Methods for treating or preventing chronic kidney disease

Abstract

Described herein are methods for treating or preventing chronic kidney disease and other diseases, comprising the administration of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone and solvates thereof.

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Application No. 63 / 037,469, filed on 10 June 2020, and U.S. Provisional Application No. 63 / 195,411, filed on 1 June 2021, both of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Chronic kidney disease refers to the progressive loss of kidney function. The kidneys filter waste products and excess fluids from the blood, which are then excreted in the urine. When chronic kidney disease reaches an advanced stage, dangerous levels of fluid, electrolytes, and waste products can accumulate in the body. Chronic kidney disease can progress to end-stage renal failure, which is fatal without dialysis or a kidney transplant. [Overview of the project] [Problems that the invention aims to solve]

[0003] New drugs for chronic kidney disease are needed to treat or prevent this condition. [Means for solving the problem]

[0004] In one embodiment, a method for treating or preventing chronic kidney disease in an individual in need thereof, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof to the individual, is described herein. In some embodiments, it is a method for treating chronic kidney disease in an individual in need thereof. In some embodiments, it is a method for preventing chronic kidney disease in an individual in need thereof.

[0005] In another aspect, a method for treating or preventing heart failure in an individual that needs it, the method comprising administering to the individual a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, is described herein. In some embodiments, it is a method for treating heart failure in an individual that needs it. In some embodiments, it is a method for preventing heart failure in an individual that needs it.

[0006] In another aspect, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney stones, renal insufficiency, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyl transferase (HPRT) deficiency, or a combination thereof in an individual that needs it, the method comprising administering to the individual a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or a solvate thereof, is described herein. In some embodiments, it is a method for treating heart failure in an individual that needs it. In some embodiments, it is a method for preventing heart failure in an individual that needs it.

[0007] In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 3 mg to about 1500 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 3 mg to about 600 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 5 mg to about 300 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 10 mg to about 200 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 10 mg to about 100 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered orally. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is taken with food. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is taken without food. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered to the individual once per day.In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered to the individual twice daily. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with at least one additional therapeutic agent. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with a xanthine oxidase inhibitor. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered with a xanthine oxidase inhibitor selected from allopurinol, oxypurinol, febuxostat, topiroxostat, and inositol. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered with a sodium-glucose cotransporter 2 (SGLT2) inhibitor. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with an SGLT2 inhibitor selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin. In some embodiments, a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with a xanthine oxidase inhibitor and an SGLT2 inhibitor.In some embodiments, a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, or a solvate thereof, is administered together with a xanthine oxidase inhibitor and an SGLT2 inhibitor, wherein the xanthine oxidase inhibitor is selected from allopurinol, oxypurinol, febuxostat, topiroxostat, and inositol, and the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin.

[0008] In another aspect, a pharmaceutical composition for use in the treatment or prevention of chronic kidney disease, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, it is a pharmaceutical composition for use in the treatment of chronic kidney disease in an individual who needs it. In some embodiments, it is a pharmaceutical composition for use in the prevention of chronic kidney disease in an individual who needs it.

[0009] In another aspect, a pharmaceutical composition for use in the treatment or prevention of heart failure, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, it is a pharmaceutical composition for use in the treatment of heart failure in an individual who needs it. In some embodiments, it is a pharmaceutical composition for use in the prevention of heart failure in an individual who needs it.

[0010] In another embodiment, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0011] In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 3 mg to about 1500 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 3 mg to about 600 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 5 mg to about 300 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 10 mg to about 200 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 10 mg to about 100 mg. In some embodiments, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is about 25 mg to about 75 mg. In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered orally. In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is taken with food. In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is taken without food.In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered to an individual once daily. In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered to an individual twice daily. In some embodiments, the pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered together with at least one additional therapeutic agent. In some embodiments, a pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with a xanthine oxidase inhibitor. In some embodiments, a pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with a xanthine oxidase inhibitor selected from allopurinol, oxypurinol, febuxostat, topiroxostat, and inositol. In some embodiments, a pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane or its solvate is administered together with an SGLT2 inhibitor. In some embodiments, pharmaceutical compositions of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone or its solvate are administered together with an SGLT2 inhibitor selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin.In some embodiments, a pharmaceutical composition of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane, or its solvate, is administered together with a xanthine oxidase inhibitor and an SGLT2 inhibitor. The xanthine oxidase inhibitor is selected from allopurinol, oxypurinol, febuxostat, topiroxostat, and inositol, and the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, and dapagliflozin / metformin.

[0012] Embedding by reference All publications, patents, and patent applications described herein are incorporated herein by reference to the extent applicable and relevant, and to the same extent that each individual publication, patent, or patent application is incorporated by reference by specific and individual reference. [Brief explanation of the drawing]

[0013] [Figure 1] The mean plasma concentration profiles of compound 1 following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state are illustrated. [Figure 2] This illustrates the mean plasma concentration profile of compound 1 following a single oral administration of 50 mg of compound 1 in a fasted versus fed state. [Figure 3] This illustrates the dose-proportionality of compound 1 AUC following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state. [Figure 4]This illustrates the dose-proportionality of compound 1 Cmax following a single oral administration of compound 1 (15 mg, 50 mg, 100 mg, and 150 mg) in a fasted state. [Figure 5] The mean serum uric acid levels (mg / dL) following a single oral administration of compound 1 at various doses under fasting conditions are illustrated. [Figure 6] The diagram illustrates the mean time-adjusted (Day 1) percentage change in serum uric acid concentration from baseline following a single oral administration of compound 1 at various doses under fasting conditions. [Figure 7] The diagram illustrates the mean time-adjusted (Day 1) percentage change in serum uric acid concentration from baseline following a single oral administration of 50 mg of compound 1 in a fasted versus fed state. [Figure 8] This illustrates the mean plasma concentration profiles of compound 1 following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions. [Figure 9] The mean serum uric acid levels (mg / dL) following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions are illustrated. [Figure 10] The diagram illustrates the mean time-adjusted (day 1) percentage change in serum uric acid concentration from baseline following 10 days of once-daily oral administration of compound 1 at various doses under fasting conditions. [Modes for carrying out the invention]

[0014] Benzbromarone is an effective uric acid excretort that lowers serum uric acid (sUA). Treatment with benzbromarone has been found to reduce sUA even after a single dose, and to continue to reduce it further after multiple doses, and chronic treatment can bring sUA to a target level of <6 mg / dL. However, in certain patients, benzbromarone is associated with hepatotoxicity. A high percentage of these patients developed acute hepatic failure leading to death or emergency liver transplantation. As a result, benzbromarone was not approved for use in the United States. In addition, the hepatotoxicity of benzbromarone led to its withdrawal in Europe in 2003. Benzbromarone is converted to reactive metabolites by CYP2C9. Benzbromarone is metabolized by CYP2C9 to 5,6-dihydroxybenzbromarone via 6-OH benzbromarone, and subsequently to a reactive ortho-quinone intermediate by oxidation of 5,6-dihydroxybenzbromarone. The mechanism of benzbromarone hepatotoxicity is thought to be a result of its hepatic metabolism by CYP2C9, as well as the possible effects of its further metabolites on 6-OH benzbromarone and mitochondrial function (Iwamura et al., Drug Metabolism and Disposition, 2011, 39, 838-846; Uchida et al., Drug Metab. Pharmacokinet., 2010, 25, 605-610).

[0015] [ka]

[0016] (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (Compound 1), a 4,5,6,7-tetradutero analog of benzbromarone, is described herein. Compound 1 showed better in vitro URAT1 efficacy than benzbromarone. Compound 1 also demonstrated an improved metabolic profile compared to benzbromarone. Compound 1 is more stable than benzbromarone in human microsomes. The compound's CYP2C9 metabolic pathway is significantly reduced, and no 6-OH benzbromarone or 5,6-di-OH benzbromarone metabolites are formed. Therefore, Compound 1 represents a promising therapeutic agent for the treatment or prevention of chronic kidney disease with an improved hepatotoxicity profile. In addition, Compound 1 is a promising therapeutic agent for the treatment or prevention of heart failure.

[0017] compound 1 In one embodiment, the compound is (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone. Compound 1 or (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone has the following structure:

[0018] [ka] This refers to compounds that possess [a certain characteristic].

[0019] In some embodiments, compound 1 includes a solvent-added form (solvate). The solvate contains either a stoichiometric or non-chemical amount of solvent and is formed during the process of product formation or isolation in a pharmaceutically acceptable solvent such as water, ethanol, methanol, tert-butyl methyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, or acetonitrile. In some embodiments, the solvate is formed using a Class 3 solvent(s). In some embodiments, the solvate is formed using a Class 2 solvent(s). Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvent Q3C(R6)" (October 2016). Hydrates are formed when the solvent is water, and alkolates are formed when the solvent is alcohol.

[0020] In some embodiments, compound 1 is solvated. In some embodiments, compound 1 is not solvated. In some embodiments, compound 1 is in the form of a pharmaceutically acceptable salt. In other embodiments, compound 1 is prepared in various forms, including, but not limited to, amorphous phase, crystalline form, milled form and nanoparticle form.

[0021] compound 2 The active metabolites of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2), i.e., (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methane (compound 1), are further described herein.

[0022] Compound 2 or (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone has the following structure:

[0023] [ka] This refers to compounds that possess [a certain characteristic].

[0024] In some embodiments, compound 2 includes a solvent-added form (solvate). The solvate contains either a stoichiometric or non-stoichiometric amount of solvent and is formed during a product formation or isolation process using a pharmaceutically acceptable solvent, such as water, ethanol, methanol, tert-butyl methyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptane, toluene, anisole, acetonitrile, etc. In some embodiments, the solvate is formed using a Class 3 solvent (one or more), but is not limited to the following. In some embodiments, the solvate is formed using a Class 2 solvent (one or more), but is not limited to the following. Solvent categories are defined, for example, in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents Q3C(R6)," (October 2016). Hydrates are formed when the solvent is water, and alkoxides are formed when the solvent is alcohol.

[0025] In some embodiments, compound 2 is solvated. In some embodiments, compound 2 is not solvated. In some embodiments, compound 2 is in the form of a pharmaceutically acceptable salt. In other embodiments, compound 2 is prepared in various forms, including, but not limited to, amorphous phase, crystalline form, milled form and nanoparticle form.

[0026] While not intended to be bound by any particular theory, a particular solid form is characterized by physical properties, such as stability, solubility, and dissolution rate suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not wishing to be bound by any particular theory, a particular solid form is characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, tackiness, tackiness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence special processes (e.g., yield, filtration, washing, drying, milling, mixing, tableting, flowability, dissolution, formulation, and freeze-drying) that make that particular solid form suitable for the manufacture of solid dosage forms. These properties can be determined using special analytical chemistry techniques, including solid-state analysis techniques (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis), as described herein.

