Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

• the invention belongs to the field of medical technology, and specifically relates to a class of compounds that can be used to lower uric acid.
• Xanthine oxidase is an important target for drug treatment of hyperuricemia and gout. Hypoxanthine in the human body will be metabolized into xanthine, and xanthine is further metabolized into uric acid. In the process of uric acid formation, XO plays a decisive role. When the activity of XO is inhibited, hypoxanthine, xanthine and uric acid will The conversion between them will be inhibited, thereby reducing the concentration of uric acid in human serum. Therefore, inhibiting the activity of XO has become the key to inhibiting uric acid production.
• hyperuricemia blood uric acid levels exceeding 420 ⁇ mol/L in men and 360 ⁇ mol/L in women are called hyperuricemia.
• hyperuricemia has become the second largest metabolic disease after diabetes, seriously threatening human health.
• Hyperuricemia is not only an important biochemical basis for gout, but is also closely related to the occurrence of hypertension, hyperlipidemia, atherosclerosis, obesity, and insulin resistance.
• the prevalence of gout among adults in the United States was 3.9% (approximately 8.3 million people) from 2007 to 2008 (Zhu Y, Pandya BJ, Choi HK.
• urate anion transporter 1 URAT1
• xanthine oxidase inhibitors urate oxidase
• URAT1 inhibitors mainly act on the urate transporter in the renal proximal tubule, inhibiting the reabsorption of uric acid and increasing its excretion, thereby reducing the concentration of uric acid in the body.
• Drugs in this class include benzbromarone, lesinurad, and probenecid.
• Benzbromarone is an effective uricosuric drug that has been approved for marketing in many countries, but has not been approved in the United States. Benzbromarone was withdrawn from the market in some European countries in 2003 due to severe liver toxicity.
• benzbromarone As a first-line uric acid-lowering drug. Lesinurad was approved for marketing in the United States in 2015. Its drug instructions include a black box warning that it may cause acute renal failure and cardiovascular disease risks (possibly fatal), and its efficacy is far inferior to benzbromarone, and it needs to be combined with allopurinol. use.
• Probenecid is recommended as a single drug for reducing urinary symptoms in the US guidelines
• Uric acid excretion drugs are the first choice in acid treatment, but their application is limited due to multiple significant interactions with some commonly used drugs (such as nonsteroidal anti-inflammatory drugs, ⁇ -lactam drugs, heparin, etc.) .
• Xanthine oxidase inhibitors mainly include allopurinol and febuxostat. Allopurinol has been widely used clinically since it was approved by the US FDA in 1966. Currently, this drug is still recommended as the first-line drug for the treatment of gout in most countries’ gout guidelines. However, allopurinol has poor efficacy. It only inhibits XO in the reduced state and has no effect on XO in the oxidized state. Relevant studies have shown that even if allopurinol is used at the maximum dose, the rate of subjects reaching the treatment endpoint is less than 50%. (Robert M, Douglas CA, Scott B.
• allopurinol induces acute liver damage , allopurinol should be used with caution when treating patients with hyperuricemia combined with liver disease (Imai H, Kamei H, Onishi Y, et al. Successful living-donor liver transplantation for cholestatic liver failure induced by allopurinol:case report[J] .Transplantation Proceedings, 2015,47(9):2778-2781).
• Other side effects of allopurinol include stomach discomfort, nausea, abdominal pain, diarrhea, leukopenia and thrombocytopenia, headache, fever, loss of appetite, weight loss, and urination Pain, hematuria, itching, and drowsiness.
• Febuxostat is a non-purine XO inhibitor developed by Teijin Company of Japan. It can inhibit the oxidation and reduction states of XO, and its activity is significantly higher than that of allopurinol. It was launched in Europe in 2008 and in the United States in 2009. With the continuous expansion of clinical application of febuxostat, its cardiovascular adverse reactions in the treatment of hyperuricemia are increasingly reported, and due to its cardiovascular toxicity (such as the risk of sudden death), the United States The Food and Drug Administration requires the addition of a black box risk warning to its drug inserts, and will adjust the prescription information in 2019 from first-line drugs to second-line drugs.
• Polyethylene glycol recombinant uricase is the main urate oxidase drug currently on the market and is administered via intravenous injection.
