Methods of treating cardiomyopathy induced by metabolic inflexibility

Abstract

Provided herein are methods of treating, preventing or delaying the onset of heart diseases, such as cardiomyopathy and heart failure, by administering a therapeutic compound to a subject in need thereof. The disclosure also generally relates to methods of using the therapeutic compounds to improve cardiac efficiency in a subject in need thereof. The disclosure also generally relates to methods of using the therapeutic compounds to inhibit the activity of pyruvate dehydrogenase kinase (PDK) in a subject in need thereof. The therapeutic compound is a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Description

Cross-references to related applications

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

[0002] Reference to the electronic sequence list The contents of the electronic serial number (286502000940SEQLIST.xml; size: 43,273 bytes; and creation date: July 18, 2024) are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure generally relates to methods for treating cardiac diseases such as cardiomyopathy and heart failure, and for preventing or delaying their onset, by administering the compounds provided herein. This disclosure also generally relates to methods for improving cardiac efficiency using the compounds provided herein. Furthermore, this disclosure generally relates to methods for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) using the compounds provided herein. Background Technology

[0004] AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis and is activated during metabolic stress, which reduces the intracellular pool of adenosine triphosphate (ATP; fasting, hypoxia, ischemia) or increases ATP consumption (physical activity / muscle contraction). AMPK is involved in multiple signaling pathways regulating energy metabolism and expenditure. Many clinical benefits of exercise or calorie restriction are mediated by increased AMPK activity. Therefore, it has become an attractive therapeutic target for a variety of diseases, including cardiovascular metabolic disorders such as obesity and diabetes.

[0005] The pleiotropic effects of AMPK activation have fueled considerable 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 an allosteric drug and metabolite (ADaM) site, formed by the interaction between the α and β subunits, the physiological function of which remains unclear. Binding to this site allosterically activates AMPK and prevents dephosphorylation. However, the specificity of activators to the ADaM site varies among different AMPK trimers, with many activators exhibiting higher activity towards β1-containing complexes compared to β2. Since β2 is the predominant isoform expressed in skeletal muscle and the liver (two major target organs for metabolic diseases), AMPK activators selective for β1-containing complexes are not ideally suited for treating metabolic diseases.

[0006] Despite advances in AMPK activators and other cardiovascular metabolic modulators, the incidence of cardiovascular metabolic diseases continues to rise. Cardiovascular metabolic disorders encompass a range of conditions such as hypertension, dyslipidemia, obesity, and diabetes. Individual responses to treatment can vary considerably due to genetic, lifestyle, and environmental factors. For individuals, these conditions remain progressive, contributing significantly to morbidity and mortality. As Western societies age, these issues are becoming an increasingly heavy social burden. There is a pressing and growing unmet medical need for therapies and interventions that can influence the incidence and progression of cardiovascular metabolic disorders, including interventions that can mimic the clinical benefits of exercise and calorie restriction. Summary of the Invention

[0007] The compound 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide has previously been identified as an AMPK activator, which works primarily by inhibiting the dephosphorylation of activated (phosphorylated) AMPK rather than by allosteric activation of AMPK. Unlike other AMPK activators discussed above, it was surprisingly observed that 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide enhanced glucose uptake without increasing glycogen content.

[0008] In some respects, this article provides methods and compositions for treating and / or preventing cardiac disease in subjects (e.g., human patients) by administering compounds of formula (I): (I), Or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Furthermore, in other respects, this article 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 human). In the foregoing respects, 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-thiadiazol-5-yl]benzamide.

[0009] Surprisingly, compounds of formula (I) were found to restore cardiac metabolic flexibility in the hearts of subjects (e.g., patients) suffering from various heart diseases or complications. The study also found that compounds of formula (I) are inhibitors of pyruvate dehydrogenase kinase (PDK) such as PDK4 and are able to increase glucose oxidation in the heart. In conjunction with other beneficial properties of compounds of formula (I) as AMPK activators, the inventors have found that compounds 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., the patient) has diabetes. In other embodiments, the subject (e.g., the patient) does not have diabetes.

[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 involving a range of risk factors, including hyperglycemia, high blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. Therefore, in some aspects, this disclosure provides a method for treating metabolic syndrome in a human subject of need 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 a heart disease as described herein. Alternatively, the subject may be a human subject potentially susceptible to diseases or conditions associated with metabolic syndrome. For example, in some embodiments, the human subject may have prediabetes. In other embodiments, the human subject may have both high blood pressure and high cholesterol, thus being susceptible to heart attack or stroke.

[0011] In some aspects, this document provides a method for treating cardiomyopathy in a subject (e.g., a patient) of need, 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), a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces hypertension in the subject (e.g., the patient). In some embodiments, administration of the compound of formula (I) reduces systolic blood pressure in the subject (e.g., the patient). In other embodiments, administration of the compound of formula (I) reduces diastolic blood pressure in the subject (e.g., the patient). In some embodiments, the subject (e.g., the patient) has diabetes. In other embodiments, the subject (e.g., the patient) does not have diabetes.

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

[0013] In some implementations, the subject (e.g., the patient) has Duchenne muscular dystrophy (DMD) cardiomyopathy. In some implementations, the subject (e.g., the patient) with DMD is approximately 5 years of age to approximately 18 years of age or approximately 7 years of age to approximately 12 years of age.

[0014] In some embodiments, the subject (e.g., the 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 aspects, this document provides a method for preventing or delaying the onset of cardiomyopathy in a subject (e.g., a patient) of need, 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 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 aspects, this document provides a method for treating heart failure in a subject (e.g., a patient) of need, 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 associated with 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., the patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the subject's diabetic cardiomyopathy is alleviated. In some embodiments, the subject (e.g., the patient) is hyperglycemic. In other embodiments, the subject (e.g., the patient) is not hyperglycemic.

[0017] In some aspects, this article provides a method for treating a subject (e.g., a patient) with atrial fibrillation (AF), 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, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof prevents the progression or onset of AF in a subject with predisposition to cardiac disease (e.g., a patient).

[0018] In some respects, this article provides a method for improving cardiac efficiency in a subject (e.g., a patient) in need, 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 cardiac disease.

[0019] In some aspects, this document provides a method for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) in a subject of need (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 has diabetes. In other embodiments, the subject does not have diabetes.

[0020] In some variations of the aforementioned aspects, the subjects are human.

[0021] In any of the foregoing embodiments, the compound of formula (I) may be applied 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-thiadiazol-5-yl]benzamide has the following formula: , Where X + It represents an alkali metal cation (such as lithium, rubidium, cesium, sodium, or potassium).

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

[0023] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient) at a dose of about 100 mg to about 1,000 mg. All references to doses 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 thereof 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 thereof 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 thereof 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 foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 40 µg / mL to about 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 40 µg / mL to about 80 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 70 µg / mL to about 120 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 90 µg / mL to about 160 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 100 µg / mL to about 150 µg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered daily to a human subject, resulting in a steady-state plasma concentration of the compound of formula (I) of about 120 µg / mL to about 140 µg / mL.

[0025] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state area under the curve (AUC) of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 It ranges from approximately 3,000 h*µg / mL to approximately 3,500 h*µg / mL.

[0026] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in the Ci 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... maxThe 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... max It is approximately 1200 µg / mL to approximately 150 µg / mL.

[0027] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered without increasing the dose of 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 with a dose that reduces the dose of glycogen content in the heart.

[0028] In any of the foregoing 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 transporter 2 (SGLT2) inhibitor. In some such embodiments, the SGLT2 inhibitor is dapagliflozin.

[0029] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof 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 aspects, this document provides a method for improving the physical condition or cardiac function of 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 has or is susceptible to a disease, for example, in some embodiments, the subject has prediabetes. In some embodiments, the subject exhibits systemic symptoms associated with early stages of heart failure. In other embodiments, the subject has high cholesterol levels. In some embodiments, the subject may improve cardiac function or enhance health by taking about 50 mg to about 400 mg of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof once daily. In some embodiments, the subject may improve cardiac function or enhance health by taking about 50 mg to about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof once daily. In some embodiments, the subject may improve cardiac function or enhance health by taking about 50 mg to about 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof once daily.

[0031] In some aspects, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in a therapy (including any of the methods described herein) is also provided. For example, in one variant, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the treatment and / or prevention of cardiac diseases, including, for example, the treatment and / or prevention of cardiac diseases and complications, including cardiomyopathy, heart failure, and atrial fibrillation. In another variant, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in 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 restoring cardiac metabolic flexibility is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment or improvement of metabolic syndrome involving a range of risk factors, including hyperglycemia, high blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment of cardiomyopathy or the prevention or delay of cardiomyopathy onset is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment of heart failure or atrial fibrillation in a subject of need is provided. In yet another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the inhibition of pyruvate dehydrogenase kinase (PDK) activity is provided.

[0032] In some aspects, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament is also provided. In some embodiments, the medicament is used in 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 preparation of a medicament for the treatment and / or prevention of heart disease (including, for example, the treatment and / or prevention of heart disease and its complications, including cardiomyopathy, heart failure, and atrial fibrillation) is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for enhancing or improving cardiac efficiency (which may include restoring metabolic flexibility and glucose oxidation) is provided. In yet another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for restoring cardiac metabolic flexibility is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment or improvement of metabolic syndrome involving a range of risk factors, including hyperglycemia, high blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment of cardiomyopathy or for the prevention or delay of cardiomyopathy onset is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment of heart failure or atrial fibrillation in a subject of need is provided. In yet another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the inhibition of pyruvate dehydrogenase kinase (PDK) activity is provided. Attached Figure Description

[0033] This application can be understood by referring to the following description in conjunction with the accompanying drawings.

[0034] Figure 1 This study describes the prevention of hyperglycemia by administering a compound of formula (I) to STZ mice. Fasting glucose levels were compared between control (n=7) and untreated STZ mice (n=6–8 / group) or those treated with 0.25 and 0.5 mg / g of the compound of formula (I) starting from day 5, respectively. Figure 1 (a) and insulin ( Figure 1 (b) Horizontal and area under the curve (AUC). Figure 1(c): Total pancreatic insulin content in control and untreated STZ mice, or treated with compound (I) at 0.25 and 0.5 mg / g, respectively, starting from day 5 (n=7-8 / group). Pancreatic islet cell area in control (n=3-5) and untreated (n=3-5) STZ mice, or treated with compound (I) at 0.25 (n=3-5) and 0.5 (n=3-6) mg / g, respectively, starting from day 5 (c): Figure 1 (d)), insulin positive (Ins+) Figure 1 (e) and glucagon-positive (Glu+) Figure 1 (f) Cell percentage. Fasting glucose levels in control (n=7) and untreated or treated STZ mice (n=8–16 / group) with compounds of formula (I) at 0.25 and 0.5 mg / g, respectively, starting on day 15. Figure 1 (g) and insulin ( Figure 1 (h) Horizontal and Area Under the Curve (AUC). Figure 1 (i) Total pancreatic insulin content in control (n=7) and untreated or treated from day 15 with compound (I) of formula (I) at 0.25 and 0.5 mg / g, respectively. Pancreatic islet cell area in control (n=3-5), untreated (n=6-10), or treated from day 15 with compound (I) of formula (I) at 0.25 (n=3-5) and 0.5 (n=6-10) mg / g, respectively. Figure 1 (j)), Ins+ ( Figure 1 (k)) and Glu+ cell ratio ( Figure 1 (l)). Please note that ( Figure 1 (a) to Figure 1 (f) control mice and ( Figure 1 (g) to Figure 1 The corresponding plot in (l) is the same. Data are presented 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 test. Figure 1 (a) to Figure 1 (d) Figure 1 (g) to Figure 1 (j)) or one-way ANOVA followed by Tukey post-hoc test (j) Figure 1 (e) to Figure 1 (f) Figure 1 (k) to Figure 1 (l)) (* p <0.05、** p <0.01、*** p<0.001) was determined, and the statistical significance between control mice and STZ mice was confirmed by the Wilcoxon test ( ). Figure 1 (a) to Figure 1 (d) Figure 1 (g) to Figure 1 (j) or by student's t-test (j) Figure 1 (e) to Figure 1 (f) Figure 1 (k) to Figure 1 (l)) (# p <0.05、## p <0.01、### p <0.001) confirmed.