[0027] A certain terminology Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to whom the claimed subject matter belongs. The above general statements and the following detailed statements are illustrative and explanatory only and should be understood not to restrict any claimed subject matter. In this application, the use of singular forms includes plural forms unless otherwise specifically indicated. Where used herein and in the appended claims, the singular forms "a," "an," and "the" should be recognized as including multiple references unless otherwise clearly indicated by the context. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the terms "including," and similarly other forms such as "include," "includes," and "included," is not limiting. The terms “comprising” (and related terms, e.g., “comprise,” “comprises,” “having,” or “including”) are not intended to exclude that other particular embodiments, e.g., embodiments of any composition in question, compositions, methods, or processes described herein, etc., may “consist of” or “be required to be from” the described features. The term “about” means, where referring to a number or numerical range, that the number or numerical range indicated is an approximation within experimental variability (or within statistical experimental error), and therefore the number or numerical range may vary between 1% and 15% of the specified number or numerical range.

[0028] Section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described herein. All documents or parts of documents cited in such applications, including but not limited to patents, patent applications, articles, books, manuals, and papers, are expressly incorporated herein by reference in their entirety.

[0029] With respect to a formulation, composition, or component, the terms “acceptable” or “pharmaceutically acceptable,” as used herein, mean that it does not have a sustained adverse effect on the overall health of the subject being treated, does not inhibit the biological activity or properties of the compound, and is relatively nontoxic.

[0030] As used herein, “remission” of symptoms of a particular disease, disorder, or condition by administration of a particular compound or pharmaceutical composition means any reduction in severity, delay in onset, slowing of progression, or reduction in duration, whether permanent or temporary, sustained or transient, that may be caused by or associated with the administration of the compound or composition.

[0031] "Bioavailability" refers to the percentage of the drug compound delivered into the systemic circulation of the animal or human being studied. Total exposure (AUC) of the drug when administered intravenously. (0-∞) ) is usually defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which compound 1 is absorbed into the systemic circulation when a pharmaceutical composition is taken orally, compared to intravenous injection.

[0032] "Blood plasma concentration" refers to the concentration of compound 1 in the plasma components of the subject's blood. It is understood that the plasma concentration of compound 1 may vary significantly between subjects due to variability related to metabolism and / or possible interactions with other therapeutic agents. According to one embodiment disclosed herein, the blood plasma concentration of compound 1 may vary from subject to subject. Similarly, the maximum plasma concentration (T max ) the maximum plasma concentration (C) that reaches max ) or time or plasma concentration-time curve (AUC (0-∞) The values ​​below, such as the total area, may vary depending on the subject. Due to this variability, the amount of compound 1 required to constitute a "therapeutic effective dose" may vary depending on the subject.

[0033] When used herein, terms such as "simultaneous administration" mean the administration of selected therapeutic agents to a single patient and are intended to include treatment regimens in which the drugs are administered by the same or different routes of administration or at the same or different times.

[0034] The terms “effective dose” or “therapeutic effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that alleviates, to some extent, one or more symptoms of the disease or condition being treated. The result may be a reduction and / or mitigation of the signs, symptoms, or causes of the disease or any other desired alteration of the biological system. For example, “effective dose” for therapeutic use is the amount of a composition containing the compound as disclosed herein that is required to provide a clinically significant reduction of disease symptoms without excessive adverse side effects. An appropriate “effective dose” in any individual case may be determined using techniques such as dose-escalation studies. The term “therapeutic effective dose” includes, for example, a prophylactic effective dose. “Effective dose” of a compound disclosed herein is the amount effective in achieving the desired pharmacological effect or therapeutic improvement without excessive adverse side effects. “Effective dose” or “therapeutic effective dose” is understood to vary from subject to subject due to variations in the metabolism of compound 1, the subject’s age, weight, general condition, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. For example only, a therapeutic effective dose may be determined by a dose-escalation clinical trial.

[0035] The terms “enhance” or “enhance” mean to increase or extend a desired effect in terms of either potency or duration. For example, “enhance” the effect of a therapeutic agent means the ability to increase or extend the effect of the therapeutic agent in the treatment of a disease, disorder, or condition in terms of either potency or duration. “Enhancement effective dose,” as used herein, means an appropriate amount to enhance the effect of a therapeutic agent in the treatment of a disease, disorder, or condition. When used in a patient, the effective dose for this use depends on the severity and progression of the disease, disorder, or condition, previous treatments, the patient’s health status and response to the drug, and the judgment of the treating physician.

[0036] As used herein, the term "preventive effective dose" refers to the amount of a composition applied to a patient that alleviates, to some extent, one or more symptoms of the disease, condition, or disorder being treated. In such preventive applications, such a dose may depend on the patient's health condition, weight, etc. For example, such a preventive effective dose can be determined by a dose-escalation clinical trial.

[0037] As used herein, the terms “subject,” “patient,” or “individual” are used to mean animals, preferably mammals including humans or non-humans. The terms individual, patient, and subject are interchangeable.

[0038] As used herein, the term “target activity” refers to a biological activity that can be modulated by a selective modulator. Certain exemplary target activities include, but are not limited to, binding affinity, signaling, enzyme activity, tumor growth, inflammation or inflammation-related processes, and remission of one or more symptoms associated with a disease or condition.

[0039] The terms “to treat,” “to treat,” or “treatment,” as used herein, include reducing, alleviating or relieving the symptoms of a disease or condition, preventing additional symptoms, relieving or preventing the underlying metabolic cause of symptoms, inhibiting a disease or condition, for example, preventing the onset of a disease or condition, mitigating a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition. The terms “to treat,” “to treat,” or “treatment,” include, but are not limited to, preventive and / or therapeutic treatments.

[0040] When used herein, IC 50This refers to the dose, concentration, or amount of a specific test compound that elicits a dose-dependent response at 50% of the maximum expression of a specific response induced, caused, or enhanced by that specific test compound.

[0041] Pharmaceutical composition / formulation Pharmaceutical compositions can be formulated in conventional ways using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation is dependent on the chosen route of administration. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995), which are incorporated herein in their entirety by reference; Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999).

[0042] In some embodiments, the pharmaceutical composition, as used herein, refers to a mixture of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) or (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) and other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. The pharmaceutical composition facilitates the administration of the compound to a mammal. In practicing the treatment or method of use provided herein, a therapeutically effective dose of compound 1 is administered in the pharmaceutical composition to a mammal having the disease, disorder, or condition to be treated. Preferably, the mammal is a human. The therapeutically effective dose can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. The compound can be used alone or in combination with one or more therapeutic agents as a component of a mixture.

[0043] In some embodiments, the pharmaceutical composition comprises (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0044] In some embodiments, a pharmaceutical composition for use in the treatment or prevention of chronic kidney disease, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition is for use in the prevention of chronic kidney disease and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of chronic kidney disease and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition for use in the treatment of chronic kidney disease comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.In some embodiments, the pharmaceutical composition for use in the prevention of chronic kidney disease comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.

[0045] In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of heart failure and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) and at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients. In some embodiments, the pharmaceutical composition is for use in the prevention of heart failure and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition is for use in the treatment or prevention of heart failure and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients. In some embodiments, the pharmaceutical composition for use in the treatment of heart failure comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.In some embodiments, the pharmaceutical composition for use in the prevention of heart failure comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.

[0046] In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of coronary artery disease and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of Lesch-Nyhan syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of Kelly-Siegmiller syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of kidney stones and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1).In some embodiments, the pharmaceutical composition is for use in the treatment of renal failure and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of diabetic nephropathy and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of urolithiasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of lead poisoning and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of hyperparathyroidism and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1).In some embodiments, the pharmaceutical composition is for use in the treatment of psoriasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of sarcoidosis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1). In some embodiments, the pharmaceutical composition is for use in the treatment of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1).

[0047] In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), wherein the therapeutically effective amount is about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hypertension and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of coronary artery disease and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of Lesch-Nyhan syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of Kelly-Siegmiller syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg.In some embodiments, the pharmaceutical composition is for use in the treatment of kidney stones and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of renal failure and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of diabetic nephropathy and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of urolithiasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg.In some embodiments, the pharmaceutical composition is for use in the treatment of lead poisoning and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hyperparathyroidism and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of psoriasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of sarcoidosis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1), the therapeutically effective amount being about 3 mg to about 1500 mg.

[0048] In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) is about 3 mg to about 1250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 1000 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 750 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 600 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 500 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 400 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 3 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 35 mg.In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 100 mg.In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 25 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 25 mg.

[0049] In some embodiments, the pharmaceutical composition comprises (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0050] In some embodiments, a pharmaceutical composition for use in the treatment or prevention of chronic kidney disease, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), the therapeutically effective amount being about 3 mg to about 1500 mg, and comprising at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients. In some embodiments, the pharmaceutical composition for use in the prevention of chronic kidney disease comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.

[0051] In some embodiments, a pharmaceutical composition for use in the treatment or prevention of heart failure, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), the therapeutically effective amount being about 3 mg to about 1500 mg, and comprising at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients. In some embodiments, the pharmaceutical composition for use in the prevention of heart failure comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), the therapeutically effective amount being about 3 mg to about 1500 mg, and also comprises at least one inactive component selected from pharmaceutically acceptable carriers, diluents and excipients.

[0052] In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of coronary artery disease and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of Lesch-Nyhan syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of Kelly-Siegmiller syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of kidney stones and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2).In some embodiments, the pharmaceutical composition is for use in the treatment of renal failure and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of diabetic nephropathy and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of urolithiasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of lead poisoning and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of hyperparathyroidism and comprises a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2).In some embodiments, the pharmaceutical composition is for use in the treatment of psoriasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of sarcoidosis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2). In some embodiments, the pharmaceutical composition is for use in the treatment of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2).

[0053] In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, comprising a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), wherein the therapeutically effective amount is about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hypertension and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of coronary artery disease and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of Lesch-Nyhan syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of Kelly-Siegmiller syndrome and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg.In some embodiments, the pharmaceutical composition is for use in the treatment of kidney stones and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of renal failure and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of diabetic nephropathy and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of joint inflammation and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of arthritis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of urolithiasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount being about 3 mg to about 1500 mg.In some embodiments, the pharmaceutical composition is for use in the treatment of lead poisoning and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hyperparathyroidism and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of psoriasis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of sarcoidosis and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), with the therapeutically effective amount ranging from about 3 mg to about 1500 mg. In some embodiments, the pharmaceutical composition is for use in the treatment of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency and contains a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2), the therapeutically effective amount being about 3 mg to about 1500 mg.

[0054] In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) is about 3 mg to about 1250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 1000 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 750 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 600 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 500 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 400 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 2 is about 3 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 35 mg.In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 100 mg.In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 25 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 25 mg.

[0055] In some embodiments, a pharmaceutical composition for use in the treatment or prevention of chronic kidney disease,

[0056] [ka]

[0057] [ka] A pharmaceutical composition comprising a compound selected from, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0058] In some embodiments, a pharmaceutical composition for use in the treatment or prevention of heart failure,

[0059] [ka]

[0060] [ka] A pharmaceutical composition comprising a compound selected from, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0061] In some embodiments, a pharmaceutical composition for use in the treatment of hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof,

[0062] [ka]

[0063] [ka] A pharmaceutical composition comprising a compound selected from, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients.

[0064] In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 1500 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 1250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 1000 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 750 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 600 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 500 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 400 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 50 mg.In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 3 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 300 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 250 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 40 mg.In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 5 mg to about 25 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 200 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 150 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 100 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 25 mg to about 75 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 50 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 45 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 40 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 35 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of any one compound from 3 to 20 is about 10 mg to about 30 mg. In some embodiments of the pharmaceutical compositions described herein, the effective therapeutic dose of compound 1 is about 10 mg to about 25 mg.