• the FDA has multiple black box warnings for this drug, and severe immune allergic side effects occur in 20%-40% of patients. Its efficacy is average, with only 47% of patients reaching the treatment endpoint of less than 0.36mmol/L.
• the object of the present invention is to provide a compound with xanthine oxidase inhibitory activity based on the existing technology.
• Another object of the present invention is to provide the use of the above compounds in the medical field.
• the object of the present invention can be achieved by the following measures:
• R is C 1-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 heterocycloalkyl or substituted C 3- 6 heterocycloalkyl; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring One or more types of alkyl or C 3-6 heterocycloalkyl;
• Ar is a substituted or unsubstituted following group:
• the substituent in the Ar group is selected from one or more of deuterium, hydroxyl, halogen, C 1-4 alkyl or C 1-4 alkoxy;
• Y is O or NR 3 ,
• R 1 is a connecting bond or a substituted or unsubstituted C 1-6 alkylene group or a substituted or unsubstituted C 2-12 alkenylene group.
• the substituent in the R 1 group is selected from deuterium, hydroxyl, amino, and cyano. , one or more of halogen, C 1-4 alkyl or C 1-4 alkoxy;
• R 2 is hydrogen, nitrooxy, carboxyl or the following substituted or unsubstituted groups: dioxole-2-one group, C 4-12 condensed heteroaromatic ring group, C 4-16 condensed hetero group Arylpyrazolylcarbonyloxy, C 4-16 fused heteroaromatic pyridylcarbonyloxy, C 4-16 fused heteroaromatic triazolylcarbonyloxy, C 2-6 ester group, pyridine base, phenyl, C 1-6 alkoxy, C 2-20 alkenyl, C 2-20 alkynyl, C 2-8 alkylcarbonyloxy or C 2-8 alkoxycarbonyloxy, R 2 The substituents in the group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, halo-substituted C 1-6 alkyl, nitrooxy-substituted C 1-6 alkyl or C 1 -6 One or more alkoxy groups;
• R 3 is hydrogen or C 1-6 alkyl.
• the compound of the present invention is selected from the group consisting of compounds represented by the general formula (II), (III) or (IV),
• Y is O or NH.
• R is C 3-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 heterocycloalkyl group or substituted C 3-6 heterocycloalkyl; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 alkyl, C 1-5 alkoxy One or more of C 3-6 cycloalkyl groups.
• R is C 3-6 alkyl, substituted C 1-6 alkyl, C 3-6 cycloalkyl, substituted C 3-6 cycloalkyl, tetrahydrofuran, substituted tetrahydrofuran, tetrahydrofuran Hydrothiophene, substituted tetrahydrothiophene, tetrahydropyrrole or substituted tetrahydropyrrole; wherein the substituents in each group involved in R are selected from deuterium, cyano, nitro, halogen, C 1-5 alkyl, One or more of C 1-5 alkoxy or C 3-6 cycloalkyl.
• R is C 3-6 alkyl, substituted C 1-3 alkyl, C 3-6 cycloalkyl or substituted C 3-6 cycloalkyl, and the substituents in the R group Selected from deuterium, halogen or C 3-6 cycloalkyl.
• R is C 3-6 alkyl or C 3-6 cycloalkyl.
• R is n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl or cyclopentyl.
• R 1 is a connecting bond or a substituted or unsubstituted C 1-4 alkylene group or a substituted or unsubstituted C 4-12 alkenylene group, and the substituent in the R 1 group is selected from deuterium , one or more of amino, cyano, halogen or C 1-4 alkoxy.
