Treatment methods for cardiomyopathy induced by metabolic inflexibility

Abstract

This specification provides methods for treating, preventing, or delaying the onset of cardiomyopathy and heart failure, among other cardiomyopathy, by administering therapeutic compounds to subjects in need. This disclosure further relates, generally speaking, to methods for improving cardiac efficiency using therapeutic compounds to subjects in need. This disclosure also relates, generally speaking, to methods for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) using therapeutic compounds to subjects in need. The therapeutic compound is a compound of formula (I): [Formula 1] JPEG2026526085000023.jpg24169 or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 514,700, filed on 20 July 2023, which is incorporated herein by reference in its entirety.

[0002] Reference to electronic sequence listings The contents of the electronic sequence listing (286502000940SEQLIST.xml, size: 43,273 bytes, created: July 18, 2024) are incorporated herein by reference in their entirety. [Technical field]

[0003] This disclosure generally relates to methods for treating, preventing, or delaying the onset of cardiomyopathy and heart failure, among other cardiomyopathy, by administering compounds provided herein. This disclosure further generally relates to methods for improving cardiac efficiency using compounds provided herein. This disclosure also generally relates to methods for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) using compounds provided herein. [Background technology]

[0004] AMP-activated protein kinase (AMPK) is a major regulator of energy equilibrium and is activated during metabolic stress (fasting, hypoxia, ischemia) that reduces the intracellular pool of adenosine triphosphate (ATP) or when ATP consumption increases (physical activity / muscle contraction). AMPK is involved in multiple signaling pathways that regulate energy metabolism and consumption. Much of the clinical benefit of exercise or calorie restriction is derived from increased AMPK activity. Therefore, it is an attractive therapeutic target in a wide range of diseases, including cardiovascular metabolic disorders such as obesity and diabetes.

[0005] The multifaceted effects of AMPK activation have generated significant interest in the development of AMPK activators for a wide range of therapeutic applications, including metabolic diseases such as diabetes and obesity, cardiovascular and renal diseases, inflammatory diseases, and aging. Many of these activators interact with the allosteric drug and metabolite (ADaM) site, which is formed by the interaction between the α and β subunits and has a still-unknown physiological function. Binding at this site allosterically activates AMPK and protects it from dephosphorylation. However, the specificity of activators to the ADaM site varies among different AMPK trimers, with many activators showing higher activity against β1-containing complexes compared to β2-containing complexes. Since β2 is the major isoform expressed in skeletal muscle and the liver, two of the major target organs for metabolic diseases, AMPK activators selective for β1-containing complexes are not ideally suited for the treatment of metabolic diseases.

[0006] Despite advances in AMPK activators and other regulators of cardiovascular metabolism, the incidence of cardiovascular metabolic disorders continues to rise. Cardiovascular metabolic disorders encompass a variety of conditions, including hypertension, dyslipidemia, obesity, and diabetes. Each individual's response to treatment can vary significantly due to genetic, lifestyle, and environmental factors. For individuals, these disorders remain progressive conditions, leading to significant morbidity and mortality. As Western societies continue to age, these conditions are becoming an increasing social burden. There is an urgent and growing unmet medical need for treatments and interventions that can influence the incidence and progression of cardiovascular metabolic disorders, including interventions that can mimic the clinical effects of exercise and calorie restriction. [Overview of the project]

[0007] The compound 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide has been previously identified as an AMPK activator and acts primarily by inhibiting the dephosphorylation of activated (phosphorylated) AMPK rather than allosterically activating AMPK. Unlike the other AMPK activators mentioned above, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide was surprisingly observed to promote glucose uptake without increasing glycogen content.

[0008] In some embodiments, the cardiac disease in a subject (e.g., a human patient) is treated with a compound of formula (I): [ka] Methods and compositions for the treatment and / or prevention of the same by administering a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided. Furthermore, in other embodiments, methods for enhancing cardiac efficiency by administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject (e.g., a human). In the aforementioned embodiments, the subject may be a patient or a healthy subject. The compound of formula (I) is also known as 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide.

[0009] Surprisingly, it was found that the compound of formula (I) can restore the flexibility of cardiac metabolism in the hearts of subjects (e.g., patients) suffering from various heart diseases or complications. It was also found that the compound of formula (I) is an inhibitor of pyruvate dehydrogenase kinase (PDK), such as PDK4, and can increase glucose oxidation in the heart. Combined with other beneficial properties of the compound of formula (I) as an AMPK activator, the inventors found that the compound of formula (I) can be used to treat or prevent various heart diseases and complications, including cardiomyopathy, heart failure, and atrial fibrillation (AF). In some embodiments, the subject (e.g., patient) is a diabetic patient. In other embodiments, the subject (e.g., patient) is not a diabetic patient.

[0010] Furthermore, based on the discovery that compounds of formula (I) improve cardiac efficiency (i.e., restore metabolic flexibility and glucose oxidation), compounds of formula (I) can be used to treat or improve metabolic syndrome, which is associated with a set of risk factors that may include hyperglycemia, elevated blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. Accordingly, in some embodiments, the Disclosure provides a method for doing so in a human subject in need of treatment for metabolic syndrome by administering a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The subject may be a human subject suffering from the heart disease described herein. Alternatively, the subject may be a human subject that is likely to develop a disease or condition associated with metabolic syndrome. For example, in some embodiments, the human subject may be prediabetic. In other embodiments, the human subject has a combination of hypertension and high cholesterol, and is therefore susceptible to heart attack or stroke.

[0011] In some embodiments, provided herein is a method of treating cardiomyopathy in a subject (e.g., a patient) who requires treatment for cardiomyopathy, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the cardiomyopathy is associated with metabolic inflexibility. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In some embodiments, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments, the cardiomyopathy is restrictive cardiomyopathy. In some embodiments, administration of the compound of formula (I), its pharmaceutically acceptable salt, solvate, or prodrug reduces hypertension in the subject (e.g., a patient). In some embodiments, administration of the compound of formula (I) reduces systolic blood pressure in the subject (e.g., a patient). In some embodiments, administration of the compound of formula (I) reduces diastolic blood pressure in the subject (e.g., a patient). In some embodiments, the subject (e.g., a patient) is a diabetic patient. In other embodiments, the subject (e.g., a patient) is not a diabetic patient.

[0012] In some embodiments, the subject (e.g., a patient) has diabetic cardiomyopathy. In some embodiments, the cardiomyopathy is induced by diabetes. In some embodiments, the subject (e.g., a patient) is a diabetic patient and has type 1 diabetes. In other embodiments, the subject (e.g., a patient) is a diabetic patient and has type 2 diabetes. In some such embodiments, the type 2 diabetes is severe insulin resistant diabetes.

[0013] In some embodiments, the subject (e.g., a patient) has Duchenne muscular dystrophy (DMD) cardiomyopathy. In some embodiments, the subject (e.g., a patient) with DMD is from about 5 years old to about 18 years old, or from about 7 years old to about 12 years old.

[0014] In some embodiments, the subject (e.g., a patient) suffers from glucocorticoid-induced cardiomyopathy. In some embodiments, the glucocorticoid-induced cardiomyopathy is anabolic steroid-induced cardiomyopathy. In some embodiments, the glucocorticoid-induced cardiomyopathy is endogenous (Cushing's syndrome) corticosteroid-induced cardiomyopathy.

[0015] In some embodiments, methods are provided herein for preventing or delaying the onset of cardiomyopathy in subjects (e.g., patients) for whom prevention or delay of the onset of cardiomyopathy is necessary, the methods comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In some embodiments, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments, the cardiomyopathy is restrictive cardiomyopathy. In some embodiments, the cardiomyopathy is diabetic cardiomyopathy.

[0016] In some embodiments, methods are provided herein for treating cardiomyopathy in subjects (e.g., patients) requiring treatment for cardiomyopathy, the methods comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject's heart failure is related to metabolic inflexibility. In some embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, the subject (e.g., patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the subject's diabetic cardiomyopathy is attenuated. In some embodiments, the subject (e.g., patient) has hyperglycemia. In other embodiments, the subject (e.g., patient) does not have hyperglycemia.

[0017] In some embodiments, this specification provides a method for treating AF in subjects (e.g., patients) who require treatment of AF, the method comprising administering to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof halts the progression or onset of AF in subjects (e.g., patients) who are susceptible to heart disease.

[0018] In some embodiments, methods are provided herein for improving cardiac efficiency in subjects (e.g., patients) who require improvement of cardiac efficiency, the methods comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject suffers from heart disease.

[0019] In some embodiments, methods are provided herein for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) in subjects (e.g., patients) requiring inhibition of PDK activity, the methods comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject is a diabetic patient. In other embodiments, the subject is not a diabetic patient.

[0020] In some variations of the aforementioned embodiments, the subject is a human being.

[0021] In any of the preceding embodiments, the compound of formula (I) may be administered as a salt. In some embodiments, the salt is an alkali metal salt. In some embodiments, the salt is a sodium salt. In some embodiments, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide is of the following formula: [ka] In the formula, X + This represents an alkali metal cation (e.g., lithium, rubidium, cesium, sodium, or potassium).

[0022] In some embodiments, the compound administered according to this disclosure is a prodrug of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. In some embodiments, the prodrug has the following structure: [ka] or having a salt thereof, in the formula, R 1 This is selected from the group consisting of -C(O)-C2H4-CO2H and -PO3H2, or their salts or solvates.

[0023] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be administered orally once daily to a subject (e.g., a patient) requiring it at a dose of about 100 mg to about 1,000 mg. All dose references discussed herein refer to the free acid (protonated) form. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be administered orally once daily at a dose of about 200 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be administered orally once daily at a dose of about 400 mg to about 800 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug may be administered orally once daily at a dose of about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily in doses of about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

[0024] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject requiring it (e.g., a patient), wherein the steady-state plasma concentration of the compound of formula (I) is approximately 40 μg / mL to approximately 200 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject requiring it (e.g., a patient), wherein the steady-state plasma concentration of the compound of formula (I) is approximately 40 μg / mL to approximately 80 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject requiring it (e.g., a patient), wherein the steady-state plasma concentration of the compound of formula (I) is approximately 70 μg / mL to approximately 120 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered orally once daily to a subject requiring it (e.g., a patient), resulting in a steady-state plasma concentration of approximately 90 μg / mL to approximately 160 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered orally once daily to a subject requiring it (e.g., a patient), resulting in a steady-state plasma concentration of approximately 100 μg / mL to approximately 150 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered daily to a human subject, resulting in a steady-state plasma concentration of approximately 120 μg / mL to approximately 140 μg / mL.

[0025] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, wherein the administration brings about the time curve (AUC) of the compound of formula (I).0-24 The steady-state region below is approximately 1,000 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,000 h*μg / mL to approximately 2,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,500 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,800 h*μg / mL to approximately 3,100 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,500 h*μg / mL to approximately 2,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 2,500 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I).0-24 becomes from about 3,000 μg / mL to about 3,500 μg / mL.

[0026] In any of the previous embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug can be orally administered once a day to a subject (e.g., a patient) that needs it, where, by this administration, the C max becomes from about 40 μg / mL to about 200 μg / mL. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug can be orally administered once a day to a subject (e.g., a patient) that needs it, where, by this administration, the C max becomes from about 70 μg / mL to about 200 μg / mL. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug can be orally administered once a day to a subject (e.g., a patient) that needs it, where, by this administration, the C max becomes from about 80 μg / mL to about 140 μg / mL. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug can be orally administered once a day to a subject (e.g., a patient) that needs it, where, by this administration, the C max becomes from about 70 μg / mL to about 100 μg / mL. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate, or prodrug can be orally administered once a day to a subject (e.g., a patient) that needs it, where, by this administration, the C max becomes from about 1,200 μg / mL to about 150 μg / mL.

[0027] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered in a dose that does not increase the glycogen content in the heart. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered in a dose that decreases the glycogen content in the heart.

[0028] In any of the preceding embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered in combination with one or more therapeutic agents. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered in combination with a sodium-glucose cotransport protein 2 (SGLT2) inhibitor. In some such embodiments, the SGLT2 inhibitor is dapaglifodine.

[0029] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered in an oral dosage form. In some embodiments, the oral dosage form is a capsule. In other embodiments, the oral dosage form is a tablet.

[0030] In some embodiments, methods are provided herein for improving physical strength or cardiac function in a subject, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject is a healthy subject. In other embodiments, the subject is diseased or susceptible to disease. For example, in some embodiments, the subject is prediabetic. In some embodiments, the subject exhibits a system associated with the early stages of heart failure. In other embodiments, the subject has high cholesterol levels. In some embodiments, the subject can improve cardiac function or increase physical strength by taking a once-daily dose of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from about 50 mg to about 400 mg. In some embodiments, the subject can improve cardiac function or increase physical strength by taking a once-daily dose of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, ranging from about 50 mg to about 200 mg. In some embodiments, subjects may improve cardiac function or increase their physical strength by taking a once-daily dose of the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug in the range of about 50 mg to about 100 mg.

[0031] In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a treatment comprising any of the methods described herein is also provided. For example, one variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating and / or preventing cardiac diseases, including, for example, treating and / or preventing cardiac diseases and complications such as cardiomyopathy, heart failure, and atrial fibrillation. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for enhancing or improving cardiac efficiency, which may include restoring metabolic flexibility and glucose oxidation. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for restoring flexibility of cardiac metabolism. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for treating or improving metabolic syndrome, which may include a set of risk factors including hyperglycemia, elevated blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for treating cardiomyopathy, or for preventing or delaying the onset of cardiomyopathy. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for treating heart failure or atrial fibrillation in subjects requiring treatment for heart failure or atrial fibrillation. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for inhibiting the activity of pyruvate dehydrogenase kinase (PDK).

[0032] In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a drug is also provided. In some embodiments, the drug is for any of the methods described herein. For example, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating and / or preventing cardiac diseases, including, for example, treating and / or preventing cardiac diseases and complications such as cardiomyopathy, heart failure, and atrial fibrillation, is provided. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for enhancing or improving cardiac efficiency, which may include restoring metabolic flexibility and glucose oxidation. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for restoring flexibility of cardiac metabolism is provided. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating or improving metabolic syndrome, which may include a set of risk factors including hyperglycemia, elevated blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating cardiomyopathy, or for preventing or delaying the onset of cardiomyopathy. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating heart failure or atrial fibrillation in subjects requiring treatment for heart failure or atrial fibrillation. In yet another modified embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) is provided. [Brief explanation of the drawing]

[0033] This application can be understood by referring to the following description, which is considered together with the attached drawings.