[0065] As used herein, the term “pharmaceutical combination” means a product resulting from the mixing or combination of more than one active ingredient, and includes both fixed and non-fixed combinations of active ingredients. The term “fixed combination” means that both the active ingredient, e.g., compound 1 or compound 2, and the co-agent are administered to the patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredient, e.g., compound 1 or compound 2, and the co-agent are administered to the patient as separate entities, simultaneously, in parallel, or sequentially, without any specific intervening time limitations, and such administrations provide effective levels of the two compounds in the patient’s body. The latter also applies to cocktail therapies, e.g., the administration of three or more active ingredients.

[0066] In some embodiments, the compounds described herein are incorporated into a pharmaceutical composition to impart a solid oral dosage form. In other embodiments, the compounds described herein are used to prepare pharmaceutical compositions other than oral solid dosage forms. The pharmaceutical formulations described herein can be administered to a target by multiple routes of administration, including, but are not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid liquids, liposome dispersions, aerosols, solid dosage forms, powders, immediate-release formulations, controlled-release formulations, fast-melting formulations, tablets, capsules, pills, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multiparticle formulations, and mixed immediate and controlled-release formulations.

[0067] Pharmaceutical compositions containing the compounds described herein can be prepared by conventional methods, for example, by conventional mixing, dissolving, granulation, sugar-coating, polishing, emulsifying, encapsulating, incorporating, or compressing processes, for example, only as an example.

[0068] method In some embodiments, a method for treating or preventing chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for preventing chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating or preventing chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for preventing chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.

[0069] In some embodiments, a method for treating or preventing heart failure in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating heart failure in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for preventing heart failure in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating or preventing heart failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating heart failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for preventing heart failure in an individual in need thereof, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.

[0070] In some embodiments, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, in an individual requiring such treatment, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating hypertension in an individual requiring such treatment, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating coronary artery disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating Lesch-Nyhan syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating Kelly-Siegmiller syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual.In some embodiments, a method for treating kidney stones in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating renal failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating diabetic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating joint inflammation in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating arthritis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating urolithiasis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating lead poisoning in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual.In some embodiments, a method for treating hyperparathyroidism in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating psoriasis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating sarcoidosis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual. In some embodiments, a method for treating hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual.

[0071] In some embodiments, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, in an individual requiring such treatment, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating hypertension in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating coronary artery disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating Lesch-Nyhan syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating Kelly-Siegmiller syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg.In some embodiments, a method for treating kidney stones in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating renal failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating diabetic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating joint inflammation in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating arthritis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating urolithiasis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg.In some embodiments, a method for treating lead poisoning in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating hyperparathyroidism in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating psoriasis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating sarcoidosis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.

[0072] In some embodiments of the methods described herein, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) is about 3 mg to about 1250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 1000 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 750 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 600 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 500 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 400 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 30 mg.In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 3 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 5 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 25 mg to about 75 mg.In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 1 is about 10 mg to about 25 mg.

[0073] In some embodiments, a method for treating or preventing chronic kidney disease, comprising administering to an individual in need of such treatment an effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) as described herein. In some embodiments, a method for treating or preventing chronic kidney disease in an individual in need of such treatment, comprising administering to the individual an effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2), wherein the effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg. In some embodiments, a method for preventing chronic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg.

[0074] In some embodiments, a method for treating or preventing heart failure, comprising administering to an individual in need of such treatment an effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) as described herein. In some embodiments, a method for treating or preventing heart failure in an individual in need of such treatment, comprising administering to the individual a effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2), wherein the effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating heart failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg. In some embodiments, a method for preventing heart failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg.

[0075] In some embodiments, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, in an individual requiring such treatment, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating hypertension in an individual requiring such treatment, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating coronary artery disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating Lesch-Nyhan syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating Kelly-Siegmiller syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual.In some embodiments, a method for treating kidney stones in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating renal failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating diabetic kidney disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating joint inflammation in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating arthritis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating urolithiasis in an individual requiring it, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual.In some embodiments, a method for treating lead poisoning in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating hyperparathyroidism in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating psoriasis in an individual in need, comprising administering a therapeutically effective amount of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methane (compound 2) to the individual. In some embodiments, a method for treating sarcoidosis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual. In some embodiments, a method for treating hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual.

[0076] In some embodiments, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic nephropathy, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, in an individual requiring such treatment, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating hypertension in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating coronary artery disease in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg. In some embodiments, a method for treating Lesch-Nyhan syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.In some embodiments, a method for treating Kelly-Siegmiller syndrome in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating kidney stones in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating renal failure in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg. In some embodiments, a method for treating diabetic nephropathy in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg. In some embodiments, a method for treating joint inflammation in an individual in need thereof, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.In some embodiments, a method for treating arthritis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating urolithiasis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating lead poisoning in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating hyperparathyroidism in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is about 3 mg to about 1500 mg. In some embodiments, a method for treating psoriasis in an individual in need thereof, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is from about 3 mg to about 1500 mg.In some embodiments, a method for treating sarcoidosis in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg. In some embodiments, a method for treating hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency in an individual requiring it, comprising administering a therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) to the individual, wherein the therapeutically effective dose is approximately 3 mg to approximately 1500 mg.

[0077] In some embodiments of the methods described herein, the therapeutically effective dose of (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) is about 3 mg to about 1250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 1000 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 750 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 600 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 500 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 400 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 35 mg.In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 3 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 5 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 5 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 5 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 5 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 5 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 10 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 10 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 10 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutic dose of compound 2 is about 10 mg to about 75 mg.In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 25 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of compound 2 is about 10 mg to about 25 mg.

[0078] In some embodiments described herein, a method for treating or preventing chronic kidney disease, provided to an individual in need thereof,

[0079] [ka] The method comprises administering a therapeutically effective amount of a compound selected from the following.

[0080] In some embodiments described herein, a method for treating or preventing heart failure, provided to an individual in need thereof,

[0081] [ka] The method comprises administering a therapeutically effective amount of a compound selected from the following.

[0082] In some embodiments described herein, a method for treating hypertension, coronary artery disease, Lesch-Nyhan syndrome, Kelly-Siegmiller syndrome, kidney stones, renal failure, diabetic kidney disease, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination thereof, provided to an individual in need thereof.

[0083] [ka] The method comprises administering a therapeutically effective amount of a compound selected from the following.

[0084] In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 1500 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 1250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 1000 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 750 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 600 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 500 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 400 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one of compounds 3 to 20 is about 3 mg to about 45 mg.In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 3 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 300 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 250 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one of compounds 3 to 20 is about 5 mg to about 30 mg.In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 5 mg to about 25 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 200 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 150 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 100 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 25 mg to about 75 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 50 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 45 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 40 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 35 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 30 mg. In some embodiments of the methods described herein, the therapeutically effective dose of any one compound from 3 to 20 is about 10 mg to about 25 mg.

[0085] Methods of medication and treatment regimens In some embodiments, compound 1 or compound 2 is used in the preparation of pharmaceuticals for the treatment of diseases or conditions that benefit from lowering serum uric acid (sUA). In addition, methods for treating any of the diseases or conditions described herein in an individual requiring such treatment involve administering to the individual a pharmaceutical composition containing compound 1 or compound 2, or a pharmaceutically acceptable solvate thereof, in a therapeutically effective amount.

[0086] In some embodiments, compositions containing compound 1 or compound 2 are administered for preventive, therapeutic, or maintenance purposes. In some embodiments, compositions containing compound 1 or compound 2 are administered for therapeutic purposes. In some embodiments, compositions containing compound 1 or compound 2 are administered for preventive purposes.

[0087] In therapeutic use, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress the symptoms of the disease or condition. The effective amount for this use depends on the severity and progression of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0088] For preventive purposes, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such amounts are defined as “effective prophylactic doses or amounts.” In this use, the exact amount also depends on the patient’s health condition, weight, etc. When used in a patient, the effective dose for this use depends on the severity and progression of the disease, disorder, or condition, previous treatments, the patient’s health condition, and response to the drug, as well as the judgment of the treating physician.

[0089] In some embodiments, compound 1 or compound 2 is administered daily. In some embodiments, compound 1 or compound 2 is administered every other day.

[0090] In some embodiments, compound 1 or compound 2 is administered once per day. In some embodiments, compound 1 or compound 2 is administered twice per day. In some embodiments, compound 1 or compound 2 is administered three times per day. In some embodiments, compound 1 or compound 2 is administered four times per day.

[0091] If the patient's condition does not improve, the compound may, at the physician's discretion, be administered chronically, i.e., for a long period of time, for example, over the entire duration of the patient's life, to alleviate, or otherwise control or limit the symptoms of the patient's disease or condition.

[0092] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, the dose, frequency, or both can be reduced as a function of symptoms to a level at which the improved disease, disability, or condition is maintained. The patient, however, may require long-term intermittent treatment in the event of any symptom relapses.

[0093] The amount of a given drug corresponding to these quantities varies depending on factors such as the specific compound, the disease or condition and its severity, and the unique characteristics of the subject or host requiring treatment (e.g., body weight). Nevertheless, it can still be determined in a manner recognized in the art, according to the specific circumstances surrounding the case, including, for example, the specific drug being administered, the route of administration, the condition being treated, and the subject or host being treated. Generally, however, doses used for adult human treatment are typically in the range of about 0.02 to about 5000 mg per day, and in some embodiments, about 1 to about 1500 mg per day. The desired dose can conveniently exist as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four or more subdose per day.

[0094] The pharmaceutical compositions described herein may be in unit dosage forms suitable for a single dose of a precise amount. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in the form of a package containing individual amounts of the formulation. Non-limiting examples include packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose non-recloseable containers. Alternatively, multi-dose recloseable containers may be used, in which case the composition typically contains preservatives. For example only, formulations for parenteral injection may be expressed in unit dosage forms, including ampoules, or in multi-dose containers with added preservatives.

[0095] Appropriate daily doses for the compounds described herein range from about 0.01 mg / kg to about 20 mg / kg. In one embodiment, the daily dose is about 0.1 mg / kg to about 10 mg / kg. In larger mammals, including but not limited to humans, the indicated daily dose ranges from about 3 mg to about 1500 mg and is conveniently administered in single doses or divided doses, for example, up to four times a day, or in extended-release form. Appropriate unit dosage forms for oral administration contain about 1 mg to about 500 mg of the active ingredient. In one embodiment, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. In another embodiment, the unit dose is approximately 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 400 mg, or 500 mg. The ranges described above are merely suggestive, as the number of variables for individual treatment plans is large and considerable movement from these recommended values ​​is not uncommon. Such dosages can be modified depending on the number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the practitioner's judgment.

[0096] The toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 50 (the dose lethal to 50% of the population) and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio between LD 50 and ED 50 . Data obtained from cell culture assays and animal studies can be used in defining the dosage range for use in humans. The dosage of such compounds is preferably within the range of circulating concentrations that includes ED 50 with minimal toxicity. The dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.