[0035] Figure 2 The stimulation of skeletal muscle glucose uptake after administration of compound of formula (I) to STZ mice was described. Figure 2 (a): Timeline of STZ treatment and FDG-PET scan (in days). Figure 2 (b) Representative PET / CT images of FDG uptake in untreated mice (top panel) and mice treated with the compound of formula (I) (bottom panel). Figure 2 (c) Estimated maximum muscle and cardiac glucose uptake (MR) at baseline (scan 1), 9–10 days after the last STZ injection (scan 2), and 1 week after treatment with 0.5 mg / g of compound (I) (n=5) (scan 3) or without treatment (n=5). glu ). ( Figure 2 (d) Glycogen content in the muscle and heart of STZ mice in control (n=6-18) and untreated (n=14-36) or treated with compounds of formula (I) from day 15 onwards (n=13-27). Figure 2 (e) In the muscles 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) Txnip , Slc2a1 , Slc2a4 , Hk2 , Pkm , Ppargc1a , Pdk4 , Pdha1 , Shda and Cox8b The relative mRNA level. Figure 2 (f) Hearts of control mice (n=5), untreated STZ mice (n=9), and STZ mice treated with the compound of formula (I) (n=6-7) Txnip , Slc2a1 , Slc2a4 , Pdk4, Ucp2 and Ucp3 The relative mRNA level. Figure 2 (g) Mitral Doppler ultrasound of STZ-treated mice at baseline (Scan 1), 15 days after STZ initiation (Scan 2), and 1 week after treatment with 0.5 mg / g of compound (I) (n=9) (Scan 3), or without treatment (n=9). Data are presented as mean ± SEM. Statistical significance between untreated STZ mice and STZ-treated mice with compound (I) was determined by Student's t-test ( Figure 2 (c): Muscle, Figure 2 (g) or by Wilcox test ( Figure 2 (c): Heart, Figure 2 (d) to Figure 2 (f))(* p <0.05,** p <0.01, *** p <0.001) was determined, and the statistical significance between control mice and STZ mice was confirmed by the Wilcoxon test ( ). Figure 2 (d) to Figure 2 (f)) ( # p <0.05, ## p <0.01, ### p <0.001) is determined, and ( Figure 2 (c) Figure 2 The statistical significance between scans in (g) was determined by one-way repeated ANOVA followed by a paired Student's t-test. ¤ p<0.05) confirmed.

[0036] Figure 3 The study described how the compound of formula (I) dose-dependently prevented hyperglycemia in db / db mice. Fasting glucose levels in BKS and untreated or treated db / db mice (n=15-20 / group) with the compound of formula (I) at 0.5 and 1.0 mg / g, respectively, were compared. Figure 3 (a) and insulin ( Figure 3 (b) Levels and Area Under the Curve (AUC). HOMA-IR in untreated or db / db mice treated with compounds of formula (I) at 0.5 and 1.0 mg / g. Figure 3 (c)) and HOMA-β ( Figure 3 (d))(by Figure 3 (a) and Figure 3 (b) Calculate the area under the curve (AUC). Figure 3(e) Glycogen content in the muscle and heart of BKS (n=5-9) and untreated (n=9-10) or treated with compounds of formula (I) (n=6-7) db / db mice. Figure 3 (f) Muscle samples from db / db mice that were BKS (n=6-13) and untreated (n=15-22) or treated with 1.0 g / kg of a compound of formula (I) (n=8-15) Txnip , Slc2a1 , Slc2a4 , Hk2 , Pkm , Ppargc1a , Pdk4 , Pdha1 , Sdha , Cox8b , Ucp2 and Ucp3 The relative mRNA level. Figure 3 (g) Hearts of BKS (n=4-5), untreated db / db mice (n=8-9), and db / db mice (n=6-7) treated with compounds of formula (I). Txnip , Slc2a1 , Slc2a4 , Pdk4 , Ucp2 and Ucp3 The relative mRNA levels. Data are presented 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 test. Figure 3 (a) to Figure 3 (d) Student's t-test Figure 3 (e) or Wilcoxon test ( Figure 3 (f) Figure 3 (g)) (* p <0.05,** p <0.01, *** p <0.001) was determined, and the statistical significance between BKS and db / db mice was confirmed by the Wilcoxon test ( ). # p <0.05, ## p <0.01, ### p <0.001)( Figure 3 (a) to Figure 3 (d) Figure 3 (f) Figure 3 (g) or by student t-test ( Figure 3 (e) is confirmed.

[0037] Figure 4 The mitochondrial uncoupling induced by compounds of formula (I) was depicted. Respiratory chromatograms of intact C2C12 myotubes treated with compounds of formula (I) at 0.625, 1.25, and 2.5 µM for + / - 4 hours followed by sequential injections of oligomycin, FCCP, and a mixture of rotenone and antimycin are shown, illustrating the oxygen consumption rate (OCR). Figure 4 (a) and extracellular acidification rate (ECAR) Figure 4 (b)). Figure 4 (c): From the last baseline measurement ( Figure 4 (a) and Figure 4 (b) Measurement 3) OCR vs ECAR plot. Figure 4 (d): According to Figure 4 Mitochondrial functional parameters calculated from OCR data in (a). Data are expressed as mean ± SEM. n=5 / condition. Figure 4 The statistical significance of the difference between untreated cells and cells treated with the compound of formula (I) in (d) was determined by one-way ANOVA followed by Tukey post-hoc test. ¤ p <0.05, ¤¤ p <0.01).

[0038] Figure 5 The preservation of β-cell mass and expression of β-cell markers in db / db mice after administration of compound (I) were described. Figure 5 (a): Representative immunostaining of pancreas from untreated or treated, respectively, with 0.5 and 1.0 mg / g of the compound of formula (I), for insulin (green) and glucagon, Glut2, Ipf1 / Pdx1, Nkx6-1, Mafa and Raldh3 (all red) (n=5 / group and antibody). Figure 5 (b): Quantification of pancreatic islet cell area. Figure 5 (b) In 6-week-old BKS and db / db mice and 15-week-old BKS and db / db mice (n=4–6 / group) that were untreated or treated with compounds of formula (I) at 0.5 and 1.0 mg / g, respectively. Figure 5(c) Percentage of insulin (Ins+) and glucagon (Glu+) positive cells in 15-week-old BKS and db / db mice that were untreated or treated with compounds of formula (I) at 0.5 and 1.0 mg / g (n=5 in all groups). Total pancreatic insulin content in 15-week-old BKS (n=9) and untreated (n=7–10) or db / db mice treated with compounds of formula (I) at 0.5 (n=9) and 1.0 mg / g (n=6–8) (n=9 and 1.0 mg / g). Figure 5 (d) and the pancreatic insulin / proinsulin ratio ( Figure 5 (e)). Figure 5 (f): Quantification of expression of Glut2, Ipf1 / Pdx1, Nkx6-1, Mafa and Raldh3 in the pancreatic islets of 15-week-old db / db mice that were untreated (n=5) or treated with compounds of formula (I) at 0.5 (n=5) and 1.0 (n=4-5) mg / g. Figure 5 (g): Pancreatic islets of 15-week-old db / db mice that were untreated (n=11-13) or treated with compounds of formula (I) at concentrations of 0.5 (n=14-15) and 1.0 (n=9-10) mg / g. Ins1 / 2 , Slc2a2 , Pdx1 , Nkx6-1 , Mafa , Ucn3 , Trpm5 , Txnip , Aldh1a3 , Hspa5 , Erp29 and Edem2 The relative mRNA levels. Data are presented 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 test. Figure 5 (b) to Figure 5 (f) or Kruskal-Wallis test followed by Dunn post-hoc test ( Figure 5 (g)) (* p <0.05,** p <0.01, *** p <0.001) was determined, and the statistical significance between BKS and db / db mice was confirmed by the Wilcoxon test ( ). Figure 5 (b) to Figure 5 (e)) ( # p <0.05, ## p <0.01, ### p<0.001) confirmed.

[0039] Figure 6 The effects of the compound of formula (I) on hyperglycemia-induced changes in pancreatic gene expression in cultured islets were described. Figure 6 (a): A MA diagram showing differentially expressed genes between mouse islets cultured at 22 mM (G22) vs 11 mM (G11) glucose and 22 mM glucose + 5 µM compound (G22+C(I)) vs 11 mM glucose. Figure 6 (b): Overexpression analysis (ORA) of the molecularly characteristic Hallmark gene set (MSIG) in mouse islets cultured at 22 mM vs 11 mM glucose and 22 mM glucose + 5 µM compound of formula (I) vs 22 mM glucose. Figure 6 (c): Mouse islets cultured with 11 mM glucose, 22 mM glucose, and 22 mM glucose + 5 µM of compound (I) Txnip Log2 fold change of normalized read counts (n=5 for all groups). Data are presented as mean ± SEM. 22 mM vs 11 mM glucose were determined by Wilcoxon test. ## p <0.01) and 22 mM glucose + 5 µM compound (I) vs 22 mM glucose (* p <0.05,** p The statistical significance was <0.01. Figure 6 (d) comes from ( Figure 6 (b) and heatmaps of normalized read counts for DEGs from enriched categories of KEGG:TCA_CYCLE. The number of genes was limited to the 20 most significant DEGs.

[0040] Figure 7 The effects of compound (I) on chronic hyperglycemia in GSIS, mTORC1, and AMPK signaling in INS-1E cells were described. Cells were cultured at 11 mM or 25 mM glucose for 4 days, untreated, and treated with 5 µM compound (I) for 4 days. Figure 7 (a)) or 2 hours ( Figure 7 (b) GSIS of INS-1E cells (n=4-5 / group). Cells were cultured for 4 days at 11 mM or 25 mM glucose, untreated, and treated for 4 days with a compound of formula (I) at 5 µM. Figure 7 (c)) or 2 hours ( Figure 7(d) The expression ratios of phosphorylated (P-) and total ACC, AMPK, RAPTOR, and S6 proteins in INS-1E (n=4–5 / group). Data are presented as mean ± SEM. * Comparison between untreated cells and cells treated with the compound of formula (I) p <0.05,** p <0.01, *** p <0.001) and the difference between cells cultured with 11mM and 25mM glucose ( ¤ p <0.05, ¤¤ p The statistical significance of <0.01 was determined by two-way ANOVA followed by Tukey post-hoc test.

[0041] Figure 8 Immunohistochemical and metabolic analyses were performed on control and STZ mice. Figure 8 (a): Representative insulin (green) and glucagon (red) double immunostaining of the pancreas from control and untreated or STZ mice (n=5 in all groups) treated with compounds of formula (I) at 0.25 and 0.5 mg / g starting from day 5. Figure 8 (b) Total pancreatic insulin content in STZ mice that were untreated or treated from day 5 with compounds of formula (I) at 0.25 and 0.5 mg / g, respectively (n=7-8 / group). Islet cell area in untreated (n=3-5) or STZ mice treated from day 5 with compounds of formula (I) at 0.25 (n=3-5) and 0.5 (n=3-6) mg / g, respectively (n=3-6). Figure 8 (c) and insulin (Ins+) Figure 8 (d) Cell ratio. Figure 8 (e): Non-fasting glucose levels and area under the curve (AUC) in STZ mice that were in control (n=6) and untreated (n=9) or treated with 0.5 (n=9) mg / g of compound (I) from day 15. Figure 8 (f): Representative insulin and glucagon double immunostainings from the pancreas of STZ mice (n=5 in all groups) that were untreated or treated from day 15 with 0.25 and 0.5 mg / g of the compound of formula (I), respectively. Figure 8 (g): Total pancreatic insulin content in STZ mice (n=8-16 / group) treated with compounds of formula (I) at 0.25 and 0.5 mg / g, respectively, starting from day 15. Pancreatic islet cell area in STZ mice (n=6-10) treated with compounds of formula (I) at 0.25 (n=3-5) and 0.5 (n=6-10) mg / g, respectively, starting from day 15. Figure 8(h)) and Ins+ ( Figure 8 (i) Cell percentage. Data are presented as mean ± SEM. * P <0.05,** P <0.01, *** P <0.001, verified by Welch's ANOVA followed by Games-Howell post-hoc testing. Figure 8 (b) Figure 8 (c) Figure 8 (g) Figure 8 (h) or one-way ANOVA followed by Tukey post-hoc test (h) Figure 8 (d) Figure 8 (i) or Student's t-test Figure 8 (f)).