[0034] [Figure 1-1]This shows the avoidance of hyperglycemia by administering the compound of formula (I) to STZ mice. a is the fasting glucose level and area under the curve (AUC) (n=6-8 / group) in the control group (n=7) and STZ mice that were untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5. b is the insulin level and area under the curve (AUC) (n=6-8 / group) in the control group (n=7) and STZ mice that were untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5. c is the total insulin content in the pancreas (n=7-8 / group) in the control group and STZ mice that were untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 5. d is the pancreatic islet cell area in STZ mice in the control group (n=3-5) and in untreated mice (n=3-5) or treated with the compound of formula (I) at 0.25 mg / g (n=3-5) and 0.5 mg / g (n=3-6), respectively. e is the fraction of insulin-positive (Ins+) cells in STZ mice in the control group (n=3-5) and in untreated mice (n=3-5) or treated with the compound of formula (I) at 0.25 mg / g (n=3-5) and 0.5 mg / g (n=3-6), respectively. f is the fraction of glucagon-positive (Glu+) cells in STZ mice in the control group (n=3-5) and in untreated mice (n=3-5) or treated with the compound of formula (I) at 0.25 mg / g (n=3-5) and 0.5 mg / g (n=3-6), respectively. Note that the control mice in (a) to (f) are the same as the control mice in the corresponding panels in (g) to (l). Data are shown as mean ± SEM.Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by Games-Howell post-hoc tests ((a)-(d), (g)-(j)) or one-way ANOVA followed by Turkey's post-hoc tests ((e)-(f), (k)-(l)) (*p<0.05, **p<0.01, *p<0.001). Statistical significance between control mice and STZ mice was determined by Wilcoxon tests ((a)-(d), (g)-(j)) or Student's t-tests ((e)-(f), (k)-(l)) (#p<0.05, ##p<0.01, ###p<0.001). [Figure 1-2]g represents fasting glucose levels and area under the curve (AUC) (n=8-16 / group) in the control group (n=7) and STZ mice that were untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15. h indicates the avoidance of hyperglycemia by administering the compound of formula (I) to STZ mice. i represents the total insulin content in the pancreas (n=8-16 / group) in the control group (n=7) and STZ mice that were untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), respectively, from day 15. j represents the islet cell area in STZ mice in the control group (n=3-5) and in untreated mice (n=6-10) or treated with the compound of formula (I) at concentrations of 0.25 (n=3-5) and 0.5 mg / g (n=6-10), respectively. 1 represents the fraction of Ins+ cells in STZ mice in the control group (n=3-5) and in untreated mice (n=6-10) or treated with the compound of formula (I) at concentrations of 0.25 (n=3-5) and 0.5 mg / g (n=6-10), respectively. l represents the fraction of Glu+ cells in STZ mice in the control group (n=3-5) and in untreated mice (n=6-10) or treated with the compound of formula (I) at concentrations of 0.25 (n=3-5) and 0.5 mg / g (n=6-10), respectively. Note that the control mice in (a) to (f) are the same as the control mice in the corresponding panels in (g) to (l). Data are shown as mean ± SEM.Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by Games-Howell post-hoc tests ((a)-(d), (g)-(j)) or one-way ANOVA followed by Turkey's post-hoc tests ((e)-(f), (k)-(l)) (*p<0.05, **p<0.01, *p<0.001). Statistical significance between control mice and STZ mice was determined by Wilcoxon tests ((a)-(d), (g)-(j)) or Student's t-tests ((e)-(f), (k)-(l)) (#p<0.05, ##p<0.01, ###p<0.001). Data are shown as mean ± SEM. The statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by one-way ANOVA followed by Tukey's post-hoc test (*p<0.05, **p<0.01, *p<0.001), and the statistical significance between control mice and STZ mice was determined by Student's t-test (#p<0.05, ##p<0.01, ###p<0.001). [Figure 2-1]This shows the stimulation of glucose uptake in skeletal muscle after administration of the compound of formula (I) to STZ mice. a is the timeline of days between STZ treatment and FDG-PET scan. Data are shown as mean ± SEM. b is representative PET / CT images of FDG uptake in untreated mice (upper panel) and mice treated with the compound of formula (I) (lower panel). Data are shown as mean ± SEM. c is the estimated maximum muscle and cardiac glucose uptake (MRglu) at baseline (scan 1), 9-10 days after the last STZ injection (scan 2), and after 1 week of treatment with 0.5 mg / g of the compound of formula (I) (scan 3) (n=5) or in the untreated group (n=5). Data are shown as mean ± SEM. Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Student's t-test (muscle) or Wilcoxon test (heart) (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between scans was determined by repeated-repeated one-way ANOVA followed by paired Student's t-test (〇p<0.05). d is the glycogen content of muscle and heart in the control group (n=6~18) and STZ mice that were either untreated (n=14~36) or treated with the compound of formula (I) (n=13~27) from day 15. Data are shown as mean ± SEM. The statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by the Wilcoxon test (*p<0.05, **p<0.01, ***p<0.001), and the statistical significance between control mice and STZ mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). [Figure 2-2]This shows the stimulation of glucose uptake in skeletal muscle after administration of the compound of formula (I) to STZ mice. e represents the relative mRNA levels of Txnip, Slc2a1, Slc2a4, Hk2, Pkm, Ppargc1a, Pdk4, Pdha1, Shda, and Cox8b in the muscle of control mice (n=5-7), untreated STZ mice (n=5-9), and STZ mice treated with the compound of formula (I) (n=6-8). Data are shown as mean ± SEM. The statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by the Wilcoxon test (*p<0.05, **p<0.01, ***p<0.001), and the statistical significance between control mice and STZ mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). f represents the relative mRNA levels of Txnip, Slc2a1, Slc2a4, Pdk4, Ucp2, and Ucp3 in the hearts of control mice (n=5), untreated STZ mice (n=9), and STZ mice treated with the compound of formula (I) (n=6-7). Data are shown as mean ± SEM. Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by the Wilcoxon test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between control mice and STZ mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). g is Doppler via the mitral valve of STZ-treated mice at baseline (Scan 1), 15 days after the start of STZ (Scan 2), and after 1 week of treatment with 0.5 mg / g of the compound of formula (I) (Scan 3) (n=9) or in the untreated group (n=9). Data are shown as mean ± SEM. Statistical significance between untreated STZ mice and STZ mice treated with the compound of formula (I) was determined by Student's t-test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between scans was determined by repeated-repeated one-way ANOVA followed by paired Student's t-test (〇p<0.05). [Figure 3-1]This study demonstrates that the compound of formula (I) avoids hyperglycemia in a dose-dependent manner in db / db mice. 'a' represents the fasting glucose level and area under the curve (AUC) (n=15-20 / group) in untreated BKS mice and db / db mice treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively. Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). b represents insulin levels and area under the curve (AUC) (n=15-20 / group) in untreated BKS mice and db / db mice treated with 0.5 mg / g and 1.0 mg / g of the compound of formula (I), respectively. Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). c represents the HOMA-IR (calculated from Figures 3(a) and 3(b)) and area under the curve (AUC) for untreated BKS mice and db / db mice treated with 0.5 and 1.0 mg / g of the compound of formula (I). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001).d represents HOMA-β (calculated from Figures 3(a) and 3(b)) and area under the curve (AUC) in untreated BKS mice and db / db mice treated with 0.5 and 1.0 mg / g of the compound of formula (I). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). [Figure 3-2] This shows that the compound of formula (I) avoids hyperglycemia in a dose-dependent manner in db / db mice. E is the glycogen content in the muscle and heart of BKS mice (n=5-9) and db / db mice that were untreated (n=9-10) or treated with the compound of formula (I) (n=6-7). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Student's t-test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by Student's t-test. f shows that the compound of formula (I) avoids hyperglycemia in a dose-dependent manner in db / db mice. The relative mRNA levels of Txnip, Slc2a1, Slc2a4, Hk2, Pkm, Ppargc1a, Pdk4, Pdha1, Sdha, Cox8b, Ucp2, and Ucp3 were determined in the muscle of BKS mice (n=6-13) and db / db mice that were untreated (n=15-22) or treated with 1.0 g / kg of the compound of formula (I) (n=8-15). Data are shown as mean ± SEM. The statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by the Wilcoxon test (*p<0.05, **p<0.01, ***p<0.001), and the statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). [Figure 3-3] This study demonstrates that the compound of formula (I) dose-dependently avoids hyperglycemia in db / db mice. g represents the relative mRNA levels of Txnip, Slc2a1, Slc2a4, Pdk4, Ucp2, and Ucp3 in the hearts of BKS mice (n=4-5), untreated db / db mice (n=8-9), and db / db mice treated with the compound of formula (I) (n=6-7). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by the Wilcoxon test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). [Figure 4-1] The following shows the induction of mitochondrial uncoupling by the compound of formula (I). a is a respiratory measurement plot showing the oxygen consumption rate (OCR) measured by sequentially injecting oligomycin, FCCP, and a cocktail of rotenone and antimycin into intact differentiated C2C12 myotubes treated with 0.625, 1.25, and 2.5 μM of the compound of formula (I) for ±4 hours. Data are shown as mean ± SEM. n=5 / condition. b is a respiratory measurement plot showing the extracellular acidification rate (ECAR) measured by sequentially injecting oligomycin, FCCP, and a cocktail of rotenone and antimycin into intact differentiated C2C12 myotubes treated with 0.625, 1.25, and 2.5 μM of the compound of formula (I) for ±4 hours. Data are shown as mean ± SEM. n=5 / condition. c is an OCR vs. ECAR plot obtained from the final baseline measurement (measurement 3 in each panel of (a) and (b)). Data are shown as mean ± SEM. n=5 / condition. [Figure 4-2]Figure 4(d) shows the induction of mitochondrial uncoupling by the compound of formula (I). d is a mitochondrial function parameter calculated from OCR data in panel (a). Data are shown as mean ± SEM. n=5 / condition. The statistical significance between untreated cells and cells treated with the compound of formula (I) in Figure 4(d) was determined by one-way ANOVA followed by Tukey's post-hoc test (〇p<0.05, 〇〇p<0.01). [Figure 5-1] This shows the conservation of β-cell mass and expression of β-cell markers in db / db mice after administration of the compound of formula (I). 'a' shows representative immunostaining (n=5 / group and antibody) for insulin (green) and glucagon, Glut2, Ipf1 / Pdx1, Nkx6-1, Mafa, and Raldh3 (all red) from pancreases of 15-week-old BKS and db / db mice, either untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively. Data are shown as mean ± SEM. [Figure 5-2]This shows the conservation of β-cell mass and expression of β-cell markers in db / db mice after administration of the compound of formula (I). b is the quantification of pancreatic islet cell area. The data are from 6-week-old BKS and db / db mice, as well as 15-week-old BKS and db / db mice that were untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively (n=4-6 / group). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). c is the insulin (Ins+) and glucagon (Glu+) positive cell fraction in 15-week-old BKS and db / db mice treated with 0.5 and 1.0 mg / g of the compound of formula (I) (n=5 for all groups). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). d is the total insulin content in the pancreas of 15-week-old BKS mice (n=9) and db / db mice treated with the compound of formula (I) at 0.5 mg / g (n=9) and 1.0 mg / g (n=6~8). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001).e is the pancreatic insulin / proinsulin ratio in 15-week-old BKS mice (n=9) and db / db mice treated with the compound of formula (I) at 0.5 mg / g (n=9) and 1.0 mg / g (n=6~8). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by the Games-Howell post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (#p<0.05, ##p<0.01, ###p<0.001). f represents the quantification of Glut2, Ipf1 / Pdx1, Nkx6-1, Mafa, and Raldh3 expression in the pancreatic islets of 15-week-old db / db mice treated with the compound of formula (I) at 0.5 mg / g (n=5) and 1.0 mg / g (n=4-5). Data are shown as mean ± SEM. Statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by Games-Howell post-hoc tests (*p<0.05, **p<0.01, ***p<0.001). [Figure 5-3] This shows the conservation of β-cell mass and expression of β-cell markers in db / db mice after administration of the compound of formula (I). g is the relative mRNA level of Ins1 / 2, Slc2a2, Pdx1, Nkx6-1, Mafa, Ucn3, Trpm5, Txnip, Aldh1a3, Hspa5, Erp29, and Edem2 in the pancreatic islets of 15-week-old db / db mice treated with the compound of formula (I) at 0.5 mg / g (n=14~15) and 1.0 mg / g (n=9~10). Data are shown as mean ± SEM. The statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by the Kruskal-Wallis test followed by the Dunn post-hoc test (*p<0.05, **p<0.01, ***p<0.001). [Figure 6-1]This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). a is an MA plot showing differential gene expression between mouse islets cultured with 22 mM (G22) vs. 11 mM (G11) glucose, and 22 mM glucose + 5 μM of the compound of formula (I) (G22 + C(I)) vs. 11 mM glucose. Data are shown as mean ± SEM. b is an ORA overexpression analysis (ORA) of the Molecular Signature Hallmark gene set (MSIG) in mouse islets cultured with 22 mM vs. 11 mM glucose, and 22 mM glucose + 5 μM of the compound of formula (I) vs. 22 mM glucose. Data are shown as mean ± SEM. c represents the log2 multiplier change in the normalized read count of Txnip in mouse pancreatic islets cultured with 11 mM glucose, 22 mM glucose, and the compound of formula (I) in a 22 mM glucose + 5 μM solution (n=5 across all groups). Data are shown as mean ± SEM. Statistical significance was determined by the Wilcoxon test (##p<0.01) for 22 mM glucose vs. 11 mM glucose, and by the Wilcoxon test (*p<0.05, **p<0.01) for the compound of formula (I) in a 22 mM glucose + 5 μM solution vs. 22 mM glucose. [Figure 6-3] This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 6-4] This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 6-5]This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 6-6] This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 6-7] This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 6-8] This shows the mitigation of hyperglycemia-induced changes in pancreatic islet gene expression in ex vivo cultured islets by the compound of formula (I). d is a heatmap of the normalized read counts of DEGs derived from the enhancement category and KEGG:TCA_CYCLE in Figure 6(b). The number of genes was limited to the 20 most significant DEGs. [Figure 7]This study demonstrates the mitigation of the effects of chronic hyperglycemia on GSIS, mTORC1, and AMPK signaling in INS-1E cells by the compound of formula (I). 'a' represents the GSIS (n=4-5 / group) of INS-1E cells cultured for 4 days under 11 mM or 25 mM glucose conditions, for both untreated and 4-day treatment with 5 μM of the compound of formula (I). Data are shown as mean ± SEM. Statistical significance was determined between untreated and 'I' treated cells by two-way ANOVA followed by Tukey's post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and between cells cultured under 11 mM and 25 mM glucose conditions by the same test (〇p<0.05, 〇〇p<0.01). b is the GSIS (n=4-5 / group) of INS-1E cells cultured for 4 days under 11 mM or 25 mM glucose conditions, for untreated cells and cells treated with 5 μM of compound (I) for 2 hours. Data are shown as mean ± SEM. Statistical significance was determined between untreated cells and cells treated with compound (I) by two-way ANOVA followed by Tukey's post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and between cells cultured under 11 mM and 25 mM glucose conditions by the same test (〇p<0.05, 〇〇p<0.01). c represents the protein expression ratios (n=4-5 / group) of phosphorylated (P-) and total amounts of ACC, AMPK, RAPTOR, and S6 in INS-1E cultured for 4 days under 11 mM or 25 mM glucose conditions, for untreated and 4-day treatment with 5 μM of compound (I). Data are shown as mean ± SEM.Statistical significance was determined by two-way ANOVA followed by Tukey's post-hoc test (*p<0.05, **p<0.01, ***p<0.001) between untreated cells and cells treated with the compound of formula (I), and by the same test (〇p<0.05, 〇〇p<0.01) between cells cultured under 11 mM and 25 mM glucose conditions. d represents the protein expression ratios (n=4~5 / group) of phosphorylated (P-) and total amounts of ACC, AMPK, RAPTOR, and S6 in untreated and 2-hour treatment of INS-1E cells cultured for 4 days under 11 mM or 25 mM glucose conditions. Data are shown as mean ± SEM. Statistical significance was determined between untreated cells and cells treated with the compound of formula (I) using two-way ANOVA followed by Tukey's post-hoc test (*p<0.05, **p<0.01, ***p<0.001), and between cells cultured in 11 mM and 25 mM glucose using the same test (〇p<0.05, 〇〇p<0.01). [Figure 8]The immunohistochemical and metabolic analyses of control and STZ mice are shown. a is representative double immunostaining for insulin (green) and glucagon (red) from the pancreas of control and STZ mice, either untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), starting from day 5 (n=5 in total groups). Data are shown as mean ± SEM. b is the total insulin content in the pancreas (n=7-8 / group) of STZ mice, either untreated or treated with 0.25 and 0.5 mg / g of the compound of formula (I), starting from day 5. Data are shown as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 were determined by Welch's ANOVA followed by Games-Howell post-hoc tests. c represents the islet cell area in STZ mice that were untreated (n=3-5) or treated with the compound of formula (I) at 0.25 mg / g (n=3-5) and 0.5 mg / g (n=3-6), respectively, starting from day 5. Data are shown as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 were determined by Welch's ANOVA followed by Games-Howell post-hoc testing. d represents the fraction of insulin (Ins+) cells in STZ mice that were untreated (n=3-5) or treated with the compound of formula (I) at 0.25 mg / g (n=3-5) and 0.5 mg / g (n=3-6), respectively, starting from day 5. Data are shown as mean ± SEM. *P<0.05, **P<0.01, and ***P<0.001 were determined by Tukey's post-hoc test following one-way ANOVA. e is the non-fasting glucose level and area under the curve (AUC) in control mice (n=6) and STZ mice treated with formula (I) at 0.5 mg / g (n=9) from day 15 onwards, either untreated (n=9). Data are shown as mean ± SEM. f is representative double immunostaining for insulin and glucagon in the pancreas of STZ mice (n=5 in total) from day 15 onwards, either untreated or treated with formula (I) at 0.25 and 0.5 mg / g, respectively. Data are shown as mean ± SEM. *P<0.05, **P<0.01, and ***P<0.001 were determined by Student's t-test.g represents the total insulin content in the pancreas (n=8-16 / group) in STZ mice that were untreated or treated with the compound of formula (I) at 0.25 mg / g and 0.5 mg / g, respectively, starting from day 15. Data are shown as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 were determined by Games-Howell post-hoc test following Welch ANOVA. h represents the islet cell area in STZ mice that were untreated (n=6-10) or treated with the compound of formula (I) at 0.25 (n=3-5) and 0.5 mg / g (n=6-10), respectively, starting from day 15. Data are shown as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 were determined by Games-Howell post-hoc test following Welch ANOVA. i is the fraction of Ins+ cells in STZ mice treated with the compound of formula (I) at 0.25 mg / g (n=3~5) and 0.5 mg / g (n=6~10) from day 15. Data are shown as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 were determined by Tukey's post-hoc test following one-way ANOVA. [Figure 9] This shows standardized uptake (SUV) values ​​during FDG-PET scans. The SUV profiles of the gastrocnemius muscle and heart are from 40-minute dynamic FDG-PET scans at baseline (Scan 1), 9-10 days after the last STZ injection (Scan 2), and after 1 week of treatment with 0.5 mg / g of compound (I) (n=5) (Scan 3) or untreated (n=5). Data are shown as mean ± SEM. [Figure 10] This shows the quantitative analysis of protein levels of p-T172 AMPK, p-S79 ACC, and TXNIP in vastus muscle extracts from control mice (n=5) and STZ mice that were either untreated (n=9) or treated with 0.5 mg / g of the compound of formula (I) from day 15 (n=9), as determined by Western blot analysis. [Figure 11]This study demonstrates that treatment with the compound of formula (I) does not increase serum lactate levels in STZ mice and db / db mice. a is the fasting glucose level (n=9 / group) of STZ mice on day 15 (i.e., before treatment) and on day 22 after 1 week of treatment with 0.5 mg / g of the compound of formula (I). Data are shown as mean ± SEM. Inter-time statistical significance was determined by Student's t-test (*P<0.05), and statistical significance between untreated db / db mice and db / db mice treated with the compound of formula (I) was determined by Welch's ANOVA followed by Games-Howell post-hoc tests (*P<0.05, **P<0.01, ***P<0.001). b is the lactate level (n=9 / group) of STZ mice on day 15 (i.e., before treatment) and on day 22 after 1 week of treatment with 0.5 mg / g of the compound of formula (I). Data are shown as mean ± SEM. c represents fasting glucose levels and area under the curve (AUC) (n=7-9 / group) in BKS mice and db / db mice that were untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively. Data are shown as mean ± SEM. Statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (##P<0.01). d represents lactate levels and area under the curve (AUC) (n=7-9 / group) in BKS mice and db / db mice that were untreated or treated with 0.5 and 1.0 mg / g of the compound of formula (I), respectively. Data are shown as mean ± SEM. Statistical significance between BKS mice and db / db mice was determined by the Wilcoxon test (##P<0.01). [Figure 12]The fractions of PP+ and Som+ cells, as well as the total proinsulin content in the pancreas, are shown for BKS mice and db / db mice. 'a' shows the fractions of pancreatic polypeptide (PP+) and somatostatin (Som+) positive cells (n=3 per group) in 15-week-old BKS mice and db / db mice treated with formula (I) at 0.5 and 1.0 mg / g, respectively. Data are shown as mean ± SEM. 'b' shows the total proinsulin content in the pancreas (n=8-10 / group) in 15-week-old BKS mice (n=8) and db / db mice treated with formula (I) at 0.5 and 1.0 mg / g, respectively. Data are shown as mean ± SEM. *P<0.05 was determined by Welch's ANOVA followed by Games-Howell post-hoc test between untreated db / db mice and db / db mice treated with formula (I). The value #P<0.05 was determined by Welch's ANOVA between BKS mice and db / db mice. [Figure 13-1] This shows the effect of the compound of formula (I) on gene expression signatures in ex vivo cultured mouse and human pancreatic islets. 'a' is an MA plot showing differential gene expression between mouse pancreatic islets cultured with 22 mM (G22) versus 11 mM (G11) glucose. b is an MA plot showing differential gene expression between 22 mM glucose + 5 μM of the compound (I) (G22 + C(I)) and 22 mM glucose. c is an MA plot showing differential gene expression between 22 mM glucose + 5 μM of the compound (I) (G22 + C(I)) and 11 mM glucose. d is an MA plot showing differential gene expression between human pancreatic islets cultured with 25 mM (G25) and 5.5 mM (G5) glucose. e is an MA plot showing differential gene expression between 25 mM glucose + 5 μM of the compound (I) (G25 + C(I)) and 25 mM glucose. f is an MA plot showing differential gene expression between 25 mM glucose + 5 μM of the compound (I) (G22 + C(I)) and 5.5 mM glucose. [Figure 13-2]The effects of the compound of formula (I) on gene expression signatures in ex vivo cultured mouse and human pancreatic islets are shown. g is the overexpression analysis (ORA) of the Molecular Signature Hallmark gene set in human pancreatic islets cultured with 22 mM vs. 11 mM glucose, and with 22 mM glucose + 5 μM of the compound of formula (I) vs. 22 mM glucose. Representative immunoblots are shown for INS-1E cells cultured for 4 days under 11 mM or 25 mM glucose conditions, both untreated and treated with 5 μM of the compound of formula (I) for 4 days (4d) or 2 hours (2h). [Figure 14] Representative immunoblots are shown for INS-1E cells cultured for 4 days under 11 mM or 25 mM glucose conditions, both untreated and treated with 5 μM of compound (I) for 4 days (4d) or 2 hours (2h). [Figure 15] A schematic model of the antidiabetic effect of the compound of formula (I) is shown. As a dual AMPK activator and mitochondrial uncoupler, the compound of formula (I) stimulates glucose uptake and utilization in muscles, and in part, through the reduction of mTORC1 signaling and Pdk expression, avoids the glucotoxic effects of hyperglycemia on β-cell function. [Modes for carrying out the invention]