• R 2 is hydrogen, nitrooxy, carboxyl or the following substituted or unsubstituted groups: dioxol-2-one, indazolyl, quinolyl, iso Quinolyl, indolyl, benzofuranyl, purinyl, indazolylpyrazolylcarbonyloxy, quinolylpyrazolylcarbonyloxy, isoquinolylpyrazolylcarbonyloxy, indole Pyrazolylcarbonyloxy, benzofurylpyrazolylcarbonyloxy, purinylpyrazolylcarbonyloxy, indazolylpyridylcarbonyloxy, quinolylpyridylcarbonyloxy, isoquinolylpyridine Carbonyloxy, indolypyridylcarbonyloxy, benzofurylpyridylcarbonyloxy, purinylpyridylcarbonyloxy, indazolyltriazolylcarbonyloxy
• R 2 is hydrogen, nitrooxy, carboxyl, or the following substituted or unsubstituted groups: dioxol-2-one, indazolylpyrazolylcarbonyloxy , Indazolylpyridylcarbonyloxy, indazolyltriazolylcarbonyloxy, indolylpyrazolylcarbonyloxy, indolylpyridylcarbonyloxy, indolyltriazolylcarbonyloxy , C 2-6 ester group, pyridyl group, phenyl group, C 1-6 alkoxy group, C 6-20 alkenyl group, C 2-8 alkylcarbonyloxy group or C 2-8 alkoxycarbonyloxy group,
• the substituents in the R 2 group are selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-6 alkyl, nitrooxy substituted C 1-6 alkyl or C 1-6 alkoxy. one or more.
• R 3 is hydrogen, methyl, ethyl, n-propyl, isopropyl or butyl.
• the compound of the present invention can be selected from:
• the present invention also includes a pharmaceutical composition, which uses the compound involved in the present application or a pharmaceutically acceptable salt thereof as an active substance, supplemented by pharmaceutically acceptable excipients.
• the compound of the present invention or its pharmaceutically acceptable salt can be used in the preparation of xanthine oxidase inhibitor drugs, especially in the preparation of anti-gout drugs or anti-hyperuricemia drugs.
• H or hydrogen, refers to protium (1H), which is the main stable isotope of hydrogen.
• D or “deuterium” refers to a stable isotope of hydrogen, also known as heavy hydrogen, and its element symbol is D.
• Halogen refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• Amino refers to the -NH 2 group.
• Alkyl refers to a saturated aliphatic hydrocarbon group containing 1-10 carbon atoms, including straight-chain and branched-chain groups (the numerical range mentioned in this application, such as “1-10", refers to the group The group, in this case an alkyl group, can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms). Alkyl groups containing 1-4 carbon atoms are called lower alkyl groups. When the lower alkyl group has no substituent, it is called unsubstituted lower alkyl group.
• 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 etc.
• Specific alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl, etc.
• Alkyl groups may be substituted or unsubstituted.
• 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 4-12 Alkenyl etc.
• Specific alkenyl groups include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, tert-butenyl, wait.
• Alkoxy means -O- (unsubstituted alkyl) and -O- (unsubstituted cycloalkyl) groups, which further means -O- (unsubstituted alkyl).
• 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 etc. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, cyclopropoxy, and the like.
• Triazolyl includes 1,2,3-triazolyl, where "1,2,3-triazolyl” means
• Condensed heteroaromatic ring group refers to an aromatic group containing two or more fused rings and heteroatoms, including but not limited to indazolyl, quinolyl, isoquinolyl, indolyl, benzoyl, etc. Furyl, purinyl, acridinyl, etc.
• Carboxy refers to the -COOH group.
• a substituted ester group means that the hydrogen in the ester group is replaced by one substituent, or that multiple hydrogens in the ester group are replaced by the same or different substituents.
• Heterocycloalkyl refers to a saturated cyclic group containing 3-10 ring atoms, and its ring atoms contain one or more heteroatoms selected from N, O, and S.
• the numerical range mentioned in this application, such as “3-6" refers to the heterocycloalkyl group at this time, which can contain 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., until Includes 6 carbon atoms as ring atoms.
• the heterocycloalkyl group can be C 3-8 heterocycloalkyl, C 3-6 heterocycloalkyl, C 3-5 heterocycloalkyl, C 3-4 heterocycloalkyl, or C 3-9 heterocycloalkyl.
• alkyl groups include, but are not limited to, tetrahydrofuran, tetrahydropyrrole, tetrahydrothiophene, 1,4-dioxane, oxospiro[3,3]heptyl, oxospiro[4,4]nonanyl , oxospiro[5,5]undecyl, oxospiro[6,6]tridecyl, oxobicyclo[1,1,1]pentyl, oxobicyclo[2,2 ,2]octyl, oxobicyl[3,2,1]octyl, azospiro[3,3]heptyl, azospiro[4,4]nonyl, azospiro[ 5,5]undecyl, azospiro[6,6]tridecyl, azobicyclo[1,1,1
• Connecting bond means that the groups at both ends are directly connected by covalent bonds. Take the group fragment YR 1 -R 2 as an example. When R 1 is a connecting bond, the group fragment is YR 2 .