[0042] Figure 9 Normalized uptake values ​​(SUVs) during FDG-PET scans were depicted. SUV distributions of the gastrocnemius muscle and heart were observed during 40-minute dynamic FDG-PET scans at baseline (Scan 1), 9–10 days after the last STZ injection (Scan 2), and 1 week after treatment with 0.5 mg / g of compound (I) (n=5) or without treatment (n=5) (Scan 3). Data are presented as mean ± SEM.

[0043] Figure 10 Western blot analysis was used to quantify protein levels in the femoral muscle extracts of STZ mice, including control (n=5) and untreated (n=9) mice or those treated with a compound of formula (I) at 0.5 mg / g starting from day 15 (n=9).

[0044] Figure 11 Treatment with the compound of formula (I) did not increase serum lactate levels in STZ and db / db mice. Fasting glucose levels in STZ mice were measured on day 15 (before treatment) and day 22 after one week of treatment with the compound of formula (I). Figure 11 (a)) and lactic acid ( Figure 11 (b) Levels (n=9 / group). Fasting glucose levels in BKS and untreated or treated db / db mice (n=7-9 / group) with compounds of formula (I) at 0.5 and 1.0 mg / g, respectively. Figure 11 (c)) and lactic acid ( Figure 11 (d) Horizontal lines and area under the curve (AUC). Data are expressed as mean ± SEM. Figure 11 The statistical significance between time points in (a) was demonstrated by the Student's t-test. P<0.05 was determined, and statistical significance between untreated and treated db / db mice with the compound of formula (I) was confirmed by Welch's ANOVA followed by Games-Howell post-hoc test (*). P <0.05,** P <0.01, *** P <0.001) is determined, and ( Figure 11 (c) Figure 11 The statistical significance between BKS and db / db mice in (d) was verified by the Wilcoxon test. ## P <0.01) confirmed.

[0045] Figure 12 The proportions of PP+ and Som+ cells and the total pancreatic proinsulin content were depicted in BKS and db / db mice. Figure 12 (a): Percentage of pancreatic polypeptide (PP+) and somatostatin (Som+) positive cells in 15-week-old BKS and db / db mice that were untreated or treated with compounds of formula (I) at 0.5 and 1.0 mg / g (n=3 per group). Figure 12 (b): Total pancreatic proinsulin content in 15-week-old BKS mice (n=8) and untreated or treated with compounds of formula (I) at 0.5 and 1.0 mg / g, respectively (n=8–10 / group). Data are presented as mean ± SEM. * P <0.05, according to Welch's ANOVA followed by Games-Howell post-hoc test, between untreated db / db mice and db / db mice treated with the compound of formula (I). # P <0.05, according to the Wilcoxon test, between BKS and db / db mice.

[0046] Figure 13 The effects of compounds of formula (I) on gene expression characterization in cultured mouse and human islets were depicted. MA diagrams illustrate the effects of 22 mM (G22) vs 11 mM (G11) glucose (G22) vs 11 mM (G11) expression. Figure 13 (a) Compounds of formula (I) consisting of 22 mM glucose and 5 µM glucose (G22+C(I)) vs 22 mM glucose ( Figure 13 (b) and 22 mM glucose + 5 µM of formula (I) compounds vs 11 mM glucose ( Figure 13 (c) Differentially expressed genes between mouse islets cultured at different temperatures. The MA diagram illustrates the differential expression of genes between 25 mM (G25) and 5.5 mM (G5) glucose. Figure 13(d) 25 mM glucose + 5 µM of compound (I) (G25+C(I)) vs 25 mM glucose ( Figure 13 (e) and 25 mM glucose + 5 µM of formula (I) compounds vs 5.5 mM glucose ( Figure 13 (f) Differentially expressed genes among human islets cultured under different conditions. Figure 13 (g): Overexpression analysis (ORA) of the molecularly characteristic Hallmark gene set in human islets cultured at 22 mM vs 11 mM glucose and 22 mM glucose + 5 µM compound of formula (I) vs 22 mM glucose. Figure 14 Representative immunoblots were depicted of INS-1E cells cultured for 4 days at 11 mM or 25 mM glucose, untreated, and treated with 5 µM of compound (I) for 4 days (4d) or 2 hours (2h).

[0047] Figure 14 Representative immunoblots were depicted of INS-1E cells cultured for 4 days at 11 mM or 25 mM glucose, untreated, and treated with 5 µM of compound (I) for 4 days (4d) or 2 hours (2h).

[0048] Figure 15 A schematic model of the antidiabetic effect of the compound of formula (I) is depicted. As a dual AMPK activator and mitochondrial uncoupling agent, compound (I) stimulates glucose uptake and utilization in muscle and avoids the glycotoxic effects of hyperglycemia on β-cell function in part by reducing mTORC1 signaling and thus reducing Pdk expression. Detailed Implementation

[0049] The following description illustrates exemplary compositions, methods, parameters, etc. However, it should be understood that this description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0050] Treatment This article provides methods and compositions for treating and / or preventing heart disease by administering compounds of formula (I): (I), Or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Furthermore, this document 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) will include the various salt forms, solvates, and prodrugs as described herein.

[0051] As described in the examples, the compound of formula (I) can reduce metabolic inflexibility in the myocardium, a phenomenon attributed in part to the compound of formula (I) inhibiting PDK4 and increasing glucose oxidation in the heart. Therefore, the compound of formula (I) can be used to improve metabolic syndrome and treat various cardiac conditions such as cardiomyopathy and heart failure.

[0052] Compounds of formula (I) stimulate glucose uptake and utilization in the myocardium. Furthermore, as shown herein, compounds of formula (I) promote gene expression profiles that favor glucose oxidation rather than glycogen storage. As established in several animal models, upon administration, compounds of formula (I) significantly improve cardiovascular function in a dose-dependent manner, as measured by exercise endurance and cardiac output. In addition, treatment with compounds of formula (I) improves peripheral perfusion, increases glucose uptake and utilization in skeletal and myocardial muscles without increasing cardiac glycogen, improves cardiac function on echocardiography without increasing heart rate, and improves exercise endurance while reducing lactate levels during exhaustion.

[0053] Increased insulin-independent glucose uptake in muscle tissue without an increase in glycogen, and increased energy expenditure observed in animal models, prompted in vitro experiments on mitochondrial function. As shown in the examples, in isolated muscle tubes, compounds of formula (I) increased basal oxygen consumption and extracellular acidification rates, indicating increased glucose utilization through increased flux through the tricarboxylic acid (TCA) cycle and through mitochondrial uncoupling oxidative phosphorylation. Therefore, the current data suggest that compounds of formula (I) are dual AMPK activators and mitochondrial uncoupling agents.

[0054] Furthermore, the compounds of formula (I) promote gene expression profiles favorable for glucose oxidation in muscle and heart. Skeletal muscle thioredoxin inhibitor (TXNIP) expression levels are negatively correlated with glucose uptake. As described herein, administration of the compounds of formula (I) reduces cardiac TXN1P levels. Specifically, compared to hyperglycemic mice, skeletal muscle treated with the compounds of formula (I) showed significantly reduced TXN1P levels. Txnip Reduced mRNA and protein levels (see Example 3) Figure 2 (e) and Figure 10 Furthermore, compared to the control, STZ mice contained Glut4-encoding... Slc2a4 Skeletal muscle expression was decreased, but normalized in hyperglycemic mice treated with the compound of formula (I), and the expression encoding Glut1 was reduced. Slc2a1 Skeletal muscle expression tends to increase. Similarly, in hyperglycemic mice, Pyruvate dehydrogenase Enzyme kinase 4 ( Pdk4 pyruvate dehydrogenase (PDH) and therefore a negative regulator of glucose oxidative metabolism) and Uncoupling protein 3 ( Ucp3,Increased expression of the compound (which is beneficial for lipids as fuel substrates) was reduced in mice treated with the compound of formula (I). Figure 2 (e) indicates 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 compounds of formula (I). Furthermore, Slc2a1 and Slc2a4 Cardiac expression of [the compound] was decreased in untreated hyperglycemic mice, but tended to increase in mice treated with the compound of formula (I). Figure 2 (f)). Therefore, the compound of formula (I) promoted changes in gene expression that were beneficial to glucose uptake, oxidative glucose metabolism and ATP production in the skeletal muscle and heart of hyperglycemic mice.

[0055] High blood sugar has shown a rapid increase. Pdk4 and Ucp3 The compound expresses in the heart and induces metabolic inflexibility and cardiac dysfunction in mice. Untreated STZ mice showed a gradually decreasing peak E velocity and an increased isovolumetric relaxation time (IVRT), indicating impaired diastolic function, while treatment with the compound of formula (I) for 1 week reduced IVRT and increased peak E velocity, thereby increasing the E / A ratio ( Figure 2 (g), Table 4). Improved left ventricular filling in mice treated with compounds of formula (I) also led to increased stroke volume and cardiac output. These findings suggest that in diabetic hyperglycemic mice, compounds of formula (I) improve hyperglycemia, reduce glycogen buildup, and reverse diabetic cardiomyopathy by stimulating insulin-independent glucose uptake and utilization.

[0056] Overall, the data from the embodiments presented in this paper indicate that cardiac expression of PDK4 and UCP3 in the STZ model ( Figure 2 (f) and db / db model ( Figure 3 Elevated levels in (g) and this increased expression was reversed by treatment with compounds of formula (I). Metabolic inflexibility leads to cardiac dysfunction, particularly defective relaxation during the diastolic phase of the cardiac cycle (e.g., resulting in poor cardiac filling). Relevant measurements of the diastolic phase of the cardiac cycle are peak E velocity and E / A ratio. Poor relaxation results in lower peak E velocity and E / A ratio. Stroke volume improves when diastolic ventricular filling improves. Surprisingly, in scan 3 ( Figure 2 (A) Schematic diagram) In STZ animals treated with the compound of formula (I) for 7 days, cardiac echo data showed improvement in 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 corrected expression and metabolic flexibility of PDK4 and UCP3 on cardiomyopathy when the compound of formula (I) is administered.

[0057] Furthermore, the compound of formula (I) reduces the expression level of TXNIP in insulin-secreting β cells. Therefore, administration of the compound of formula (I) leads to a reduction in glucosinotoxic effects, such as oxidative stress, apoptosis, inhibition of insulin production, and amyloid formation. Thus, in one aspect, this disclosure provides a method for inducing β cell rest and preservation.

[0058] In one aspect, this document provides a method for restoring cardiac metabolic flexibility in the heart of a subject (e.g., a patient) suffering from various cardiac diseases or complications. In some embodiments, restoration of metabolic flexibility is associated with reduced TXNIP expression levels. In some aspects, restoration of cardiac metabolic flexibility is associated with inhibition of PDK proteins such as PDK4. In some embodiments, restoration of metabolic flexibility is associated with increased glycolysis and increased glucose oxidation. The combination of increased metabolic flexibility and increased glucose oxidation results in increased cardiac efficiency. Therefore, this disclosure provides a method for improving or restoring the efficiency of 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 a disease as described herein (particularly cardiac disease). The subject may also be a person without any specific disease. In such cases, the 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.

[0059] On the other hand, this disclosure provides a method for treating or improving metabolic syndrome in a person in need (e.g., a human patient), 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 a heart disease as described herein. Alternatively, the subject may be a human subject potentially susceptible to diseases or conditions associated with metabolic syndrome. For example, in some embodiments, the human subject may have prediabetes. In other embodiments, the human subject may have both high blood pressure and high cholesterol, thus being susceptible to heart attack or stroke.

[0060] In some aspects, this document provides a method for treating a subject (e.g., a patient) with metabolic heart disease. For example, this disclosure provides a method for treating cardiomyopathy in a subject (e.g., a patient) of need, 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 a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces hypertension in the subject (e.g., the patient). In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces systolic blood pressure in the subject (e.g., the patient). In other embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof reduces diastolic blood pressure in the subject (e.g., the patient). In some embodiments, the subject has diabetes. In other embodiments, the subject does not have diabetes.