[0035] The following description concerns exemplary compositions, methods, parameters, etc. However, it should be noted that such description is not intended to limit the scope of this disclosure, but rather is provided as a description of exemplary embodiments.

[0036] Treatment methods In this specification, compounds of formula (I): [ka] Methods and compositions for the treatment and / or prevention of the disease by administering a pharmaceutically acceptable salt, solvate, or prodrug thereof are provided. Furthermore, this specification provides methods for enhancing cardiac efficiency by administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject (e.g., a patient or a healthy subject). In the following disclosure, references to the administration of a compound of formula (I) include the various salt forms, solvates, and prodrugs described herein.

[0037] As shown in the examples, the compound of formula (I) can reduce metabolic inflexibility in the myocardium, a phenomenon that is partly due to the discovery that the compound of formula (I) inhibits PDK4 and increases glucose oxidation in the heart. As a result, the compound of formula (I) can be used to improve metabolic syndrome and treat various cardiac conditions such as cardiomyopathy and heart failure.

[0038] The compound of formula (I) stimulates glucose uptake and glucose utilization in the myocardium. Furthermore, as shown herein, the compound of formula (I) promotes gene expression profiles that favor glucose oxidation over glycogen storage. As established in several animal models, after administration, the compound of formula (I) significantly and dose-dependently improves cardiovascular function as measured by exercise endurance and cardiac output. In addition, treatment with the compound of formula (I) improves peripheral perfusion without increasing myocardial glycogen, increases glucose uptake and utilization in skeletal muscle and myocardium, improves echocardiographic cardiac function without increasing heart rate, and improves exercise endurance without reducing fatigue lactate levels.

[0039] The observation of increased insulin-independent glucose uptake in muscle tissue without increasing glycogen levels, and increased energy expenditure in animal models, prompted in vitro experiments on mitochondrial function. As shown in the examples, in isolated myotubes, the compound of formula (I) increased basal oxygen consumption and extracellular acidification rate, suggesting increased glucose utilization through increased flux via the tricarboxylic acid (TCA) cycle and increased oxidative phosphorylation through mitochondrial uncoupling. Therefore, the current data indicate that the compound of formula (I) is a dual activator and mitochondrial uncoupling agent of AMPK.

[0040] Furthermore, the compound of formula (I) promotes gene expression profiles that facilitate glucose oxidation in muscle and heart. Skeletal muscle thioredoxin inhibitor protein (TXNIP) expression levels show a negative correlation with glucose uptake. As described herein, administration of the compound of formula (I) reduces cardiac TXN1P levels. In particular, Txnip mRNA and protein levels were reduced in skeletal muscle treated with the compound of formula (I) compared to hyperglycemic mice (see Example 3, Figure 2(e), and Figure 10). In addition, skeletal muscle expression of Slc2a4 encoding Glut4 was decreased in STZ mice compared to controls, but normalized in hyperglycemic mice treated with the compound of formula (I), and skeletal muscle expression of Slc2a1 encoding Glut1 tended to increase. Similarly, in hyperglycemic mice, increased expression of pyruvate dehydrogenase (PDH) and consequently pyruvate dehydrogenase kinase 4 (Pdk4), a negative regulator of oxidative glucose metabolism, and uncoupling protein 3 (Ucp3), which favors lipids as fuel substrates, was decreased in mice treated with compound (I) (Figure 2(e)), indicating that the compound of formula (I) counteracts metabolic inflexibility in the skeletal muscle of hyperglycemic diabetic mice. Txnip expression was also increased in the hearts of hyperglycemic mice, but relatively decreased in hyperglycemic mice treated with compound (I). Furthermore, cardiac expression of Slc2a1 and Slc2a4 was decreased in untreated hyperglycemic mice, but tended to increase in mice treated with compound (I) (Figure 2(f)). Therefore, the compound of formula (I) promoted changes in gene expression that promote glucose uptake, oxidative glucose metabolism, and ATP production in the skeletal muscle and heart of hyperglycemic mice.

[0041] Hyperglycemia has been shown to rapidly increase the cardiac expression of Pdk4 and Ucp3, inducing metabolic inflexibility and cardiac dysfunction in mice. Untreated STZ mice showed a gradual decrease in peak E velocity and an increase in isovolumetric relaxation time (IVRT), indicating impaired diastolic function. On the other hand, one week of treatment with the compound of formula (I) reduced IVRT and increased peak E velocity and consequently the E / A ratio (Figure 2(g), Table 4). Improved left ventricular filling in mice treated with the compound of formula (I) also resulted in increased stroke volume and cardiac output. These findings suggest that in diabetic hyperglycemic mice, the compound of formula (I) improved hyperglycemia by stimulating insulin-independent glucose uptake and utilization, reduced glycogen accumulation, and reversed diabetic cardiomyopathy.

