Xanthine oxidase inhibitor

Abstract

The present invention relates to a xanthine oxidase inhibitor, which is a compound represented by formula (I) or a pharma- ceutical acceptable salt thereof, and has excellent xanthine oxidase inhibitory activity and potential application value in the fields of anti-gout drugs, anti-hyperuricemia drugs and the like. [Formula 1] TIFF2024516040000032.tif1619(I)

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and specifically relates to a compound having an inhibitory effect on xanthine oxidase.

Background Art

[0002] Gout is a disease caused by long-term purine metabolism disorders in the human body, which causes excessive uric acid production and / or uric acid excretion disorders, continuous increase in serum uric acid (sUA) levels, crystallization of sodium urate, and deposition in the body. Its main symptoms include repeated attacks of red, swollen, hot, and painful joints with dysfunction, and furthermore, joint deformity, nephrolithiasis, and uric acid nephropathy.

[0003] In recent years, with the improvement of living standards, people's diet has also changed, and the number of gout patients has increased significantly. Gout has already become the second most common metabolic disease after diabetes. Such diseases have already been regarded as one of the twenty difficult diseases in the 21st century by the United Nations. According to the data of the National Health and Nutrition Examination Survey in the United States, between 2007 and 2008, the prevalence of gout in adults in the United States was 3.9% (about 8.3 million people) (Non-Patent Document 1). According to a Meta-analysis, in China, the overall prevalence of hyperuricemia is 13.3%, and that of gout is 1.1% (Non-Patent Document 2). In the past few decades, due to the prevalence of comorbid diseases promoting hyperuricemia (such as hypertension, obesity, metabolic syndrome, type 2 diabetes, chronic kidney disease), the incidence of gout has gradually increased (Non-Patent Document 3).

[0004] The treatment of gout includes both drug treatment and non-drug treatment. Non-drug treatment is an important component of gout treatment and includes dietary control and lifestyle adjustment (such as diet and exercise). The drug treatment of chronic gout usually focuses on reducing the sUA level (Non-Patent Document 4). Currently, the drugs for gout mainly include three types: anti-acute gouty arthritis drugs, uric acid excretion-promoting drugs, and uric acid production-inhibiting drugs.

[0005] Medications for acute gouty arthritis include, for example, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormones, glucocorticoids, etc. They are mainly used for the treatment of acute gouty arthritis and can relieve the patient's temporary pain. Colchicine is always accompanied by adverse reactions such as diarrhea, vomiting, and abdominal pain cramps. NSAIDs can relieve pain in the short term, but most NSAIDs are accompanied by serious gastrointestinal reactions. Adrenocorticotropic hormones and glucocorticoids can suppress non-infectious inflammation, relieve congestive edema, inhibit inflammatory cell migration, reduce the autoimmune level, and are used for the treatment of patients with severe acute gout accompanied by systemic symptoms. However, such drugs have a strong rebound effect.

[0006] Uricosuric agents mainly include probenecid, lesinurad, and benzbromarone. Such drugs can inhibit the reabsorption of uric acid by renal tubules, act on the uric acid transporters in the proximal renal tubules, thereby inhibiting the reabsorption of uric acid and increasing its excretion, thus reducing the uric acid concentration in the body. Probenecid is the first choice for promoting uricosuric agents in single-drug uric acid reduction therapy in the US guidelines. However, there are multiple significant interactions between it and some commonly used drugs (such as non-steroidal anti-inflammatory drugs, β-lactam antibiotics, heparin, etc.), restricting its application. Lesinurad is a new inhibitor of urate transporter 1 (URAT1) approved by the FDA in 2015, and its drug label warns in a black box that it may cause the risk of acute kidney injury and cardiovascular diseases (which may be life-threatening). Due to the above reasons, lesinurad is not recommended for patients with uncontrolled hypertension, unstable angina pectoris, recent myocardial infarction, or heart failure with a NYHA classification of III-IV. It is prohibited for patients with end-stage renal failure, kidney transplantation, or dialysis (Non-patent Document 5). Benzbromarone is an effective uricosuric agent and has already been marketed in many countries, but it has not been approved in the US yet. Due to severe hepatotoxicity, benzbromarone was withdrawn from the market in a certain European country in 2003, but it is still used for the treatment of gout in some countries. So far, in Japan, Australia, New Zealand, and a certain European country, benzbromarone is regarded as an effective drug and is used for gout patients with hypersensitivity to allopurinol caused by cyclosporine treatment after organ transplantation. Since there are ethnic differences in liver-related adverse events related to benzbromarone, the Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019) recommend benzbromarone as a first-line uric acid reduction drug.

[0007] In the metabolic process of the human body, xanthine oxidase catalyzes the last two steps in the purine metabolic process, oxidizing hypoxanthine to xanthine and xanthine to uric acid. The continuous increase in blood uric acid concentration leads to the occurrence of various diseases including gout. Therefore, xanthine oxidase is closely related to the occurrence of gout. By inhibiting xanthine oxidase, the pathway of purine metabolism into uric acid in the human body can be blocked, effectively reducing the sUA level, and preventing and treating the occurrence and development of gout and hyperuricemia. Compounds with xanthine oxidase inhibitory activity that have already been disclosed include compounds with the structure represented by formula (G) disclosed in Patent Document 1, and compounds with the structure represented by formula (F) disclosed in Patent Document 2 previously filed by the applicant, etc. Currently, such commercially available drugs mainly include allopurinol and febuxostat.

[0008] [Chemical formula]

[0009] Allopurinol is an analogue of hypoxanthine and is recommended as a first-line therapeutic drug for the treatment of chronic gout. However, the therapeutic effect of allopurinol is poor. According to relevant research, even when allopurinol is used at the maximum dose, less than 50% of the subjects reached the treatment endpoint (Non-Patent Document 6). In addition, allopurinol causes rashes including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as other rare but fatal side reactions, with a fatality rate of about 10% - 30% (Non-Patent Document 7). Other side reactions of allopurinol include poor stomach condition, nausea, abdominal pain, diarrhea, leukopenia and thrombocytopenia, headache, fever, loss of appetite, weight loss, pain during urination, hematuria, itching, and drowsiness.

[0010] Febuxostat is a new generation of XOI that can suppress the oxidized and reduced states of xanthine oxidase. However, due to its cardiovascular toxicity (such as the risk of sudden death), the US Food and Drug Administration has required a black box warning on its drug label. Furthermore, in 2019, the prescribing information was adjusted, changing the first-line drug to a second-line drug. In March 2018, the New England Journal of Medicine published the research results of 6,190 gout patients. After an average of 32 months of treatment, the researchers found that the risk of adverse cardiovascular events in the overall febuxostat and allopurinol treatment groups was similar (HR 1.03, 95% CI, 0.87 - 1.23), but the all-cause mortality and cardiovascular disease mortality in the febuxostat group were higher than those in the allopurinol group. The patients in the febuxostat group had a 34% increase in cardiovascular mortality (HR 1.34, 95% CI, 1.03 - 1.73) and a 22% increase in all-cause mortality (HR 1.22, 95% CI, 1.01 - 1.47). Among the causes of cardiovascular death, sudden cardiac death was the most common, with 83 cases (2.7%) in the febuxostat group and 56 cases (1.8%) in the allopurinol group (Non-Patent Document 8). In addition, febuxostat may also cause serious gastrointestinal toxic side effects, kidney toxic side effects, liver function abnormalities, etc.