[0061] In some embodiments, the subject (e.g., a patient) suffers from diabetic cardiomyopathy. In some embodiments, the cardiomyopathy is induced by diabetes. In some such embodiments, the subject (e.g., a patient) has diabetes and has type 1 diabetes. In other embodiments, the subject (e.g., a patient) has diabetes and has type 2 diabetes. In some such embodiments, the 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.

[0062] In some implementations, the subject (e.g., the patient) has Duchenne muscular dystrophy (DMD) cardiomyopathy. In some implementations, the subject (e.g., the patient) with DMD is approximately 5 years of age to approximately 18 years of age or approximately 7 years of age to approximately 12 years of age.

[0063] In some embodiments, the subject (e.g., the 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.

[0064] In some implementations, the subject (e.g., the patient) suffers from arrhythmogenic cardiomyopathy. In some implementations, the cardiomyopathy is arrhythmogenic right ventricular cardiomyopathy.

[0065] In some embodiments of the aforementioned method, the subject (e.g., the patient) has type 1 diabetes. In some embodiments of the aforementioned method, the subject (e.g., the patient) has type 2 diabetes. In some embodiments of the aforementioned method, the subject (e.g., the patient) has hypertension.

[0066] In some aspects, this document provides a method for treating heart failure in a subject (e.g., a patient) of need, 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 associated with 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., the patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the subject's diabetic cardiomyopathy is alleviated. In some embodiments, the subject (e.g., the patient) is hyperglycemic. In other embodiments, the subject (e.g., the patient) is not hyperglycemic.

[0067] In some aspects, this document provides a method for preventing or delaying the onset of heart failure in a subject (e.g., a patient) in need, 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 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 subject's diabetic cardiomyopathy is alleviated.

[0068] In some aspects, this document provides a method for improving one or more systems associated with heart failure in a subject (e.g., a patient) in need, 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 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., the patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the diabetic cardiomyopathy of the subject (e.g., the patient) is alleviated. In some embodiments, diastolic blood pressure of the subject (e.g., the patient) decreases following administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the subject (e.g., the patient) also suffers from diabetic cardiomyopathy. In some such embodiments, the diabetic cardiomyopathy of the subject is alleviated. In other embodiments, systolic blood pressure of the subject (e.g., the patient) decreases following administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0069] In some embodiments of the foregoing method, the subject with heart failure (e.g., the patient) is hyperglycemic. In some embodiments, the subject with heart failure (e.g., the patient) is not hyperglycemic. In some embodiments, the subject's heart failure is associated with hyperinsulinemia. In some embodiments, the subject with heart failure (e.g., the patient) has diabetic cardiomyopathy. In some embodiments, the subject with heart failure (e.g., the patient) has diabetic dilated cardiomyopathy, diabetic hypertrophic cardiomyopathy, diabetic arrhythmogenic cardiomyopathy, diabetic restrictive cardiomyopathy, diabetic left ventricular cardiomyopathy, or diabetic Takotsubo cardiomyopathy. In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug of it to a subject with heart failure and diabetic cardiomyopathy (e.g., the patient) alleviates the subject's (e.g., the patient's) diabetic cardiomyopathy. In some of the foregoing embodiments, the subject with heart failure (e.g., the patient) has diabetes. In some embodiments, the subject with heart failure (e.g., the patient) has type 1 diabetes. In some implementations, the subject with heart failure (e.g., the patient) also has type 2 diabetes. In some implementations, the subject with heart failure (e.g., the patient) does not have diabetes.

[0070] As described below, this disclosure also provides various other activators that can be used in combination with compounds of formula (I) or their pharmaceutically acceptable salts, solvates, or prodrugs to treat cardiac disease. In some embodiments, methods of treating a subject in need (e.g., a patient) with heart failure, preventing or delaying its onset, further include administering a sodium-glucose transporter 2 (SGLT2) inhibitor to the subject. In some embodiments, the SGLT2 inhibitor is empagliflozin or dapagliflozin. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin.

[0071] 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 in need (e.g., a patient) reduces the subject's systolic blood pressure. In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof to a subject in need (e.g., a patient) reduces the subject's diastolic blood pressure. 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 an SGLT2 inhibitor to a subject in need (e.g., a patient) reduces the subject's systolic blood pressure. In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof and an SGLT2 inhibitor to a subject in need (e.g., a patient) reduces the subject's diastolic blood pressure. 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 in need (e.g., a patient) reduces the subject's systolic blood pressure. In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvation, or prodrug thereof, along with empagliflozin, to a subject in need (e.g., a patient) reduces the subject's diastolic blood pressure. In some embodiments of the methods provided herein, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvation, or prodrug thereof, along with dapagliflozin, to a subject in need (e.g., a patient) reduces the subject's systolic blood pressure. In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvation, or prodrug thereof, along with dapagliflozin, to a subject in need (e.g., a patient) reduces the subject's diastolic blood pressure.

[0072] In some aspects, this article provides a method 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 suffers from cardiac disease.

[0073] In some embodiments of the aforementioned method, 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.

[0074] In some variations of the aforementioned aspects, the subjects are human.

[0075] The compound of formula (I) acts as a motion mimic because it increases cardiac function and exercise capacity without promoting glycogen accumulation in cardiac tissue. The compound of formula (I) promotes mitochondrial uncoupling in myotubules. Mitochondrial uncoupling dissipates the potential energy gradient across the inner mitochondrial membrane. This potential energy is converted into heat rather than 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, thereby promoting glucose utilization in cells rather than glycogen accumulation.

[0076] In some of the foregoing embodiments, the methods provided herein restore metabolic flexibility in subjects (e.g., patients) in need by avoiding gene expression changes associated with metabolic inflexibility. In some of the foregoing embodiments, the methods provided herein increase the metabolic needs of subjects (e.g., patients). In some of the foregoing embodiments, the methods provided herein increase glucose uptake in subjects (e.g., patients). In some of the foregoing embodiments, the methods provided herein increase glucose oxidation in subjects (e.g., patients). In some of the foregoing embodiments, the methods provided herein reduce glycogen accumulation in the heart.

[0077] In some embodiments, this document provides a method for inhibiting the activity of pyruvate dehydrogenase kinase (PDK) in a subject of need (e.g., a patient), the method comprising administering a compound of formula (I) to the subject. In some embodiments of the foregoing method, 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.

[0078] In some aspects, this article provides a method for treating a subject (e.g., a patient) with atrial fibrillation (AF), 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, administration of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof prevents the progression or onset of AF in a subject with predisposition to cardiac disease (e.g., a patient).

[0079] In some embodiments of the aforementioned method, the subject (e.g., the patient) has diabetes. In some embodiments, the subject (e.g., the patient) has type 1 diabetes. In some embodiments, the subject (e.g., the patient) has type 2 diabetes. In some embodiments, the subject (e.g., the patient) does not have diabetes.

[0080] Improved physical fitness / heart function In some aspects, this document provides a method for improving the physical condition or cardiac function of 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 has or is susceptible to a disease. For example, in some embodiments, the subject has prediabetes. In some embodiments, the subject exhibits systemic symptoms associated with early stages of heart failure. In other embodiments, the subject has high cholesterol levels.

[0081] In some embodiments, a subject may improve cardiac function or enhance health by taking about 20 mg to about 500 mg of the compound of formula (I) once daily. In some embodiments, a subject may improve cardiac function or enhance health by taking about 50 mg to about 400 mg of the compound of formula (I) once daily. In some embodiments, a subject may improve cardiac function or enhance health by taking about 50 mg to about 200 mg of the compound of formula (I) once daily. In some embodiments, a subject may improve cardiac function or enhance health by taking about 50 mg to about 100 mg of the compound of formula (I) once daily. In some embodiments, a subject may improve cardiac function or enhance health by taking about 50 mg to about 100 mg of the compound of formula (I) once daily.

[0082] Therapeutic compounds In some of the foregoing embodiments, the therapeutic compound includes exemplary compounds described in further detail below. Compounds used in the methods provided herein may include their salts, solvates, or prodrugs.

[0083] In some embodiments, the compound is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide or a salt, solvate or prodrug thereof.

[0084] In some embodiments, the compound is an alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. An "alkali metal" is a metal present in Group I of the periodic table along with hydrogen. Alkali metals are lithium, sodium, potassium, rubidium, cesium, and francium. Therefore, it should be understood that an "alkali metal salt" is a compound consisting of an aggregate of one or more alkali metal cations and associated anions. Thus, the term "alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide" refers to a compound 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-thiadiazol-5-yl]benzamide. For example, the alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide are shown below: .

[0085] Where X + It represents an alkali metal cation (such as lithium, rubidium, cesium, sodium, or potassium).

[0086] It should be understood that a "sodium salt" is a compound composed of an aggregate of sodium cations and associated anions. Therefore, the term "sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide" refers to a compound containing both sodium cations and anions of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. For example: , Na + It represents sodium cation.

[0087] Technicians 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-thiadiazol-5-yl]benzamide can dissociate into its anionic and cationic components.

[0088] Throughout this specification, structures may or may not be presented by chemical name. In case of any naming issues, the structure shall prevail. Where compounds may exist as tautomers (e.g., in alternative resonance forms), the depicted structure represents one of the possible tautomer forms, wherein the actual tautomer form 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: To avoid any doubt, the alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide are solids under ambient conditions, and therefore the scope of this invention includes all its amorphous, crystalline and partially crystalline forms.

[0089] Alkali metal salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared using techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be reacted with a suitable alkali metal hydroxide or an alternative alkali metal compound. Salt conversion techniques can also be used to convert one salt into another.

[0090] Sodium salts of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be prepared using techniques well known to those skilled in the art. For example, 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide can be reacted with sodium hydroxide or alternative sodium base compounds. Salt conversion techniques can also be used to convert one salt into another.

[0091] 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 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 can be prepared according to the technique described in International Patent Application WO 2011 / 004162.

[0092] Unless otherwise stated, all technical and scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0093] In a specific embodiment, the alkali metal salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide is a 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 a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazole-5-yl]benzamide.

[0094] In some embodiments, the compounds used in the methods provided herein are compounds of formula (II): (II), or its salt, wherein 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 is capable of being metabolized in vivo to form 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide. In some embodiments, the compound is a salt. For example, the salts of the compound include: , Where X + The cation represents an alkali metal, alkaline earth metal, or quaternary ammonium (e.g., lithium, magnesium, calcium, ammonium, tetramethylammonium, especially sodium and potassium) cation, with appropriate stoichiometric adjustments made according to the charge of the ion. In some embodiments, X + It represents an alkali metal cation (e.g., lithium, rubidium, cesium, or especially sodium or potassium).

[0095] Drug dosage form Therapeutic compounds are administered to human subjects in need in the form of pharmaceutical formulations, which are also referred to herein as pharmaceutical dosage forms.

[0096] In one embodiment, the therapeutic compound is the only active pharmaceutical ingredient present in the dosage form. In another embodiment, the therapeutic compound is present in the dosage form along with one or more other active pharmaceutical ingredients, or may be administered as part of a combination therapy with one or more other active pharmaceutical ingredients.

[0097] In specific embodiments, the therapeutic compound is provided in the form of particles having a particle size distribution defined by a D90 of less than about 10 µm (e.g., as measured using laser diffraction). In one embodiment, particles containing the therapeutic compound may have a particle size distribution defined by a D90 of less than about 10 µm (e.g., from about 5 µm to about 10 µm) (e.g., as measured using laser diffraction). The particle size distribution may alternatively be defined by a D90 of less than about 8 µm (e.g., from about 5 µm to about 8 µm). In another embodiment, particles composed of the therapeutic compound may have a particle size distribution defined by a D50 of less than about 6 µm (e.g., from about 0.5 µm to about 6 µm). In yet another embodiment, the particle size distribution of particles composed of the therapeutic compound may be further defined by a D10 of less than about 2 µm (e.g., from about 0.2 µm to about 2 µm). The above particle size distribution parameters may be applied individually or in combination. For example, in a specific embodiment, the dosage form comprises particles containing a therapeutic compound having a particle size distribution defined by a D90 of less than about 10 µm and a D50 of less than about 6 µm. More specifically, the particles may have a particle size distribution defined by a D90 of less than 9 µm, a D50 of less than 6 µm or less than 5 µm, and a D10 of less than 2 µm or less than 1.5 µm. The particle size distribution of the particles containing the therapeutic compound can be measured using, for example, a commercially available particle size analyzer via laser diffraction.