[0042] Overall, the data from the examples provided herein show that cardiac expression of PDK4 and UCP3 is elevated in both the STZ model (Figure 2(f)) and the db / db model (Figure 3(g)), and that treatment with the compound of formula (I) reverses this increase in expression. Metabolic inflexibility leads to cardiac dysfunction, including diastolic flaccidity, particularly during the diastolic phase of the cardiac cycle (e.g., insufficient cardiac filling). Relevant measurements from the diastolic portion of the cardiac cycle are peak E velocity and E / A ratio. Insufficient flaccidity leads to decreased peak E velocity and E / A ratio. Improved diastolic ventricular filling leads to improved stroke volume. Surprisingly, in scan 3 (schematic diagram in Figure 2(a)), echocardiographic data from STZ animals treated with the compound of formula (I) for 7 days showed improved peak E velocity and E / A ratio (Figure 2(g), Table 4), resulting in improved stroke volume (Table 4). Therefore, this data confirms the effect of corrective measures on PDK4 and UCP3 expression on cardiomyopathy and metabolic flexibility when administered with the compound of formula (I).

[0043] Furthermore, the compound of formula (I) reduces the TXNIP expression level in insulin-secreting β-cells. As a result, administration of the compound of formula (I) reduces glucotoxic effects such as oxidative stress, apoptosis, suppression of insulin production, and amyloid formation. Thus, in one embodiment, the present disclosure provides a method for inducing rest and preservation of β-cells.

[0044] In one embodiment, this specification provides a method for restoring cardiac metabolic flexibility in the heart of a subject (e.g., a patient) suffering from various heart diseases or complications and requiring restoration of cardiac metabolic flexibility. In some embodiments, the restoration of metabolic flexibility is associated with a decrease in TXNIP expression levels. In some embodiments, the restoration of cardiac metabolic flexibility is associated with the inhibition of PDK proteins such as PDK4. In some embodiments, the restoration of metabolic flexibility is associated with increased glycolysis and increased glucose oxidation. A combination of increased metabolic flexibility and increased glucose oxidation results in improved cardiac efficiency. Accordingly, this disclosure provides a method for improving or restoring efficiency in a subject by administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The subject may be a human patient suffering from one of the diseases described herein, particularly heart disease. The subject may also be a human being not suffering from any particular disease. In such cases, a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be used, for example, to increase cardiac output and improve endurance.

[0045] In another embodiment, the Disclosure provides a method for treating or improving metabolic syndrome in a human being (e.g., a human patient) who requires treatment or improvement of metabolic syndrome, the method comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. The subject may be a human subject suffering from the heart disease described herein. Alternatively, the subject may be a human subject who is at risk of developing a disease or condition associated with metabolic syndrome. For example, in some embodiments, the human subject may be prediabetic. In other embodiments, the human subject may have a combination of hypertension and high cholesterol, and thus be prone to heart attack or stroke.

[0046] In some embodiments, methods for treating metabolic heart disease in subjects (e.g., patients) are provided herein. For example, the disclosure provides a method for treating cardiomyopathy in a subject (e.g., a patient) requiring treatment for cardiomyopathy, the method comprising administering to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the cardiomyopathy is associated with metabolic inflexibility. In some embodiments, the cardiomyopathy is dilated cardiomyopathy. In some embodiments, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments, the cardiomyopathy is restrictive cardiomyopathy. In some embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces hypertension in the subject (e.g., a patient). In some embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces systolic blood pressure in the subject (e.g., a patient). In other embodiments, administration of a compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate, or a prodrug lowers diastolic blood pressure in a subject (e.g., a patient). In some embodiments, the subject is a diabetic patient. In other embodiments, the subject is not a diabetic patient.

[0047] In some embodiments, the subject (e.g., a patient) suffers from diabetic cardiomyopathy. In some embodiments, the cardiomyopathy is induced by diabetes. In some embodiments, the subject (e.g., a patient) is a diabetic patient and has type 1 diabetes. In other embodiments, the subject (e.g., a patient) is a diabetic patient and has type 2 diabetes. In some such embodiments, type 2 diabetes is severe insulin-resistant diabetes. In some embodiments, diabetic cardiomyopathy is selected from the group consisting of diabetic dilated cardiomyopathy, diabetic hypertrophic cardiomyopathy, diabetic arrhythmogenic cardiomyopathy, diabetic restrictive cardiomyopathy, diabetic left ventricular cardiomyopathy, and diabetic takotsubo cardiomyopathy.

[0048] In some embodiments, the subject (e.g., patient) has Duchenne muscular dystrophy (DMD) cardiomyopathy. In some embodiments, the subject (e.g., patient) with DMD is approximately 5 to 18 years old, or approximately 7 to 12 years old.

[0049] In some embodiments, the subject (e.g., a patient) suffers from glucocorticoid-induced cardiomyopathy. In some embodiments, the glucocorticoid-induced cardiomyopathy is anabolic steroid-induced cardiomyopathy. In some embodiments, the glucocorticoid-induced cardiomyopathy is endogenous (Cushing's syndrome) corticosteroid-induced cardiomyopathy.

[0050] In some embodiments, the subject (e.g., a patient) suffers from arrhythmogenic cardiomyopathy. In some embodiments, the cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy.

[0051] In some embodiments of the above-described method, the subject (e.g., patient) has type 1 diabetes. In some embodiments of the above-described method, the subject (e.g., patient) has type 2 diabetes. In some embodiments of the above-described method, the subject (e.g., patient) has hypertension.

[0052] In some embodiments, methods are provided herein for treating heart failure in subjects (e.g., patients) requiring treatment for heart failure, the methods comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject's heart failure is related to metabolic inflexibility. In some embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, the subject (e.g., patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the subject's diabetic cardiomyopathy is attenuated. In some embodiments, the subject (e.g., patient) has hyperglycemia. In other embodiments, the subject (e.g., patient) does not have hyperglycemia.

[0053] In some embodiments, methods are provided herein for preventing or delaying the onset of cardiomyopathy in subjects (e.g., patients) in need thereof, the methods comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, the subject (e.g., patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the diabetic cardiomyopathy of the subject is attenuated.

[0054] In some embodiments, methods are provided herein for improving one or more systems associated with heart failure in a subject requiring such improvement, the method comprising administering to the subject an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the heart failure is heart failure with preserved ejection fraction (HFpEF). In some embodiments, the heart failure is heart failure with reduced ejection fraction (HFrEF). In some embodiments, the subject (e.g., a patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the diabetic cardiomyopathy in the subject (e.g., a patient) is attenuated. In some embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof lowers the diastolic blood pressure of the subject (e.g., a patient) with heart failure. In some embodiments, the subject (e.g., a patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the diabetic cardiomyopathy in the subject is attenuated. In other embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, reduces systolic blood pressure in a subject (e.g., a patient) with heart failure.

[0055] In some embodiments of the above-described method, the subject (e.g., patient) with heart failure is hyperglycemic. In some embodiments, the subject (e.g., patient) with heart failure is not hyperglycemic. In some embodiments, the subject's heart failure is associated with hyperinsulinemia. In some embodiments, the subject (e.g., patient) with heart failure has diabetic cardiomyopathy. In some embodiments, the subject (e.g., patient) with heart failure has diabetic dilated cardiomyopathy, diabetic hypertrophic cardiomyopathy, diabetic arrhythmogenic cardiomyopathy, diabetic restrictive cardiomyopathy, diabetic left ventricular cardiomyopathy, or diabetic takotsubo cardiomyopathy. In some embodiments, the diabetic cardiomyopathy of the subject (e.g., patient) with heart failure and diabetic cardiomyopathy is alleviated by administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments of the above-described method, the subject (e.g., patient) with heart failure has diabetes. In some embodiments, the subject (e.g., patient) with heart failure has type 1 diabetes. In some embodiments, the subject (e.g., patient) with heart failure has type 2 diabetes. In some embodiments, the subject (e.g., patient) with heart failure does not have diabetes.

[0056] As described below, the disclosure also provides a variety of other activators that can be used in combination with the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment of heart disease. In some embodiments, a method for treating, preventing, or delaying the onset of heart failure in a subject (e.g., a patient) requiring it further comprises administering a sodium-glucose cotransport protein 2 (SGLT2) inhibitor to the subject. In some embodiments, the SGLT2 inhibitor is empagliflozin or dapaglifodine. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is dapaglifodine.

[0057] In some embodiments of the methods provided herein, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject (e.g., a patient) who requires it, lowers the systolic blood pressure of the subject. In some embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject (e.g., a patient) who requires it, lowers the diastolic blood pressure of the subject. In some embodiments of the methods provided herein, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as well as an SGLT2 inhibitor, to a subject (e.g., a patient) who requires it, lowers the systolic blood pressure of the subject. In some embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, as well as an SGLT2 inhibitor, to a subject (e.g., a patient) who requires it, lowers the diastolic blood pressure of the subject. In some embodiments of the methods provided herein, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and empagliflozin to a subject (e.g., a patient) who requires it, lowers the systolic blood pressure of the subject. In some embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and empagliflozin to a subject (e.g., a patient) who requires it, lowers the diastolic blood pressure of the subject. In some embodiments of the methods provided herein, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and dapagliflozin to a subject (e.g., a patient) who requires it, lowers the systolic blood pressure of the subject. In some embodiments, administration of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and dapagliflozin to a subject (e.g., a patient) who requires it, lowers the diastolic blood pressure of the subject.

[0058] In some embodiments, methods are provided herein for improving cardiac efficiency in a subject (e.g., a patient), the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject is suffering from heart disease.

[0059] In some embodiments of the method described above, the subject has diabetes. In some embodiments, the subject (e.g., a patient) has type 1 diabetes. In some embodiments, the subject (e.g., a patient) has type 2 diabetes.

[0060] In some variations of the aforementioned embodiments, the subject is a human being.

[0061] The compound of formula (I) acts as an exercise mimetic in that it enhances cardiac function and exercise capacity without promoting glycogen accumulation in cardiac tissue. The compound of formula (I) promotes mitochondrial uncoupling within myotubes. Mitochondrial uncoupling dissipates the potential-energy gradient across the inner mitochondrial membrane. This potential energy is converted into thermal energy rather than being used for oxidative phosphorylation (the process of converting ADP to ATP). Therefore, administration of the compound of formula (I) generates a metabolic demand for glucose that promotes glucose utilization rather than glycogen accumulation within cells.

[0062] In some embodiments described above, the methods provided herein restore metabolic flexibility in subjects (e.g., patients) who require restoration of metabolic flexibility by avoiding changes in gene expression associated with metabolic inflexibility. In some embodiments described above, the methods provided herein increase metabolic demand in subjects (e.g., patients). In some embodiments described above, the methods provided herein increase glucose uptake in subjects (e.g., patients). In some embodiments described above, the methods provided herein increase glucose oxidation in subjects (e.g., patients). In some embodiments described above, the methods provided herein decrease glycogen storage in the heart.

[0063] In some embodiments, methods are provided herein for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) in subjects (e.g., patients) requiring inhibition of PDK activity, the methods comprising administering a compound of formula (I) to the subject. In some embodiments of the above-described methods, the PDK inhibitor is a PDK1 inhibitor. In some embodiments, the PDK inhibitor is a PDK2 inhibitor. In some embodiments, the PDK inhibitor is a PDK3 inhibitor. In some embodiments, the PDK inhibitor is a PDK4 inhibitor.

[0064] In some embodiments, this specification provides a method for treating AF in subjects (e.g., patients) who require treatment of AF, the method comprising administering to the subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, administration of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof halts the progression or onset of AF in subjects (e.g., patients) who are susceptible to heart disease.

[0065] In some embodiments of the method described above, the subject (e.g., patient) is a diabetic patient. In some embodiments, the subject (e.g., patient) has type 1 diabetes. In some embodiments, the subject (e.g., patient) has type 2 diabetes. In some embodiments, the subject (e.g., patient) is not a diabetic patient.

[0066] Improved physical fitness / improved cardiac function In some embodiments, methods are provided herein for improving physical strength or cardiac function in a subject, the method comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject is a healthy subject. In other embodiments, the subject is diseased or susceptible to disease. For example, in some embodiments, the subject is prediabetic. In some embodiments, the subject exhibits a system associated with the early stages of heart failure. In other embodiments, the subject has high cholesterol levels.

[0067] In some embodiments, subjects can improve cardiac function or increase their physical fitness level by taking a once-daily dose of the compound of formula (I) in the range of about 20 mg to about 500 mg. In some embodiments, subjects can improve cardiac function or increase their physical fitness level by taking a once-daily dose of the compound of formula (I) in the range of about 50 mg to about 400 mg. In some embodiments, subjects can improve cardiac function or increase their physical fitness level by taking a once-daily dose of the compound of formula (I) in the range of about 50 mg to about 200 mg. In some embodiments, subjects can improve cardiac function or increase their physical fitness level by taking a once-daily dose of the compound of formula (I) in the range of about 50 mg to about 100 mg. In some embodiments, subjects can improve cardiac function or increase their physical fitness level by taking a once-daily dose of the compound of formula (I) in the range of about 50 mg to about 100 mg.

[0068] therapeutic compounds In some of the embodiments described above, the therapeutic compound includes exemplary compounds, which are described in more detail below. Compounds used in the methods provided herein may include salts, solvates, or prodrugs thereof.

[0069] In some embodiments, the compound is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide, or a salt thereof, solvate, or prodrug.

[0070] In one embodiment, the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. "Alkali metals" are metals that, along with hydrogen, belong to Group I of the periodic table. Alkali metals include lithium, sodium, potassium, rubidium, cesium, and francium. Therefore, it can be understood that an "alkali metal salt" is a compound consisting of an aggregate of one or more alkali metal cations and anions associated with them. Therefore, the term "alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide" refers to compounds containing an alkali metal cation (e.g., lithium, rubidium, cesium, sodium, and potassium) and an anion of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. For example, alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide are as follows: [ka] In the formula, X + This represents an alkali metal cation (e.g., lithium, rubidium, cesium, sodium, or potassium).

[0071] It will be understood that a "sodium salt" is a compound consisting of a sodium cation and an anion associated with it. Therefore, the term "sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide" refers to a compound containing a sodium cation and the anion of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. For example: [ka] In the formula, Na + This represents a sodium cation.

[0072] Those skilled in the art will recognize that, when dissolved in a suitable solvent (e.g., water), the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide can dissociate into its anionic and cationic components.