[0011] So far, xanthine oxidase inhibitors, including allopurinol and febuxostat, have a significant risk of sudden death and various serious toxicity problems in the kidneys, liver, gastrointestinal tract, etc., greatly limiting the use of such drugs, and there are still few types of drugs developed that target xanthine oxidase as an inhibitor.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0013] [Non-Patent Document 1] Zhu Y, Pandya BJ, Choi HK. Prevalence of Gout and Hyperuricemia in the US General Population: The National Health and Nutrition Examination Survey 2007-2008[J]. Arthritis Rheum, 2011, 63(10): 3136-3141 [Non-Patent Document 2] Liu R, Han C, Wu D, et al. Prevalence of hyperuricemia and gout in mainland China from 2000 to 2014: A systematic review and meta-analysis[J]. Biomed Research International, 2015: 1-12 [Non-Patent Document 3] 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 [Non-Patent Document 4] Qaseem A, Harris R, Foricea MA. Clinical Guidelines Committee of the ACP. Management of Acute and Recurrent Gout: A Clinical Practice Guideline from the American College of Physicians[J]. Annalsof Internal Medicine, 2017, 166(1): 58-68 [Non-Patent Document 5] Bardin T, Richette P. Novel uricosurics[J]. Rheumatology, 2018, 57(suppl. 1): i42-i46 [Non-Patent Document 6] Robert M, Douglas CA, Scott B. Less than half of patients treated with high-Dose allopurinol reach serum uric acid target[J]. ACR / ARHP Annual Meeting, 2017, Abstract Number: 1120 [Non-Patent Document 7] Bocquet H, Bagot M, Roujeau JC. Drug-induced pseudolymphoma and drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms: DRESS[J]. Seminars in Cutaneous Medicine and Surgery, 1996, 15(4): 250-257 [Non-Patent Document 8] William B, Kenneth G, Michael A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout[J]. The New England Journal of Medicine, 2018, 378: 1200-1210

Summary of the Invention

Problems to be Solved by the Invention

[0014] An object of the present invention is to provide a compound having xanthine oxidase inhibitory activity based on the prior art.

[0015] Another object of the present invention is to provide the production of the above-mentioned compound and its use in the pharmaceutical field.

Means for Solving the Problems

[0016] The technical solution of the present invention is as follows.

[0017] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

[0018] In the formula, Y is N or C-R 6 ; R 1 is a cyano group, a nitro group or a halogen; R 2 , R 3 or R 4 are each independently hydrogen, deuterium, a cyano group, a halogen, a hydroxyl group, an amino group, a nitro group, C 1-6 alkyl group, substituted C 1-6 alkyl group, C 1-6 alkoxy group or substituted C 1-6 alkoxy group, provided that R 2 , R3 or R 4 The substituents of each group related to are each independently deuterium, a hydroxyl group, a cyano group, a halogen, C 1-4 alkyl group or C 1-4 alkoxy group, and are one or more selected from; R 5 is a C 1-6 alkyl group, a substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, a substituted C 3-6 cycloalkyl group, a C 3-6 heterocycloalkyl group or a substituted C 3-6 heterocycloalkyl group, provided that the substituents of each group related to R 5 are deuterium, a cyano group, a nitro group, a halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 3-6 cycloalkyl group or C 3-6 heterocycloalkyl group, and are one or more selected from; R 6 is hydrogen, deuterium, a halogen, a cyano group, C 1-6 alkyl group, a substituted C 1-6 alkyl group, C 1-6 alkoxy group, a substituted C 1-6 alkoxy group, C 3-6 cycloalkyl group or a substituted C 3-6 cycloalkyl group, provided that the substituents of each group related to R 6 are deuterium, a cyano group, a nitro group, a halogen, C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylthio group or C 3-6 cycloalkyl group, and are one or more selected from; Ar is unsubstituted or substituted 1,2,3-triazole, pyrazolyl, pyridyl or thienyl, provided that the substituents of each group related to Ar are deuterium, a halogen or C 1-3 alkyl group, and are one or more selected from; when Y is C-R 6 Ar is only unsubstituted or substituted 1,2,3-triazole; R7 is a carboxyl group or a C 2-6 ester group.

[0019] In a preferred embodiment, Ar is a substituted or unsubstituted group selected from the following.

Chemical formula

[0020] In a preferred embodiment, Ar is a substituted or unsubstituted group selected from the following, provided that "*" is the bonding site of Ar and the benzene ring.

Chemical formula

[0021] In a preferred embodiment, the substituent of each group related to Ar is one or more selected from deuterium, halogen or C 1-3 alkyl group.

[0022] In a preferred embodiment, R 2 , R 3 or R4 is each independently hydrogen, deuterium, a cyano group or a halogen.

[0023] In a preferred embodiment, R 5 is a C 3-6 alkyl group, a substituted C 1-6 alkyl group, a C 3-6 cycloalkyl group, a substituted C 3-6 cycloalkyl group, a C 3-6 heterocycloalkyl group or a substituted C 3-6 heterocycloalkyl group, provided that the substituent of each group related to R 5 is one or more selected from deuterium, cyano group, nitro group, halogen, C 1-5 alkyl group, C 1-5 alkoxy group or C 3-6 cycloalkyl group.

[0024] In a preferred embodiment, R 5 is C 3-6Alkyl group, substituted C 1-6 Alkyl group, C 3-6 Cycloalkyl group, substituted C 3-6 A cycloalkyl group, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrothiophene, substituted tetrahydrothiophene, pyrrolidine or substituted pyrrolidine, provided that R 5 The substituents of each group for are deuterium, cyano group, nitro group, halogen, C 1-5 Alkyl group, C 1-5 Alkoxy group or C 3-6 Selected from one or more of cycloalkyl groups.

[0025] In a more preferred embodiment, R 5 Is isopropyl, n-butyl group, isobutyl group, cyclopropyl, cyclobutyl, cyclopropylmethyl, tetrahydrofuran, tetrahydrothiophene or pyrrolidine.

[0026] In a preferred embodiment, R 6 Is hydrogen, deuterium, halogen, cyano group or C 1-5 Alkyl group.

[0027] In a preferred embodiment, the compound of the present invention is selected from the following.

Chemical formula

[0028] The present invention further includes a pharmaceutical composition using the compound according to the present application or a pharmaceutically acceptable salt thereof as an active substance and using pharmaceutically acceptable auxiliary components as auxiliary ones.

[0029] The compound of the present invention or a pharmaceutically acceptable salt thereof is used in the manufacture of a xanthine oxidase inhibitor drug, particularly in the manufacture of an anti-gout drug or an anti-hyperuricemia drug.

Mode for Carrying Out the Invention

[0030] Each group described in the present invention has the following meanings unless otherwise specified.

[0031] "H" is hydrogen, referring to protium (1H), which is the main stable isotope of hydrogen.

[0032] "D", or "deuterium", refers to a stable form isotope of hydrogen, also called heavy hydrogen, and its element symbol is D.

[0033] "Halogen" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0034] "Hydroxyl group" refers to the -OH group.

[0035] "Amino group" refers to the -NH2 group.

[0036] "Alkyl group" refers to a saturated aliphatic radical having 1 to 10 carbon atoms, including linear and branched groups (the numerical ranges described in this application, for example, "1-10", mean that this group is an alkyl group at this time, including cases where the number of carbon atoms is 1, 2, 3, etc. up to 10 carbon atoms). An alkyl group containing 1 to 4 carbon atoms is called a lower alkyl group. When a lower alkyl group has no substituent, it is called an unsubstituted lower alkyl group. The alkyl group can be 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 group, etc. can be selected. Specific alkyl groups include, but are not limited to, methyl group, ethyl group, propyl group, 2-propyl group, n-butyl group, isobutyl group or tert-butyl, etc. The alkyl group may be substituted or unsubstituted.

[0037] "Cycloalkyl group" refers to a saturated cyclic aliphatic radical having 3 to 10 carbon atoms. The numerical range described in the present application, for example, "3 - 10", means that this group which is a cycloalkyl group at this time includes cases where the number of carbon atoms of the cyclic atoms is 3, 4, 5, etc. up to 10 carbon atoms. The cycloalkyl group is C 3-8 cycloalkyl group, C 3-6 cycloalkyl group, C 3-5 cycloalkyl group, C 3-4 cycloalkyl group, C 3-9 cycloalkyl group, C 4-6 cycloalkyl group, etc. can be selected. Specific alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. The cycloalkyl group may be substituted or unsubstituted.

