}ethyl ester (11)

[0088]

[0089] 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 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed successively with water (10 mL × 2) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The solvent was removed 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-carboxylic acid {1-[(ethoxycarbonyl)oxy]}ethyl ester (11) (51 mg). The yield was 36.5%. 1 H NMR (DMSO-d6, 400MHz) δ9.31 (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] + .

[0090] Example 8: Synthesis of ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (2-acetoxy) ester (12)

[0091]

[0092] The experimental procedure for synthesizing compound 12 using compound 3 and ethylene glycol monoacetate as raw materials is described in Example 4. 1 HNMR (DMSO-d6, 400MHz) δ9.25 (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] + .

[0093] Example 9: Synthesis of ethyl (2-methoxy)-1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (13)

[0094]

[0095] The experimental procedure for synthesizing compound 13 using compound 3 and ethylene glycol monomethyl ether as raw materials is described in Example 4. 1 HNMR (DMSO-d6, 400MHz) δ9.23 (s, 1H), 8.58 (s, 1H), 8.22 (d, J = 2.0Hz, 1H), 8.15 (s, 1H), 7.96-7.89 (m, 2 H), 4.96-4.89 (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] + .

[0096] Example 10: Synthesis of cinnamyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (14)

[0097]

[0098] The experimental procedure for synthesizing compound 14 using compound 3 and cinnamyl alcohol as raw materials is described in Example 4. 1H NMR (DMSO-d6, 400MHz) δ9.29 (s, 1H), 8.57 (s, 1H), 8.23-8.21 (m, 2H), 7.97-7.90 (m, 2H), 7.52-7.50 (m, 2H) ), 7.38-7.29 (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] + .

[0099] Example 11: Synthesis of ethyl 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid (1-isobutyryloxy) ester (15)

[0100]

[0101] The experimental procedure for synthesizing compound 15 using compound 3 and 1-chloroethyl isobutyrate as raw materials is described in Example 7. 1 H NMR (DMSO-d6, 400MHz) δ9.28 (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] + .

[0102] Example 12: Synthesis of methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl) ester (17)

[0103]

[0104] Using 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid (16) (the experimental procedures for synthesizing compound 16 are described in Examples 2 and 3 of patent CN115160299) and 4-chloromethyl-5-methyl-1,3-dioxane-2-one as raw materials, the experimental procedures for synthesizing compound 17 are described in step D of Example 1. 1H NMR (CDCl3, 400MHz) δ8.56 (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] + .

[0105] Example 13: Synthesis of bis[2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid]prop-1,3-diester (18)

[0106]

[0107] The experimental procedure for synthesizing compound 18 using compound 16 and 1,3-dibromopropane as raw materials is described in Example 2. 1 HNMR (CDCl3, 400MHz) δ8.44 (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] + .

[0108] Example 14: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid {1-[(ethoxycarbonyl)oxy]}ethyl ester (19)

[0109]

[0110] The experimental procedure for synthesizing compound 19 using compound 16 and 1-chloroethyl ethyl carbonate as raw materials is described in Example 7. 1H NMR (CDCl3, 400MHz) δ8.56 (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=5.2Hz, 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] + .

[0111] Example 15: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid (3,7,11-trimethyldodecyl-2,6,10-trien-1-yl) ester (20)

[0112]

[0113] The experimental procedure for synthesizing compound 20 using compound 16 and 3,7,11-trimethyldodecyl-2,6,10-trien-1-ol as raw materials is described in Example 4. 1 H NMR (DMSO-d6, 400MHz) δ8.65 (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] - .

[0114] Example 16: Synthesis of methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid (pyridin-2-yl) ester (21)

[0115]

[0116] 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 overnight at room temperature. Insoluble matter was removed by filtration, and the filter cake was washed with dichloromethane (5 mL). The solvent was removed under reduced pressure, and the product was purified by column chromatography (200–300 mesh silica gel, eluted with dichloromethane) to give methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazol-4-carboxylic acid (pyridine-2-yl) ester (21) (69 mg). The yield was 65.9%. 1 H NMR (CDCl3, 400MHz) δ8.65-8.64 (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, 1 H), 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] + .