[0097] Combination Treatments The compounds 1 or 2 described herein, and their compositions, can also be used in combination with other therapeutic agents selected for their therapeutic value for the condition to be treated. Generally, in embodiments where the compositions described herein, and combination therapies are used, the other agents may not be administered in the same pharmaceutical composition and may have to be administered by different routes due to their different physical and chemical characteristics. Where possible, determination of the mode of administration in the same pharmaceutical composition and suitability of administration are well within the knowledge of the clinician. Initial administration can be made according to established protocols recognized in the art and then, based on the observed effects, the dosage, mode of administration and timing of administration can be modified by the clinician.

[0098] In certain cases, it may be appropriate to administer compound 1 or compound 2 described herein in combination with another therapeutic agent. For example only, if one of the side effects experienced by a patient in response to one of the compounds described herein, such as compound 1 or compound 2, is nausea, it may be appropriate to administer an antiemetic agent in combination with the initial therapeutic agent. Alternatively, for example only, the therapeutic efficacy of one of the compounds described herein may be enhanced by the administration of an adjuvant (i.e., an adjuvant may have a minimal therapeutic benefit on its own, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, for example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein together with another therapeutic agent (including a therapeutic regimen) that also has a therapeutic benefit. In any case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by a patient may simply be the additive benefit of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0099] In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being allopurinol. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being oxypurinol. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being febuxostat. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being topiroxostat. In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor, the xanthine oxidase inhibitor being ositol.

[0100] In some embodiments, compound 1 or compound 2 and a xanthine oxidase inhibitor are administered in combination as a single dosage form. In some embodiments, compound 1 or compound 2 and a xanthine oxidase inhibitor are administered in combination as separate dosage forms.

[0101] In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, or dapagliflozin / metformin. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being canagliflozin. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being dapagliflozin. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being empagliflozin. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being empagliflozin / linagliptin. In some embodiments, compound 1 or compound 2 is administered in combination with an SGLT2 inhibitor, the SGLT2 inhibitor being empagliflozin / metformin.

[0102] In some embodiments, compound 1 or compound 2 and the SGLT2 inhibitor are administered in combination as a single dosage form. In some embodiments, compound 1 or compound 2 and the SGLT2 inhibitor are administered in combination as separate dosage forms.

[0103] In some embodiments, compound 1 or compound 2 is administered in combination with a xanthine oxidase inhibitor and an SGLT2 inhibitor, where the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol, and the SGLT2 inhibitor is canagliflozin, dapagliflozin, empagliflozin, empagliflozin / linagliptin, empagliflozin / metformin, or dapagliflozin / metformin.

[0104] In some embodiments, compound 1 or compound 2, a xanthine oxidase inhibitor, and an SGLT2 inhibitor are administered in combination as a single dosage form. In some embodiments, compound 1 or compound 2, a xanthine oxidase inhibitor, and an SGLT2 inhibitor are administered in combination as separate dosage forms.

[0105] The specific selection of compounds to be used depends on the attending physician's diagnosis, as well as their judgment of the patient's condition and the appropriate treatment protocol. These compounds may be administered in parallel (e.g., simultaneously, necessarily at the same time, or within the same treatment protocol) or sequentially, depending on the nature of the disease, disorder, or condition, the patient's condition, and the actual selection of compounds to be used. The determination of the order of administration, and the number of repetitions of each therapeutic agent in the treatment protocol, is within the physician's knowledge after an assessment of the disease being treated and the patient's condition.

[0106] The therapeutically effective dose may vary when a drug is used in a combination of treatments. Methods for experimentally determining the therapeutically effective dose of a drug and other drugs for use in combination treatment regimens are described in the literature. For example, the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects, is extensively described in the literature. Combination treatments may further include periodic treatments initiated and discontinued at various times to assist in the clinical management of the patient.

[0107] For the combination therapies described herein, the dosage of compounds administered concurrently will naturally vary depending on the type of co-drug used, the specific drug used, the disease or condition being treated, and other factors. In addition, when administered concurrently with one or more bioactive drugs, the compounds provided herein can be administered either simultaneously with or sequentially to the bioactive drugs(s). If administered sequentially, the attending physician will determine the appropriate order for administering the protein in combination with the bioactive drugs(s).

[0108] In any case, multiple therapeutic agents (one of which is Compound 1 or Compound 2 as described herein) may be administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents may be provided in a single integrated form or in multiple forms (for example, as a single pill or as two separate pills). One therapeutic agent may be given in multiple doses, or both may be given in multiple doses. If not administered simultaneously, the timing between doses may vary from more than zero weeks to less than four weeks. In addition, the combination method, composition and formulation should not be limited to the use of only two agents; the use of multiple therapeutic combinations is also conceivable.

[0109] Dosage regimens for treating, preventing, or relieving one or more conditions requiring relief can be modified according to various factors. These factors include the disorder or condition the subject suffers from, as well as the subject's age, weight, sex, diet, and medical condition. Therefore, the dosing regimens used in practice may vary widely and thus deviate from those described herein.

[0110] The pharmaceutical agents constituting a combination therapy disclosed herein may be a combined dosage form or separate dosage forms intended for substantially simultaneous administration. The pharmaceutical agents constituting a combination therapy may also be administered sequentially, or any of the therapeutic compounds may be administered by a regimen requiring two-step administration. A two-step administration regimen may require sequential administration of the active agents or intervald administration of separate active agents. The time intervals between multiple administration steps can range from several minutes to several hours, depending on the characteristics of each pharmaceutical agent, e.g., their potency, solubility, bioavailability, plasma half-life, and kinetic profile. Circadian fluctuations in target molecule concentrations may also determine the optimal dose interval.

[0111] In addition, the compounds described herein may also be used in combination with procedures that can provide additional or synergistic benefits to patients. For example, a patient is expected to find therapeutic and / or preventive benefits in the methods described herein, and combinations of the compounds disclosed herein with pharmaceutical compositions and / or other therapies may be combined with genetic testing to determine whether an individual is a carrier of a mutant gene associated with a particular disease or condition.

[0112] The compounds and combination therapies described herein can be administered before, during, or after the onset of a disease or condition, and the timing of administration of compositions containing the compounds may vary. For example, the compounds can be used as prophylactic agents and, by continuous administration to subjects prone to developing a condition or disease, can prevent the onset of the disease or condition. Initial administration can be via any practical route, such as intravenous injection, bolus injection, infusion over approximately 5 minutes to approximately 5 hours, pills, capsules, transdermal patches, buccal delivery, or a combination thereof. The compounds are preferably administered as soon as practically possible after the onset of the disease or condition is detected or suspected, and for a duration necessary for treating the disease or condition. The duration of treatment may vary for each subject, and the duration can be determined using specific criteria. [Examples]

[0113] List of abbreviations When used throughout the description of this invention, the following abbreviations should be understood to have the following meanings unless otherwise indicated: ACN or MeCN acetonitrile Bn Benzyl BOC or Boc tert-butyl dicarbonate t-Butyl Cy Cyclohexyl DCE (Dichloroethane (ClCH2CH2Cl)) DCM Dichloromethane (CH2Cl2) DIPEA or DIEA: Diisopropylethylamine DMAP 4-(N,N-dimethylamino)pyridine DMF Dimethylformamide DMA N,N-dimethylacetamide DMSO (Dimethyl Sulfoxide) eq or equiv equivalent Et ethyl Et2O Diethyl ether EtOH Ethanol HCl ethyl acetate HPLC (High-Performance Liquid Chromatography) Me methyl MeOH methanol MS mass spectrometry GC Gas Chromatography h time KF Karl Fischer min MsOH Methanesulfonic acid NMR nuclear magnetic resonance RP-HPLC Reverse-Phase High-Performance Liquid Chromatography rt room temperature TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) TLC (Thin-Layer Chromatography) V Volume

[0114] I. Chemical synthesis Unless otherwise noted, reagents and solvents were used as received from their commercial suppliers. Anhydrous solvents and oven-dried glassware were used for moisture and / or oxygen-sensitive synthetic conversions. Yields were not optimized. Reaction times were approximate and not optimized. Column chromatography and thin-layer chromatography (TLC) were performed on silica gel unless otherwise noted. [Examples]

[0115] Preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1)

[0116] [ka]

[0117] Step 1: 2-Hydroxybenzaldehyde-3,4,5,6-d4(Int-1)

[0118] [ka] A solution of phen-d6-ol (1.0 equivalent), magnesium chloride (1.5 equivalents), and triethylamine (3.7 equivalents) in ACN(10V) was stirred at 20°C for 0.5 hours. Formaldehyde (8.0 equivalents) was added, and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, and a 10% HCl solution (10V) was added. The mixture was extracted with SiO2 (3×6V). The combined organic layer was washed with brine (6V), dried over Na2SO4, and concentrated to obtain 2-hydroxybenzaldehyde-3,4,5,6-d4(Int-1) as a yellow oil.

[0119] Step 2: 1-(benzofuran-2-yl-4,5,6,7-d4)ethane-1-one (Int-2)

[0120] [ka] A solution of 2-hydroxybenzaldehyde-3,4,5,6-d4(Int-1) (1.0 equivalent), bromopropanone (1.0 equivalent), and potassium carbonate (3.0 equivalents) in acetone (14V) was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated, and the crude product was recrystallized to obtain (petroleum ether / SiO2 10:1), 1-(benzofuran-2-yl-4,5,6,7-d4)ethane-1-one (Int-2) as a yellow solid.

[0121] Step 3: 2-Ethylbenzofuran-4,5,6,7-d4(Int-3)

[0122] [ka] A solution of 1-(benzofuran-2-yl-4,5,6,7-d4)ethane-1-one (Int-2) (1.0 equivalent) in diethylene glycol (16V) was heated at 120°C. N2H4.H2O (2.0 equivalents) and water (1V) were added. The reaction mixture was heated at 180°C for 10 minutes and then cooled to 120°C. KOH (2.0 equivalents) was added, and the reaction mixture was heated at 120°C for 6 hours. The reaction mixture was cooled, poured into water, and extracted with ELISA (20V x 3). The combined organic layers were washed with brine (20V) and concentrated to obtain 2-ethylbenzofuran-4,5,6,7-d4 (Int-3) as a colorless oil.

[0123] Step 4: (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone(Int-4)

[0124] [ka] A solution of 2-ethylbenzofuran-4,5,6,7-d4(Int-3) (1.0 equivalent) and 4-methoxybenzoyl chloride (1.15 equivalents) in DCM (30V) was cooled to 0°C, and AlCl3 (1.1 equivalents) was added. The reaction mixture was stirred at 0°C for 2 hours. D2O (2V) was added dropwise to the mixture at 5°C, and the mixture was stirred for 0.5 hours. Water (8V) was added. The organic layer was separated, washed with brine (10V), dried over Na2SO4, and concentrated under vacuum at 40°C to obtain (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone (Int-4) as a yellow solid. 1 LCMS: 285 [M+H] + .