• Nirooxy refers to the -ONO 2 group.
• “Pharmaceutically acceptable salts” are salts comprising compounds of general formula (I) formed with organic or inorganic acids, meaning those salts which retain the biological effectiveness and properties of the parent compound. Such salts include, but are not limited to:
• inorganic acid such as (but not limited to) hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid, etc.
• organic acids such as (but not limited to) acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -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,
• “Pharmaceutical composition” refers to a mixture of one or more compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients .
• the purpose of pharmaceutical compositions is to facilitate the administration of compounds to an organism.
• the present invention further claims a pharmaceutical composition
• a pharmaceutical composition comprising any of the above-mentioned compounds, pharmaceutically acceptable salts thereof or readily hydrolyzable prodrugs thereof and other pharmaceutically active ingredients.
• the present invention also includes any of the above compounds and their pharmaceutically acceptable salts, which can be formulated into any clinically or pharmaceutically acceptable dosage form in a manner known in the art.
• oral administration it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc.
• oral preparations appropriate fillers, binders, disintegrants, lubricants, etc. can be added.
• parenteral administration it can be made into injections, including injection liquid, sterile powder for injection and concentrated solution for injection.
• injections conventional methods in the existing pharmaceutical field can be used.
• no additives may be added, or appropriate additives may be added according to the properties of the drug.
• the compound provided by the invention can significantly reduce the serum uric acid level in a hyperuricemia rat model, and has potential application value in anti-gout drugs, anti-hyperuricemia drugs, and the like. Because febuxostat is associated with severe sudden cardiac death, severe kidney toxicity and liver toxicity, the compounds provided by the present invention may have certain advantages in reducing drug toxicity and have good drug development prospects.
• Step A Combine 5-bromo-1H-indazole-3-carbonitrile (3.0g, 13.5mmol), isopropane iodide (9.19g, 54.1mmol), and cesium carbonate. A mixture of (8.80 g, 27.0 mmol) and DMF (50 mL) was stirred at 80°C for 1.5 hours. Cool to room temperature and filter to remove insoluble matter. Water (200 mL) was added, extracted with ethyl acetate (80 mL ⁇ 3), the combined organic phases were washed with water (50 mL ⁇ 2) and saturated brine (50 mL), and dried over anhydrous sodium sulfate.
• Step B Mix the mixture containing 1H-pyrazole-4-carboxylic acid ethyl ester (1.06g, 7.56mmol), compound 1 (1.0g, 3.79mmol), potassium carbonate (833mg, 6.04mmol), copper iodide (1.05g, A mixture of 5.51 mmol), (1S,2S)-1,2-diaminocyclohexane (432 mg, 3.78 mmol) and DMF (20 mL) was stirred at 110°C overnight under nitrogen.
• Step A A mixture containing compound 2 (500 mg, 1.55 mmol), lithium hydroxide hydrate (623 mg, 14.8 mmol), water (1.5 mL), methanol (1.5 mL) and THF (1.5 mL) was stirred at 20°C for 2 hours. . Part of the solvent was evaporated under reduced pressure, water (8 mL) was added, and the pH value was adjusted to 1-2 with 6M hydrochloric acid. Filter, and the filter cake is recrystallized with acetonitrile to obtain 1-(3-carbamoyl-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid (3) (300 mg). The yield is 61.8%. MS (ESI, m/z): 313.9[M+H] + .
• Step B Add trifluoroacetic anhydride (906 mg, 4.31 mmol) and triethylamine (873 mg, 8.63 mmol) to a solution of compound 3 (300 mg, 0.958 mmol) in dichloromethane (5 mL) under an ice-water bath, and complete the addition. Afterwards, the resulting mixture was stirred at room temperature overnight. Add saturated brine (20 mL), extract with dichloromethane (20 mL ⁇ 2), wash the combined organic phases with saturated brine (20 mL ⁇ 2), and dry over anhydrous sodium sulfate.