[0117] Example 17: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinic acid (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl) methyl ester (27)

[0118]

[0119] Step A: To a mixture containing pinacol 5-indoleboronic acid (7.29 g, 30.0 mmol), methyl 2-bromopyridine-4-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(diphenylphosphine)ferrocene]palladium dichloride (1.09 g, 1.50 mmol) was added. After the addition was complete, the mixture was stirred at 80 °C for 3 hours under nitrogen. Most of the solvent was removed by vacuum distillation, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:5 elution) to give methyl 2-(1H-indol-5-yl)isonicotinic acid (22) (1.30 g). The yield was 17.2%.

[0120] Step B: Cesium carbonate (3.35 g, 10.3 mmol) and iodine (2.62 g, 10.3 mmol) were added to a DMF (25 mL) solution of compound 22 (1.30 g, 5.15 mmol). After the addition was complete, the mixture was stirred overnight at room temperature. Water (60 mL) and 2 M sodium thiosulfate solution (20 mL) were added. The mixture was filtered, and the filter cake was dissolved in ethyl acetate (200 mL). The insoluble matter was removed by filtration and then dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to give methyl 2-(3-iodo-1H-indol-5-yl)isonicotinic acid (23) (1.10 g). Yield: 51.4%. MS (ESI, m / z): 379.1 [M+H] + .

[0121] Step C: A mixture containing compound 23 (1.10 g, 2.91 mmol), potassium carbonate (480 mg, 3.47 mmol), bromoisopropane (530 mg, 4.31 mmol), potassium iodide (100 mg, 0.602 mmol), and DMF (20 mL) was stirred overnight at 60 °C. After cooling to room temperature, water (80 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed successively with water (30 mL × 2) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The solvent was removed 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)isonicotinic acid (24) (600 mg). The yield was 49.1%.

[0122] Step D: The mixture containing compound 24 (600 mg, 1.43 mmol), cuprous cyanide (200 mg, 2.33 mmol), and DMF (6 mL) was stirred overnight at 120 °C. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added, and the mixture was filtered to remove insoluble matter. The layers were separated; the aqueous layer was extracted with ethyl acetate (20 mL × 3), and the combined organic layers were washed successively with water (15 mL × 2) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to give methyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinic acid (25) (267 mg). The yield was 58.5%.

[0123] Step E: The mixture containing compound 25 (267 mg, 0.836 mmol), 2M sodium hydroxide solution (4 mL), methanol (1.3 mL), and THF (1.3 mL) was stirred at room temperature for 30 minutes. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL), with the product in the aqueous phase. The pH of the aqueous phase was adjusted to 5–6 with 2M citric acid solution. Filtration yielded 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinic acid (26) (255 mg). The yield was 99.9%.

[0124] The experimental procedure for step F is the same as step D in Example 1, yielding 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinic acid (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl) methyl ester (27). 1 H NMR (CDCl3, 400MHz) δ8.88 (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] + .

[0125] Example 18: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)isonicotinic acid {1-[(ethoxycarbonyl)oxy]}ethyl ester (28)

[0126]

[0127] The experimental procedure for synthesizing compound 28 using compound 26 and 1-chloroethyl ethyl carbonate as raw materials is described in Example 7. 1 H NMR (CDCl3, 400MHz) δ8.86 (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] + .

[0128] Example 19: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [4-(nitrooxy)]butyl ester (30)

[0129]

[0130] Step A: The mixture containing 4-bromobutylacetate (1.0 g, 5.13 mmol), silver nitrate (1.30 g, 7.65 mmol), and acetonitrile (15 mL) was refluxed and stirred overnight in the dark. After cooling to room temperature, insoluble matter was removed by filtration. Water (60 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and then 2M sodium hydroxide solution (2.5 mL) and methanol (5 mL) were added to the residue. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, petroleum ether:ethyl acetate = 5:1 elution) to give (4-hydroxy)butyl nitrate (29) (400 mg). The yield was 57.5%.

[0131] The experimental procedure for step B is described in Example 4, yielding 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [4-(nitrooxy)]butyl ester (30). 1 H NMR (DMSO-d6, 400MHz) δ9.22 (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] + .