[0038] "Heterocycloalkyl group" refers to a saturated cyclic group having 3 to 10 ring atoms, and one or more heteroatoms selected from N, O, and S are included in the ring atoms. The numerical range described in the present application, for example, "3 - 6", means that this group which is a heterocycloalkyl group at this time includes cases where the number of carbon atoms of the ring atoms is 3, 4, 5, etc. up to 6 carbon atoms. The heterocycloalkyl group is C 3-8 heterocycloalkyl group, C 3-6 heterocycloalkyl group, C 3-5 heterocycloalkyl group, C 3-4 heterocycloalkyl group, C 3-9 heterocycloalkyl group, C 4-6A heterocycloalkyl group or the like can be selected. Specific alkyl groups include, but are not limited to, tetrahydrofuran, pyrrolidine, tetrahydrothiophene, 1,4-dioxane, oxaspiro[3.3]heptyl, oxaspiro[4.4]nonyl, oxaspiro[5.5]undecyl, oxaspiro[6.6]tridecyl, oxabicyclo[1.1.1]pentyl, oxabicyclo[2.2.2]octyl, oxabicyclo[3.2.1]octyl, azaspiro[3.3]heptyl, azaspiro[4.4]nonyl, azaspiro[5.5]undecyl, azaspiro[6.6]tridecyl, azabicyclo[1.1.1]pentyl, azabicyclo[2.2.2]octyl or azabicyclo[3.2.1]octyl. The heterocycloalkyl group may be substituted or unsubstituted.

[0039] The "haloalkyl group" refers to an alkyl group in which one, two, three, four or more hydrogens of the alkyl group are substituted with one or more kinds of halogens, among 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 An alkyl group or the like can be selected. It includes, but is not limited to, fluoromethyl group, difluoromethyl group, trifluoromethyl group, monochloromethyl group, dichloromethyl group, trichloromethyl group, monobromomethyl group, fluoroethyl group, difluoroethyl group, trifluoroethyl group, etc.

[0040] The "alkoxy group" represents -O-(unsubstituted alkyl group) and -O-(unsubstituted cycloalkyl group), and further represents -O-(unsubstituted alkyl group). 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 2-4An alkyl group or the like can be selected. Representative examples include, but are not limited to, a methoxy group, ethoxy, propoxy, cyclopropyloxy, and the like.

[0041] The "alkylthio group" refers to an -S-(unsubstituted alkyl group) and an -S-(unsubstituted cycloalkyl group), and further refers to an -S-(unsubstituted alkyl group). 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 An alkyl group or the like can be selected. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, cyclopropylthio, and the like.

[0042] The "cyano group" refers to a -CN group.

[0043] The "nitro group" refers to a -NO2 group.

[0044] The "carboxyl group" refers to a -COOH group.

[0045] "1,2,3-triazole" refers to

Chemical formula

[0046] "Pyrazole" refers to

Chemical formula

[0047] "Thiophene" refers to

Chemical formula

[0048] The "ester group" refers to the group of "-C(=O)-O-alkyl group", and 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. can be selected. Representative examples include, but are not limited to, methyl formate, ethyl formate, n-propyl formate, isopropyl formate, etc. A substituted ester group means that the hydrogen in the ester group is substituted by a substituent, or a plurality of hydrogens in the ester group are each substituted by the same or different substituents.

[0049] The "pharmaceutically acceptable salt" is a salt composed of the compound of formula (I) and an organic acid or an inorganic acid, and is a salt that retains the biological effectiveness and properties of the parent compound. These salts include, but are not limited to, the following.

[0050] (1) A salt with an acid, which is obtained by the reaction of the free alkali of the parent compound with an inorganic acid or an organic acid. Inorganic acids include, but are not limited to, for example, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, and perchloric acid. Organic acids include, but are not limited to, for example, 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, ethylsulfonic acid, naphthyl-1-sulfonic acid, naphthyl-2-sulfonic acid, paratoluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, or malonic acid.

[0051] (2) Those in which the acidic protons present in the parent compound are replaced by metal ions or salts formed with organic alkali complex compounds. Examples of the metal ions include alkali metal ions, alkaline earth metal ions, or aluminum ions, and examples of the organic alkali include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, and the like.

[0052] "Pharmaceutical composition" refers to one or more of the compounds described herein, or pharmaceutically acceptable salts and prodrugs thereof, and other chemical components, and examples include mixtures of pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0053] The present invention further intends to protect a drug composition containing any of the above-described compounds, pharmaceutically acceptable salts thereof, or prodrugs thereof that are easily hydrolyzable, and other pharmaceutically active ingredients.

[0054] The present invention further includes any of the above-described compounds and pharmaceutically acceptable salts thereof, and can be used in any clinically or pharmaceutically acceptable dosage form prepared by known methods in the art. When used for oral administration, it can be prepared into ordinary solid preparations, such as tablets, capsules, pills, granules, and the like. It can also be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, and the like. When preparing oral preparations, appropriate fillers, adhesives, disintegrants, lubricants, and the like can be added. When used for parenteral administration, it can be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When preparing injections, it can be prepared by methods commonly used in the conventional pharmaceutical field. When preparing injections, additives may not be added, or appropriate additives may be added depending on the properties of the drug.

[0055] The compounds provided by the present invention have excellent xanthine oxidase inhibitory activity, and they can significantly reduce the serum uric acid level in a hyperuricemia mouse model, having potential application value in aspects such as anti-gout drugs and anti-hyperuricemia drugs. Since febuxostat has serious sudden cardiac death, serious kidney toxicity and liver toxicity, the compounds provided by the present invention have certain advantages in reducing drug toxicity and have good prospects for drug development.

Example

[0056] The detection method of the present invention will be further described by the following examples, but these examples do not limit the present invention.

[0057] Example 1: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid (7)

Chemical formula

[0058] Step A: In an ice-water bath, an aqueous solution (20 mL) of sodium nitrite (3.13 g, 45.4 mmol) was added dropwise to a mixture containing 5-aminoindole (5.0 g, 37.8 mmol), water (80 mL) and 6M hydrochloric acid (18.9 mL). After the addition, the mixture was stirred at this temperature for 30 minutes. Then, ethyl acetoacetate (10.8 g, 83.2 mmol) was added dropwise, and then an aqueous solution (100 mL) of sodium acetate (93.1 g, 1.13 mol) was added dropwise to adjust the pH value to neutral. After the addition, stirring was continued at this temperature for 30 minutes. The mixture was filtered, and the filtrate was extracted with dichloromethane (300 mL × 3). The organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:10 - 2:3) to obtain ethyl 2-[2-(1H-indol-5-yl)hydrazino]-3-oxobutyrate (1) (1.77 g). The yield was 14.3%.

[0059] Step B: A mixture containing Compound 1 (1.50 g, 5.49 mmol), ammonium acetate (4.23 g, 54.9 mmol), copper(II) chloride (1.62 g, 12.1 mmol), and alcohol (20 mL) was stirred under reflux conditions overnight. It was cooled to room temperature, and the pH value was adjusted to 1 - 2 with 1 M hydrochloric acid. It was filtered, and the filter cake was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:10 - 1:2) to obtain ethyl 2-(1H-indol-5-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylate (2) (700 mg). The yield was 47.2%.