[0125] Step 5: (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5)

[0126] [ka] To a solution of (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-methoxyphenyl)methanone (Int-4) (1.0 equivalent) in DCM (10V), BBr3 (2.2 equivalents) was added dropwise at 0-5°C at 0°C. The reaction mixture was heated to room temperature and stirred for 14 hours. Ice water (10V) was added, and the mixture was stirred for 0.5 hours. The organic layer was separated, washed with brine (10V), dried over Na2SO4, and concentrated under vacuum at 40°C to obtain (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5) as a brown solid. 1LCMS: 271 [M+H] + .

[0127] Step 6: (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6)

[0128] [ka] To a solution of (2-ethylbenzofuran-3-yl-4,5,6,7-d4)(4-hydroxyphenyl)methanone (Int-5) (1.0 equivalent) in DCM (10V), NBS (1.7 equivalents) was added dropwise at 0-5°C at 10°C. The reaction mixture was heated to 18°C ​​and stirred for 16 hours. Additional NBS (0.14 equivalents) was added to the reaction mixture at 10°C and stirred at 18°C ​​for 16 hours. Additional NBS (0.05 equivalents) was added to the reaction mixture at 10°C and stirred at 18°C ​​for 3 hours. Water (15V) was added and the mixture was stirred for 0.5 hours. The organic layer was separated, washed with brine (15V), dried over Na2SO4, and concentrated under vacuum at 40°C to obtain a yellow solid. The yellow solid was slurryed in ELISA / n-heptane (1V / 10V) at 60°C for 2 hours. The mixture was cooled to 10°C and filtered to obtain (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): δ 11.05 (s, 1H), 7.92 (s, 2H), 2.84-2.75 (q, 2H), 1.27-1.20 (t, 3H); LCMS: 429 [M+H] + .

[0129] Step 7: 2,6-Dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-7)

[0130] [ka] A solution of (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl-4,5,6,7-d4)methanone (Int-6) (1.0 equivalent) and triethylamine (2.5 equivalents) in DCM(10V) was prepared, and acetyl chloride (2.0 equivalents) was added dropwise at 0-5°C at 0°C. The reaction mixture was heated to 15°C and stirred for 2 hours. Water (10V) was added. The organic layer was separated, washed with brine (10V), dried over Na2SO4, and concentrated under vacuum at 40°C to obtain a crude solid. The crude solid was decolorized with activated carbon (0.5 w / w) in ELISA (10V) at 50°C for 1 hour. The mixture was cooled to 30°C and filtered with a Kiesselgould auxiliary to remove the activated carbon. The filtrate was concentrated under vacuum at 40°C. The residue was dissolved in i-PrOH(2V) and heated at 60°C for 1 hour. The solution was cooled to 45°C, seed crystals (0.5% w / w) were added, and the mixture was stirred for 1 hour. The mixture was cooled to 25°C and stirred for 16 hours. The mixture was filtered, and the solid was dried to obtain 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (Int-7) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): δ 8.08 (s, 2H), 2.81-2.74 (q, 2H), 2.44 (s, 3H), 1.27-1.22 (t, 3H); LCMS: 471 [M+H] + .

[0131] Step 8: 2,6-Dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,7-d4)phenyl acetate (Int-8)

[0132] [ka] A mixture of 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenyl acetate (Int-7) (1.0 eq)NBS (1.1 eq) and AIBN (0.1 eq) in chlorobenzene (10 V) was heated at 55°C for 6 hours with stirring. The reaction mixture was cooled to 25°C, water (10 V) was added, and the mixture was stirred for 1 hour. The organic layer was separated, dried over Na2SO4, and concentrated to 1.5 to 2 V under vacuum. Heptane (5 V) was added to the solution and concentrated to 1.5 to 2 V under vacuum. This was repeated three times. Heptane (3 V) was added to the solution, cooled to 5°C, and stirred for 4 hours. The mixture was filtered, the solid was washed with heptane (1V x 2), and dried to obtain 2,6-dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,7-d4)phenyl acetate (Int-8) as a yellow solid. 1 LCMS: 469 [M+H - HBr] + .

[0133] Step 9: 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9)

[0134] [ka] A mixture of 2,6-dibromo-4-(2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,6,7-d4)phenyl acetate (Int-8) (1.0 eq) and CsOAc (5.0 eq) in N-methylpyrrolidine (8V) was stirred at 25°C for 12 hours. The reaction mixture was filtered. Water (15V) and HCl (10V) were added to the filtrate. The pH of the resulting mixture was adjusted from 2 to 3 with 12N HCl. The mixture was stirred for 1 hour, then allowed to stand for 0.5 hours. The organic solution was collected, and the aqueous solution was extracted with HCl (10V). The combined organic solution was washed with water (10V x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography to obtain 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9) as an off-white solid. 1 LCMS: 427 [M+H - CH3CO2H] + .

[0135] Step 10: (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1)

[0136] [ka] Cs2CO3 (3.0eq) was added to a mixture of 1-(3-(3,5-dibromo-4-hydroxybenzoyl)benzofuran-2-yl-4,5,6,7-d4)ethyl acetate (Int-9) (1.0eq) in methanol (10V). The reaction mixture was stirred at 28°C for 12 hours. Water (20V) was added, and the pH of the resulting mixture was adjusted to 2 to 3 with 12N HCl. The mixture was stirred for 1 hour. The mixture was filtered, and the filtered cake was washed with water (2V x 2). The filtered cake, a solution of ELISA (15V) and 1N HCl (5V) was stirred at 25°C for 1 hour. The organic solution was collected, dried over Na2SO4, and concentrated to 2 to 3V under vacuum. The solution was heated at 50°C for 1 hour, a seed crystal (1% w / w) was added, and the mixture was heated at 50°C for 2 hours. n-heptane (10V) was added dropwise, and the mixture was heated at 50°C for 2 hours. The mixture was cooled to 25°C and stirred for 12 hours. The solid was recovered by filtration and dried to obtain (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 1) as an off-white solid. 1 LCMS: 427 [M+H -H2O] + . [Examples]

[0137] Preparation of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d4)methanone (compound 2)

[0138] [ka]

[0139] Step 1: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-nitrobenzofuran-3-yl-4,5,7-d3)methanone (Int-10)

[0140] [ka] To a mixture of 2,6-dibromo-4-(2-ethylbenzofuran-3-carbonyl-4,5,6,7-d4)phenylacetate (34 g, 72.3 mmol) (Int-7) in dichloromethane (250 mL), nitronium tetrafluoroborate (11.5 g, 86.8 mmol) was slowly added at 0°C. The reaction mixture was stirred overnight at room temperature. The mixture was quenched with brine and extracted with dichloromethane. The organic phase was washed with brine, dried on sodium sulfate, and evaporated to dryness. The crude product was purified by column chromatography on silica gel to obtain (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-nitrobenzofuran-3-yl-4,5,7-d3)methanone (Int-10) (12.5 g, 37%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.1 (bs, 1 H), 7.98 (s, 2 H), 2.87 (q, J =7.2 Hz, 2 H), 1.3 (t, J =7.2 Hz, 3 H).

[0141] Step 2: (6-amino-2-ethylbenzofuran-3-yl-4,5,7-d3)(3,5-dibromo-4-hydroxyphenyl)methanone (Int-11)

[0142] [ka] A mixture of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-nitrobenzofuran-3-yl-4,5,7-d3)methanone(Int-10) (12.5 g, 26.5 mol), iron powder (7.4 g, 132 mmol), concentrated hydrochloride (1.2 mL, 13.3 mmol), ethanol (250 mL), and H2O (50 mL) was heated under reflux for 2 hours. The mixture was filtered to remove the iron powder. The solution was evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain (6-amino-2-ethylbenzofuran-3-yl-4,5,7-d3)(3,5-dibromo-4-hydroxyphenyl)methanone(Int-11) (9.2 g, 79%) as a yellow solid. ESIMS (m / z): 441.9, 439.9, 437.9 (M+H) + .

[0143] Step 3: 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-diazonium-4,5,7-d3 tetrafluoroborate (Int-12)

[0144] [ka] A mixture of (6-amino-2-ethylbenzofuran-3-yl-4,5,7-d3)(3,5-dibromo-4-hydroxyphenyl)methanone (Int-11) (9.2 g, 20.8 mmol) and fluoroboric acid (4.2 g, 22.9 mmol) in H2O (100 mL) was slowly added to a solution of sodium nitrite (1.58 g, 22.9 mmol) in H2O. The reaction mixture was stirred overnight at room temperature. The resulting suspension was then filtered under vacuum. The residue was washed with ice water and dried under vacuum to obtain 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-diazonium-4,5,7-d3 tetrafluoroborate (Int-12) (11 g, 98%) as a pink solid, which was used for the next step without further purification. ESIMS (m / z): 455.9, 453.9, 451.9 (M+H) + .

[0145] Step 4: (3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-yl-4,5,7-d3)boronic acid (Int-13)

[0146] [ka] To a mixture of diboronic acid (3.65 g, 40.6 mmol) in DMF (160 mL), 3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-diazonium-4,5,7-d3 tetrafluoroborate (Int-12) (11 g, 20.3 mmol) was added at room temperature. The reaction mixture was stirred at the same temperature for 2 hours. The mixture was quenched with brine and extracted with ethyl acetate. The organic phase was washed with brine, dried on sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain (3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-yl-4,5,7-d3)boronic acid (Int-13) (3.9 g, 41%) as a white solid. ESIMS (m / z): 473.9, 471.9, 469.9 (M+H) + .

[0147] Step 5: (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxybenzofuran-3-yl-4,5,7-d3)methanone (Int-14)

[0148] [ka] A mixture of (3-(3,5-dibromo-4-hydroxybenzoyl)-2-ethylbenzofuran-6-yl-4,5,7-d3)boronic acid (Int-13) (3.9 g, 8.28 mmol) and sodium hydroxide (662 mg, 16.6 mmol) in THF (60 mL) was to be to which hydrogen peroxide (w / w 48%, 1.2 g, 16.6 mmol) was added dropwise at 0°C. The mixture was stirred at room temperature for 2 hours. It was quenched to pH 5-6 with 1 M hydrochloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxybenzofuran-3-yl-4,5,7-d3)methanone (Int-14) (3.0 g, 83%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.9 (bs, 1 H), 9.68 (bs, 1 H), 7.91 (s, 2 H), 2.74 (q, J=7.6 Hz, 2 H), 1.24 (t, J =7.6 Hz, 3 H). ESIMS (m / z): 445.9, 443.9, 441.9 (M+H) + .

[0149] Step 6: 4-(6-acetoxy-2-ethylbenzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenylacetate (Int-15)

[0150] [ka] A mixture of (3,5-dibromo-4-hydroxyphenyl)(2-ethyl-6-hydroxybenzofuran-3-yl-4,5,7-d3)methanone (Int-14) (3.0 g, 6.78 mmol) and triethylamine (1.71 g, 17.0 mmol) in dichloromethane (60 mL) was to be mixed with acetyl chloride (1.06 g, 13.6 mmol) dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with brine and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain 4-(6-acetoxy-2-ethylbenzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-15) (2.8 g, 78%) as a white solid.

[0151] Step 7: 4-(6-acetoxy-2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenylacetate(Int-16)

[0152] [ka] A mixture of 4-(6-acetoxy-2-ethylbenzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-15) (2.8 g, 5.31 mmol), N-bromosuccinimide (945 mg, 5.31 mmol), and 2,2'-azobis(2-methylpropionitrile) (87 mg, 0.53 mmol) in perchloromethane (80 mL) was heated overnight under reflux. The mixture was evaporated to dryness. The crude product was purified by column chromatography on silica gel to obtain 4-(6-acetoxy-2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-16) (3.06 g, 95%) as a white solid.