[0098] oral dosage form In some variations, the therapeutic compound may be provided in tablet or capsule form. For example, capsules containing a single therapeutic compound or in combination with a suitable medium (e.g., vegetable oil, fat, etc.), such as soft gelatin capsules, may be prepared. Similarly, hard gelatin capsules may contain a single therapeutic compound or in combination with solid powder ingredients such as disaccharides (e.g., lactose or sucrose), alcoholic sugars (e.g., sorbitol or mannitol), plant starches (e.g., potato starch or corn starch), polysaccharides (e.g., amylopectin or cellulose derivatives), or gelling agents (e.g., gelatin).

[0099] The drug formulations described herein can be prepared according to standard and / or recognized pharmaceutical practices. Drug formulations are typically provided as mixtures comprising a therapeutic compound and one or more pharmaceutically acceptable excipients. One or more pharmaceutically acceptable excipients can be selected based on standard pharmaceutical practices, taking into account the intended route of administration. Such pharmaceutically acceptable excipients are preferably chemically inert to the active compound and preferably do not have harmful side effects or toxicity under the conditions of use. Suitable drug formulations can be found, for example, in Remington, The Science and Practice of Pharmacy, 19th edition, 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).

[0100] Those skilled in the art will understand that the pharmaceutical dosage forms described herein can act systemically and therefore can be administered accordingly using suitable techniques known to those skilled in the art. Pharmaceutical dosage forms as described herein are typically administered orally, for example, as oral pharmaceutical dosage forms. Therefore, in some variations, an oral pharmaceutical dosage form is provided comprising about 100 to about 1000 mg of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In one variation, an oral pharmaceutical dosage form is provided comprising about 200 to about 1000 mg of a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0101] Dosage forms intended for oral administration may also include an enteric coating to prevent or minimize dissolution or disintegration in the gastric environment. Therefore, oral formulations (e.g., capsules or tablets) coated with an enteric coating can provide 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., on the surface of a tablet or capsule), or each particle containing the therapeutic compound may be coated with an enteric coating. Therefore, in specific embodiments, pharmaceutical dosage forms used in the methods of the present invention further include an enteric coating.

[0102] In some implementations, the enteric coating is present on the drug dosage form, and in some variations, the coating may be provided as an outer layer on the drug dosage form.

[0103] Alternatively, the particles containing the therapeutic compound can be coated individually with an enteric coating, and the coated particles can be formulated into a pharmaceutical dosage form. Therefore, in a specific embodiment, the pharmaceutical dosage form contains particles comprising the therapeutic compound, and each particle is coated with an enteric coating.

[0104] The term "enteric coating" refers to a substance (e.g., a polymer) incorporated into an orally administered drug (e.g., applied to the surface of tablets, capsules, granules, or pills) and inhibiting the dissolution or disintegration of the drug in the gastric environment. Enteric coatings are generally stable at the highly acidic pH of the stomach but rapidly decompose at the relatively alkaline pH of the small intestine. Therefore, enteric coatings prevent the release of the active ingredient in the drug until it reaches the small intestine.

[0105] Any enteric coating known to those skilled in the art can be used in this invention. Specific enteric coating materials that may be mentioned include those comprising beeswax, shellac, alkyl cellulose polymer resins (e.g., ethyl cellulose polymer, carboxymethyl ethyl cellulose, or hydroxypropyl methyl cellulose phthalate), or acrylic polymer resins (e.g., acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, methacrylate copolymers, methacrylic acid copolymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), alkylamide methacrylate copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), polymethacrylate, methyl methacrylate copolymers, poly(methyl methacrylate) copolymers, polyacrylamide, poly(methacrylic anhydride) and glycidyl methacrylate copolymers), cellulose acetate phthalate, and polyvinyl acetate phthalate.

[0106] In some variations, 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. Specifically, the at least one pharmaceutically acceptable excipient may be a lubricant, binder, filler, surfactant, diluent, anti-adhesion agent, coating agent, flavoring agent, coloring agent, flow aid, preservative, sweetener, disintegrant, adsorbent, buffer, antioxidant, chelating agent, solubility enhancer, solubility inhibitor, or wetting agent.

[0107] Specific pharmaceutically acceptable excipients that may be mentioned include mannitol, PVP (polyvinylpyrrolidone) K30, lactose, sucrose, sorbitol, starch, amylopectin, cellulose derivatives, gelatin or other suitable ingredients, as well as disintegrants and lubricants such as sodium lauryl sulfate, sodium docusate, magnesium stearate, calcium stearate, sodium stearoyl fumarate, and polyethylene glycol wax. In preparing pharmaceutical dosage forms of therapeutic compounds for oral administration, particles (preferably ground) containing the therapeutic compound may be mixed together with or separately from mannitol, PVP (polyvinylpyrrolidone) K30, and sodium lauryl sulfate.

[0108] In preparing a pharmaceutical dosage form, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof may be mixed together or separately with one or more of the pharmaceutical excipients listed above (including basic excipients).

[0109] A mixture of a therapeutic compound and one or more pharmaceutically acceptable excipients can be processed into pills or granules, or compressed into tablets. Therefore, the pharmaceutical dosage form of the method of the present invention can be a tablet, microtablet, block, pill, granule, powder, or granule for oral administration.

[0110] The pharmaceutical formulations that may be mentioned include those in which the compound of formula (I) or its pharmaceutically acceptable salt, solvate or prodrug is present in a total amount of at least 1% (or at least 10%, at least 30% or at least 50%) by weight of the formulation. That is, the weight ratio of the therapeutic compound to all components of the pharmaceutical formulation (i.e., the therapeutic compound and all pharmaceutical excipients, such as adjuvants, diluents and carriers) is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50).

[0111] Dosage of oral formulations As used herein, “therapeutic effective amount,” “effective amount,” or “dosage” means the amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof sufficient to produce a desired effect, which may be a therapeutic effect and / or a beneficial effect. Effective amounts or dosages will vary with individual or subject (e.g., human) age or general condition, the severity of the condition being treated, the specific drug administered, the duration of treatment, the nature of any concurrent treatments, the pharmaceutically acceptable carrier used, and similar factors within the knowledge and expertise of those skilled in the art.

[0112] As used herein, when referring to measurable values ​​such as the amount of a compound, dosage, time, temperature, etc., the term "about" refers to a variation of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It is anticipated that, in each case, such a term could be replaced by a symbol such as "±10%" (or by indicating the variance of a specific amount calculated based on the relevant value). It is also anticipated that, in each case, such a term could be removed.

[0113] It should be understood that the dosage and pharmacokinetic parameters described below relate to the treatment of patients with specific diseases, particularly heart diseases as described herein. The dosage and pharmacokinetic parameters may also be applied to human subjects taking the drug to improve physical condition or cardiac function. As mentioned above, in some embodiments, lower amounts of the compound of formula (I) may be required to improve physical condition or cardiac function compared to administration of the compound to a subject with heart disease (e.g., a patient).

[0114] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (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 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 thereof 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 thereof 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 at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg.

[0115] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 40 µg / mL to about 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 or a subject in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 40 µg / mL to about 80 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 or a subject in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 70 µg / mL to about 120 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 90 µg / mL to about 160 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 in need (e.g., a patient), wherein the administration results in a steady-state plasma concentration of the compound of formula (I) of about 100 µg / mL to about 150 µg / mL. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof is administered daily to a human subject, resulting in a steady-state plasma concentration of the compound of formula (I) of about 120 µg / mL to about 140 µg / mL.

[0116] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 The concentration 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 may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in a steady-state AUC of the compound of formula (I). 0-24 It ranges from approximately 3,000 h*µg / mL to approximately 3,500 h*µg / mL.

[0117] In any of the foregoing embodiments, the compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof may be administered orally once daily to a subject in need (e.g., a patient), wherein such administration results in the Ci 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... maxThe 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 in need (e.g., a patient), wherein such administration results in the C1 of the compound of formula (I) being... max It is approximately 1200 µg / mL to approximately 150 µg / mL.

[0118] In some embodiments, the compound of formula (I) is provided in tablet form having the components shown in Table 1.

[0119] Table 1: Exemplary composition of sodium salt tablets containing formula (I)

[0120] *The free acid form corresponding to the compound of formula (I) in 400 mg form. Combination therapy Those skilled in the art will understand that the methods of the present invention may include further treatments (e.g., in combination) for the same condition.

[0121] Specifically, when treating a disease or condition that is improved by activating AMPK, the salt of the present invention can be administered in combination with one or more other (i.e. different) therapeutic agents that can be used to treat the disease or condition.

[0122] Such combination therapy may involve administering the salt of the invention in combination with different therapeutic agents in the same formulation or preferably in separate formulations (e.g., sequentially or simultaneously) to a subject. The term "administration in conjunction with" (and similarly "administered in conjunction with") includes the sequential or simultaneous administration of the respective active ingredients as part of a medical intervention for the treatment of the relevant condition. "Simultaneously" means the side-by-side administration of the salt of the invention and different therapeutic agents in a single pharmaceutical dosage form comprising both active ingredients or in separate dosage forms for simultaneous administration.

[0123] Therefore, for the purposes of this invention, the term "administration in conjunction with" (and similarly "administered in conjunction with") includes administering the salt of this invention together with different therapeutic agents, or at sufficiently close times, to produce a greater beneficial effect on the patient during the treatment of the relevant condition than either agent alone in the absence of the other component during the same treatment. Determining whether the combination provides a greater beneficial effect in the treatment of a particular condition and during the treatment of that condition will depend on the condition to be treated, but can be conventionally performed by those skilled in the art.

[0124] Furthermore, in the context of this invention, the term "in combination with" includes the possibility that one or the other of two active ingredients may be applied before, after, and / or simultaneously with the other (optionally repeatedly). When used in this context, the terms "simultaneous application" and "simultaneous application with" include the application of individual doses of the salt of the invention and different therapeutic agents within 6 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, or 10 minutes of each other.

[0125] Other therapeutic agents that can be used to treat diseases or conditions that improve by AMPK activation (such as heart failure, diabetic nephropathy, diabetes, etc., as described herein) will be well known to those skilled in the art. Preferably, the other therapeutic agent will be a sodium-glucose transporter 2 (SGLT2) inhibitor, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, such that the combination can be used to treat diseases such as type 2 diabetes. In another embodiment, the method of the invention comprises sequentially or simultaneously administering a sodium salt of 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide and an SGLT2 inhibitor.

[0126] Those skilled in the art will understand that sodium-glucose transporter 2 inhibitors are substances or agents that cause a reduction in one or more functions of sodium-glucose transporter 2, and by "reduction in the function of sodium-glucose transporter 2," we include the cessation of one or more functions of sodium-glucose transporter 2, or a reduction in the rate of a specific function. The specific function that can be completely or partially inhibited is the ability of sodium-glucose transporter 2 to act as a glucose transporter.

[0127] In a specific implementation, the sodium-glucose transporter 2 inhibitor is glibenclamide. Glibenclamide is a class of known small-molecule sodium-glucose transporter 2 inhibitors. Hawley et al. (Diabetes, 2016, 65, 2784–2794) and Villani et al. (Molecular Metabolism, 2016, 5, 1048–1056) recently discussed the possible mechanisms of action of some glibenclamides. Specific glibenclamides that may be mentioned include dapaglibenclamide, canaglibenclamide, empaglibenclamide, iogglibenclamide, toraglibenclamide, seraglibenclamide (such as seraglibenclamide etanerate), remogglibenclamide (such as remogglibenclamide etanerate), elegglibenclamide, and soraglibenclamide. In another specific implementation, the sodium-glucose transporter 2 inhibitor is dapaglibenclamide.