[0060] Step C: In an ice-water bath, DMF (30.5 mg, 0.418 mmol) was added dropwise to a dichloromethane (3 mL) solution of oxalyl chloride (53.00 mg, 0.418 mmol). After the addition, the mixture was stirred at this temperature for 0.5 h. Then, Compound 2 (100 mg, 0.370 mmol) was added, and the resulting mixture was stirred under reflux conditions for 1 h. THF (8 mL) and an aqueous solution of ammonium acetate (1.80 g, 23.4 mmol) (8 mL) were added. The temperature was raised to 80 °C and stirred for 0.5 h. It was cooled to room temperature, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product (100 mg) of ethyl 2-(3-formyl-1H-indol-5-yl)-5-methyl-1,2,3-triazole-4-carboxylate (3). This compound was reacted directly in the next step without purification. MS (ESI, m / z): 299.2 [M+H] + 。

[0061] Procedure D: A mixture containing the crude product of compound (3) (100 mg), hydroxylammonium chloride (26.5 mg, 0.381 mmol), and pyridine (3 mL) was stirred under reflux conditions for 1 hour. It was cooled to room temperature, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate:petroleum ether = 1:10 - 1:3), to obtain ethyl 2-{3-[(hydroxyimino)methyl]-1H-indol-5-yl}-5-methyl-2H-1,2,3-triazole-4-carboxylate (4) (80 mg). The total reaction yield of Procedures C and D was 76.4%. MS (ESI, m / z): 314.2 [M+H] + 。

[0062] Procedure E: A mixture containing compound 4 (80 mg, 0.255 mmol), THF (1 mL), and thiocarbonyldiimidazole (132 mg, 0.740 mmol) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate:petroleum ether = 1:10 - 1:3), to obtain ethyl 2-(3-cyano-1H-indol-5-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylate (5) (75 mg). The yield was 99.6%. 1 H NMR (DMSO-d6, 400 MHz) δ 12.52 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.00 - 7.97 (m, 1H), 7.74 (d, J = 9.2 Hz, 1H), 4.39 (q, J = 6.8 Hz, 2H), 2.56 (s, 3H), 1.36 (t, J = 6.8 Hz, 3H).

[0063] Procedure F: A mixture containing compound 5 (75 mg, 0.254 mmol), isopropyl iodide (95 mg, 0.559 mmol), cesium carbonate (166 mg, 0.508 mmol) and acetonitrile (3 mL) was stirred at 80 °C overnight. It was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:15 - 1:4) to obtain ethyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylate (6) (70 mg). The yield was 81.7%.

[0064] Procedure G: A mixture containing compound 6 (60 mg, 0.178 mmol), lithium hydroxide monohydrate (30 mg, 0.715 mmol), water (0.8 mL) and THF (3.2 mL) was stirred at room temperature overnight. The pH value was adjusted to 3 - 4 with 1 M hydrochloric acid. The solvent was evaporated under reduced pressure, and the product was separated and purified by preparative HPLC to obtain 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-5-methyl-2H-1,2,3-triazole-4-carboxylic acid (7). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.60 (s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.02 - 7.94 (m, 2H), 4.95 - 4.89 (m, 1H), 2.55 (s, 3H), 1.51 (d, J = 6.8 Hz, 6H). MS (ESI, m / z): 310.2 [M + H] + 。

[0065] Example 2: Synthesis of ethyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (14)

Chemical formula

[0066] Project A: A mixture containing 5-nitro-1H-indole (30.0 g, 185 mmol), isopropyl iodide (69.2 g, 407 mmol), cesium carbonate (121 g, 370 mmol) and acetonitrile (500 mL) was stirred at 80 °C overnight. It was cooled to room temperature, filtered, and the filter cake was eluted with ethyl acetate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:50 - 1:20) to obtain 1-isopropyl-5-nitro-1H-indole (8) (38.0 g). The yield was 100%.

[0067] Project B: 10% palladium (4.0 g) was added to a solution of compound 8 (38.0 g, 185 mmol) in THF (50 mL) and methanol (200 mL). After addition, the resulting mixture was stirred at room temperature under hydrogen for 60 hours. It was filtered through diatomaceous earth, and the filter cake was eluted with ethyl acetate. The solvent was evaporated under reduced pressure to obtain 5-amino-1-isopropyl-1H-indole (9) (30.0 g). The yield was 93.1%.

[0068] Project C: An aqueous solution of sodium nitrite (4.40 g, 63.8 mmol) in (30 mL) was added dropwise to a mixture containing compound 9 (10 g, 57.4 mmol), water (200 mL) and 3M hydrochloric acid (54 mL) in an ice-water bath. After the addition, stirring was continued at this temperature for 1 hour. Then, this mixture in the ice-water bath was added dropwise to a mixture containing ethyl 3-(N,N-dimethylamino)acrylate (15.2 g, 106 mmol), sodium acetate (78.5 g, 957 mmol) and water (500 mL). After the addition, stirring was continued at this temperature for 30 minutes. It was extracted with dichloromethane (300 mL × 3), the organic phases were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated 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 obtain ethyl 2-[2-(1-isopropyl-1H-indol-5-yl)hydrazino]-3-oxo-propionate (10) (1.50 g). The yield was 8.67%.

[0069] Procedure D: A mixture containing compound 10 (1.50 g, 4.98 mmol), ammonium acetate (2.60 g, 33.7 mmol), copper(II) chloride (1.26 g, 7.42 mmol) and alcohol (18 mL) was stirred overnight under reflux conditions. It was cooled to room temperature and water (80 mL) was added. It was extracted with ethyl acetate (40 mL × 2), the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200 - 300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 1:7) to obtain ethyl 2-(1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (11) (310 mg). The yield was 20.9%. 1 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.00 (dd, J = 2.0, 8.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 3.2 Hz, 1H), 6.61 (d, J = 3.2 Hz, 1H), 4.75 - 4.68 (m, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.56 (d, J = 6.8 Hz, 6H), 1.45 (t, J = 7.2 Hz, 3H). MS (ESI, m / z): 299.1 [M + H] + 。

[0070] The experimental operations of Procedures E, F and G refer to C, D and E in Example 1 in sequence to obtain ethyl 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (14). 1 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (s, 1H), 8.61 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.08 - 7.98 (m, 2H), 4.98 - 4.89 (m, 1H), 8.40 (q, J = 7.2 Hz, 2H), 1.51 (d, J = 6.4 Hz, 6H), 1.36 (t, J = 7.2 Hz, 3H). MS (ESI, m / z): 324.2 [M + H] + 。

[0071] Example 3: Synthesis of 2-(3-cyano-1-isopropyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (15)

Chem.

[0072] Using compound 14 as a raw material, the experimental operation for synthesizing compound 15 was referred to step G in Example 1. 1 H NMR (DMSO-d6, 400 MHz) δ 8.62 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 8.07 - 7.97 (m, 2H), 4.95 - 4.92 (m, 1H), 1.51 (d, J = 5.6 Hz, 6H). MS (ESI, m / z): 296.1 [M + H] + .

[0073] Example 4: Synthesis of 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (24)

Chem.

[0074] Step A: In an ice-water bath, an aqueous solution (50 mL) of sodium nitrite (4.35 g, 63.1 mmol) was added dropwise to 3M hydrochloric acid (53 mL) of 5-amino-1H-indazole (7.0 g, 52.6 mmol). After the addition, stirring was continued at this temperature for 0.5 h. Then, in an ice-water bath, this mixture was added dropwise to a mixture containing ethyl 3-(N,N-dimethylamino)acrylate (15.1 g, 105 mmol), sodium acetate (77.6 g, 946 mmol), alcohol (40 mL) and water (400 mL). After the addition, the resulting mixture was stirred at room temperature for 2 h. It was filtered, and the filter cake was eluted with water to obtain a crude product (20.0 g) of ethyl 2-[2-(1H-indazol-5-yl)hydrazino]-3-oxo-propionate (16). This compound was directly reacted in the next step without purification.

[0075] Process B: Hydroxylammonium chloride (8.01 g, 115 mmol) and sodium acetate (18.9 g, 231 mmol) were added to a mixture containing the crude product of compound 16 (20.0 g), alcohol (100 mL) and water (50 mL). After dropping, the resulting mixture was stirred at room temperature for 3 hours. Water (500 mL) was added, and the mixture was extracted with dichloromethane (200 mL×2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain a crude product (14.5 g) of ethyl 2-[2-(1H-indazol-5-yl)hydrazino]-3-(hydroxyimino)propionate (17). This compound was reacted directly in the next step without purification.