• the filter cake was purified by column chromatography (200-300 mesh silica gel, eluent with dichloromethane) to obtain 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole -4-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (6).
• Step A A mixture containing compound 4 (200 mg, 0.677 mmol), Boc-L-threonine methyl ester (189 mg, 0.810 mmol), DCC (210 mg, 1.02 mmol) and dichloromethane (5 mL) was stirred at room temperature. overnight. Insoluble matter was removed by filtration, and the filter cake was rinsed with dichloromethane (5 mL).
• Step B A solution of compound 10 (340 mg, 0.666 mmol) and trifluoroacetic acid (0.3 mL) in dichloromethane (5 mL) was stirred at room temperature overnight. Add water (20 mL) and adjust the pH to 7-8 with saturated sodium bicarbonate solution. Extract with dichloromethane (20 mL ⁇ 2), wash the combined organic phases with saturated brine (10 mL ⁇ 2), and dry over anhydrous sodium sulfate.
• Step A To a solution containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-indazole (8.40g, 34.4mmol), [1,1'- After the addition of bis(diphenylphosphine)ferrocene]palladium dichloride (1.20 g, 1.47 mmol), the resulting mixture was stirred at 80°C under nitrogen for 3 hours. Cool to room temperature, filter, and rinse the filter cake with a small amount of ethyl acetate.
• Step B To a solution of compound 16 (2.75g, 10.9mmol) in DMF (30mL), add cesium carbonate (7.08g, 21.7mmol) and iodine (5.50g, 21.7mmol). After the addition is completed, the resulting mixture is stirred at room temperature. 2 hours. Water (120 mL) and 2M sodium thiosulfate solution (20 mL) were added. Filter, dissolve the filter cake with ethyl acetate (300 mL), filter to remove insoluble matter, and then dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain methyl 2-(3-iodo-1H-indazol-5-yl)isonicotinate (17) (3.90g). The yield is 94.5%.
• Step C Add a solution containing compound 17 (3.90g, 10.3mmol), potassium carbonate (1.70g, 12.3mmol), isopropane bromide (1.90g, 15.4mmol), potassium iodide (340mg, 2.05mmol) and DMF (40mL) The mixture was stirred at 60°C overnight. Cool to room temperature, add water (160 mL), extract with ethyl acetate (100 mL ⁇ 2), wash the combined organic phases with water (40 mL ⁇ 2) and saturated brine (40 mL), and dry over anhydrous sodium sulfate.
• Step D A mixture containing compound 18 (3.81 g, 9.04 mmol), copper cyanide (1.14 g, 12.7 mmol) and DMF (30 mL) was stirred at 120°C overnight. Cool to room temperature, add ethyl acetate (100 mL) and water (100 mL), and filter to remove insoluble matter. The layers were separated, and the aqueous layer was extracted with ethyl acetate (100 mL ⁇ 2). The combined organic phases were washed with water (40 mL ⁇ 2) and saturated brine (40 mL) in sequence, and dried over anhydrous sodium sulfate.
• Step A A mixture containing compound 19 (1.0 g, 3.12 mmol), 2M sodium hydroxide solution (15 mL), methanol (5 mL) and THF (5 mL) was stirred at room temperature for 30 minutes. Water (20 mL) was added, extracted with ethyl acetate (50 mL), and the product was in the aqueous phase. Use 2M citric acid solution to adjust the pH value of the aqueous phase to 5-6. Filter to obtain 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (20) (688 mg). The yield is 72.0%.
• step B For the experimental operation of step B, refer to Example 4 to obtain 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid isopropyl ester (21).
• MS ESI, m/z: 349.1[M+H] + .
• Example 22 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinate (2-methoxy)ethyl ester (30) and 2-(3-cyano) Synthesis of -1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester hydrobromide (31)
• Step A Using compound 20 and ethylene glycol monomethyl ether as raw materials, refer to Example 8 for the experimental operation of synthesizing compound 30.