[0073] Throughout this specification, structures may or may not be presented by their chemical names. In the event of any question regarding nomenclature, the structure takes precedence. Where a compound can exist as a tautomer (e.g., in an alternative resonance form), the structure shown represents one of the possible tautomer forms, and the tautomer form(s) actually observed may vary depending on environmental factors such as solvent, temperature, or pH. All tautomer (and resonance) forms and mixtures thereof are included within the scope of this invention. For example, the following tautomers are included within the scope of this invention: [ka]

[0074] To avoid misunderstanding, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide is solid under ambient conditions, and therefore the scope of the present invention includes all of its amorphous, crystalline, and partially crystalline forms.

[0075] Alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide can be prepared according to techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide may be reacted with a suitable alkali metal hydroxide or an alternative alkali metal base compound. Salt switching techniques can also be used to convert one salt to another.

[0076] The sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide can be prepared according to techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide may be reacted with sodium hydroxide or an alternative sodium base compound. Salt switching techniques can also be used to convert one salt to another.

[0077] When the salt is prepared from 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide can be prepared according to the art well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide can be produced according to the art described in international patent application WO2011 / 004162.

[0078] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains.

[0079] In certain embodiments, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide is the sodium or potassium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. In one embodiment, the salt is the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide.

[0080] In some embodiments, the compounds used in the methods provided herein are compounds of formula (II): [ka] or a salt thereof, where R 1 The compound is selected from the group consisting of -C(O)-C2H4-CO2H and -PO3H2, or their salts or solvates. In some embodiments, the compound can be metabolized in vivo to form 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide. In some embodiments, the compound is a salt. For example, salts of the compound include: [ka] In the formula, X + is an alkali metal, alkaline earth metal, or quaternary ammonium (e.g., lithium, magnesium, calcium, ammonium, tetramethylammonium, especially sodium and potassium) cation, and appropriate stoichiometric adjustments are made considering the ion's charge. In one embodiment, X +This represents an alkali metal cation (e.g., lithium, rubidium, cesium, or especially sodium or potassium).

[0081] Pharmaceutical dosage forms The therapeutic compound is administered to human subjects in need in the form of a pharmaceutical formulation, which is also referred to herein as a pharmaceutical dosage form.

[0082] In one embodiment, the therapeutic compound is the sole active pharmaceutical ingredient present in the dosage form. In further embodiments, the therapeutic compound may be present in the dosage form together with one or more other active pharmaceutical ingredients, or administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0083] In certain embodiments, the therapeutic compound is provided in the form of particles having a particle size distribution defined by D90 less than about 10 μm (e.g., measured using laser diffraction). In one embodiment, particles containing the therapeutic compound may have a particle size distribution defined by D90 less than about 10 μm (e.g., about 5 μm to about 10 μm) (e.g., measured using laser diffraction). Alternatively, the particle size distribution may be defined by D90 less than about 8 μm (e.g., about 5 μm to about 8 μm). In further embodiments, particles consisting of the therapeutic compound may have a particle size distribution defined by D50 less than about 6 μm (e.g., about 0.5 μm to about 6 μm). In even further embodiments, the particle size distribution of particles consisting of the therapeutic compound is further defined by D10 less than about 2 μm (e.g., about 0.2 μm to about 2 μm). The above particle size distribution parameters may be applied individually or in combination. For example, in certain embodiments, the dosage form comprises particles containing a therapeutic compound, the particles having a particle size distribution defined by D90 less than about 10 μm and D50 less than about 6 μm. Furthermore, the particles may have a particle size distribution defined by D90 less than 9 μm, D50 less than 6 μm or less than 5 μm, and D10 less than 2 μm or less than 1.5 μm. The particle size distribution of the particles containing the therapeutic compound may be measured, for example, by laser diffraction using a commercially available particle size analyzer.

[0084] Oral dosage form In some variations, the therapeutic compound may be provided in the form of a tablet or capsule. For example, capsules such as soft gelatin capsules may be prepared containing the therapeutic compound alone or together with a suitable vehicle, such as vegetable oil or fat. Similarly, hard gelatin capsules may contain the therapeutic compound alone or in combination with solid powder components such as disaccharides (e.g., lactose or saccharose), alcoholic sugars (e.g., sorbitol or mannitol), vegetable starches (e.g., potato starch or corn starch), polysaccharides (e.g., amylopectin or cellulose derivatives), or gelling agents (e.g., gelatin).

[0085] The pharmaceutical dosage forms described herein may be prepared in accordance with standard and / or known pharmaceutical practice. The pharmaceutical dosage forms are generally provided as mixtures comprising a therapeutic compound and one or more pharmaceutically acceptable excipients. The one or more pharmaceutically acceptable excipients may be selected in accordance with standard pharmaceutical practice, taking into account the intended route of administration. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and preferably free from adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found, for example, in Remington, The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). A brief overview of drug delivery methods can also be found, for example, in Langer, Science 249, 1527 (1990).

[0086] Those skilled in the art will understand that the pharmaceutical dosage forms described herein may act systemically and, therefore, may be administered using appropriate techniques known to those skilled in the art. The pharmaceutical dosage forms described herein are typically administered orally, for example, as oral pharmaceutical dosage forms. Accordingly, several variants provide oral pharmaceutical dosage forms comprising about 100 to about 1000 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide or a pharmaceutically acceptable salt, solvate, or prodrug thereof. One variant provides an oral pharmaceutical dosage form comprising about 200 to about 1000 mg of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide.

[0087] Dosage forms intended for oral administration may further include an enteric coating to prevent or minimize dissolution or disintegration in the gastric environment. Thus, oral formulations coated with an enteric coating (e.g., capsules or tablets) may result in targeted release of the therapeutic compound in the small intestine. For example, the enteric coating may be present on the surface of the formulation (e.g., the surface of the tablet or capsule), or each particle containing the therapeutic compound may be coated with the enteric coating. Therefore, in certain embodiments, the pharmaceutical dosage forms used in the method of the present invention further include an enteric coating.

[0088] In certain embodiments, the enteric coating is present on the pharmaceutical dosage form, and in some variations, the coating may be provided as an outer layer on the pharmaceutical dosage form.

[0089] Alternatively, particles containing the therapeutic compound may be individually coated with an enteric coating, and the coated particles may be prepared into a pharmaceutical dosage form. Thus, in certain embodiments, the pharmaceutical dosage form contains particles containing the therapeutic compound, each particle being coated with an enteric coating.

[0090] The term "enteric coating" refers to a substance (e.g., a polymer) incorporated into an oral medication (e.g., applied to the surface of a tablet, capsule, particle, or pellet) that inhibits the dissolution or breakdown of the medication in the gastric environment. Enteric coatings are typically stable at the highly acidic pH found in the stomach but rapidly decompose at the relatively basic pH of the small intestine. Therefore, the enteric coating prevents the release of the active ingredient in the medication until it reaches the small intestine.

[0091] Any enteric coating known to those skilled in the art can be used in the present invention. Specific enteric coating materials that may be mentioned include beeswax, shellac, alkylcellulose polymer resins (e.g., ethylcellulose polymer, carboxymethylethylcellulose, or hydroxypropylmethylcellulose phthalate), or acrylic polymer resins (e.g., acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, methacrylate copolymer, methacrylic acid copolymer, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkyl methacrylate amide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylate, methyl methacrylate copolymer, poly(methyl methacrylate) copolymer, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer).

[0092] In some modified embodiments, the pharmaceutical composition comprises a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and at least one pharmaceutically acceptable excipient. In particular, the at least one pharmaceutically acceptable excipient may be a lubricant, binder, filler, surfactant, diluent, anti-adhesion agent, coating agent, flavoring agent, coloring agent, fluidizer, preservative, sweetener, disintegrant, adsorbent, buffer, antioxidant, chelating agent, dissolution accelerator, dissolution retarder, or wetting agent.

[0093] Specific pharmaceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, saccharose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable ingredients, as well as disintegrants and lubricants such as sodium lauryl sulfate, sodium doxate, magnesium stearate, calcium stearate, sodium stearyl fumarate, and polyethylene glycol wax. In the preparation of pharmaceutical dosage forms of therapeutic compounds for oral administration, particles containing the therapeutic compound (preferably ground) may be mixed with mannitol, PVP (polyvinylpyrrolidone) K30, and sodium lauryl sulfate, either together or separately.

[0094] In the preparation of pharmaceutical dosage forms, the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, may be mixed with one or more pharmaceutical excipients (including basic excipients), either together or separately.

[0095] A mixture of a therapeutic compound and one or more pharmaceutically acceptable excipients can be processed into pellets or granules, or compressed into tablets. Therefore, the pharmaceutical dosage forms of the method of the present invention may be tablets, small tablets, blocks, pellets, particles, granules, or orally administered powders.

[0096] Pharmaceutical formulations that may be mentioned include those in which the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is present in an amount of at least 1% by weight (or at least 10% by weight, at least 30% by weight, or at least 50% by weight) of the total weight of the formulation. That is, the weight ratio of the therapeutic compound to the total weight of the components of the pharmaceutical formulation (i.e., the therapeutic compound and all pharmaceutical excipients, e.g., adjuvants, diluents, and carriers) is at least 1:99 (or at least 10:90, at least 30:70, or at least 50:50).

[0097] Dosage in oral formulation As used herein, “therapeutably effective amount,” “effective amount,” or “dose” means an amount of the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, sufficient to produce a desired effect, which may be a therapeutic and / or beneficial effect. The effective amount or dose will vary depending on the age or general condition of the individual or subject (e.g., human), the severity of the condition being treated, the specific drug administered, the duration of treatment, the nature of any concurrent treatment, the pharmaceutically acceptable carrier used, and similar factors within the scope of the knowledge and expertise of those skilled in the art.

[0098] As used herein, the term “about” when referring to measurable values ​​such as the amount, dose, time, or temperature of a compound refers to a variation of a specific amount of 20%, 10%, 5%, 1%, 0.5%, or even 0.1%. In each example, it is intended that such a term may be replaced by notation such as “±10%” or similar notation (or by indicating a variation of a specific amount calculated based on the relevant value). It is also intended that such a term may be deleted in each example.

[0099] It will be understood that the dosages and pharmacokinetic parameters described below relate to the treatment of specific diseases, particularly patients with the heart disease described herein. The dosages and pharmacokinetic parameters may also apply to human subjects taking drugs for physical enhancement or cardiac improvement. As described above, in some embodiments, a smaller amount of the compound of formula (I) may be required to improve physical strength or cardiac function compared to when the compound of formula (I) is administered to a subject (e.g., a patient) with heart disease.

[0100] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be orally administered once daily to a subject requiring it (e.g., a patient) at a dose of about 100 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be orally administered once daily at a dose of about 200 mg to about 1,000 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be orally administered once daily at a dose of about 400 mg to about 800 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be orally administered once daily at a dose of about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily in doses of about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

[0101] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) that requires it, thereby resulting in a steady-state plasma concentration of the compound of formula (I) of approximately 40 μg / mL to approximately 200 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject or a subject (e.g., a patient) that requires it, thereby resulting in a steady-state plasma concentration of the compound of formula (I) of approximately 40 μg / mL to approximately 80 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally once daily to a subject or a subject (e.g., a patient) that requires it, thereby resulting in a steady-state plasma concentration of the compound of formula (I) of approximately 70 μg / mL to approximately 120 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered orally once daily to a subject or subject requiring it (e.g., a patient), resulting in a steady-state plasma concentration of approximately 90 μg / mL to approximately 160 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered orally once daily to a subject or subject requiring it (e.g., a patient), resulting in a steady-state plasma concentration of approximately 100 μg / mL to approximately 150 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug is administered daily to a human subject, resulting in a steady-state plasma concentration of approximately 120 μg / mL to approximately 140 μg / mL.

[0102] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, wherein the administration provides a steady-state AUC of the compound of formula (I).0-24 The AUC is approximately 1,000 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,000 h*μg / mL to approximately 2,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,500 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,800 h*μg / mL to approximately 3,100 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 1,500 h*μg / mL to approximately 2,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24 The AUC is approximately 2,500 h*μg / mL to approximately 4,000 h*μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof can be administered orally once daily to a subject (e.g., a patient) requiring it, where the administration provides the steady-state AUC of the compound of formula (I). 0-24This ranges from approximately 3,000 μg / mL to approximately 3,500 μg / mL.

[0103] In any of the prior embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject (e.g., a patient) requiring it, wherein the C of the compound of formula (I) max The concentration is approximately 40 μg / mL to approximately 200 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject (e.g., a patient) requiring it, wherein the administration provides the C of the compound of formula (I). max The concentration is approximately 70 μg / mL to approximately 200 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject (e.g., a patient) requiring it, wherein the C of the compound of formula (I) is administered. max The concentration is approximately 80 μg / mL to approximately 140 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject (e.g., a patient) who requires it, wherein the administration provides the C of the compound of formula (I). max The concentration is approximately 70 μg / mL to approximately 100 μg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject (e.g., a patient) who requires it, wherein the administration of the compound of formula (I) results in the C max This ranges from approximately 1200 μg / mL to approximately 150 μg / mL.

[0104] In some embodiments, the compound of formula (I) is provided as a tablet having the components shown in Table 1. [Table 1]

[0105] Combination therapy Those skilled in the art will understand that the method of the present invention may include (for example, be combined with) further treatments for the same condition.

[0106] In particular, when treating diseases or disorders that are improved by activating AMPK, the salts of the present invention may be administered in combination with one or more other (i.e., different) therapeutic agents useful in treating the disease or disorder.

[0107] Such combination therapy may involve administering the salt of the present invention to a subject in combination with (e.g., sequentially or simultaneously) different therapeutic agents in the same formulation or, preferably, in separate formulations. "Administered in combination with" (and similarly, "administered in combination with") means that each active ingredient is administered sequentially or simultaneously as part of a medical intervention aimed at treating the condition in question. "Simultaneously" means that the salt of the present invention and the different therapeutic agent are administered in parallel with each other, either in a single pharmaceutical dosage form containing both active ingredients or in separate dosage forms administered simultaneously.

[0108] Accordingly, with respect to the present invention, the terms “administered in combination with ~” (and similarly “administered in combination with ~”) include the fact that the salts of the present invention and different therapeutic agents are administered either together or in sufficiently close temporal proximity, enabling them to produce a greater beneficial effect on the patient over the course of treatment of the relevant condition, and in the same course of treatment, than if either agent were administered alone in the absence of the other component. Whether a combination provides a more beneficial effect with respect to the treatment of a particular condition and over the course of treatment of a particular condition depends on the condition being treated, but can be routinely achieved by those skilled in the art.