[0128] In a specific implementation, the sodium-glucose transporter 2 inhibitor is a pharmaceutically acceptable salt of gliflozin. For example, other active ingredients may be pharmaceutically acceptable salts of dapagliflozin, canagliflozin, empagliflozin, ioggliflozin, tolagliflozin, seragliflozin (such as seragliflozin etanerate), remoggliflozin (such as remoggliflozin etanerate), eleggliflozin, or soagliflozin.

[0129] In another embodiment, the sodium-glucose transporter 2 inhibitor is a solvation of gliflozin. For example, other active ingredients may be solvations of dapagliflozin, canagliflozin, empagliflozin, ioggliflozin, toragliflozin, seragliflozin (such as seragliflozin etanercept), remoggliflozin (such as remoggliflozin etanercept), eleggliflozin, or soagliflozin.

[0130] In another embodiment, the sodium-glucose transporter 2 inhibitor is a prodrug of gliflozin. For example, other active ingredients may be prodrugs of dapagliflozin, canagliflozin, empagliflozin, ioggliflozin, tolagliflozin, seragliflozin (such as seragliflozin etanercept), remoggliflozin (such as remoggliflozin etanercept), eleggliflozin, or soagliflozin.

[0131] The methods of the present invention disclosed herein (and the oral dosage forms used in such methods) also have the following advantages: dose-effective methods using the salts of the present invention can be more effective, less toxic, have a longer duration of action, be more potent, produce fewer side effects, be more easily absorbed, and / or have better pharmacokinetic characteristics (e.g., higher oral bioavailability and / or lower clearance) than other therapies known in the prior art, whether for the aforementioned indications or other indications. Specifically, due to the dose-effective properties of the salts of the present invention, the methods of the present invention can have the following advantages: they are more effective in vivo and / or exhibit advantageous properties, such as fewer side effects.

[0132] Uses of compounds In some respects, the use of compounds of formula (I) or pharmaceutically acceptable salts, solvates or prodrugs thereof in therapies (including any of the methods described herein) is also provided.

[0133] For example, in one variant, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment and / or prevention of heart disease, including, for example, the treatment and / or prevention of heart disease and complications, including cardiomyopathy, heart failure, and atrial fibrillation. In another variant, 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). In yet another variant, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for restoring cardiac metabolic flexibility. In yet another variant, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment or improvement of metabolic syndrome involving a range of risk factors, which may include hyperglycemia, high blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment of cardiomyopathy or the prevention or delay of cardiomyopathy onset is provided. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the treatment of heart failure or atrial fibrillation in a subject of need is provided. In yet another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof for the inhibition of pyruvate dehydrogenase kinase (PDK) activity is provided.

[0134] In some respects, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament is also provided. In some embodiments, the medicament is used in any of the methods described herein.

[0135] For example, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment and / or prevention of heart disease (including, for example, the treatment and / or prevention of heart disease and its complications, including cardiomyopathy, heart failure, and atrial fibrillation). In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for enhancing or improving cardiac efficiency (which may include restoring metabolic flexibility and glucose oxidation). In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for restoring cardiac metabolic flexibility. In another variation, the use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for the treatment or improvement of metabolic syndrome involving a range of risk factors, which may include hyperglycemia, high blood pressure, excess body fat, high triglyceride or LDL cholesterol levels, insulin resistance, and / or low HDL cholesterol levels. In another variation, use is provided for a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for treating cardiomyopathy or preventing or delaying the onset of cardiomyopathy. In another variation, use is provided for a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for treating heart failure or atrial fibrillation in a subject of need. In yet another variation, use is provided for a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof in the preparation of a medicament for inhibiting the activity of pyruvate dehydrogenase kinase (PDK).

[0136] Example The subject matter disclosed herein will be better understood by referring to the following embodiments, which are provided as examples of the invention and not as limitations.

[0137] In this document, unless otherwise stated, “Cmpd-(I)” or “the compound of formula (I)” is mentioned in the experiments detailed in the following examples and is 4-chloro-N-[2-[(4-chlorophenyl)methyl]-3-oxo-1,2,4-thiadiazol-5-yl]benzamide.

[0138] Mice. Mice were housed in certified animal facilities with a 12-hour light / dark cycle and free access to appropriate food. Male BKS.Cg-Dock7m + / + Leprdb / J (db / db) and C57BLKS / J (BKS) mice with leptin receptor deficiency were obtained. F1 mice were obtained by crossing male C57BL / 6J mice with female CBA / CaCrl. Nine-week-old male F1 mice were treated with multiple low-dose streptozotocin (50 mg / kg*day for 5 consecutive days; freshly prepared in 0.1 mM sodium citrate, pH 4.5) to induce diabetes. Mice were randomly fed a D10001 diet or D10001 formulated with compounds of formula (I) at 0.25 mg / g, 0.5 mg / g, and 1 mg / g (CAS # 1261289-04-6). BKS, db / db, and F1 mice were housed in cohorts of 4–5 mice per cage. Mice with significant health problems, such as weight loss >10% or fighting, were excluded; no differences were observed between groups. Within each cohort, mice were randomly assigned to cages based on weight and fasting blood glucose, either by cage or, if possible, individually to different treatments to minimize the impact of starting weight and glucose homeostasis. For in vitro analyses, such as Western blotting, qPCR, histological, and immunohistochemical work, samples from 5–9 mice per diet were randomly selected. All in vivo analyses were performed between 9:00 AM and 3:00 PM.

[0139] PET analysis of glucose uptake in vivo. All in vivo experiments were successfully replicated 2-3 times. In vitro analyses of tissues were successfully replicated 2-3 times with different cohorts. Mice were fasted for three hours prior to each scan. Mice were sedated with <2% isoflurane in oxygen (800 mL / min) prior to scan and cannulated via the tail vein using a 27G needle and a specially designed catheter. Dynamic (frames 8x30s, 8x60s, 6x180s, 2x300s) 40-minute PET acquisitions were initiated by injection of 50-70 μL of 13.9+2.3 MBq [18F]-fluorodeoxyglucose (FDG) dissolved in saline. Patlak analysis of the PET data was used in conjunction with measured glucose concentrations to calculate the maximum metabolic rate (MRglu) of glucose. PET / CT imaging was initiated from 50 kV, 0.088 mAs, spiral CT acquisition and reconstructed to voxel size of 0.375x0.375x0.377 mm. 3Images were constructed. PET images were reconstructed to voxel size (0.4x0.4x0.4) using Tera-Tomo 3D iterative reconstruction for 4 iterations and 4 subsets, with attenuation, scattering, and random corrections applied. Image analysis and Patlak pharmacokinetic calculations were performed using imlook4d software. Mice were supervised on a temperature-controlled bed during scanning, and blood glucose was measured using tail vein blood at 10, 20, and 40 minutes post-injection. In the coronal view, the region of interest (ROI) consisting of the left and right gluteus medius / rectus femoris muscles was defined as a 10-layer cylinder with a diameter of 10 pixels. The myocardial ROI was defined by thresholding the search volume manually drawn in the last PET frame at 40% of the highest voxel. The inferior vena cava ROI was defined as the voxel representing more than 60% of the highest voxel in the first frame of uptake. An image-derived input function was approximated using a time-activity curve from the inferior vena cava ROI. Patlak analysis was performed using the image-derived input function described above, and irreversible uptake rates were determined by linear regression between 16 and 40 minutes. K i Patlak K i Values ​​were calculated at the ROI level for quantification and at the voxel level for illustration. Saturated glucose consumption was estimated as follows: With Michaelis-Menten K m = 130 mg / dL, and the average blood glucose level was measured from three samples collected during the scan. C glu .

[0140] Echocardiography. For echocardiography, use 1.5%-2% isoflurane (0.8 L / min). -1 Mice were sedated with O2(g) and placed on a temperature-controlled platform. Chest hair was removed using depilatory cream. Respiration and ECG were monitored during scanning, and anesthesia was adjusted to avoid respiratory depression. The total scanning time did not exceed 15 minutes. Stroke volume, cardiac output, and wall thickness were measured in the parasternal long-axis section using B-mode and M-mode images. Diastolic left ventricular inflow was observed in the apical four-chamber view using mitral Doppler. Offline analysis was performed blinded.

[0141] Mitochondrial respiration analysis. C2C12 myoblasts were cultured in a medium containing 10% fetal bovine serum and 20 U / ml penicillin-streptomycin. To obtain myotubes, C2C12 myoblasts were cultured at 7500 cells / cm². 2Cells were seeded in poly-L-lysine-coated XF96 culture dishes and cultured in growth medium for 3 days until 80% confluence, after which they were switched to differentiation medium (DM; growth medium with 2% horse serum instead of FBS, cultured for 6 days, with medium changed every 2 days). Respiration was measured using a Seahorse XFe96 extracellular flux analyzer according to the manufacturer's "Mitochondrial Stress" protocol and mitochondrial parameters. Briefly, differentiated myotube cells were pretreated for 4 hours by switching to growth medium containing 1% horse serum and the compound of formula (I) (sodium salt preparation). Myotube cells were then equilibrated for 1 hour in hippocampal assay medium (1 mM sodium pyruvate, 10 mM glucose, 2 mM L-glutamine) adjusted to pH 7.4, supplemented with the compound of formula (I) during pretreatment. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measurements were collected as baseline values, followed by the sequential addition of 1 µM oligomycin, 2 µM FCCP, and 0.5 µM rotenone + 0.5 µM antimycin A. Mitochondrial functional parameters were calculated according to the manufacturer's recommendations.

[0142] Western blot analysis. Femoral muscle was isolated from non-fasted mice and crushed in a mortar using a pestle and liquid nitrogen. Femoral muscle and INS-1E cell samples were homogenized in ice-cold protein lysis buffer (100 mM Tris pH 6.8, 2% SDS), with a mixture of protease inhibitors and phosphatase inhibitors added, and then sonicated. The femoral muscle supernatant was collected after 10 minutes at 14,000 rpm. Protein concentration was measured using a BCA kit, followed by dilution and denaturation in Laemmli buffer. Protein samples of 20 µg Vastus and 7 µg INS-1E cells were separated on 4%–15% Criterion™ TGX Stain-Free™ protein gels and blotted onto low-fluorescence PVDF or nitrocellulose membranes, respectively. Primary and secondary antibodies are listed in Table 2. Values ​​were normalized to unstained total protein signal or β-actin.

[0143] Table 2 qRT-PCR. Total RNA from isolated pancreatic islets was prepared using the RNeasy Micro Kit. Total RNA from the gastrocnemius muscle and left ventricle was prepared using the RNeasy Fibrous Tissue Micro Kit after the tissue was first crushed in liquid nitrogen using a pestle. First-strand cDNA synthesis was performed using SuperScript III according to the manufacturer's instructions. Primers used for qRT-PCR are listed in Table 3. Tbp The expression was used to normalize samples from the pancreas, gastrocnemius muscle, and left ventricle. Through Rpl32 Validated in left ventricular samples and gastrocnemius muscle. Tbp Normalization.

[0144] Table 3 Islet isolation and culture. Mouse islets were substantially isolated and cultured for 48 h in a medium supplemented with 11 mM glucose or 22 mM glucose plus / min 5 µM of compound (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 islets from non-diabetic donors were cultured for 48 h in a medium supplemented with 5.5 mM glucose or 25 mM glucose plus / min 5 µM of compound (I) (CMRL medium, 10% fetal bovine serum, 20 U / ml Pen:Strep and 1X GlutaMax).

[0145] RNA-seq. Perform RNA-seq. Prepare an RNA-seq library from 150 ng of total RNA using the Illumina TruSeq Chain mRNA Library Kit, and then perform 100 bp paired-end sequencing on a NovaSeq 6000 Illumina sequencer. Process RNA-seq reads. Perform quality checks on Fastq files with 100-nt paired-end sequencing reads, aligning them to mouse or human genomes (GRCm39 or GRCh38). Count fragment-gene hits. Use software packages. DESeq2 Subsequent analyses were performed in R using clusterProfiler. A batch-corrected profile (referencing islet preparation batches and human donors respectively), independent filtering (α=0.05), and false detection rate (FDR) <0.05 were used. DESeq2 Normalization and differential expression analysis were performed. Genes with baseMean expression > filterThreshold were considered expressed and constituted subsequently used. clusterProfiler For the genetic background used in ORA and GSEA analyses, pvalueCutoff=0.05 and qvalueCutoff=0.2 for overrepresented gene classes.