[0153] Step 8: 4-(6-acetoxy-2-(1-hydroxyethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenylacetate(Int-17)

[0154] [ka] A mixture of 4-(6-acetoxy-2-(1-bromoethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-16) and silver(I) oxide (1.75 g, 7.57 mmol) in N,N-dimethylformamide (40 mL) and H2O (8 mL) was heated at 70°C for 6 hours. The mixture was filtered to remove silver(I) oxide. The filtrate was quenched with brine and extracted with ethyl acetate. The organic phase was washed with brine, dried on sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel to obtain 4-(6-acetoxy-2-(1-hydroxyethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-17) (2.3 g, 84%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.7 (bs, 1 H), 8.14 (bs, 1 H), 5.65 (d, J=4.8 Hz, 1 H), 4.80 (dd, J=6.8 Hz, 4.8 Hz, 1 H), 2.45 (s, 3 H), 2.33 (s, 3 H), 1.48 (d, J=4.8 Hz, 3 H). ESIMS (m / z): 527.9, 525.9, 523.9 (M+H) + .

[0155] Step 9: (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (Compound 2)

[0156] [ka] A mixture of 4-(6-acetoxy-2-(1-hydroxyethyl)benzofuran-3-carbonyl-4,5,7-d3)-2,6-dibromophenyl acetate (Int-17) (2.3 g, 4.24 mmol) and lithium hydroxide hydrate (427 mg, 10.2 mmol) in methanol (40 mL) and H2O (5 mL) was stirred at room temperature for 2 hours. The mixture was poured into 30 mL of H2O and evaporated under vacuum to remove the methanol. The resulting solution was acidified to pH 5-6 with 1 M hydrochloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and evaporated to dryness. Purification of the residue by column chromatography on silica gel yielded (3,5-dibromo-4-hydroxyphenyl)(6-hydroxy-2-(1-hydroxyethyl)benzofuran-3-yl-4,5,7-d3)methanone (compound 2) (1.06 g, 55%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.1 (bs, 1 H), 9.75 (bs, 1 H), 7.92 (s, 2 H), 5.47 (bs, 1 H), 4.77 (d, J=6.8 Hz, 1 H), 1.45 (d, J=6.8 Hz, 3 H). ESIMS (m / z): 443.9, 441.9, 439.9 (M+H) + .

[0157] II. Biological Data [Examples]

[0158] In vitro interaction studies of compound 1, compound 2, benzobromarone, and 1'-OH benzbromarone with the human URAT1 uptake transporter. Uptake experiments were performed using MDCKII cells that stably express the human URAT1 uptake transporter. Cells were cultured at 37±1°C in a 95:5 air:CO2 atmosphere and cultured on standard 96-well tissue culture plates at the cell counts listed in Table 1.

[0159] [Table 1]

[0160] Before the experiment, remove the culture medium and fill the cells with Cl - The samples were washed twice with 100 μL of HBSS without any residue. The uptake experiment was performed at 37±1°C in a solution containing the probe substrate (20 μM uric acid) and the test material (TA) or solvent at pH 7.4. - The procedure was performed in 50 μL of HBSS without any additives. The organic solvent concentration was equal in all wells and did not exceed 1% (v / v).

[0161] The treatment groups are shown in Table 2.

[0162] [Table 2]

[0163] After the experiment, the cells were cleaned with Cl - The samples were washed twice with 100 μL of ice-cold HBSS (without chlorine) and dissolved in 50 μL of 0.1 M NaOH. Radiolabeled probe substrate transport was determined by measuring aliquots (35 μL) from each well for liquid scintillation counting.

[0164] Results: The test materials (compound 1, compound 2, benzbromarone, and 1'-OH benzbromarone) were dissolved in HBSS buffer at all tested concentrations, with the highest tested concentration being 10 μM. Compound 1 was found to reduce URAT1-mediated uric acid accumulation, and IC12 was reduced. 50 Compound 2 inhibited URAT1-mediated uric acid accumulation at a concentration of 10 μM, at a rate of 0.067 μM. Compound 2 inhibited URAT1-mediated uric acid accumulation. 50 =0.913 μM inhibited it. Benzbromarone inhibits URAT1-mediated uric acid accumulation. 50 =0.196 μM inhibited 98% at a concentration of 10 μM. 1'-OH benzbromarone inhibits URAT1-mediated uric acid accumulation. 50 At a concentration of 1.67 μM, the inhibitory effect was 94% at 0.050 μM. [Examples]

[0165] Renal function safety pharmacology study in rats following single oral administration of compound 1. Sixty-four Sprague Dolly rats (32 per sex) were randomly assigned to four groups (8 animals per sex per group) and received either a single oral gastrointestinal feeding of 0.5% methylcellulose (MC) in water (0 mg / kg of compound 1), or compound 1 at doses of 10, 30, and 100 mg / kg for males and 5, 15, and 50 mg / kg for females. Clinical observations, body weight, water consumption, blood clinical chemistry, urine chemistry, and urinalysis were performed, both lateral and detailed, in the cage. Osmolality, osmolality gap, urine volume, water intake rate, fluid balance, urinary excretion, renal creatinine clearance, renal clearance, free water clearance, and fractionated electrolyte clearance were calculated and evaluated. All animals were euthanized on day 2 after planned observation. Blood samples for clinical chemistry analysis were collected from all animals 24 hours after administration, and each animal was subsequently euthanized. Urine samples and urinalysis results for clinical chemistry were collected from all animals before administration (approximately 24 hours prior) and at 0 to 6 hours and 6 to 24 hours after administration.

[0166] As shown in Table 3, compound 1 reduced the urinary albumin-to-creatinine ratio (UACR) in rats. Since UACR is a key marker for chronic kidney disease, compound 1 may be potentially beneficial for patients with CKD.

[0167] [Table 3-1]

[0168] [Table 3-2] [Examples]

[0169] In vitro metabolism of compound 1 and benzbromarone in human liver microsomes The incubation mixture consisted of human liver microsomes (0.5 mg / mL protein), potassium phosphate buffer (100 mM, pH 7.4), 10 mM MgCl2, and the test material (2 μM compound 1) in a total volume of 0.5 mL. The mixture was preheated at 37°C for 5 minutes, then 1 mM NADPH was added to initiate the reaction, and the mixture was incubated in a shaking water bath at 37°C for 60 minutes. The reaction was terminated by adding 0.5 mL of acetonitrile cooled with ice. Time 0 incubation was also carried out by adding acetonitrile, after which microsomes were added to the incubation mixture as reference samples for each species. Following vortex stirring and centrifugation at 15,000 g for 3 minutes at room temperature, the resulting supernatant was concentrated at 33°C under a nitrogen stream until approximately 0.5 mL of sample remained. The extract was then transferred to a 1.5 mL centrifugation vial and centrifuged at 15,000 g for 3 minutes. Finally, aliquots of the supernatant were transferred to HPLC vials and subjected to HPLC-MS analysis.

[0170] HPLC analysis: Metabolic profile of compound 1, reversed phase C 18 This is done using columns, and the conditions are summarized below:

[0171] JPEG0007857235000038.jpg114155

[0172] MS Analysis: Mass spectral analysis was performed using an Agilent single quadrupole mass spectrometer equipped with an Agilent 1100HPLC system. The mass spectrometer was equipped with an electrospray ionization (ESI) source and operated in negative scan mode between 400 amu and 500 amu. JPEG0007857235000039.jpg57161

[0173] Results: Compound 1 remained stable in human microsomes after 60 minutes of incubation, with 82.5% of the parent compound remaining. Compound 1 was converted to its carbonyl metabolite (M1) and monooxidized metabolite (M3) in human liver microsomes in the presence of NADPH. JPEG0007857235000040.jpg25168

[0174] Metabolic profiling of benzbromarone was performed using a method similar to that described above. Following incubation, the majority of benzbromarone was metabolized to 6-OH benzbromarone, 1'-OH benzbromarone, and two dihydroxy metabolites of benzbromarone, with benzbromarone accounting for 13.1% of the final mixture. JPEG0007857235000041.jpg30153 [Examples]

[0175] Four-week toxicity study of compound 1 in Sprague Dolly rats Study design: The study groups are shown in Table 4.

[0176] [Table 4]

[0177] The animals were administered compound 1 with a vehicle (0.5% (w / v) methylcellulose (MC) in water for injection) or via oral gastric tube feeding at a dose volume of 10 mL / kg, as summarized in Table 4, for 28 consecutive days. On day 29, the living TS animals (all animals in the study) were euthanized and subjected to a complete gross necropsy, which included a gross examination of the external surface of the body, all orifices, the cranial cavity, the external surface of the brain, the thoracic, abdominal and pelvic cavities, and their internal organs, cervical region, sacrificial bodies, and genitals. Organs were weighed as soon as possible from all major study animals during the planned necropsy. Tissues from groups 1 and 5 animals at the time of final sacrificial death, tissues from animals found dead or sacrificially killed, and gross lesions from all animals were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and microscopically examined by a certified veterinary pathologist.

[0178] Results: No deaths were observed in any of the dose groups (2, 5, 15, and 50 mg / kg / day) following administration of compound 1 on day 28. No abnormal clinical signs were observed. In addition, there was no effect on body weight and food consumption in any of the animals in the study. Liver weight increased by 50 mg / kg / day in males and ≥15 mg / kg / day in females, and kidney weight increased by 50 mg / kg / day in females. Findings at high or moderately high doses were resolved after a 4-week recovery period. NOAEL levels were established at 50 mg / kg (equivalent to 500 mg in humans). [Examples]

[0179] Four-week toxicity study of compound 1 in cynomolgus monkeys. Study design: The study groups are shown in Table 5.

[0180] [Table 5]

[0181] The animals were administered compound 1 with a vehicle (0.5% (w / v) methylcellulose (MC) in water for injection) or via oral intubation at a dose volume of 5 mL / kg, as summarized in Table 5, for 28 consecutive days, followed by rinsing with approximately 5 mL of drinking water. On day 29, the living TS animals (all animals in the study) were euthanized and subjected to a complete gross necropsy, which included a gross examination of the external surface of the body, all orifices, the cranial cavity, the external surface of the brain, the thoracic, abdominal and pelvic cavities, and their internal organs, cervical region, sacrificial bodies, and genitals. Organs were weighed as soon as possible from all major study animals during the planned necropsy. Tissues from animals at the time of final sacrificial death, tissues from animals found dead or sacrificially killed, and gross lesions from all animals were embedded in paraffin, sectioned, stained with hematoxylin and eosin, and microscopically examined by a certified veterinary pathologist. Results: No deaths were observed in any of the administration groups (10, 30, and 150 mg / kg / day) following administration of compound 1 on day 28. No abnormal clinical signs were observed. In addition, there was no effect of body weight on food consumption in any of the animals in the study. Liver weight tended to be higher at 150 mg / kg / day in males, but the difference was not statistically significant. There were no findings after the 4-week recovery period. NOAEL levels were confirmed at 30 mg / kg (equivalent to 600 mg in humans). [Examples]

[0182] Phase 1 clinical trial with Compound 1 (single dose) Compound 1 was tested in Phase 1, and a randomized, double-blind, placebo-controlled human first-dose study was conducted to evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and the prior food effect of a single dose of Compound 1 in healthy adult males. The treatment groups included Cohort 1 (15 mg or placebo, fasted, oral suspension), Cohort 2 (50 mg or placebo, fasted, suspension), Cohort 3 (100 mg or placebo, fasted, oral suspension), Cohort 4 (150 mg or placebo, fasted, oral suspension), Cohort 6 (50 mg or placebo, fed, oral suspension), and Cohort 7 (50 mg or placebo, fasted, oral capsule). A total of 35 subjects received a single dose of Compound 1 (15 to 150 mg) in a fed or fasted state. An additional 8 subjects received placebo.