[0109] Furthermore, in the context of the present invention, the term “in combination with ~” includes the possibility that one or the other of the two active ingredients may be administered before, after, and / or simultaneously with the other (optionally repeated). As used in this context, the terms “administered simultaneously” and “administered simultaneously as ~” include the possibility that individual doses of the salt of the present invention and different therapeutic agents are administered to each other within 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes.

[0110] Other therapeutic agents useful for treating diseases or disorders that are improved by activating AMPK (such as heart failure, diabetic nephropathy, and diabetes as described herein) are well known to those skilled in the art. Preferably, the other therapeutic agents are sodium-glucose cotransport protein 2 (SGLT2) inhibitors, or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and such combinations are useful for treating diseases such as type 2 diabetes. In further embodiments, the method of the present invention comprises sequential or simultaneous administration of the sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide and an SGLT2 inhibitor.

[0111] Those skilled in the art will understand that sodium-glucose cotransport protein 2 inhibitors are substances or agents that induce a reduction in one or more functions of sodium-glucose cotransport protein 2. Furthermore, “reduction in sodium-glucose cotransport protein 2 function” includes the cessation of one or more functions of sodium-glucose cotransport protein 2, or a reduction in the rate of a particular function. The particular function that may be completely or partially inhibited is the ability of sodium-glucose cotransport protein 2 to act as a glucose transporter.

[0112] In certain embodiments, the sodium-glucose cotransport protein 2 inhibitor is glipflozin. Glipflozin is a known class of small-molecule sodium-glucose cotransport protein 2 inhibitors. Hawley et al. (Diabetes, 2016, 65, 2784-2794) and Villani et al. (Molecular Metabolism, 2016, 5, 1048-1056) recently discussed possible mechanisms of action for specific glipflozins. Specific glipflozins that may be mentioned include dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, cergliflozin (e.g., cergliflozin etavonate), remogliflozin (e.g., remogliflozin etavonate), erzgliflozin, and sotagliflozin. In even more specific embodiments, the sodium-glucose cotransport protein 2 inhibitor is dapagliflozin.

[0113] In certain embodiments, the sodium-glucose cotransport protein 2 inhibitor is a pharmaceutically acceptable salt of gliflozin. For example, further active ingredients may be pharmaceutically acceptable salts of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, cergliflozin (e.g., cergliflozin etavonate), remogliflozin (e.g., remogliflozin etavonate), erzgliflozin, or sotagliflozin.

[0114] In further embodiments, the sodium-glucose cotransport protein 2 inhibitor is a solvate of gliflozin. For example, further active ingredients may be solvates of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, cergliflozin (such as cergliflozin etavonate), remogliflozin (such as remogliflozin etavonate), erzgliflozin, or sotagliflozin.

[0115] Furthermore, in a further embodiment, the sodium-glucose cotransport protein 2 inhibitor is a prodrug of gliplozin. For example, the further active ingredient may be a prodrug of dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, tofogliflozin, cergliflozin (such as cergliflozin etavonate), remogliflozin (such as remogliflozin etavonate), erzgliflozin, or sotagliflozin.

[0116] The methods of the present invention disclosed herein (and oral dosage forms used in such methods) may also have the advantage that dose-efficient methods using the salts of the present invention are more effective, less toxic, longer-acting, more potent, have fewer side effects, are more easily absorbed, and / or have a better pharmacokinetic profile (e.g., high oral bioavailability and / or low clearance) compared to other therapies known in the prior art. In particular, the methods of the present invention may have the advantage of exhibiting favorable properties such as being more effective and / or having fewer side effects in vivo as a result of the dose-efficient properties of the salts of the present invention.

[0117] Use of compounds In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a treatment comprising any of the methods described herein is also provided.

[0118] For example, one variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating and / or preventing cardiomyopathy, heart failure, atrial fibrillation, and other cardiomyopathy and complications. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for enhancing or improving cardiac efficiency, which may include restoring metabolic flexibility and glucose oxidation. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for restoring flexibility of cardiac metabolism. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for treating or improving metabolic syndrome, which may include a set of risk factors, such as hyperglycemia, elevated blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for treating cardiomyopathy or for preventing or delaying the onset of cardiomyopathy. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for treating heart failure or atrial fibrillation in subjects requiring treatment for heart failure or atrial fibrillation. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is provided for inhibiting the activity of pyruvate dehydrogenase kinase (PDK).

[0119] In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a drug is also provided. In some embodiments, the drug is for any of the methods described herein.

[0120] Examples include the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating and / or preventing cardiac diseases, including, for example, treating and / or preventing cardiac diseases and complications such as cardiomyopathy, heart failure, and atrial fibrillation. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for enhancing or improving cardiac efficiency, which may include restoring metabolic flexibility and glucose oxidation. Another variant provides the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for restoring flexibility of cardiac metabolism. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating or improving metabolic syndrome, which may include a set of risk factors including hyperglycemia, elevated blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating cardiomyopathy, or for preventing or delaying the onset of cardiomyopathy. In yet another variant, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for treating heart failure or atrial fibrillation in subjects requiring treatment for heart failure or atrial fibrillation. In yet another modified embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the manufacture of a drug for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) is provided. [Examples]

[0121] The subject matter of this disclosure will be better understood by referring to the following embodiments, which are provided as examples of the present invention, rather than as limitations.

[0122] In this specification, unless otherwise specified, “Cmpd-(I)” or “compound of formula (I)” as referred to in the experiments detailed in the following examples is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide.

[0123] Mice. Mice were housed in a certified animal facility under a 12-hour light / dark cycle and given free access to their respective diets. Leptin receptor-deficient male BKS.Cg-Dock7m + / + Leprdsb / J(db / db) mice and C57BLKS / J(BKS) mice were obtained. Male C57BL / 6J mice were mated with female CBA / CaCrl mice to obtain F1 mice. Male F1 mice at 9 weeks of age were treated with multiple low doses of streptozotocin (50 mg / kg* days for 5 consecutive days; freshly prepared in 0.1 mM sodium citrate (pH 4.5)) to induce diabetes. Mice were freely administered either a D10001 diet or D10001 formulated with the compound of formula (I), containing 0.25 mg / g, 0.5 mg / g, and 1 mg / g of the compound of formula (I) (CAS number 1261289-04-6). Cohorts of BKS, db / db, and F1 mice were housed in groups of 4-5 mice / cage. Mice with more than 10% weight loss or obvious health problems such as fighting were excluded to avoid intergroup differences. In different cohorts, mice were randomly assigned to cages based on body weight and fasting blood glucose, and assigned to different treatments per cage or, where possible, per individual, to minimize the effects of starting body weight and glucose homeostasis. Samples were randomly selected from 5-9 mice / diet for in vitro analyses such as Western blotting, qPCR, histological, and immunohistochemical studies. All in vivo analyses were performed between 9 a.m. and 3 p.m.

[0124] PET analysis of glucose uptake in vivo. All in vivo experiments were successfully repeated 2-3 times. In vitro tissue analysis was successfully repeated 2-3 times in different cohorts. Mice were starved for 3 hours before each scan. Before scanning, mice were sedated with less than 2% isoflurane in oxygen (800 mL / min), and a cannula was inserted via the tail vein using a 27G needle and a custom-made catheter. Dynamic PET acquisition for 40 minutes (frames 8x30s, 8x60s, 6x180s, 2x300s) was initiated by injecting 50-70 μL of 13.9+2.3 MBq[18F]-fluorodeoxyglucose (FDG) dissolved in physiological saline. The maximum metabolic rate of glucose, MRglu, was calculated using Patlak analysis of PET data combined with measured glucose concentration. PET / CT imaging was performed on a 0.375x0.375x0.377 mm scale. 3 The study began with a 50kV, 0.088mAs helical CT acquisition, reconstructed into voxel-sized images. PET images were reconstructed to voxel size (0.4x0.4x0.4) in four iterations and four subsets using Tera-Tomo 3D iterative reconstruction with attenuation, scattering, and random correction. Image analysis and Patlak pharmacokinetic calculations were performed using imlook4d software. During scanning, mice were monitored on temperature-controlled beds, and blood glucose was measured using tail vein blood 10, 20, and 40 minutes after injection. Regions of interest (ROIs) consisting of both left and right gluteus medius / rectus femoris muscles were defined as cylinders with a 10-pixel diameter and 10 slices in the coronal view. Myocardial ROIs were defined by thresholding the search volume, manually depicted in the last PET frame, to 40% of the maximum voxels. Vena cava ROIs were defined as voxels exceeding 60% of the maximum voxels in the first frame showing uptake. The image derivation input function was approximated using a time-radioactivity curve from a vena cava ROI. Patlak analysis was performed using the above image derivation input function, and the irreversible acquisition rate K was determined by linear regression between 16 and 40 minutes. i Patlak K made the decision. iValues ​​were calculated at the ROI level for quantification and at the voxel level for visualization. Saturated glucose consumption is as follows:

number

[0125] Echocardiography. For echocardiography, mice are subjected to 0.8 L·min. -1 Subjects were sedated with 1.5-2% isoflurane in O2(g) and placed on a temperature-controlled table. Chest hair was removed using depilatory cream. Respiration and ECG were monitored during the scan, and anesthesia was adjusted to avoid respiratory depression. The total scan time did not exceed 15 minutes. Stroke volume, cardiac output, and wall thickness were measured in a parasternal long-axis view using B-mode and M-mode images. Diastolic left ventricular inflow was measured using mitral valve inflow Doppler in a apical four-chamber view. Offline analysis was performed blinded.

[0126] Mitochondrial respiration analysis. C2C12 myoblasts were kept in growth medium containing 10% fetal bovine serum and 20 U / ml penicillin-streptomycin. To obtain myotubes, 7500 cells / cm³ of C2C12 myoblasts were placed in an XF96 plate coated with poly-L-lysine. 2The myotubes were seeded and cultured in growth medium for 3 days until 80% confluence, then switched to differentiation medium (DM; FBS was replaced with 2% horse serum for 6 days, with the medium changed every 2 days). Respiratory assays were performed using a Seahorse XFe96 extracellular flux analyzer according to the manufacturer's "Mito-stress" protocol and mitochondrial parameters. Briefly, differentiated myotubes were pre-treated for 4 hours in growth medium containing 1% horse serum along with the compound of formula (I) (sodium salt preparation). The myotubes were then equilibrated for 1 hour in Seahorse assay medium (1 mM Na-pyruvate, 10 mM glucose, 2 mM L-glutamine) adjusted to pH 7.4 and supplemented with the compound of formula (I) as in the pre-treatment. As baseline, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measurements were collected, followed by sequential addition of 1 μM oligomycin, 2 μM FCCP, and 0.5 μM rotenone + 0.5 μM antimycin A. Mitochondrial function parameters were calculated according to the manufacturer's recommendations.

[0127] Western blot analysis. Vastus muscle was isolated from non-fasted mice and lysed in a mortar and pestle using liquid nitrogen. Vastus muscle and INS-1E cell samples were homogenized in ice-cold protein lysis buffer (100 mM Tris pH 6.8, 2% SDS) with a protease inhibitor cocktail and a phosphatase inhibitor cocktail, and then sonicated. After centrifugation at 14,000 rpm for 10 minutes, the vastus muscle supernatant was collected. Protein concentrations were measured using a BCA kit, and then the samples were diluted in Laemmli buffer and denatured. 20 μg of vastus muscle and 7 μg of INS-1E cell protein samples were separated on 4–15% Criterion® TGX Stain-Free® protein gel and blotted to low-fluorescence PVDF or nitrocellulose membranes, respectively. Primary and secondary antibodies are listed in Table 2. Values ​​were normalized to stain-free total protein signal or β-actin. [Table 2]

[0128] qRT PCR. Total RNA was prepared from isolated pancreatic islets using the RNeasy Micro Kit. Total RNA from gastrocnemius muscle and left ventricle was prepared using the RNeasy Fibrous Tissue Mini Kit after first disrupting the tissue in liquid nitrogen using a pestle. First-strand cDNA synthesis was performed using SuperScript III according to the manufacturer's instructions. The primers used for qRT-PCR are listed in Table 3. Tbp expression was used to normalize samples from pancreatic islets, gastrocnemius muscle, and left ventricle. Tbp normalization was validated with Rpl32 in left ventricular samples and gastrocnemius muscle. [Table 3]

[0129] Isolation and culture of pancreatic islets. Mouse pancreatic islets were essentially isolated and cultured for 48 hours in medium supplemented with 11 mM glucose or 22 mM glucose + / - 5 μM of the compound of formula (I) (RPMI 1640 medium, 1% fetal bovine serum, 10 mM HEPES, 1 mM sodium pyruvate, 50 μM 2-mercaptoethanol, 50 U / ml Pen:Strep). Human pancreatic islets from non-diabetic donors were cultured for 48 hours in medium supplemented with 5.5 mM glucose or 25 mM glucose + / - 5 μM of the compound of formula (I) (CMRL medium, 10% fetal bovine serum, 20 U / ml Pen:Strep and 1X GlutaMax).

[0130] RNA-seq was performed. An RNA-seq library was prepared from 150 ng of total RNA using the Illumina TruSeq stranded mRNA Library Kit, followed by 100 bp paired-end sequencing using a NovaSeq 6000 Illumina Sequencer. RNA-seq reads were processed. Fastq files containing 100 nt paired-end sequencing reads were quality-checked and aligned to mouse or human genomes (GRCm39 or GRCh38). Fragment-gene hits were counted. Subsequent analysis was performed in R using DESeq2 and the clusterProfiler package. Normalization and differential expression analysis were performed using DESeq2 with batch correction (referring to islet preparation batches and human donors, respectively), independent filtering (α=0.05), and false discovery rate (FDR) < 0.05. Genes whose baseMean expression exceeded the filter threshold were considered expressed, and for the overexpressed gene category, pvalueCutoff=0.05 and qvalueCutoff=0.2 were used to consider them as constituting the gene background for subsequent ORA and GSEA analyses using clusterProfiler.