[0132] Example 20: Synthesis of 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [3-(nitrooxy)methyl]phenyl ester (32)

[0133]

[0134] Step A: A mixture containing m-hydroxybenzyl bromide (500 mg, 2.67 mmol), silver nitrate (500 mg, 2.94 mmol) and acetonitrile (5 mL) was stirred in the dark in an ice-water bath for 5 hours. The insoluble matter was removed by filtration. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (silica gel 200 - 300 mesh, eluted with petroleum ether:ethyl acetate = 35:1) to obtain (3-hydroxy)benzyl nitrate (31) (230 mg). The yield was 50.9%.

[0135] For the experimental operation of Step B, see Example 4 to obtain 1-(3-cyano-1-isopropyl-1H-indol-5-yl)-1H-pyrazole-4-carboxylic acid [3-(nitrooxymethyl)phenyl] ester (32). 1 H NMR (DMSO-d6, 400 MHz) δ9.49 (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 = 6.4 Hz, 6H). MS (ESI, m / z): 446.1 [M + H] + .

[0136] Example 21: Experimental study on the treatment of hyperuricemia in rats by the compound

[0137] 1. Experimental materials

[0138] (1) Test drugs

[0139] Both compounds 30 and 32 were off-white powders. Before use, they were ground with 0.5% CMC-Na and formulated into a 0.4 mg / mL suspension for gavage.

[0140] Febuxostat, purchased from Sigma, was ground with 0.5% CMC-Na before use and formulated into a 0.4 mg / mL suspension for gavage.

[0141] (2) Animals and feeding

[0142] a. Animal species and sources

[0143] Sprague Dawley (SD) rats, SPF grade, 30 males, weighing 230 - 250 g, were purchased from Shanghai Slake Experimental Animal Co., Ltd., production license number: SCXK (Shanghai) 2022 - 0004, quality certificate number: 20220004017238.

[0144] b. Feeding conditions

[0145] All rats were housed in individually ventilated cages with an air cleanliness level of 10,000, a laboratory temperature of 26±2℃, a relative humidity of 60% to 80%, an air exchange rate of 10-15 times per hour, and a light cycle of 12 (day) / 12 (night) hours, with 3 rats per cage.

[0146] Feed: Complete pelleted feed for rats, purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., whose quality meets GB14924.1-2001 "General Quality Standard for Compound Feed for Laboratory Animals".

[0147] Bedding material: Sterile granular bedding material, purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd.

[0148] Drinking water: Purified water is available for free consumption after acidification.

[0149] (3) Main instruments and equipment

[0150] The Varioskan LUX multi-functional microplate reader was purchased from Thermo, USA; the BS210S precision electronic balance (0.1mg~10g) was purchased from Sartorius, Germany; the FEJ-200 electronic balance (0.1~200g) was purchased from Fuzhou Fuzhiheng Electronics Co., Ltd.; and the Pacific TII+Genpure XCAD PLUS UV / TOC / UF pure water and ultrapure water system was purchased from Thermo, USA.

[0151] (4) Main reagents

[0152] Uric acid test kit (phosphotungstic acid reduction method), batch number: 20230224, purchased from Nanjing Jiancheng Bioengineering Institute; potassium oxonate, catalog number 00164, batch number T6GKM-TA, purchased from Tokyo Chemical Industry Co., Ltd. (TCI), Japan; sodium carboxymethyl cellulose (CMC-Na), batch number 20170810, chemically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.

[0153] 2. Experimental Methods

[0154] (1) Grouping

[0155] Thirty male SD rats, after one week of acclimatization, weighing approximately 220-240g, were randomly divided into 5 groups of 6 rats each, based on body weight: (1) normal group (0.5% CMC-Na), (2) model group (0.5% CMC-Na), (3) febuxostat 2mg / kg, (4) compound 30, 2mg / kg, and (5) compound 32, 2mg / kg. Each group received a suspension of the corresponding concentration, administered at a volume of 0.5mL / 100g.