[0076] Process C: A mixture containing the crude product of compound 17 (14.5 g), acetic acid (100 mL) and acetic anhydride (100 mL) was stirred at 60 °C for 4 hours. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:30 - 1:7) to obtain ethyl 2-(1-acetyl-1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylate (18) (1.80 g). The total reaction yield of Processes A, B and C was 11.4%. 1 H NMR (CDCl3, 400 MHz) δ 8.59 - 8.56 (m, 1H), 8.52 (d, J = 1.6 Hz, 1H), 8.42 - 8.39 (m, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 4.49 (q, J = 7.2 Hz, 2H), 2.82 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H). MS (ESI, m / z): 300.2 [M + H] + 。

[0077] Process D: A mixture containing compound 18 (1.80 g, 6.01 mmol), methanol (20 mL) and sodium hydroxide (962 mg, 24.1 mmol) was stirred at room temperature overnight. It was adjusted to pH 1 - 2 with 1 M hydrochloric acid. Filtered, the filter cake was eluted with water and dried to obtain 2-(1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (19) (1.30 g). The yield was 94.3%.

[0078] Process E: In an ice-water bath, thionyl chloride (3.37 g, 28.4 mmol) was added dropwise to a solution of compound 19 (1.30 g, 5.67 mmol) in methanol (20 mL). After the addition, the resulting mixture was stirred overnight under reflux conditions. The solvent was evaporated under reduced pressure and then beaten with dichloromethane to obtain methyl 2-(1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylate (20) (1.30 g). The yield was 94.2%.

[0079] Process F: In an ice-water bath, potassium carbonate (2.73 g, 19.7 mmol) and iodine (2.50 g, 9.87 mmol) were added to a solution of compound 20 (1.2 g, 4.93 mmol) in DMF (6 mL). After the addition, the resulting mixture was stirred overnight at room temperature. Water (50 mL) was added, and the excess iodine was quenched with a sodium thiosulfate solution. The mixture was extracted with ethyl acetate (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 2-(3-iodo-1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylate (21) (790 mg). The yield was 43.4%. MS (ESI, m / z): 370.0 [M+H] + 。

[0080] Process G: A mixture containing compound 21 (780 mg, 2.11 mmol), DMF (10 mL), zinc cyanide (520 mg, 4.43 mmol), and tetrakis(triphenylphosphine)palladium (244 mg, 0.211 mmol) was stirred overnight at 120 °C under nitrogen. The mixture was filtered to remove insolubles. Ethyl acetate (90 mL) was added, and the mixture was washed with saturated brine (50 mL × 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 2-(3-cyano-1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylate (22) (400 mg). The yield was 70.7%. MS (ESI, m / z): 269.1 [M+H] + 。

[0081] The experimental operations of steps H and I refer to steps F and G in Example 1, and 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (24) was obtained. 1 H NMR (DMSO-d6, 400 MHz) δ 13.74 (s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.31 - 8.23 (m, 2H), 5.32 - 5.22 (m, 1H), 1.55 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 296.9 [M+H] + 。

[0082] Example 5: Synthesis of 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)thiophene-2-carboxylic acid (28)

Chemical formula

[0083] Step A: A mixture containing 5-bromo-1H-indazole-3-benzonitrile (3.0 g, 13.5 mmol), isopropyl iodide (9.19 g, 54.1 mmol), cesium carbonate (8.80 g, 27.0 mmol) and DMF (50 mL) was stirred at 80 °C for 1.5 h. It was cooled to room temperature and filtered to remove insoluble matters. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined and washed successively with water (50 mL × 2) and saturated brine (50 mL), and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:50 - 1:30) to obtain 5-bromo-1-isopropyl-1H-indazole-3-benzonitrile (25) (2.10 g) and 5-bromo-2-isopropyl-2H-indazole-3-benzonitrile (26) (230 mg). The yields were 58.9% and 6.45% respectively. Compound 25: 11H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 1.2 Hz, 1H), 7.55 (dd, J = 1.2, 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 4.93 - 4.87 (m, 1H), 1.61 (d, J = 6.4 Hz, 6H). Compound 26: 1 1H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.46 - 7.44 (m, 1H), 5.12 - 5.05 (m, 1H), 1.70 (d, J = 6.4 Hz, 6H).

[0084] Step B: A mixture containing palladium acetate (16.6 mg, 0.0735 mmol), 2 - dicyclohexylphosphine - 2’,6’ - dimethoxybiphenyl (S - Phos) (60.3 mg, 0.147 mmol) and THF (2 mL) was stirred with nitrogen for 30 minutes, and then an aqueous solution (1 mL) of compound 25 (200 mg, 0.735 mmol), methyl 2 - thiophenecarboxylate - 5 - boronic acid (150 mg, 0.808 mmol) and potassium carbonate (508 mg, 3.67 mmol) was added. After dropping, the resulting mixture was stirred at 45 °C overnight. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated 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 obtain methyl 2 - (3 - cyano - 1 - isopropyl - 1H - indazol - 5 - yl) - thiophene - 2 - carboxylate (27) (160 mg). The yield was 66.9%.

[0085] The experimental operation of Step C refers to Step G in Example 1 to obtain 2 - (3 - cyano - 1 - isopropyl - 1H - indazol - 5 - yl) - thiophene - 2 - carboxylic acid (28). 1HNMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.96 - 7.93 (m, 1H), 7.75 (s, 2H), 5.27 - 5.17 (m, 1H), 1.53 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 312.2 [M+H] + 。

[0086] Example 6: Synthesis of 1-(3-cyano-1-isobutyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (32)

Chemical formula

[0087] Step A: A mixture containing ethyl 1H-pyrazole-4-carboxylate (3.79 g, 27.0 mmol), 5-bromo-1H-indazole-3-benzonitrile (3.0 g, 13.5 mmol), potassium carbonate (3.73 g, 27.0 mmol), copper(I) iodide (2.57 g, 13.5 mmol), N,N'-dimethylethylenediamine (1.19 g, 13.5 mmol) and DMF (30 mL) was stirred at 110 °C overnight under nitrogen. After cooling to room temperature, ethyl acetate (300 mL) was added, and the mixture was filtered. The filtrate was washed with saturated brine (300 mL × 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC to obtain ethyl 1-(3-cyano-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (29) (600 mg). The yield was 15.8%.

[0088] Process B: A mixture containing compound 29 (300 mg, 1.07 mmol), isopropyl iodide (328 mg, 1.78 mmol), cesium carbonate (581 mg, 1.78 mmol) and acetonitrile (3 mL) was stirred at 70 °C for 3 hours. It was cooled to room temperature, filtered, and the insoluble matter was removed. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:35 - 1:7), and ethyl 1-(3-cyano-1-isobutyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (30) (182 mg) was obtained. The yield was 50.4%.

[0089] Process C: A mixture containing compound 30 (100 mg, 0.296 mmol), lithium hydroxide monohydrate (49.8 mg, 1.19 mmol), water (0.6 mL) and THF (3.4 mL) was stirred at 40 °C overnight. The solvent was evaporated under reduced pressure, water (20 mL) was added, and the pH was adjusted to 1 - 2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and a crude product (129 mg) of 1-(3-formylamino-1-isobutyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (31) was obtained. This compound was reacted directly in the next step without purification.

[0090] Process D: Trifluoroacetic anhydride (792 mg, 3.77 mmol) and pyridine (1.03 g, 13.0 mmol) were added dropwise to a solution of the crude product of compound 31 (120 mg) in dichloromethane (2 mL), and the resulting mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was washed with 1 M hydrochloric acid (50 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC to obtain 1-(3-cyano-1-isobutyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (32). 11H NMR (DMSO-d6, 400 MHz) δ 12.67 (s, 1H), 9.23 (s, 1H), 8.44 (s, 1H), 8.22 - 8.13 (m, 3H), 4.43 (d, J = 7.2 Hz, 2H), 2.30 - 2.23 (m, 1H), 0.88 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 310.3 [M + H] + 。

[0091] Example 7: Synthesis of 1-(3-cyano-1-propyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (35)

Chemical formula

[0092] For the experimental procedure for synthesizing compound 35, refer to Steps B, C, and D in Example 6, and use 1-bromopropane instead of isobutyl iodide in Step B of Example 6. 1 1H NMR (DMSO-d6, 400 MHz) δ 9.22 (s, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.22 - 8.13 (m, 3H), 4.56 (t, J = 6.8 Hz, 2H), 1.95 - 1.88 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). MS (ESI, m / z): 296.3 [M + H] + 。