[0131] Insulin secretion assay. GSIS was performed in UB buffer (125 mM NaCl, 6 mM KCl, 1.3 mM CaCl2, 1.2 mM MgCl2, 25 mM Hepes (pH 7.3), 2 mM glucose, 0.1% BSA) at 37°C under normal atmospheric conditions. Briefly, INS-1E cells were washed, equilibrated in UB buffer for 1 hour, transferred to UB buffer containing either 2 or 20 mM glucose for 30 minutes, and insulin levels in the supernatant were measured by ELISA. Insulin secretion was normalized to protein content.

[0132] Cell lines. INS-1E and C2C12 were commercially available and therefore not certified after purchase. PCR testing confirmed that these cells did not contain mycoplasma.

[0133] Statistical analysis. The experimental design consisted of a non-diabetic control group (BKS or control, i.e., vehicle-injected F1 mice), a diabetic control group (db / db mice or STZ mice, i.e., STZ-injected F1 mice), and a group(s) treated with the compound of formula (I) (db / db mice or STZ mice continuously fed a diet formulated with the compound of formula (I)). First, the validity of the diabetes model was tested by comparing the control group with the diabetic group. Second, the effect of the diet with the compound of formula (I) was evaluated by comparing the group(s) treated with the compound of formula (I) with the diabetic group. The parametricity and heterogeneity of the data were assessed using the Shapiro-Wilk test and the Rubine test, and used to select the appropriate statistical test. For two-group comparisons, the unequal t-test or Wilcoxon test was used, along with Holm correction for multiple testing. For multiple groups, ANOVA analysis was used, followed by appropriate post-hoc analysis (see legend in the figure). A p-value of <0.05 was considered statistically significant. Data analysis, statistical analysis, and visualization were performed using the tidyverse, rstatix, and ggpubr packages in R.

[0134] Example 1: The compound of formula (I) prevents the development of diabetes in STZ mice. To evaluate whether the compound of formula (I) can improve diabetes in insulin-deficient conditions, β-cell function was resected in mice by streptozotocin (STZ) injection. STZ mice were treated with a diet formulated with 0.25 or 0.5 mg / g of the compound of formula (I), indicated as Cmpd-(I)-(0.25) and Cmpd-(I)-(0.5), starting from day 5 or day 15. In untreated STZ mice, insulin levels rapidly decreased while glucose levels increased (Figure 1(a), 1(b)). In contrast, treatment with the compound of formula (I) starting from day 5 normalized glucose levels (Figure 1(a)) without increasing plasma insulin levels (Figure 1(b)). Pancreatic insulin content was 10 to 20 times lower in mice treated with the compound of formula (I) compared to non-diabetic control mice (Figure 1(c), 8(b)). In both untreated STZ mice and STZ mice treated with the compound of formula (I), the islet cell area and the percentage of Ins+ cells decreased, while the percentage of Glu+ islet cells increased (Figures 1(d)-1(f), 8(a), 8(c), 8(d)). The compound of formula (I) rapidly reduced glucose levels in STZ mice without increasing plasma insulin levels, even when treatment was first initiated on day 15, i.e., when the mice had already developed apparent diabetes (Figures 1(g), 1(h), 8(e)). Pancreatic insulin content was also approximately 20 times lower in mice treated with the compound of formula (I) compared to control mice (Figures 1(i), 8(g)). Similarly, in untreated mice and STZ mice treated with the compound of formula (I), the islet cell area and the percentage of Ins+ cells decreased, while the percentage of Glu+ islet cells increased (Figures 1(j)-1(l), 8(f), 8(h), 8(i)). In summary, these findings indicate that the compound of formula (I) potently and insulin-independently reverses diabetes in a mouse model of insulin-deficiency diabetes.

[0135] Example 2: The compound of formula (I) improves hyperglycemia in STZ mice by stimulating muscle glucose uptake. The potent reduction in glucose levels in STZ mice treated with the compound of formula (I) provides evidence that the compound of formula (I) promotes insulin-independent glucose uptake in vivo. Continuous dynamic [ 18 [F]-Fluorodeoxyglucose PET analysis reveals the maximum metabolic rate of glucose in skeletal muscle (MR). glu It was shown that MR was significantly enhanced in STZ mice one week after treatment with the compound of formula (I) (Scan 3) compared to both pre-treatment (Scan 2) and untreated STZ mice at 22 days (Scan 3) (Figures 2(a)-2(c), 9). Furthermore, MR glu In the hearts of diabetic STZ mice, glucose decreased at days 14-15, i.e., scan 2, but normalized to baseline levels one week after treatment with the compound of formula (I) (Figure 2(c)). To address the metabolic fate of glucose in STZ mice treated with the compound of formula (I), glycogen content in skeletal muscle and cardiac muscle was analyzed. Glycogen content in muscle and cardiac muscle was increased in the muscles and hearts of untreated STZ mice compared to control mice, but decreased in STZ mice treated with the compound of formula (I) compared to untreated STZ mice (Figure 2(d)). Therefore, under hyperglycemic conditions, treatment with the compound of formula (I) stimulates insulin-independent glucose uptake and glucose utilization, but does not stimulate glycogen storage.

[0136] Example 3: The compound of formula (I) promotes a gene expression profile that facilitates glucose oxidation in the muscle and heart of STZ mice. Skeletal muscle TXNIP expression levels are negatively correlated with glucose uptake. Simultaneously with enhanced glucose uptake in skeletal muscle, Txnip mRNA and protein levels were decreased in the skeletal muscle of STZ mice treated with the compound of formula (I) compared to untreated STZ mice (Figure 2(e), 10). Furthermore, the expression of Slc2a4, which encodes Glut4, in skeletal muscle was decreased in STZ mice compared to controls, but normalized in STZ mice treated with the compound of formula (I), and the expression of Slc2a1, which encodes Glut1, in skeletal muscle tended to increase in STZ mice treated with the compound of formula (I) (p=0.059) (Figure 2(e)). Similarly, in STZ mice, increased expression of pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 4 (Pdk4), a negative regulator of oxidative glucose metabolism, and uncoupling protein 3 (Ucp3), which favors lipids as fuel substrates, was decreased in mice treated with compound (I) (Figure 2(e)), suggesting that the compound of formula (I) counteracts metabolic inflexibility in the skeletal muscle of STZ diabetic mice. Txnip expression was also increased in the hearts of STZ mice, but relatively decreased in STZ mice treated with the compound of formula (I) (Figure 2(f)). Furthermore, cardiac expression of Slc2a1 and Slc2a4 was decreased in untreated STZ mice, but tended to increase in mice treated with the compound of formula (I) (both p=0.088) (Figure 2(f)). Pdk4, Ucp2, and Ucp3 expression was increased in the hearts of untreated STZ mice but attenuated in STZ mice treated with the compound of formula (I) (p=0.055 for Ucp2) (Figure 2(f)). Therefore, the compound of formula (I) promoted changes in gene expression that promote glucose uptake, oxidative glucose metabolism, and ATP production in the skeletal muscle and heart of STZ mice (Figures 2(e), 2(f)). Hyperglycemia has been shown to rapidly increase cardiac expression of Pdk4 and Ucp3 and induce metabolic inflexibility and cardiac dysfunction in mice

[34] . In untreated STZ mice, peak E rate was gradually decreased and isovolumetric relaxation time (IVRT) was increased, indicating impaired diastolic function.On the other hand, a one-week treatment with the compound of formula (I) reduced IVRT and increased peak E velocity and consequently the E / A ratio (Figure 2(g), Table 4). Improved left ventricular filling in mice treated with the compound of formula (I) also resulted in increased stroke volume and cardiac output (Table 4). Overall, these findings indicate that in diabetic STZ mice, the compound of formula (I) improved hyperglycemia, reduced glycogen accumulation, and reversed diabetic cardiomyopathy by stimulating insulin-independent glucose uptake and utilization. [Table 4]

[0137] Table 4 shows echocardiographic measurements of left ventricular dimensions in parasternal long axis (PLAX) B-mode or M-mode. HR: Heart rate; SV: Stroke volume; CO: Cardiac output; EDV: End-diastolic volume; ESV: End-systolic volume; AWd / s: Diastolic / systolic anterior wall thickness; LVID d / s: Diastolic / systolic left ventricular diameter; PWd / s: Diastolic / systolic posterior wall thickness; EF: Ejection fraction; FS: Shortening fraction; E / A: Ratio of peak wave velocities of E and A; Deceleration time: Deceleration time from peak of E wave to estimated baseline; IVRT: Isovolumetric relaxation time. Statistics were performed using one-way repeated ANOVA with Tukey's post-hoc test. *P<0.05 between RD and the compound of formula (I) at the same time point compared to baseline. # P<0.05. Compared to scan 2, P<0.05. Data is mean ± SD.

[0138] Example 4: The compound of formula (I) improves hyperglycemia and promotes a gene expression profile that facilitates glucose oxidation in the muscle of db / db mice. To investigate the potential of the compound of formula (I) to improve hyperglycemia in association with severe insulin resistance, db / db mice were treated for 9 weeks with a diet formulated with the compound of formula (I) at concentrations of 0.5 or 1.0 mg / g, denoted as (Cmpd-(I)-(0.5) and Cmpd-(I)-(1.0). BKS mice were used as controls. Compensatory hyperinsulinemia was evident in db / db mice at 6 weeks of age (Figure 3(a), 3(b)). Untreated db / db mice subsequently developed insulin resistance. This was not possible, and as a result of decreased insulin levels, blood glucose levels rapidly increased (Figure 3(a), 3(b)). The compound of formula (I) dose-dependently increased insulin levels and consequently attenuated the increase in blood glucose levels compared to both baseline and untreated db / db mice (Figure 3(a), 3(b)). These findings provide evidence that the compound of formula (I) maintained the compensatory insulin secretion response of β-cells, and calculations of the homeostasis model assessment of β-cell function (HOMA-β) showed that the decline in β-cell function was reduced when treated with the compound of formula (I). Attenuation was demonstrated in db / db mice (Figure 3(c)). The attenuation of hyperglycemia by the compound of formula (I) in db / db mice was accompanied by a reduction in glycogen storage in skeletal muscle and heart (Figure 3(d)), suggesting that the compound of formula (I) stimulated glucose utilization even in diabetic db / db mice. Compared to untreated db / db mice, the expression of Txnip, Pdk4, and Ucp3 was reduced in the skeletal muscle of db / db mice treated with the compound of formula (I), and Slc2a4, mitochondrial biosynthesis, and respiration were also reduced. The increased expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α (Ppargc1a), a positive regulator of this process, and Cox8b, a driver of oxidative phosphorylation, supports this idea (Figure 3(f)). Furthermore, the increased cardiac expression of Slc2a1 and the attenuation of Txnip, Pdk4, and Ucp3 expression in mice treated with the compound of formula (I) compared to untreated db / db mice (Figure 3(g)) are consistent with those observed in STZ mice treated with the compound of formula (I).Notably, the compound of formula (I) did not increase serum lactate levels in STZ mice and db / db mice treated with the compound of formula (I) (Figure 11). In summary, these findings provide evidence that the compound of formula (I) evades the genetic signature associated with metabolic inflexibility related to diabetes and diabetic cardiomyopathy in both STZ and db / db diabetic mice.

[0139] Example 5: The compound of formula (I) stimulates mitochondrial uncoupling in myotubes. The increased glucose utilization and decreased glycogen content observed in the skeletal muscle and heart of STZ and db / db mice treated with the compound of formula (I) suggest that the compound of formula (I) generates metabolic demands and increases energy expenditure via unproductive cycles and / or mitochondrial uncoupling. To clarify the potential uncoupling ability of the compound of formula (I), mitochondrial and glycolytic functions were tested in intact differentiated C2C12 myotubes. The compound of formula (I) dose-dependently increased the oxygen consumption rate (OCR), an indicator of oxidative phosphorylation, and the ratio of basal OCR to basal ECAR (extracellular acidification rate) in C2C12 myotubes (Figure 4(a)-4(c)), indicating that the compound of formula (I) enhanced the cell's preference for oxidative metabolism. The compound of formula (I) also showed a reduced decrease in OCR in response to oligomycin, which blocks ATP synthase, and consequently an increase in proton leak (Figures 4(a), 4(d)). However, consistent with our previously published findings, the compound of formula (I) did not significantly reduce cellular ATP levels (Figure 4(d)). Overall, these results indicate that the compound of formula (I) increases cellular respiration by acting as a mitochondrial uncoupling agent, thereby providing evidence that the compound of formula (I) induces metabolic demands that enhance energy expenditure by stimulating TCA flux and oxidative metabolism.

[0140] Example 6: The compound of formula (I) maintains the function and mass of β-cells in db / db mice.Consistent with the initial compensatory increase in β-cell volume in the described db / db mice, islet cell area increased at 6 weeks of age in db / db mice compared to BKS mice (Figure 5(a), 5(b)). In untreated db / db mice, islet cell area relatively decreased by 15 weeks of age compared to 6 weeks of age (p=0.09), but was maintained in a dose-dependent manner in mice treated with the compound of formula (I) (Figure 5(a), 5(b)). The proportion of Ins+ cells increased in mice treated with the compound of formula (I) compared to untreated db / db mice, but the proportion of cells positive for other pancreatic endocrine hormones tended to decrease in db / db mice treated with the compound of formula (I) (Figure 5(c), Figure 12(a)). Consequently, pancreatic insulin and proinsulin content, as well as the pancreatic insulin:proinsulin ratio, a measure of the efficiency of proinsulin processing, were increased in db / db mice treated with the compound of formula (I) compared to untreated db / db mice (Figures 5(d), 5(e), 12(b)). Overall, these data provide evidence that the compound of formula (I) avoids β-cell loss and maintains β-cell function in db / db mice. Protein expression of the glucose transporter Glut2 encoded by Src2a2 was partially restored in the pancreatic islets of db / db mice treated with the compound of formula (I) (Figures 5(a), 5(f)). Expression of the transcription factors Nkx6.1 and MafA, markers of mature β-cell identity, increased, and Ipf1 / Pdx1 tended to increase in the pancreatic islets of db / db mice treated with the compound of formula (I) (Figures 5(a), 5(f)). The expression of Raldh3, encoded by aldehyde dehydrogenase 1a3 (Aldh1a3), which is upregulated in diabetic islets, remained unchanged (Figure 5(a), 5(f)). mRNA expression analysis of isolated islets showed increased expression of urocortin 3 (Ucn3), a marker of mature β-cells and a regulator of insulin secretion, and Nkx6.1 in islets of db / db mice treated with compound (I) of formula (Figure 5(g)).Treatment with the compound of formula (I) did not alter Aldh1a3 expression, but the expression of Txnip, which adversely affects insulin transcription and induces oxidative stress in β cells, was reduced in the pancreatic islets of db / db mice treated with Cmpd-(I)-(1.0) compared to untreated db / db mice (Figure 5(g)). Similarly, the expression of endoplasmic reticulum protein 29 (Erp29), an ER stress-related gene, and α-mannosidase-like 2 (Edem2), which enhances ER degradation, was reduced in the pancreatic islets of db / db mice treated with the compound of formula (I) (Figure 5(g)). These data suggest that the reduction in the expression of Txnip and ER stress genes, along with the increase in the expression of genes that regulate β cell identity and insulin secretion, contributes to compensatory β cell function, GSIS, and maintenance of β cell volume in insulin-resistant db / db mice via the compound of formula (I). The maintained compensatory insulin secretion in db / db mice treated with the compound of formula (I) may explain the lack of altered Aldh1a3 expression, suggesting that increased Aldh1a3 expression is a marker of metabolically problematic β-cells.