• Step B Pour hydrogen bromide into a solution of compound 30 (48 mg, 0.132 mmol) in dichloromethane (10 mL) to make the solution strongly acidic, then evaporate the dichloromethane and recrystallize with ethyl acetate/petroleum ether. 2-(3-cyano-1-isopropyl-1H-indazol-5-yl)isonicotinic acid (2-methoxy)ethyl ester hydrobromide (31) was obtained.
• Step A The mixture containing 4-bromobutylacetate (1.0g, 5.13mmol), silver nitrate (1.30g, 7.65mmol) and acetonitrile (15mL) was stirred under reflux overnight in the dark. Cool to room temperature and filter to remove insoluble matter. Water (60 mL) was added, 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 evaporated 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 resulting mixture was stirred at room temperature for 2 hours.
• Step B A mixture containing compound 4 (80 mg, 0.272 mmol), compound 37 (40 mg, 0.296 mmol), DCC (84 mg, 0.407 mmol), DMAP (4 mg, 0.0327 mmol) and dichloromethane (5 mL) was added to room temperature. Stir overnight. Filter to remove insoluble matter.
• Step A Combine m-hydroxybenzyl bromide (500 mg, 2.67 mmol), silver nitrate (500 mg, 2.94 mmol) and acetonitrile (5 mL). The mixture was stirred in an ice-water bath in the dark for 5 hours. Filter to remove insoluble matter. Water (20 mL) was added, extracted with ethyl acetate (20 mL ⁇ 2), the combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate.
• step B For the experimental operation of step B, refer to step B in Example 28 to obtain 1-(3-cyano-1-isopropyl-1H-indazol-5-yl)-1H-pyrazole-4-carboxylic acid [3- (Nitrooxy)methyl]phenyl ester (42).
• Example 34 Experimental study on the treatment of hyperuricemia in rats by compound 22
• Compound 22 is a light yellow powder. Before use, it is ground with 0.5% CMC-Na and prepared into a suspension of corresponding concentration for intragastric administration.
• Febuxostat purchased from Sigma, was ground with 0.5% CMC-Na before use and prepared into a suspension of corresponding concentration for intragastric administration.
• Rats are kept in independent air-supply cages with air cleanliness level 10000, laboratory temperature 26 ⁇ 2°C; relative humidity 60% ⁇ 80%; number of air exchanges per hour: 10-15 times/hour; light cycle: 12 (day)/12 (night) hours, 3 animals per cage.
• Rat full-price pellet feed was purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd., and its quality complied with GB14924.1-2001 "General Quality Standard for Compound Feed for Experimental Animals".
• Bedding material sterilized granular bedding material, purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd.
• Drinking water Drink purified water, drink it freely after acidification.
• Varioskan LUX multifunctional microplate reader was purchased from Thermo, USA; BS210S precision electronic balance (0.1mg ⁇ 10g) was purchased from Sartorius, Germany; FEJ-200 electronic balance (0.1 ⁇ 200g) was purchased from Fuzhou Furi Hengzhibao Electronics Co., Ltd.; Pacific TII+Genpure XCAD PLUS UV/TOC/UF pure water ultrapure water system was purchased from Thermo in the United States.
• Uric acid detection kit (phosphotungstic acid reduction method), batch number: 20220305, purchased from Nanjing Jiancheng Bioengineering Research Institute; potassium oxacinate, product number 00164, batch number GR4VI-RK, purchased from Tokyo Chemical Industry Co., Ltd. (TCI), Japan; Sodium carboxymethylcellulose (CMC-Na), batch number 20170810, chemically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.
• Rats in each group were purchased and adapted to be raised, fasted for 12 hours, and modeled with potassium oxonate at a dose of 300 mg/kg ip, and each test drug group was administered intragastrically once 0.5 h after modeling. Blood was collected from the retroorbital venous plexus before the injection of potassium oxonate and 1, 3, and 5 hours after the injection of potassium oxonate, and centrifuged at 3500 rpm for 10 min. 30 ⁇ L of serum was taken to measure the uric acid level at each time point.
• the measurement data of each test are expressed as (mean) ⁇ s standard deviation).
• the comparison between groups uses ANOVA-Dunnett T test to examine the significance. P ⁇ 0.05 is used as the significance index, and P ⁇ 0.01 is used as the extremely significant index.