[0156] (2) Model establishment, dosing regimen and detection indicators

[0157] After rats were purchased and acclimatized, they were fasted for 12 hours and then injected with potassium oxonate at a dose of 300 mg / kg via intraperitoneal injection to induce uric acid modeling. 0.5 hours after modeling, each group of rats was administered the drug via gavage once. This treatment was repeated for 3 days. On the third day, blood was collected from the retro-orbital venous plexus before potassium oxonate injection and at 1, 3, and 5 hours after potassium oxonate injection. The blood samples were centrifuged at 3500 rpm for 10 minutes, and 30 μL of serum was collected to determine uric acid levels at each time point.

[0158] (3) Data processing and statistical methods

[0159] All experimental measurement data are expressed as mean ± standard deviation. The ANOVA-Dunnett T test was used to examine the significance of intergroup comparisons, with P<0.05 as the significance index and P<0.01 as the extremely significant index.

[0160] 3. Experimental Results

[0161] Compared with the solvent group, the potassium oxonate model group showed significantly higher serum uric acid levels at 1, 3, and 5 hours post-modeling (P<0.01). Compared with the model group at the same time point, febuxostat significantly reduced serum uric acid levels after modeling (P<0.01). Compared with the model group at the same time point, compounds 30 and 32 significantly reduced serum uric acid levels after modeling (P<0.01 or P<0.05). The results are shown in Table 1.

[0162] Table 1. Effect of potassium oxonate administration for 3 days on serum uric acid levels in rats with potassium oxonate-induced hyperuricemia.

[0163]

[0164] ## P<0.01, compared with the solvent group at the same time point; *P<0.05, **P<0.01, compared with the model group at the same time point.

[0165] Example 22: In vivo pharmacokinetic experiment of compound 11 in SD rats

[0166] 1. Experimental Materials

[0167] (1) Test drug

[0168] Preparation of compound stock solution: Weigh appropriate amounts of compound solid powder, add a certain amount of DMSO, and vortex sonicate to obtain a stock solution of 10 mg / mL.

[0169] Preparation of test compounds for gavage: Take an appropriate amount of the compound stock solution, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of physiological saline, mix thoroughly to obtain a 1 mg / mL solution.

[0170] Preparation of test compounds for intravenous injection: Take an appropriate amount of the compound stock solution, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of physiological saline, mix thoroughly to obtain a 0.5 mg / mL solution.

[0171] (2) Laboratory animals

[0172] Male SD rats, SPF grade, 6-8 weeks old. Purchased from JH Laboratory Animal Co.LTD. License No.: SCXK(SH)2022-0009, Certificate No.: 20220009004139.

[0173] 2. Experimental Methods

[0174] (1) Dosage and method of administration

[0175] The experimental animals were fasted overnight before gavage administration, and were given food 4 hours after administration, with free access to water during this period. Each test compound was divided into two groups: an intravenous administration group and an oral administration group. The specific dosage and administration method are shown in Table 2 below.

[0176] Table 2. Dosage and administration method of compound 11 in SD rats

[0177] Group Animal numbers Dosage (mg / kg) Dosage volume (mL / kg) Concentration (mg / mL) route of administration Intravenous administration group 3 1 2 0.5 Intravenous injection Oral administration group 3 10 10 1 oral

[0178] (2) Experimental Operation

[0179] Blood samples (150 μL / sample) were collected from the jugular vein of SD rats before administration and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. The samples were placed in centrifuge tubes containing the anticoagulant sodium heparin and centrifuged at 2000g for 5 minutes at 4°C to separate the plasma. The plasma samples were analyzed by LC / MS / MS to determine the concentration of each test compound.

[0180] (3) Pharmacokinetic analysis

[0181] The relevant parameters of the non-compartment model are provided by Calculated using Professional software.

[0182] 3. Experimental Results

[0183] The pharmacokinetic parameters of the test compounds obtained by the above method in SD rats are shown in Table 3. The pharmacokinetic parameters of the compounds in the examples of this invention are good, and their bioavailability is high.

[0184] Table 3. Pharmacokinetic parameters of each compound administered orally or intravenously in SD rats

[0185]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, 。 2. A pharmaceutical composition comprising, as the active substance, the compound of claim 1 or a pharmaceutically acceptable salt thereof, and supplemented with pharmaceutically acceptable excipients.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an anti-gout drug or an anti-hyperuricemia drug.

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