[0146] Insulin secretion assay. GSIS was performed at 37°C and atmospheric pressure 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). Briefly, INS-1E cells were washed and equilibrated in UB buffer for 1 h, transferred to UB buffer containing 2 or 20 mM glucose for 30 min, and insulin levels in the supernatant were measured by ELISA. Insulin secretion was normalized to protein content.

[0147] Cell lines. INS-1E and C2C12 are commercially available and therefore not certified after purchase. The cells are mycoplasma-free, as determined by PCR.

[0148] Statistical Analysis. The experimental design consisted of a non-diabetic control group (BKS or control (i.e., F1 mice injected with the medium), a diabetic control group (db / db mice or STZ mice, i.e., F1 mice injected with STZ), and a compound treatment group of formula (I) (db / db mice or STZ mice maintained on a diet formulated with the compound of formula (I)). First, the effectiveness of the diabetes model was tested by comparing the control and diabetic groups. Second, the effect of the compound diet of formula (I) was evaluated by comparing the compound treatment group of formula (I) with the diabetic group. The parametric nature and heteroscedasticity of the data were assessed using the Shapiro-Wilk test and the Leven test, and appropriate statistical tests were selected. For comparisons between two groups, the heteroscedasticity t-test or Wilcoxon test was used for multiple tests with Holm correction. For multiple groups, ANOVA analysis was used, followed by appropriate post-hoc analyses (see figure). P A value <0.05 was considered statistically significant. tidyverse , rstatix and ggpubr The software package performs data analysis, statistical analysis, and visualization in R.

[0149] Example 1: The compound of formula (I) prevents the development of diabetes in STZ mice.

[0150] To evaluate whether the compound of formula (I) could improve diabetes in insulin-deficient mice, β-cell function was ablated by injection of streptozotocin (STZ). Starting on day 5 or 15, STZ mice were treated with a diet formulated with 0.25 or 0.5 mg / g of the compound of formula (I) (denoted as Cmpd-(I)-(0.25) and Cmpd-(I)-(0.5)). In untreated STZ mice, insulin levels decreased rapidly in tandem with an increase in glucose levels. Figure 1 (a) Figure 1(b)). Conversely, treatment with the compound of formula (I) starting on day 5 normalized glucose levels. Figure 1 (a)) without increasing plasma insulin levels ( Figure 1 (b)). Compared with non-diabetic control mice, mice treated with the compound of formula (I) showed a reduction in pancreatic insulin levels to 1 / 20–1 / 10 ( Figure 1 (c) Figure 8 (b)). In both untreated STZ mice and STZ mice treated with the compound of formula (I), the islet cell area and the proportion of Ins+ cells decreased, while the proportion of Glu+ islet cells increased. Figure 1 (d) to Figure 1 (f) Figure 8 (a) Figure 8 (c) Figure 8 (d)). When treatment was first initiated on day 15, when mice showed obvious signs of diabetes, the compound of formula (I) also rapidly reduced glucose levels in STZ mice without increasing plasma insulin levels. Figure 1 (g) Figure 1 (h) Figure 8 (e)). Compared with control mice, the pancreatic insulin content of mice treated with the compound of formula (I) was again reduced to about 1 / 20 ( Figure 1 (i) Figure 8 (g)). Similarly, in untreated mice and STZ mice treated with compounds of formula (I), islet cell area and the proportion of Ins+ islet cells decreased, while the proportion of Glu+ islet cells increased. Figure 1 (j) to Figure 1 (l) Figure 8 (f) Figure 8 (h) Figure 8 (i)). In summary, these findings demonstrate that the compound of formula (I) effectively reverses diabetes in an insulin-deficient mouse model in an insulin-independent manner.

[0151] Example 2: The compound of formula (I) improves hyperglycemia in STZ mice by stimulating muscle glucose uptake.

[0152] The effective reduction in glucose levels in STZ mice treated with compounds of formula (I) provides evidence that compounds of formula (I) promote insulin-independent glucose uptake in vivo. Continuous dynamics [ 18 PET analysis of F-fluorodeoxyglucose showed that, compared with STZ mice before treatment (scan 2) and untreated mice on day 22 (scan 3), the maximum metabolic rate of glucose in skeletal muscle of STZ mice was significantly higher after 1 week of treatment with the compound of formula (I) (scan 3). glu Greatly enhanced ( Figure 2(a) to Figure 2 (c) Figure 9 Furthermore, on days 14–15, i.e., at scan 2, MR in the hearts of diabetic STZ mice glu The levels decreased, but normalized to baseline after one week of treatment with compounds of formula (I). Figure 2 (c)). Glycogen content in skeletal muscle and heart was analyzed to assess the metabolic fate of glucose in STZ mice treated with the compound of formula (I). Compared to control mice, untreated STZ mice showed increased muscle and cardiac glycogen content in both muscle and heart, but STZ mice treated with the compound of formula (I) showed decreased muscle and cardiac glycogen content compared to untreated STZ mice. Figure 2 (d) Therefore, under hyperglycemic conditions, treatment with compounds of formula (I) stimulates insulin-independent glucose uptake and glucose utilization, but does not stimulate glycogen storage.

[0153] Example 3: The compound of formula (I) promotes the expression profile of genes that are beneficial to glucose oxidation in the muscles and heart of STZ mice.

[0154] Skeletal muscle TXNIP expression levels were negatively correlated with glucose uptake. While skeletal muscle glucose uptake was enhanced, TXNIP expression in the skeletal muscle of STZ mice treated with the compound of formula (I) was significantly higher than that in untreated STZ mice. Txnip Decreased mRNA and protein levels Figure 2 (e) Figure 10 Furthermore, compared to the control, STZ mice contained Glut4-encoding... Slc2a4 Skeletal muscle expression was decreased, but normalized in STZ mice treated with the compound of formula (I), and the expression of Glut1-encoding Glut1 was reduced in STZ mice treated with the compound of formula (I). Slc2a1 Skeletal muscle expression tends to increase ( p =0.059) ( Figure 2 (e)). Similarly, in STZ mice, Pyruvate dehydrogenase kinase 4 ( Pdk4 pyruvate dehydrogenase (PDH) and therefore a negative regulator of glucose oxidative metabolism) and Uncoupling protein 3 ( Ucp3 Increased expression of (which is beneficial for lipids as fuel substrates) was reduced in mice treated with compounds of formula (I). Figure 2 (e) indicates 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 compounds of formula (I). Figure 2 (f)). Furthermore... Slc2a1 and Slc2a4Cardiac expression of [the compound] was decreased in untreated STZ mice, but tended to increase in mice treated with compounds of formula (I) (both...). p =0.088) ( Figure 2 (f)). Pdk4 , Ucp2 and Ucp3 The expression of [the compound] was increased in the hearts of untreated STZ mice, but decreased in STZ mice treated with compounds of formula (I) (for Ucp2, [the expression was] attenuated). p =0.055) ( Figure 2 (f)). Therefore, the compound of formula (I) promoted changes in gene expression that favored glucose uptake, oxidative glucose metabolism, and ATP production in the skeletal muscle and heart of STZ mice. Figure 2 (e) Figure 2 (f)). High blood sugar has shown a rapid increase. Pdk4 and Ucp3 The compound expresses in the heart and induces metabolic inflexibility and cardiac dysfunction in mice

[34] . Untreated STZ mice showed a gradually decreasing peak E velocity and an increased isovolumetric relaxation time (IVRT), indicating impaired diastolic function, while treatment with the compound of formula (I) for 1 week reduced IVRT and increased peak E velocity, thereby increasing the E / A ratio ( Figure 2 (g), Table 4). Improved left ventricular filling in mice treated with compounds of formula (I) also led to increased stroke volume and cardiac output (Table 4). In summary, these findings suggest that compounds of formula (I) improve hyperglycemia, reduce glycogen buildup, and reverse diabetic cardiomyopathy in diabetic STZ mice by stimulating insulin-independent glucose uptake and utilization.

[0155] Table 4 Table 4 shows the echocardiographic measurements of left ventricular dimensions in parasternal long axis (PLAX) mode B 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; LVIDd / s, diastolic / systolic left ventricular diameter; PWd / s, diastolic / systolic posterior wall thickness; EF, ejection fraction; FS, fractional shortening; E / A, peak wave velocity ratio of E to A; deceleration time, deceleration time of the E wave from peak to predicted baseline; IVRT, isovolumetric relaxation time. Statistical analysis was performed using one-way repeated ANOVA and Tukey. afterwards Test. The relationship between RD and the compound of formula (I) at the same time point* P <0.05. Compared to baseline, # P <0.05. Compared to scan 2, ¤P <0.05. Data are mean ± SD.

[0156] Example 4: The compound of formula (I) improves hyperglycemia and promotes gene expression profiles that favor glucose oxidation in the muscles of db / db mice.

[0157] To explore the potential of the compound of formula (I) to improve hyperglycemia in cases of severe insulin resistance, db / db mice were treated 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)) for 9 weeks. BKS mice were used as controls. Compensatory hyperinsulinemia (CMP) was observed in db / db mice at 6 weeks of age. Figure 3 (a) Figure 3 (b)). Untreated db / db mice were unable to compensate for the resulting insulin resistance, and due to the decrease in insulin levels, blood glucose levels rose rapidly. Figure 3 (a) Figure 3 (b)). Compared with starting values ​​and untreated db / db mice, the compound of formula (I) dose-dependently increased insulin levels, thus attenuating the increase in blood glucose levels. Figure 3 (a) Figure 3 (b)). These findings provide evidence that the compound of formula (I) maintains the compensatory β-cell insulin secretion response, and HOMA-β calculations of β-cell function homeostasis modeling show that the decline in β-cell function is attenuated in db / db mice treated with the compound of formula (I). Figure 3 (c)). The reduction in hyperglycemia mediated by the compound of formula (I) in db / db mice paralleled the decrease in glycogen accumulation in skeletal muscle and heart. Figure 3 (d) indicates that the compound of formula (I) also stimulates glucose utilization in diabetic db / db mice. Compared with untreated db / db mice, skeletal muscle of db / db mice treated with the compound of formula (I) showed increased glucose utilization. Txnip , Pdk4 and Ucp3 Decreased expression of Slc2a4, Peroxisome proliferator-activated receptor γ-coactivator (PGC)-1α ( Ppargc1a Increased expression of Cox8b (a positive regulator of mitochondrial biogenesis and respiration) and Cox8b (a driver of oxidative phosphorylation) supports this view. Figure 3 (f)). Compared with untreated db / db mice, treated db / db mice showed increased cardiac expression of Slc2a1 and Txnip , Pdk4 and Ucp3 The weakening expression ( Figure 3(g) is also consistent with what was observed in STZ mice treated with compounds of formula (I). Notably, in STZ mice and db / db mice treated with compounds of formula (I), compounds of formula (I) did not increase serum lactate levels. Figure 11 In summary, these findings provide evidence that compounds of formula (I) avoid genetic traits associated with metabolic inflexibility, which is linked to diabetes and diabetic cardiomyopathy, in STZ and db / db diabetic mice.

[0158] Example 5: The compound of formula (I) stimulates the uncoupling of mitochondria in myotubules.

[0159] Increased glucose utilization and decreased glycogen content observed in the skeletal muscle and heart of STZ and db / db mice treated with compounds of formula (I) suggest that compounds of formula (I) increase energy expenditure by generating metabolic demand via inefficient cycling and / or mitochondrial uncoupling. Studies of mitochondrial and glycolytic function in intact, differentiated C2C12 myotubes were conducted to elucidate the potential uncoupling potential of compounds of formula (I). Compounds of formula (I) dose-dependently increased the oxygen consumption rate (OCR) (a measure of oxidative phosphorylation) and the ratio of basal OCR to basal ECAR (extracellular acidification rate) in C2C12 myotubes. Figure 4 (a) to Figure 4 (c) indicates that the compounds of formula (I) increase the cell's preference for oxidative metabolism. The compounds of formula (I) also show a reduced OCR in response to oligomycin (which blocks ATP synthase), thus increasing proton leakage. Figure 4 (a) Figure 4 (d)). However, consistent with our previously published findings, the compound of formula (I) did not significantly reduce cellular ATP levels ( Figure 4 (d)). In summary, these results indicate that compounds of formula (I) increase cellular respiration by acting as mitochondrial uncoupling agents, providing evidence that compounds of formula (I) induce enhanced metabolic demand for energy expenditure by stimulating TCA flux and oxidative metabolism.