[0183] Pharmacokinetics In a Phase 1 study of compound 1 in healthy adult males, plasma PK was evaluated following a single dose of compound 1 or placebo. Compound 1 was administered as a racemic compound in a 1:1 ratio of its two enantiomers. Both the R-enantiomer and S-enantiomer of compound 1 were observed following a single oral dose of racemic compound 1. The absorption rate of compound 1 was measured under fasting conditions, with a median T value ranging from 3 to 5 hours post-administration. maxwas moderate (Figure 1 and Table 6). Absorption was delayed (median T of 8 hours) when Compound 1 was administered in the fed state (Figure 2 and Table 6). The plasma concentration of Compound 1 decreased with an average terminal half-life value of approximately 10 to 13 hours (Table 6). The total plasma clearance of Compound 1 was approximately 1.0 L / hour with a volume of distribution in the range of 14 to 18 L. In circulation, it was observed that the exposure of the S-enantiomer of Compound 1 was higher than that of the R-enantiomer of Compound 1. The S / R ratio was approximately 1.7 to 1.8 for AUC max (Figure 2 and Table 6). The plasma concentration of Compound 1 decreased with an average terminal half-life value of approximately 10 to 13 hours (Table 6). The total plasma clearance of Compound 1 was approximately 1.0 L / hour with a volume of distribution in the range of 14 to 18 L. In circulation, it was observed that the exposure of the S-enantiomer of Compound 1 was higher than that of the R-enantiomer of Compound 1. The S / R ratio was approximately 1.7 to 1.8 for AUC inf and 1.1 to 1.3 for C max (Table 11). The results were consistent with the observations in animal studies, and the higher exposure of the S-enantiomer contributed to the in vivo conversion of the R-enantiomer.

[0184]

Table 6

[0185]

Table 7

[0186] The statistical evaluation of dose proportionality showed that the plasma exposure AUC (AUC inf ) of Compound 1 showed a dose-proportional increase in the dose range of 15 to 150 mg under fasting conditions (power model exponential function = 1.0, CI95% within the limit of 0.8 to 1.25), while C max showed a slightly less increase than dose-proportional increase (power model exponential function = 0.88, CI95% outside the limit of 0.8 to 1.25) (Table 8). Figures 3 and 4 show the increase in AUC (Figure 3) and C max (Figure 4) with the dose and their deviation from the line of identity or dose proportionality.

[0187]

Table 8

[0188] The effect of food was evaluated at the 50 mg dose level. The group with compound 1 administered in the fed state (high-fat, high-calorie diet) showed slower absorption (T max was 3 to 5 hours later at 8 hours after dosing than in the fasting state) and lower exposure (Tables 6 and 9) compared to when compound 1 was administered under fasting conditions. The effect of administration in the fed state was more pronounced for C max than for AUC (Tables 9 and Figure 2). In the fed state, C max was approximately 33%, while AUC decreased by approximately 13% with food.

[0189]

Table 9

[0190] Pharmacodynamics When a single oral dose of compound 1 at 15, 50, 100, and 150 mg was administered under fasting conditions, the mean sUA level showed a dose-dependent decrease at doses of 50 mg and above compared to the placebo group (Tables 10 and Figure 5). The decrease in sUA appeared to reach a plateau at 100 mg and below. At doses of 50 mg and above, the onset of the sUA-lowering effect was observed at 6 hours after dosing, and the minimum was achieved at 24 to 36 hours after dosing. sUA remained lower than the baseline level for up to 72 hours after dosing, indicating a sustained sUA-lowering effect and a PD effect significantly longer than the PK half-life of compound 1. Under fasting conditions, administration of 15, 50, 100, and 150 mg of compound 1 resulted in mean decreases of approximately -6%, -42%, -59%, and -59%, respectively, compared to an approximately 0.2% increase in the pooled placebo group at the sUA level at 24 hours after dosing (Tables 11 and Figure 6). The decrease in the sUA level at 24 hours after dosing is partially contributed by the formation of the compound 1 metabolite, 6-OH compound 1.

[0191]

Table 10

[0192] [Table 11]

[0193] C as a result of the eating state max Despite the decrease in sUA, no difference was observed in the decrease in sUA over 120 hours after administration when compound 1 was administered with or without food (50 mg) (Figure 7). [Examples]

[0194] Phase 1 clinical trial of Compound 1 (multiple dose escalations). Compound 1 was tested in a Phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple doses of Compound 1 in healthy adult males. A total of 24 subjects received multiple doses (25 to 75 mg) of Compound 1 under fasting conditions. An additional 6 subjects received placebo.

[0195] Pharmacokinetics Mild to moderate accumulation was observed following once-daily administration of compound 1 at 25, 50, or 75 mg for 10 days. Accumulation was C max Then it is approximately 1.3 to 1.4 times, AUC 0-24 The ratio was 1.4 to 1.5 times (Table 12 and Figure 8).

[0196] [Table 12-1]

[0197] [Table 12-2]

[0198] Pharmacodynamics When compound 1 was administered once daily in oral capsules of 25, 50 or 75 mg under fasting conditions for 10 days, the mean sUA levels showed a dose-dependent decrease when compared to the placebo group (Figure 9). On day 10, compound 1 significantly decreased the sUA concentration by up to 44% (41% at trough) at a 25 mg dose for 10 days, up to 67% (58% at trough) at 50 mg, and up to 69% (65% at trough) at a 75 mg dose (Figure 10). In comparison, in the placebo group, only a 7.2% decrease was observed on day 10 before dosing. The steady-state sUA lowering effect was achieved approximately 5 days later.

Example

[0199] Phase 2a clinical trial with compound 1 In phase 2a, adults with gout (sUA > 7 mg / dL) were randomized in a single-site, 2-sequence, crossover study to receive once-daily treatment for 3 weeks with compound 1 50 mg alone, febuxostat 40 mg alone, or a combination of compound 1 50 mg and febuxostat 40 mg. In additional arms in this study, allopurinol 300 mg alone or a combination of compound 1 50 mg and allopurinol 300 mg was included. Serial blood samples were collected at the end of the treatment week (days 7, 14, and 21) for measurement of sUA, compound 1, febuxostat, or allopurinol pharmacokinetics and pharmacodynamics. Urine samples were collected for assessment of uric acid excretion. Experimental safety tests, vital signs, and electrocardiograms were collected throughout the study.

[0200] Following treatment with compound 1, 96% of patients had sUA levels below 6 mg / dL, and 93% had levels below 5 mg / dL. Compound 1 reduced sUA from the mean baseline (8.9 mg / dL) to 4.2 mg / dL on day 7 / 21, which represents a 53% reduction. In comparison, febuxostat 40 mg reduced the mean sUA level to a maximum of 5.5 mg / dL (38.9%) on day 7 / 21, reducing levels below 6 mg / dL in 67% of patients and below 5 mg / dL in 33% of patients. Allopurinol 300 mg reduced the mean sUA level to a maximum of 5.8 mg / dL on day 7 / 21, reducing levels below 6 mg / dL in 56% of patients and below 5 mg / dL in 11% of patients. The combination of compound 1 with febuxostat further reduced the mean sUA level to 2.7 mg / dL (a 70.7% reduction), with patient ejection fractions of 100%, 100%, and 88% for <6, 5, and 4 mg / dL, respectively. The combination of compound 1 with allopurinol further reduced the mean sUA level to 3.0 mg / dL (a 66.0% reduction), with patient ejection fractions of 100%, 100%, and 100% for <6, 5, and 4 mg / dL, respectively. Taking into account the increased BMI and body weight of gout patients in the study, the pharmacokinetics of compound 1 in gout patients were similar to those in healthy subjects. Compound 1 showed similar exposure levels in normal patients and patients with mild renal impairment. In patients with mild renal impairment, compound 1 reduced sUA from 8.6 ± 1.1 mg / dL to 4.5 ± 0.8 mg / dL. Compound 1 was well tolerated. No clinically significant experimental or ECG abnormalities were observed. Finally, subjects in studies with albuminuria showed a significant decrease in the urinary albumin-to-creatinine ratio (UACR), which decreased from 96 mg / g at baseline to 41 mg / g after 7 days of treatment with compound 1 (Table 13). 7 days of administration of compound 1 in combination with allopurinol further reduced the UACR to 35 mg / g (day 14). However, after a further 7 days of treatment with allopurinol alone, the subjects' UACR increased to 55 mg / g (day 21).

[0201] [Table 13]

[0202] In summary, compound 1 demonstrated a remarkable ability to reduce sUA levels with a high response rate at 50 mg in patients with gout. Following a 7-day administration of compound 1, sUA levels decreased to less than 6 mg / dL post-administration 24 hours in all patients. [Examples]

[0203] Phase II clinical trial of compound 1 or compound 2 in heart failure with preserved ejection fraction (HFpEF) The primary objective of this Phase 2 study is to evaluate the effects of the combination of compound 1 or compound 2 with allopurinol on motor function in patients with HFpEF.

[0204] Patients: Eligible individuals are men and women aged 40 or older.