• Example 35 Experimental study on the treatment of hyperuricemia in rats by compounds 13, 38 and 41
• Compound 13 is a light yellow powder, and compounds 38 and 41 are off-white powders. Before use, they are ground with 0.5% CMC-Na and prepared into a 0.4 mg/mL suspension for intragastric administration.
• Febuxostat purchased from Sigma, was ground with 0.5% CMC-Na before use and prepared into a 0.4 mg/mL suspension for intragastric administration.
• Rats are kept in independent air-supply cages with air cleanliness level 10000, laboratory temperature 26 ⁇ 2°C; relative humidity 60% ⁇ 80%; number of air exchanges per hour: 10-15 times/hour; light cycle: 12 (day)/12 (night) hours, 3 animals per cage.
• Rat full-price pellet feed was purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd., and its quality complied with GB14924.1-2001 "General Quality Standard for Compound Feed for Experimental Animals".
• Bedding material sterilized granular bedding material, purchased from Jiangsu Synergy Pharmaceutical Bioengineering Co., Ltd.
• Drinking water Drink purified water, drink it freely after acidification.
• Varioskan LUX multifunctional microplate reader was purchased from Thermo, USA; BS210S precision electronic balance (0.1mg ⁇ 10g) was purchased from Sartorius, Germany; FEJ-200 electronic balance (0.1 ⁇ 200g) was purchased from Fuzhou Furi Hengzhibao Electronics Co., Ltd.; Pacific TII+Genpure XCAD PLUS UV/TOC/UF pure water ultrapure water system was purchased from Thermo in the United States.
• Uric acid detection kit (phosphotungstic acid reduction method), batch number: 20230224, purchased from Nanjing Jiancheng Bioengineering Research Institute; potassium oxonate, product number 00164, batch number T6GKM-TA, purchased from Tokyo Chemical Industry Co., Ltd. (TCI), Japan; Sodium carboxymethylcellulose (CMC-Na), batch number 20170810, chemically pure, purchased from Sinopharm Chemical Reagent Co., Ltd.
• Rats in each group were purchased and adapted to be raised, fasted for 12 hours, and modeled with potassium oxonate at a dose of 300 mg/kg ip, and each test drug group was administered intragastrically once 0.5 h after modeling. The administration was continued for 3 days. On the third day, blood was collected from the retroorbital venous plexus before the injection of potassium oxonate and 1, 3, and 5 hours after the injection of potassium oxonate. The blood was centrifuged at 3500 rpm for 10 min. 30 ⁇ L of serum was taken to measure the uric acid level at each time point.
• the measurement data of each test are expressed as (mean) ⁇ s standard deviation).
• the comparison between groups uses ANOVA-Dunnett T test to examine the significance. P ⁇ 0.05 is used as the significance index, and P ⁇ 0.01 is used as the extremely significant index.
• Example 36 In vivo pharmacokinetic experiment of compounds in SD rats
• Preparation of compound stock solution Weigh an appropriate amount of compound solid powder, add a certain amount of DMSO, and vortex and sonicate to obtain a 10 mg/mL stock solution.
• test compounds for intragastric administration Pipette appropriate amounts of compound stock solutions, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of normal saline, and mix thoroughly to obtain a 1 mg/mL solution.
• test compounds for intravenous injection Pipette appropriate amounts of compound stock solutions, add a certain amount of Solutol HS15 solution, vortex for 1 minute, then add a certain amount of normal saline, and mix thoroughly to obtain a 0.5 mg/mL solution.
• test animals were fasted overnight before intragastric administration and were given food 4 hours after administration. During this period, the animals had free access to water.
• Each test compound is divided into two groups, namely intravenous administration and oral administration groups.
• the specific dosage and method of administration are shown in Table 3 below.
• Jugular vein blood samples (150 ⁇ L/ sample), and placed in a centrifuge tube containing the anticoagulant heparin sodium, centrifuged at 2000 g for 5 minutes at 4°C to separate the plasma.
• Plasma samples were analyzed using LC/MS/MS to detect the concentration of each test compound in the plasma samples.
• the pharmacokinetic parameters of SD rats for each test compound obtained according to the above method are shown in Table 4.
• Each compound of the present invention has good pharmacokinetic parameters and high bioavailability.

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