[0093] Example 8: Synthesis of 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (38)

Chemical formula

[0094] For the experimental procedure for synthesizing compound 38, refer to Steps B, C, and D in Example 6, and use isopropyl bromide instead of isobutyl iodide in Step B of Example 6. 11H NMR (DMSO-d6, 400 MHz) δ 9.10 (s, 1H), 8.39 (d, J = 1.6 Hz, 1H), 8.21 - 8.12 (m, 2H), 8.05 (s, 1H), 5.27 - 5.20 (m, 1H), 1.53 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 296.2 [M+H] + 。

[0095] Example 9: Synthesis of 2-(3-cyano-1-cyclopropylmethyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (41)

Chemical Structure

[0096] Step A: A mixture containing 5-bromo-1H-indole-3-benzonitrile (1.0 g, 4.52 mmol), cyclopropylbromomethane (1.83 g, 13.57 mmol), cesium carbonate (4.42 g, 13.57 mmol) and acetonitrile (10 mL) was stirred at 80 °C for 4 hours. It was cooled to room temperature, filtered, and the filter cake was eluted with ethyl acetate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:4) to obtain 5-bromo-1-cyclopropylmethyl-1H-indole-3-benzonitrile (39) (1.18 g). The yield was 94.9%.

[0097] Step B: To a solution of compound 39 (940 mg, 3.42 mmol) and methyl 1,2,3-triazole-4-carboxylate (1.30 g, 10.3 mmol) in benzene (25 mL) were added potassium phosphate (2.18 g, 10.25 mmol), bis(dibenzylideneacetone)palladium (295 mg, 0.512 mmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropylbiphenyl (493 mg, 1.02 mmol). After addition, the resulting mixture was stirred at 115 °C overnight under nitrogen. Ethyl acetate (100 mL) was added, and the mixture was filtered. The filtrate was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 2:7) to give methyl 2-(3-cyano-1-cyclopropylmethyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylate (40) (211 mg). The yield was 19.2%.

[0098] Step C: A mixture containing compound 40 (50 mg, 0.155 mmol), lithium hydroxide monohydrate (26.1 mg, 0.622 mmol), water (1 mL) and THF (4 mL) was stirred at room temperature overnight. Water (10 mL) was added, and the pH was adjusted to 1 - 2 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL × 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC to give 2-(3-cyano-1-cyclopropylmethyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (41). 1 H NMR (DMSO-d6, 400 MHz) δ 8.54 (s, 1H), 8.52 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.08 - 7.98 (m, 2H), 4.20 (d, J = 7.2 Hz, 2H), 1.37 - 1.32 (m, 1H), 0.59 - 0.55 (m, 2H), 0.48 - 0.45 (m, 2H). MS (ESI, m / z): 307.9 [M + H] + 。

[0099] Example 10: Synthesis of 2-[3-cyano-1-(tetrahydrofuran-3-yl)-1H-indol-5-yl]-2H-1,2,3-triazole-4-carboxylic acid (44) [Chemical formula]

[0100] For the experimental procedure for synthesizing Compound 44, refer to Example 9, and use 3-iodotetrahydrofuran instead of cyclopropylbromomethane in Step A of Example 9. 1 H NMR (DMSO-d6, 400 MHz) δ 8.53 (s, 1H), 8.48 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.09 - 8.00 (m, 2H), 5.44 - 5.40 (m, 1H), 4.20 - 4.12 (m, 1H), 3.99 - 3.98 (m, 2H), 3.87 - 3.83 (m, 1H), 2.58 - 2.54 (m, 1H), 2.22 - 2.21 (m, 1H). MS (ESI, m / z): 323.9 [M+H] + .

[0101] Example 11: Synthesis of 2-(3-cyano-1-cyclobutyl-1H-indol-5-yl)-2H-1,2,3-triazole-4-carboxylic acid (47) [Chemical formula]

[0102] For the experimental procedure for synthesizing Compound 47, refer to Example 9, and use cyclobutyl bromide instead of cyclopropylbromomethane in Step A of Example 9. 1 H NMR (DMSO-d6, 400 MHz) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 8.04 (dd, J = 2.0, 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 5.15 - 5.11 (m, 1H), 2.55 - 2.52 (m, 2H), 2.49 - 2.48 (m, 2H), 1.91 - 1.86 (m, 2H). MS (ESI, m / z): 308.0 [M+H] + .

[0103] Example 12: Synthesis of 1-(3-cyano-1-cyclopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (50)

Chemical formula

[0104] Step A: A mixture containing 5-bromo-1H-indazole-3-benzonitrile (2.0 g, 9.01 mmol), cyclopropylboronic acid (1.55 g, 18.0 mmol), copper acetate (1.64 g, 9.01 mmol), potassium tert-butoxide (1.01 g, 9.01 mmol), DMAP (3.30 g, 27.0 mmol) and benzene (400 mL) was stirred at 95 °C overnight under nitrogen. After cooling to room temperature, ethyl acetate (400 mL) was added, and the mixture was filtered through diatomaceous earth to remove insoluble matters. The filtrate was washed with saturated brine (100 mL × 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 1:7) to obtain 5-bromo-1-cyclopropyl-1H-indazole-3-benzonitrile (48) (630 mg). The yield was 26.7%.

[0105] Step B: A mixture containing ethyl 1H-pyrazole-4-carboxylate (53.5 mg, 0.382 mmol), compound 48 (100 mg, 0.382 mmol), potassium carbonate (105 mg, 0.763 mmol), copper(I) iodide (72.7 mg, 0.382 mmol), N,N'-dimethylethylenediamine (33.6 mg, 0.382 mmol) and DMF (2 mL) was stirred at 110 °C for 3 hours under nitrogen. It was cooled to room temperature, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (20 mL × 2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluting with ethyl acetate:petroleum ether = 1:4) to obtain ethyl 1-(3-cyano-1-cyclopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (49) (100 mg). The yield was 81.5%.

[0106] Step C: A mixture containing compound 49 (100 mg, 0.311 mmol), lithium hydroxide monohydrate (26.1 mg, 0.622 mmol), water (0.5 mL) and THF (2 mL) was stirred at room temperature overnight. Water (10 mL) was added, and the pH value was adjusted to 3 - 4 with 1 M hydrochloric acid. Then, it was extracted with ethyl acetate (10 mL × 3) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and purified by preparative HPLC to obtain 1-(3-cyano-1-cyclopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (50). 1 H NMR (DMSO-d6, 400 MHz) δ 12.68 (s, 1H), 9.23 (s, 1H), 8.45 (t, J = 0.8 Hz, 1H), 8.26 - 8.23 (m, 1H), 8.11 - 8.09 (m, 2H), 4.10 (t, J = 5.2 Hz, 1H), 1.24 - 1.22 (m, 4H). MS (ESI, m / z): 293.9 [M + H] + 。

[0107] Example 13: Synthesis of 1-(7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (54) [Chemical formula]

[0108] Process A: A mixture containing ethyl 1H-pyrazole-4-carboxylate (1.30 g, 9.30 mmol), 5-bromo-7-fluoro-1H-indazole (2.0 g, 9.30 mmol), potassium carbonate (2.57 g, 18.6 mmol), copper(I) iodide (1.77 g, 9.30 mmol), N,N'-dimethylethylenediamine (820 mg, 9.30 mmol) and DMF (40 mL) was stirred at 110 °C for 3 hours under nitrogen. It was cooled to room temperature, water (120 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate:petroleum ether = 1:30 - 5:1) to obtain ethyl 1-(7-fluoro-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (51) (2.10 g). The yield was 82.3%.

[0109] Process B: Under an ice-water bath, potassium carbonate (4.23 g, 30.6 mmol) and iodine (3.89 g, 15.3 mmol) were added to a solution of compound 51 (2.10 g, 7.66 mmol) in DMF (40 mL). After dropping, the resulting mixture was stirred at room temperature overnight. Water (120 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 2). The organic phases were combined, washed successively with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluted with ethyl acetate:petroleum ether = 1:5 - 5:1) to obtain ethyl 1-(7-fluoro-3-iodo-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (52) (1.0 g). The yield was 32.6%.