[0205] standard: Registration criteria: ● Signed informed consent can be granted in the informed consent form, including compliance with the requests and regulations listed in the protocol. ● Provision of signed and dated written informed consent forms before any mandatory research-specific procedures, sampling, and analysis. ● Providing signed and dated written genetic informed consent before collecting samples for genetic analysis. ● The patient must be 40 years of age or older at the time of signing the informed consent form. ● Patients with hyperuricemia defined as a serum uric acid level >6 mg / dL. ● Patients with a recorded diagnosis of symptomatic heart failure with preserved ventricular ejection fraction according to all of the following criteria: ● At the time of participation, the participant must have a New York Cardiology Functional Classification (FCL) of 2 to 3. ● Prior to participation, participants must have a history of typical symptoms / signs of heart failure >6 weeks, which are stably medically managed with at least intermittent need for diuretic treatment. Typical symptoms of heart failure include shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, decreased exercise tolerance, fatigue, tiredness, increased recovery time after exercise, and ankle swelling. Typical signs associated with heart failure include elevated jugular venous pressure, hepatijugal reflux, and a third heart sound (gallop rhythm). Less specific symptoms include weight gain (>2 kg / week), weight loss (in advanced heart failure), tissue wasting (cachexia), heart murmur, peripheral edema (ankle, sacrum, scrotum), pulmonary crackles, decreased airflow and bluntness to percussion at the base of the lungs (pleural effusion), tachycardia, irregular pulse, tachypnea, Cheyne-Stokes respiration, hepatomegaly, ascites, cold extremities, oliguria, and narrow pulse pressure. ●Left ventricular ejection fraction ≥45% ● For patients without ongoing atrial fibrillation / flutter, N-terminal pro-β natriuretic peptide (N-terminal pro-β natriuretic peptide) ≥ 125 pg / mL (≥ 14.75 pmol / L) in Visit 2. If ongoing atrial fibrillation / flutter is present at the time of sample collection, N-terminal pro-β natriuretic peptide must be ≥ 250 pg / mL (≥ 29.51 pmol / L), or the patient must have a history of pulmonary capillary wedge pressure ≥ 15 mmHg at rest, or pulmonary capillary wedge pressure ≥ 20 mmHg during exercise. ● Patients who, during the cardiopulmonary exercise test performed during screening, are able to exercise to near exhaustion during the cardiopulmonary exercise test, as indicated by a respiratory exchange rate of ≥1.05. If a patient does not achieve a respiratory exchange rate of ≥1.05, the cardiopulmonary exercise test may be repeated once after the initial test (but before randomization), at least 48 hours but less than 2 weeks, in which case the second test will serve as the baseline. ● Patients with a projected peak oxygen volume of ≤75% on a treadmill or a projected peak oxygen volume of ≤68% on a cycle ergometer, based on normal values. ● Patients with heart failure with preserved ventricular ejection fraction who are being treated according to locally recognized guidelines in medical standards. Therapy should be individually optimized and stable for ≥4 weeks (excluding diuretics), and should include treatment for hypertension (targeting systolic blood pressure <130 mmHg as suggested in the 2017 American College of Cardiology / American Heart Association / Heart Failure Society of American Heart Failure guidelines), ischemic heart disease, and atrial fibrillation, unless contraindicated or tolerable. Patients being treated with a sodium-glucose transporter protein 2 inhibitor or sacubitril / valsartan must have been receiving the treatment stably for ≥4 weeks prior to randomization. ● Male or female ● Negative pregnancy test (urine or serum) for women of childbearing age. Female patients must be one year postmenopausal, sterilized, or using an acceptable method of contraception (with a failure rate of <1% per year) for the duration of the study (from the time they sign the consent) and for four weeks after the last dose of the study treatment to prevent pregnancy. Patient consent to complete abstinence, presumably as part of the patient's normal lifestyle, may also be included. Exclusion criteria: ● Estimated glomerular filtration rate <30 ml / min / 1.73 m 2 (Based on the formula from the Chronic Kidney Disease Epidemiology Collaboration) ● Severe liver damage (Child Pew Class C) ● The presence of any condition that interferes with the exercise test, e.g.: ● Lameness that limits exertion ● Uncontrolled bradyarrhythmia or tachyarrhythmia (Pacemaker intervention is permitted at the discretion of the principal investigator, provided that the same pace mode / activity can be used in baseline and follow-up cardiopulmonary exercise tests). ● A clinically significant musculoskeletal disorder or orthopedic condition that limits the ability to perform cardiopulmonary exercise tests (e.g., arthritis, or injury to the foot, leg, knee, or buttocks). ● Severe obesity (Obesity Index ≥ 50.0 kg / m²) 2 ) ● Amputation with prosthetics without stable prosthesis function within the past 3 months ● Any symptoms that, in the opinion of the principal investigator, are considered contraindications for cardiopulmonary exercise testing evaluation (e.g., severe visual impairment). ● In the opinion of the principal investigator, any condition other than heart failure that is a major limitation on exercise ● Known history of recorded left ventricular ejection fraction <40% ● In the opinion of the principal investigator, a highly probable alternative or concomitant diagnosis that could explain the patient's symptoms and signs of heart failure (e.g., anemia, hypothyroidism) ● Human leukocyte antigen HLA-B * Known carriers of the 58:01 allele. Patients suspected to be of Han Chinese, Korean, or Thai descent, and therein is human leukocyte antigen (HLA). * Patients from a population known to have high levels of the B58:01 allele will undergo genetic testing; for other patients, genetic testing will be conducted at the discretion of the principal investigator. ● Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome ● Patients who are severely physically or mentally incapacitated, and patients who, in the opinion of the principal investigator, are unable to perform the tasks related to the protocol. ● In the opinion of the principal investigator, there is no indication of any condition that would place the patient at excessive risk, or any condition that could jeopardize the quality of the resulting data. ● Current acute decompensated heart failure, or hospitalization due to decompensated heart failure prior to participation <4 weeks prior to participation ● Myocardial infarction, unstable angina, coronary artery regeneration (percutaneous coronary intervention or coronary artery bypass grafting), atrial flutter / fibrillation ablation, valve repair / replacement, implantation of cardiac resynchronization therapy device, stroke, or transient ischemic attack within 6 months prior to participation. ● Planned coronary artery regeneration, atrial flutter / fibrillation ablation, and / or valve repair / replacement. ● Atrial fibrillation with a sustained resting heart rate > 110 beats per minute ● Primary pulmonary hypertension, chronic pulmonary embolism, severe lung disease, including chronic obstructive pulmonary disease (COPD) (i.e., requiring home oxygen supplementation, use of chronic oral corticosteroid therapy at doses equivalent to 10 mg or more of prednisone, or hospitalization for an exacerbation of chronic obstructive pulmonary disease (COPD) requiring respiratory support within 12 months prior to participation). ● Previous heart transplantation or complex congenital heart disease. Planned cardiac resynchronization therapy. Previous implantation of ventricular assist devices or similar devices, or implantation anticipated during the course of research. ● Heart failure resulting from known infiltrative myocardium (e.g., amyloid, sarcoid, lymphoma, endocardial fibrosis, hemochromatosis), active myocarditis, constrictive pericarditis, cardiac tamponade, known hereditary hypertrophic myocardial disorder or obstructive hypertrophic myocardium, arrhythmic right ventricular cardiomyopathy / dysplasia, or severe primary valvular disease that has not been corrected. ●Patients with a QT interval >470 msec and QRS interval (<120 ms) corrected by the Fridericia formula (QTcF) include patients diagnosed with long QT syndrome and those with a family history of long QT syndrome. ● Uncontrolled hypertension with systolic blood pressure > 160 mmHg and / or diastolic blood pressure > 100 mmHg ●History of blood disorders: bone marrow suppression (e.g., thrombocytopenia, leukopenia, granulocytopenia, pancytopenia) and aplastic anemia ● Patients with the following bilateral upper or lower arm pathologies may be randomized during this study, but will not be permitted to participate in reactive hyperemia assessment. ● Presence of fistula / arteriovenous (AV) shunt ● Other structural or vascular abnormalities ● Six months prior to randomization, patients were treated with any medication for hyperuricemia. Medications for hyperuricemia include all xanthine oxidase inhibitors (allopurinol, febuxostat, and topiroxostat), as well as uric acid transporter 1 inhibitors (resinurad, berinurad, probenecid, and benzbromarone), and uric acid oxidases (pegroticase, rasburicase). ● Treated with potent or moderate organic anion transport polypeptides (OATPs) ● Inhibitor (Entresto is not considered a potent or moderate organic anion transport polypeptide (OATP) inhibitor). ● Patients being treated with potent P-glycoprotein and / or CYP3A4 inhibitors due to potential drug-drug interactions with colchicine. ● Participation in another clinical trial using the administered investigational drug (currently or within one month prior to screening). ● Participants are currently participating in or planning to begin an organized exercise training program within one month prior to screening. ● Claustrophobia ● Involvement in the planning and / or execution of the research (applicable to both AZ staff and / or staff at the research site). ● The principal investigator's judgment that the patient should not participate in the study if the patient has a tendency to fail to comply with the study procedures, rules, and requirements. ●In this study, participants were screened in more than one or previous randomization rounds. ●Known hypersensitivity to allopurinol or any organic anion transport polypeptide inhibitor, including known hypersensitivity to previous analytic reactions or severe skin adverse reactions triggered by allopurinol. ● Patients who are pregnant (confirmed by pregnancy testing), breastfeeding, or planning to become pregnant.

[0206] Research Design: ● Allocation: Randomization ● Therapeutic intervention model: Parallel allocation ● Masking: Triple-blind (participant, healthcare provider, principal investigator) ●Main purpose: Treatment

[0207] Measuring the first outcome: ● To evaluate the effect of compound 1 or 2 + allopurinol on athletic performance compared to placebo, we measured the change in peak V02 from baseline at 28 weeks in athletic performance (compound 1 or 2 + allopurinol vs. placebo) [Timeframe: from baseline at 28 weeks].

[0208] Measuring the second outcome: ● To evaluate the effect of compound 1 or 2 + allopurinol on exercise capacity compared to allopurinol monotherapy, we measured the change in peak V02 from baseline at 28 weeks in exercise capacity (compound 1 or 2 + allopurinol vs. placebo + allopurinol) [Timeframe: from baseline at 28 weeks]. ● Change from baseline at 28 weeks in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) [Timeframe: from baseline at 28 weeks] to evaluate the effect of compound 1 or 2 + allopurinol on the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) compared to placebo. Scores range from 0 to 100, with higher scores indicating better patient outcomes. ● Change from baseline at 28 weeks in the Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) [Timeframe: from baseline at 28 weeks] to evaluate the effect of compound 1 or 2 + allopurinol compared to allopurinol monotherapy. Scores range from 0 to 100, with higher scores indicating better patient outcomes.

[0209] [Table 14]

[0210] The examples and embodiments described herein are for illustrative purposes only, and in some embodiments, various modifications or changes will be included in the scope of this disclosure and the appended claims.

Claims

1. A pharmaceutical composition for use in the treatment or prevention of chronic kidney disease, Therapeutic dose of (3,5-dibromo-4-hydroxyphenyl)(2-(1-hydroxyethyl)benzofuran-3-yl-4,5,6,7-d ４ ) comprising methanone, and at least one inactive component selected from pharmaceutically acceptable carriers, diluents, and excipients, The effective therapeutic dose is approximately 10 mg to approximately 200 mg. The aforementioned therapeutically effective dose is administered orally. The aforementioned therapeutically effective dose is administered once a day. Pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the therapeutically effective dose is approximately 10 mg to approximately 100 mg.

3. The pharmaceutical composition according to claim 2, wherein the therapeutically effective amount is about 75 mg.

4. The pharmaceutical composition according to claim 2, wherein the therapeutically effective amount is about 50 mg.

5. A pharmaceutical composition according to any one of claims 1 to 4, further comprising a xanthine oxidase inhibitor.

6. The pharmaceutical composition according to claim 5, wherein the xanthine oxidase inhibitor is allopurinol, oxypurinol, febuxostat, topiroxostat, or inositol.

7. The pharmaceutical composition according to claim 5, wherein the xanthine oxidase inhibitor is allopurinol.

8. The pharmaceutical composition according to claim 5, wherein the xanthine oxidase inhibitor is febuxostat.

9. A pharmaceutical composition according to any one of claims 1 to 4, further comprising an SGLT2 inhibitor.

10. The pharmaceutical composition according to claim 9, wherein the SGLT2 inhibitor is canagliflozin, dapagliflozin, or empagliflozin.

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