[0141] Example 7: The compound of formula (I) mitigates changes in pancreatic islet gene expression caused by acute hyperglycemia. To investigate the ability of compounds of formula (I) to directly modulate the pancreatic islet response to glucotoxic conditions, the inventors performed ex vivo RNA-seq analysis of mouse and human pancreatic islets cultured at low glucose (11 mM) and high glucose (22 mM) + / - 5 μM with compounds of formula (I). Mouse pancreatic islets responded to high glucose, with 1924 differentially expressed genes (DEGs) upregulated and 1568 downregulated (Figure 6(a), 13(a)-13(c)). At high glucose, compounds of formula (I) reduced the number of DEGs to 143 upregulated and 208 downregulated (Figure 6(a), 13(a)-13(c)). As expected, exposure of mouse pancreatic islets to high glucose significantly increased Txnip expression, which was attenuated by compounds of formula (I) (Figure 6(b)). Overexpression analysis (ORA) of the Molecular signature Hallmark, KEGG, and Wiki-pathways gene sets revealed that gene sets associated with enhancing β-cell activity, such as "Protein Secretion," "Unfolded protein response," and "Pancreas beta-cells," were upregulated by high glucose but overexpressed in DEGs avoided by the compound of formula (I) (Figure 6(c)). The metabolic pathways "Fatty acid metabolism," "Glycolysis," and "Hypoxia" were also regulated by high glucose and overexpressed in DEGs deregulated by the compound of formula (I), along with the "KEGG:TCA cycle" (P=0.073). Hierarchical clustering of the top 20 most significant DEGs of these pathways, regardless of direction, showed opposite regulation by the addition of high glucose and the compound of formula (I) (Figure 6(d)). These results demonstrate the ability of the compound of formula (I) to directly conserve important metabolic gene expression patterns in β-cells under glucotoxic conditions. The gene expression differences in human pancreatic islets were dominated by the donor effect, and DEG was hardly detected even after batch correction (Figures 13(d)-13(f)).Nevertheless, gene set enrichment analysis (GSEA) showed that high glucose induces genes in the "Pancreatic beta-cells" gene set, which are reversed by the compound of formula (I), and that the compound of formula (I) induces upregulation of genes in the "Hypoxia" and "Glycolysis" gene sets, similar to what was observed in mouse pancreatic islets (Figure 13(g)).

[0142] Example 8: The compound of formula (I) prevents the adverse effects of hyperglycemia on GSIS in INS-1E cells. Chronic hyperglycemia activates mTORC1 signaling and suppresses AMPK signaling in β-cells in vitro, resulting in decreased glucose metabolism and impaired glucose-stimulated insulin secretion (GSIS). Consistently, our RNA-seq analysis has confirmed that mTORC1 signaling is upregulated in pancreatic islets exposed to high glucose (22 mM), and this was prevented by exposure to the compound of formula (I) (Figure 6(c)). To investigate the effect of the compound of formula (I) on GSIS under chronic hyperglycemia conditions, INS-1E cells were cultured under 25 mM glucose for 4 days (days), resulting in impaired GSIS. However, these adverse effects were avoided when cells were simultaneously exposed to the compound of formula (I) throughout the entire 4-day culture period (Figure 7(a)). Short-term (2-hour) exposure of INS-1E cells to the compound of formula (I) at the end of a 4-day culture period also partially reversed the adverse effects of hyperglycemia on GSIS (Figure 7(b)). Thus, the compound of formula (I) prevented and reversed the adverse effects of hyperglycemia on GSIS. Analysis of the downstream targets of mTORC1, namely ribosomal protein 6 (pS6), and the downstream targets of AMPK, namely acetyl-CoA carboxylase (ACC) and Raptor, showed that long-term and short-term exposure of INS1-E cells to the compound of formula (I) under high glucose conditions resulted in decreased pS6-Ser240 / 244 levels, but increased pACC-Ser79 and pRaptor-Ser792 levels (Figures 7(c), 7(d), 14). In summary, these findings provide evidence that the compound of formula (I) conserves β-cell function under hyperglycemic conditions by antagonizing mTORC1 and maintaining AMPK signaling.

Claims

1. A method for treating cardiomyopathy associated with metabolic inflexibility in a person in need thereof, comprising an effective amount of a compound having the following structure: 【Chemistry 1】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

2. A method for preventing or delaying the onset of cardiomyopathy associated with metabolic inflexibility, comprising an effective amount of a compound having the following structure: 【Chemistry 2】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The method according to claim 1 or 2, wherein an alkali metal salt of the compound is administered.

4. The method according to claim 3, wherein the alkali metal salt is a sodium salt.

5. The method according to any one of claims 1 to 4, wherein the cardiomyopathy is diabetic cardiomyopathy.

6. The method according to any one of claims 1 to 5, wherein the subject is suffering from type 1 diabetes.

7. The method according to any one of claims 1 to 5, wherein the subject is suffering from type 2 diabetes.

8. The method according to any one of claims 1 to 7, wherein the subject is suffering from hypertension.

9. The method according to any one of claims 1 to 8, wherein the administration restores the flexibility of cardiac metabolism in the target heart.

10. The method according to any one of claims 1 to 9, wherein the compound, or a pharmaceutically acceptable salt thereof, solvate, or prodrug, is administered as a pharmaceutical composition.

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a tablet or a capsule.

12. The method according to any one of claims 1 to 11, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 100 mg to about 1,000 mg.

13. The method according to claim 12, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 200 mg to about 600 mg.

14. The method according to claim 12, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 400 mg to about 800 mg.

15. The method according to claim 12, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 400 mg.

16. The method according to any one of claims 1 to 15, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is approximately 70 μg / mL to approximately 120 μg / mL.

17. The method according to any one of claims 1 to 15, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 90 μg / mL to about 160 μg / mL.

18. The method according to claim 17, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 100 μg / mL to about 150 μg / mL.

19. The method according to claim 17, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 120 μg / mL to about 140 μg / mL.

20. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally to the subject once daily, and the steady state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof ０－２４ The method according to any one of claims 1 to 19, wherein the concentration is approximately 1,500 h*μg / mL to approximately 4,000 h*μg / mL.

21. The steady-state AUC of the aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 20, wherein the concentration is approximately 1,800 h*μg / mL to approximately 3,100 h*μg / mL.

22. The steady-state AUC of the aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 20, wherein the concentration is approximately 1,500 h*μg / mL to approximately 2,000 h*μg / mL.

23. The steady-state AUC of the aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 20, wherein the concentration is approximately 2,500 h*μg / mL to approximately 4,000 h*μg / mL.

24. The steady-state AUC of the aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 20, wherein the concentration is approximately 3,000 h*μg / mL to approximately 3,500 h*μg / mL.

25. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 20 to 24, wherein the concentration is approximately 70 μg / mL to approximately 200 μg / mL.

26. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 20 to 24, wherein the concentration is approximately 80 μg / mL to approximately 140 μg / mL.

27. The aforementioned compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 20 to 24, wherein the concentration is approximately 70 μg / mL to approximately 100 μg / mL.

28. The C of the compound or its pharmaceutically acceptable salt, solvate, or prodrug ｍａｘ is from about 120 μg / mL to about 150 μg / mL, the method according to any one of claims 20 to 24.

29. A method for preventing and / or treating heart failure in a person in need thereof, comprising an effective amount of a compound having the following structure: 【Transformation 3】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

30. A method for improving symptoms related to heart failure in a subject requiring it, comprising an effective amount of a compound having the following structure: 【Chemistry 4】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

31. The method according to claim 29 or 30, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF).

32. The method according to claim 29 or 30, wherein the heart failure is heart failure with reduced ejection fraction (HFrEF).

33. The method according to any one of claims 29 to 32, wherein an alkali metal salt of the compound is administered.

34. The method according to claim 33, wherein the alkali metal salt is a sodium salt.

35. The method according to any one of claims 29 to 34, wherein the administration restores the flexibility of cardiac metabolism in the target heart.

36. The method according to any one of claims 29 to 35, wherein the administration increases glucose oxidation in the subject.

37. The method according to any one of claims 29 to 36, wherein the subject is suffering from diabetic cardiomyopathy.

38. The method according to claim 37, wherein the administration reduces the diabetic cardiomyopathy of the subject.

39. The method according to any one of claims 29 to 38, wherein the subject is hyperglycemia.

40. The method according to any one of claims 29 to 38, wherein the subject is not hyperglycemia.

41. The method according to any one of claims 29 to 40, wherein the heart failure in the subject is related to hyperinsulinemia.

42. The method according to any one of claims 29 to 40, wherein the heart failure in the subject is not related to hyperinsulinemia.

43. The method according to any one of claims 29 to 42, wherein the subject is a diabetic patient.

44. The method according to claim 43, wherein the subject is suffering from type 1 diabetes.

45. The method according to claim 43, wherein the subject is suffering from type 2 diabetes.

46. The method according to any one of claims 29 to 36 or 37 to 42, wherein the subject is not a diabetic patient.

47. The method according to any one of claims 28 to 46, wherein the administration reduces the glycogen content in the heart.

48. The method according to any one of claims 29 to 47, further comprising administering a sodium-glucose cotransport protein 2 (SGLT2) inhibitor to the subject.

49. The method according to claim 48, wherein the SGLT2 inhibitor is dapaglifodine.

50. The method according to any one of claims 29 to 49, wherein the administration reduces the systolic blood pressure of the subject.

51. The method according to any one of claims 29 to 50, wherein the administration lowers the systolic blood pressure of the subject.

52. The method according to any one of claims 29 to 51, wherein the compound, or a pharmaceutically acceptable salt thereof, solvate, or prodrug, is administered as a pharmaceutical composition.

53. The method according to claim 52, wherein the pharmaceutical composition is a tablet or a capsule.

54. The method according to any one of claims 29 to 53, wherein the compound, or a pharmaceutically acceptable salt thereof, solvate, or prodrug, is orally administered to the subject once daily at a dose of about 100 mg to about 1,000 mg.

55. The method according to claim 54, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 200 mg to about 600 mg.

56. The method according to claim 54, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 400 mg to about 800 mg.

57. The method according to claim 54, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 400 mg.

58. The method according to any one of claims 29 to 57, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 70 μg / mL to about 120 μg / mL.

59. The method according to any one of claims 29 to 57, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 90 μg / mL to about 160 μg / mL.

60. The method according to any one of claims 29 to 57, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is about 100 μg / mL to about 150 μg / mL.

61. The method according to claim 60, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered once daily to the subject, and the steady-state plasma concentration of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is approximately 120 μg / mL to approximately 140 μg / mL.

62. The compound is administered orally to the subject once daily, and the steady state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof ０－２４ The method according to any one of claims 29 to 61, wherein the concentration is approximately 1,500 h*μg / mL to approximately 4,000 h*μg / mL.

63. The steady-state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 62, wherein the concentration is approximately 1,800 h*μg / mL to approximately 3,100 h*μg / mL.

64. The steady-state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 62, wherein the concentration is approximately 1,500 h*μg / mL to approximately 2,000 h*μg / mL.

65. The steady-state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 62, wherein the concentration is approximately 2,500 h*μg / mL to approximately 4,000 h*μg / mL.

66. The steady-state AUC of the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. ０－２４ The method according to claim 62, wherein the concentration is approximately 3,000 h*μg / mL to approximately 3,500 h*μg / mL.

67. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 62 to 66, wherein the concentration is approximately 70 μg / mL to approximately 200 μg / mL.

68. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 62 to 66, wherein the concentration is approximately 80 μg / mL to approximately 140 μg / mL.

69. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 62 to 66, wherein the concentration is approximately 70 μg / mL to approximately 100 μg / mL.

70. The compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, C ｍａｘ The method according to any one of claims 62 to 66, wherein the concentration is approximately 120 μg / mL to approximately 150 μg / mL.

71. A method for improving cardiac efficiency in a subject, comprising an effective amount of a compound having the following structure: 【Transformation 5】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

72. The method according to claim 71, wherein the compound is an alkali metal salt.

73. The method according to claim 72, wherein the alkali metal salt is a sodium salt.

74. The method according to any one of claims 71 to 73, wherein the subject is suffering from type 1 diabetes.

75. The method according to any one of claims 71 to 73, wherein the subject is suffering from type 2 diabetes.

76. A method for inhibiting the activity of pyruvate dehydrogenase kinase (PDK), comprising a compound having the following structure: 【Transformation 6】 The method comprises administering the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is orally administered to the subject once daily at a dose of about 100 mg to about 1,000 mg.

77. The method according to claim 76, wherein the PDK inhibitor is a PDK4 inhibitor.

78. The method according to claim 76 or 77, wherein the compound, or a pharmaceutically acceptable salt thereof, solvate, or prodrug, is orally administered to the subject once daily at a dose of about 200 mg to about 1,000 mg.

79. The method according to claim 76 or 77, wherein the compound, or a pharmaceutically acceptable salt thereof, solvate, or prodrug, is orally administered to the subject once daily at a dose of about 400 mg to about 800 mg.

80. The method according to claim 78, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered to the subject once daily at a dose of about 400 mg.

81. The method according to any one of claims 76 to 80, wherein the subject is non-diabetic.

82. A method for improving physical strength or cardiac function in a subject, wherein the subject contains a compound having the following structure: 【Transformation 7】 The method comprising administering a pharmaceutically acceptable salt, solvate, or prodrug thereof.

83. The method according to claim 82, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily in a dose of about 50 mg to about 400 mg.

84. The method according to claim 82, wherein the compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, is administered orally once daily in a dose of about 50 mg to about 100 mg.

85. The method according to any one of the prior claims, wherein the subject is a human.

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