[0110] Procedure C: A mixture containing compound 52 (790 mg, 1.97 mmol), isopropyl bromide (720 mg, 5.85 mmol), cesium carbonate (1.92 g, 5.89 mmol) and acetonitrile (14 mL) was stirred at 60 °C overnight. It was cooled to room temperature, filtered to remove insolubles. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200 - 300 mesh silica gel, eluting with ethyl acetate: petroleum ether = 1:20 - 1:3) to obtain ethyl 1-(7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylate (53) (550 mg). The yield was 69.8%.

[0111] Procedure D: A mixture containing compound 53 (220 mg, 0.497 mmol), 2 M sodium hydroxide solution (4 mL) and THF (1 mL) was stirred at 50 °C for 0.5 h. Water (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 2). The product was in the aqueous phase. The aqueous phase was adjusted to pH 2 - 3 with 2 M hydrochloric acid, filtered, and the filter cake was recrystallized from ethyl acetate / petroleum ether to obtain 1-(7-fluoro-3-iodo-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (54). 1 1H NMR (DMSO-d6, 400 MHz) δ 9.21 (s, 1H), 8.13 (s, 1H), 8.09 (d, J = 1.6 Hz, 0.5H), 8.06 (d, J = 1.6 Hz, 0.5H), 7.84 (d, J = 1.6 Hz, 1H), 5.11 - 5.05 (m, 1H), 1.54 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 414.9 [M + H] + 。

[0112] Example 14: Synthesis of 1-(3-cyano-7-fluoro-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (55)

Chemical Structure

[0113] The experimental procedure for synthesizing Compound 55 using Compound 54 as a raw material was referred to Step G in Example 4. 1 1H NMR (DMSO-d6, 400 MHz) δ 9.28 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.17 - 8.14 (m, 2H), 5.24 - 5.19 (m, 1H), 1.59 (d, J = 6.4 Hz, 6H). MS (ESI, m / z): 314.1 [M+H] + 。

[0114] Example 15: Synthesis of 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (57)

Chemical formula

[0115] Step A: A mixture containing Compound 25 (500 mg, 1.89 mmol), bis(pinacolato)diboron (721 mg, 2.84 mmol), potassium acetate (557 mg, 5.68 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (139 mg, 0.190 mmol) and dioxane (10 mL) was stirred at 80 °C overnight. It was cooled to room temperature, filtered, and the filter cake was eluted with ethyl acetate. The solvent was evaporated 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 obtain 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole-3-benzonitrile (56) (360 mg). The yield was 61.2%.

[0116] Project B: To a mixture containing compound 56 (200 mg, 0.642 mmol), 2-bromopyridine-4-carboxylic acid (130 mg, 0.643 mmol), potassium carbonate (178 mg, 1.29 mmol), dioxane (2.5 mL) and water (0.5 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (52 mg, 0.064 mmol) was added. After addition, the resulting mixture was stirred at 85 °C for 2 hours under nitrogen. It was cooled to room temperature, water (50 mL) was added, and it was extracted with ethyl acetate (30 mL × 2). The product was in the aqueous phase. The aqueous phase was adjusted to a pH value of 3 - 4 with 1 M hydrochloric acid, and then extracted with ethyl acetate (30 mL × 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by preparative HPLC to obtain 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (57). 1 H NMR (DMSO-d6, 400 MHz) δ 8.88 (d, J = 4.8 Hz, 1H), 8.65 (s, 1H), 8.50 (s, 1H), 8.40 (dd, J = 1.6, 9.2 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 5.30 - 5.23 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H). MS (ESI, m / z): 307.3 [M + H] + 。

[0117] Example 16: Xanthine Oxidase Activity Inhibition Test

[0118] I. Principle Xanthine oxidase (XO), horseradish peroxidase (HRP), and its substrate, a dual enzyme, are subjected to a coupling reaction to measure the inhibition of xanthine oxidase activity. First, xanthine oxidase oxidizes hypoxanthine to produce xanthine and hydrogen peroxide, and further, oxidized xanthine produces uric acid and hydrogen peroxide. Then, horseradish peroxidase catalyzes the reaction of hydrogen peroxide and 10-acetyl-3,7-dihydroxyphenoxazine (Ampliflu Red) to produce the strong fluorescent compound resorufin, and a fluorescence microplate reader is used to measure whether the fluorescence intensity of resorufin is directly proportional to the xanthine oxidase activity.

[0119] II. Test Reagents and Equipment Febuxostat was purchased from Beijing Lianben Pharmaceutical Chemistry Technology Co., Ltd. XO, Ampliflu Red, and hypoxanthine were purchased from Sigma-Aldrich Co., LLC. HRP was purchased from Shanghai Yuanye Biotechnology Co., Ltd. The 96-well polypropylene reaction plate was purchased from Greiner BioOne. DMSO was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0120] The Vitor X4 microplate reader was purchased from Perkin Elmer, Inc.

[0121] III. Preparation of Test Compounds and Reaction Solutions Specific amounts of test compounds 15, 24, 28, 32, 35, 38, 41, 44, 47, 50, 57 and the reference compound febuxostat were dissolved in DMSO (product of Sinopharm Chemical Reagent Co., Ltd.). In the 96-well polypropylene reaction plate, the test compounds were serially diluted 2.5-fold with DMSO to a 200-fold concentrated solution. Further, it was diluted with ultrapure water to obtain a 3-fold serially diluted solution.

[0122] Reaction solution A: A 6 mU / mL xanthine oxidase solution was prepared with 0.1 M Tris-HCl (pH 7.5) buffer.

[0123] Reaction solution B: A mixed solution of 0.6 U / mL horseradish peroxidase solution, 0.15 mM AmplifluRed and 0.3 mM hypoxanthine was prepared with 0.1 M Tris-HCl (pH 7.5) buffer. This solution was shielded from light at 4°C and used immediately after preparation.

[0124] IV. Test methods and results 9 μL of reaction solution A and 9 μL of a three-fold concentration series dilution solution of the test compound were mixed in a 96-well test plate, placed on a plate oscillator, and mixed at 30°C and 100 rpm for 30 minutes. Then 9 μL of reaction solution B was added. An enzyme reaction was carried out at 30°C for 30 minutes. The fluorescence intensity at the excitation wavelength of 530 nm and the emission wavelength of 590 nm was measured using a microplate reader. The fluorescence intensity in the absence of xanthine oxidase was 0%, and the fluorescence intensity in the absence of the test compound was 100%. The 50% inhibitory concentration (IC 50 ) of the test compound and the reference compound was calculated using the software GraphPad Prism 5.

[0125] The test results are shown in Table 1. From the results in Table 1, it can be seen that the compounds provided by the present invention showed excellent xanthine oxidase inhibitory effects in in vitro pharmacological tests.

[0126]

Table 1

[0127] Example 17: Experimental study on the treatment of hyperuricemia in mice with compounds

[0128] I. Experimental materials 1. Test drugs Compounds 15, 24, and 38 are all white powders, and compound 57 is a pale yellow powder. They were ground with 0.5% CMC-Na immediately before use and prepared into suspensions at the corresponding concentrations (0.2 and 0.4 mg / mL) for intragastric administration.

[0129] Febuxostat was purchased from Sigma. It was ground with 0.5% CMC-Na immediately before use and prepared into suspensions at the corresponding concentrations (0.2 and 0.4 mg / mL) for intragastric administration.

[0130] 2. Animals and Breeding 2.1 Animal Species and Sources SD rats were of SPF grade, male, with a body weight of 180 - 220 g. They were purchased from Shanghai Slack Experimental Animal Co., Ltd., with the production license number SCXK(▲Filter▼)2017 - 0005 and the quality certificate number 20170005050604.

[0131] 2.2 Breeding Conditions All mice were bred in individually ventilated cages. The air cleanliness was Class 10,000, the laboratory temperature was 26 ± 2°C, the relative humidity was 60% - 80%, the number of air exchanges per hour was 10 - 15 times / hour, the light cycle was 12 (day) / 12 (night) hours, and there were 3 mice in each cage.