[0160] Example 6: The compound of formula (I) maintains β-cell function and quality in db / db mice.

[0161] Consistent with the described initial compensatory increase in β-cell mass in db / db mice, the islet cell area in db / db mice increased at 6 weeks of age compared to BKS mice. Figure 5 (a) Figure 5 (b)). In untreated db / db mice, the islet cell area at 15 weeks of age was relatively reduced compared to that at 6 weeks of age. p=0.09), but in mice treated with compounds of formula (I), the concentration was retained in a dose-dependent manner. Figure 5 (a) Figure 5 (b) Compared with untreated db / db mice, the percentage of Ins+ cells increased in mice treated with the compound of formula (I), while the percentage 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)). Therefore, compared with untreated db / db mice, db / db mice treated with the compound of formula (I) showed increased pancreatic insulin and proinsulin levels, as well as an increased pancreatic insulin:proinsulin ratio (a measure of proinsulin processing efficiency). Figure 5 (d) Figure 5 (e) Figure 12 (b)). These data together provide evidence that the compound of formula (I) avoids β-cell loss and preserves β-cell function in db / db mice. In the islets of db / db mice treated with the compound of formula (I), by Slc2a2 Partial restoration of protein expression of the encoded glucose transporter Glut2 ( Figure 5 (a) Figure 5 (f)). In the islets of db / db mice treated with compounds of formula (I), the expression of transcription factors Nkx6.1 and MafA, markers of mature β-cell identity, was increased, and Ipf1 / Pdx1 tended to increase ( Figure 5 (a) Figure 5 (f)). Upregulated in diabetic pancreatic islets Aldehyde dehydrogenase 1a3 ( Aldh1a3 The expression of Raldh3 encoded by ) remains unchanged. Figure 5 (a) Figure 5 (f)). Analysis of isolated islet mRNA expression showed that in the islets of db / db mice treated with the compound of formula (I), Urocorticin 3 ( Ucn3 (Markers of mature β cells and regulators of insulin secretion) and Nkx6.1 Increased expression ( Figure 5 (g)). Treatment with compounds of formula (I) does not alter Aldh1a3 The expression of [something] was observed in the islets of db / db mice treated with compound (I)-(1.0) compared to untreated db / db mice. Txnip Decreased expression of Txnip negatively impacts insulin transcription and induces oxidative stress in β cells. Figure 5 (g)). Similarly, in the islets of db / db mice treated with compounds of formula (I), ER stress-related genes... Endoplasmic reticulum protein 29 ( Erp29 )and ER degradation enhances α-mannan Glucosidase-like 2 ( Edem2 The expression of ) decreased ( Figure 5 (g)). These data indicate that, Txnip Decreased expression of ER stress genes and increased expression of genes regulating β-cell properties and insulin secretion contribute to the compensatory β-cell function, GSIS, and β-cell mass maintenance mediated by compounds of formula (I) in insulin-resistant db / db mice. The compensatory insulin secretion maintained in db / db mice treated with compounds of formula (I) may explain... Aldh1a3 The unchanged expression indicates Aldh1a3 Increased expression is a marker of metabolically challenged β cells.

[0162] Example 7: The compound of formula (I) alleviates the changes in pancreatic islet gene expression caused by acute hyperglycemia.

[0163] To investigate the ability of the compound of formula (I) to directly regulate the islet response to glucosinolate conditions, we performed RNA-seq analysis on mouse and human islets cultured in vitro under low (11 mM) and high (22 mM) glucose + / - 5 µM of the compound of formula (I). Mouse islets responded to high glucose (1924 differentially expressed genes) and (22 mM) differentially expressed genes (DEGs) by upregulating and downregulating 1568 differentially expressed genes (DEGs). Figure 6 (a) Figure 13 (a) to Figure 13 (c)). Under high glucose conditions, the compounds of formula (I) reduced the number of DEG upregulations to 143 and downregulations to 208. Figure 6 (a) Figure 13 (a) to Figure 13 (c)). As expected, exposure of mouse islets to high glucose led to Txnip The expression was significantly increased, and its expression was weakened by the compound of formula (I). Figure 6 (b) Overexpression analysis (ORA) of gene sets from the molecular signature Hallmark, KEGG, and Wiki pathways revealed that gene sets associated with enhanced β-cell activity, such as “protein secretion,” “folded protein response,” and “pancreatic β-cells,” were overexpressed in DEG, which is upregulated by high glucose but avoided by compounds of formula (I) under high glucose conditions. Figure 6 (c) The metabolic pathways “fatty acid metabolism,” “glycolysis,” and “hypoxia,” along with the “KEGG:TCA cycle,” are also overrepresented in the DEG, which is regulated by high glucose and counterregulated by compounds of formula (I). P =0.073). Regardless of direction, hierarchical clustering of the top 20 most significant DEGs in these pathways showed opposing regulation by compounds with high glucose and added (I) formulations. Figure 6(d)). These results demonstrate the ability of the compound of formula (I) to directly preserve the expression patterns of key metabolic genes in β cells under glycotoxic conditions. Gene expression differentials in human islets are dominated by donor effects, and DEG (degenerative genes) are rarely detected even after batch correction. Figure 13 (d) to Figure 13 (f)). Nevertheless, gene set enrichment analysis (GSEA) showed that high glucose induced genes in the "pancreatic β-cell" gene set, which were inversely regulated by the compound of formula (I), and similarly as observed for mouse islets, the compound of formula (I) induced upregulation of genes in the "hypoxia" and "glycolysis" gene sets. Figure 13 (g)).

[0164] Example 8: The compound of formula (I) prevents the negative effects of hyperglycemia on GSIS in INS-1E cells.

[0165] Chronic hyperglycemia activates mTORC1 signaling in β-cells and inhibits AMPK signaling in vitro, leading to reduced glucose metabolism and impaired glucose-stimulated insulin secretion (GSIS). Consistently, our RNA seq analysis identified that mTORC1 signaling was upregulated in islets exposed to high (22 mM) glucose, which was blocked by exposure to compounds of formula (I). Figure 6 (c)). To explore the effects of the compound of formula (I) on GSIS under chronic hyperglycemic conditions, INS-1E cells were cultured at 25 mM glucose for 4 days (d), which impaired GSIS, while exposure to the compound of formula (I) throughout the 4-day culture period avoided these negative effects. Figure 7 (a)). At the end of the 4-day culture period, short-term (2 hours) exposure of INS-1E cells to the compound of formula (I) also partially reversed the negative effects of hyperglycemia on GSIS. Figure 7 (b) Therefore, the compound of formula (I) both prevented and reversed the negative effects of hyperglycemia on GSIS. Analysis of downstream targets of mTORC1 (i.e., ribosomal protein 6 (pS6)) and AMPK (i.e., acetyl-CoA carboxylase (ACC) and Raptor) showed that both long-term and short-term exposure of INS1-E cells to the compound of formula (I) under hyperglycemic conditions reduced pS6-Ser240 / 244 levels, but increased pACC-Ser79 and pRaptor-Ser792 levels. Figure 7 (c) Figure 7 (d) Figure 14 In summary, these findings provide evidence that compounds of formula (I) preserve β-cell function under hyperglycemic conditions by antagonizing mTORC1 and preserving AMPK signaling.

Claims

1. A method of treating a subject in need of cardiomyopathy associated with metabolic inflexibility, comprising administering an effective amount of a compound having the following structure: ， Or a pharmaceutically acceptable salt, solvate, or prodrug.

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

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

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

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

6. The method of any one of claims 1-5, wherein the subject has type 1 diabetes.

7. The method of any one of claims 1-5, wherein the subject has type 2 diabetes.

8. The method of any one of claims 1-7, wherein the subject suffers from hypertension.

9. The method of any one of claims 1-8, wherein the administration restores the cardiac metabolic flexibility of the subject's heart.

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

11. The method of claim 10, wherein the pharmaceutical composition is a tablet or capsule.

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

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

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

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

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

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

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

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

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

21. The method of claim 20, wherein the steady-state AUC of said compound or its pharmaceutically acceptable salt, solvate, or prodrug is... 0-24 It ranges from approximately 1,800 h*µg / mL to approximately 3,100 h*µg / mL.

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

23. The method of claim 20, wherein the steady-state AUC of said compound or its pharmaceutically acceptable salt, solvate, or prodrug is... 0-24 It ranges from approximately 2,500 h*µg / mL to approximately 4,000 h*µg / mL.

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

25. The method of any one of claims 20-24, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 70 µg / mL to approximately 200 µg / mL.

26. The method of any one of claims 20-24, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 80 µg / mL to approximately 140 µg / mL.

27. The method of any one of claims 20-24, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 70 µg / mL to approximately 100 µg / mL.

28. The method of any one of claims 20-24, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It is approximately 120 µg / mL to approximately 150 µg / mL.

29. A method of treating and / or preventing heart failure in a subject in need, comprising administering an effective amount of a compound having the following structure: ， Or a pharmaceutically acceptable salt, solvate, or prodrug.

30. A method for improving symptoms associated with heart failure in a subject in need, comprising administering an effective amount of a compound having the following structure: ， Or a pharmaceutically acceptable salt, solvate, or prodrug.

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

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

33. The method of any one of claims 29-32, wherein an alkali metal salt of the compound is applied.

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

35. The method of any one of claims 29-34, wherein the administration restores the cardiac metabolic flexibility of the subject's heart.

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

37. The method of any one of claims 29-36, wherein the subject suffers from diabetic cardiomyopathy.

38. The method of claim 37, wherein the administration alleviates the diabetic cardiomyopathy of the subject.

39. The method of any one of claims 29-38, wherein the subject is hyperglycemic.

40. The method of any one of claims 29-38, wherein the subject is not hyperglycemic.

41. The method of any one of claims 29-40, wherein the heart failure of the subject is associated with hyperinsulinemia.

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

43. The method of any one of claims 29-42, wherein the subject is a person with diabetes.

44. The method of claim 43, wherein the subject has type 1 diabetes.

45. The method of claim 43, wherein the subject has type 2 diabetes.

46. ​​The method of any one of claims 29-36 or 37-42, wherein the subject is not diabetic.

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

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

49. The method of claim 48, wherein the SGLT2 inhibitor is dapagliflozin.

50. The method of any one of claims 29-49, wherein the administration reduces the subject's systolic blood pressure.

51. The method of any one of claims 29-50, wherein the administration reduces the diastolic blood pressure of the subject.

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

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

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

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

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

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

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

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

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

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

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

63. The method of claim 62, wherein the steady-state AUC of said compound or its pharmaceutically acceptable salt, solvate, or prodrug is... 0-24 It ranges from approximately 1,800 h*µg / mL to approximately 3,100 h*µg / mL.

64. The method of claim 62, wherein the steady-state AUC of said compound or its pharmaceutically acceptable salt, solvate, or prodrug is... 0-24 It ranges from approximately 1,500 h*µg / mL to approximately 2,000 h*µg / mL.

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

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

67. The method of any one of claims 62-66, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 70 µg / mL to approximately 200 µg / mL.

68. The method of any one of claims 62-66, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 80 µg / mL to approximately 140 µg / mL.

69. The method of any one of claims 62-66, wherein the C of said compound or a pharmaceutically acceptable salt, solvate or prodrug thereof max It ranges from approximately 70 µg / mL to approximately 100 µg / mL.

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

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

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

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

74. The method of any one of claims 71-73, wherein the subject has type 1 diabetes.

75. The method of any one of claims 71-73, wherein the subject has type 2 diabetes.

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

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

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

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

80. The method of 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 of any one of claims 76-80, wherein the subject is not diabetic.

82. A method for improving the physical condition or cardiac function of a subject, comprising administering to the subject a compound having the following structure: ， Or a pharmaceutically acceptable salt, solvate, or prodrug.

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

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

85. The method as described in any of the preceding claims, wherein the subject is a human.

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