[0132] The feed was a complete feed for mice, purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd., and its quality met the GB14924.1 - 2001 "General Quality Standard for Experimental Animal Formulated Feed".

[0133] The bedding was sterilized granular bedding, purchased from Jiangsu Xietong Pharmaceutical Biotechnology Co., Ltd. The drinking water was purified water, which was acidified and then freely available for drinking.

[0134] 3. Main Instruments and Equipment The Varioskan LUX multifunctional microplate reader was purchased from Thermo in the United States, the BS210S precision electronic balance (0.1 mg - 10 g) was purchased from Sartorius in Germany, the FEJ-200 electronic balance (0.1 - 200 g) was purchased from Fuzhou Furihang Henghengzhibao Electronic Co., Ltd., and the Pacific TII + Genpure XCAD PLUS UV / TOC / UF pure water and ultrapure water system was purchased from Thermo in the United States.

[0135] 4. Main Reagents The uric acid measurement kit (phosphotungstic acid reduction method) has a lot number of 20210515 and was purchased from Nanjing Jiancheng Bioengineering Research Institute. Potassium oxonate has a product number of O0164 and a lot number of T6GKM-TA and was purchased from Tokyo Chemical Industry Co., Ltd. (TCI) in Japan. Sodium carboxymethyl cellulose (CMC-Na) has a lot number of 20170810, is of CP grade, and was purchased from Sinopharm Chemical Reagent Co., Ltd.

[0136] II. Experimental Methods 1. Grouping There were 72 male SD mice. After one week of adaptation, their body weights were approximately 200 - 230 g. They were randomly divided into 10 groups based on body weight, with 6 mice in each group, as follows: (1) Normal group (0.5% CMC-Na), (2) Model group (0.5% CMC-Na), (3) Febuxostat 1 mg / kg, (4) Febuxostat 2 mg / kg, (5) Compound 15, 1 mg / kg, (6) Compound 15, 2 mg / kg, (7) Compound 24, 1 mg / kg, (8) Compound 24, 2 mg / kg, (9) Compound 38, 1 mg / kg, (10) Compound 38, 2 mg / kg, (11) Compound 57, 1 mg / kg, (12) Compound 57, 2 mg / kg. The drugs for each group were prepared into corresponding concentration suspensions, and the administration volume was 0.5 mL / 100 g for all.

[0137] 2. Model Establishment, Administration Scheme, and Detection Indicators After acclimating and raising each group of mice, they were fasted for 12 hours, and then each was intraperitoneally injected with potassium oxonate at a dose of 300 mg / kg. After 0.5 hours had passed since the injection, each test drug group was given a single intragastric administration. Blood was collected from the retro-orbital venous plexus before the injection of potassium oxonate and at 1, 3, and 5 hours after the injection of potassium oxonate. The blood was centrifuged at 3500 rpm for 10 minutes, and 30 μL of serum was taken to measure the uric acid level at each time point.

[0138] After that, for two consecutive days, potassium oxonate was used on the mice every day, and each was intraperitoneally injected at a dose of 300 mg / kg. At the same time, after the injection, each test drug group was given a single intragastric administration. On the third day after administration, the mice after 12 hours of fasting were taken, and blood was collected from the retro-orbital venous plexus before the injection of potassium oxonate and at 1, 3, and 5 hours after the injection of potassium oxonate in the same way as the test method on the first day. The blood was centrifuged at 3500 rpm for 10 minutes, and 30 μL of serum was taken to measure the uric acid level at each time point.

[0139] 3. Data processing and statistical methods All test measurement data were expressed as (mean) ± s (standard deviation). The comparison between groups was detected and analyzed for significance by ANOVA-Dunnett T. P < 0.05 was used as the significance index, and P < 0.01 was used as the extremely significant index.

[0140] III. Experimental results 1. Effect of single-dose administration on the serum uric acid level in mice Compared with the normal group, the serum uric acid levels in the model group were significantly increased at 1, 3, and 5 h after molding (P<0.01). Compared with the model group at the same time points, both the 1 and 2 mg / kg groups of febuxostat significantly decreased the serum uric acid levels at 1, 3, and 5 h after molding (P<0.01). Compared with the model group, the 2 mg / kg group of compound 15 significantly decreased the serum uric acid level at 1 h after molding (P<0.01), the 1 and 2 mg / kg groups of compound 24 significantly decreased the serum uric acid level at 1 h after molding (P<0.01), both the 1 and 2 mg / kg groups of compound 38 significantly decreased the serum uric acid levels at 1, 3, and 5 h after molding (P<0.01), and the 1 and 2 mg / kg of compound 57 significantly decreased the serum uric acid levels at 1, 3, and 5 h after molding (P<0.01 or P<0.05). The results were referred to Table 2.

[0141]

Table 2

[0142] 2.3 Effects of daily administration on mouse serum uric acid levels Compared with the normal group, the serum uric acid levels in the potassium oxonate model group were significantly increased at 1 and 3 h after molding (P<0.01). Compared with the model group at the same time points, both the 1 and 2 mg / kg groups of febuxostat significantly decreased the serum uric acid levels at 1, 3, and 5 h after molding (P<0.05 or P<0.01). Compared with the model group, the 2 mg / kg group of compound 24 significantly decreased the serum uric acid level at 3 h after molding (P<0.01), both the 1 and 2 mg / kg groups of compound 38 significantly decreased the serum uric acid levels at 1, 3, and 5 h after molding (P<0.01), and the 1 and 2 mg / kg of compound 57 significantly decreased the serum uric acid levels at 1 and 3 h after molding (P<0.01). The results were referred to Table 3.

[0143]

Table 3

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the formula, Y is N or C—R ６ wherein; R １ is a cyano group; R ２ 、 R ３ and R ４ are hydrogen; R ５ is a C １－６ alkyl group, a substituted C １－６ alkyl group, a C ３－６ cycloalkyl group, a substituted C ３－６ cycloalkyl group, a C ３－６ heterocycloalkyl group or a substituted C ３－６ heterocycloalkyl group, provided that the substituents of each group for R ５ are one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C １－６ alkyl group, a C １－６ alkoxy group, a C ３－６ cycloalkyl group or a C ３－６ heterocycloalkyl group; R ６ is hydrogen; Ar is an unsubstituted or substituted group selected from the following: 【Chemical Formula 2】 However, the substituents of each group related to Ar are one or more selected from deuterium, halogen or C １－３ alkyl group, and when Y is C—R ６ , Ar is only an unsubstituted or substituted group described below; 【Chemical Formula 4】 R ７ is a carboxyl group or a C ２－６ ester group.

2. R ５ is a C ３－６ alkyl group, a substituted C １－６ alkyl group, a C ３－６ cycloalkyl group, a substituted C ３－６ cycloalkyl group, a C ３－６ heterocycloalkyl group or a substituted C ３－６ heterocycloalkyl group, provided that the substituents of each group regarding R ５ are one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C １－５ alkyl group, a C １－５ alkoxy group or a C ３－６ cycloalkyl group, and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ５ is a C ３－６ alkyl group, a substituted C １－６ alkyl group, a C ３－６ cycloalkyl group, a substituted C ３－６ cycloalkyl group, tetrahydrofuran, a substituted tetrahydrofuran, tetrahydrothiophene, a substituted tetrahydrothiophene, pyrrolidine or a substituted pyrrolidine, provided that the substituent of each group regarding R ５ is one or more selected from deuterium, a cyano group, a nitro group, a halogen, a C １－５ alkyl group, a C １－５ alkoxy group or a C ３－６ cycloalkyl group, the compound according to claim 2 or a pharmaceutically acceptable salt thereof.

4. R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is a carboxyl group.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following: 【Chemical Formula 3】

6. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable auxiliary component as an auxiliary.

7. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a xanthine oxidase inhibitor drug.

8. Use of the compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of an anti-gout drug or an anti-hyperuricemia drug.

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