Pharmaceutical use of GLP-1 receptor agonist

Abstract

The present disclosure relates to pharmaceutical use of a GLP-1 receptor agonist. In particular, the present disclosure relates to pharmaceutical use of a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof in preventing or treating heart failure and a method for preventing or treating heart failure with a GLP-1 receptor agonist or a pharmaceutically acceptable salt thereof.

Description

Medical Uses of GLP-1 Receptor Agonists Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to methods and pharmaceutical uses of GLP-1 receptor agonists for the prevention or treatment of heart failure. Background Technology

[0002] Chronic heart failure (HF) is a complex clinical syndrome caused by various factors leading to structural and / or functional changes in the heart, resulting in impaired systolic and / or diastolic function. Based on the degree of reduction in left ventricular ejection fraction (LVEF), heart failure is classified into three categories: HF with reduced ejection fraction (HFrEF, LVEF ≤ 40%), HF with mildly reduced ejection fraction (HFmrEF, 40% < LVEF < 50%), and HF with preserved ejection fraction (HFpEF, LVEF ≥ 50%). HFpEF is a highly heterogeneous group of diseases primarily characterized by impaired left ventricular diastolic function, with different pathogenesis and treatment strategies than HFrEF. HFpEF accounts for approximately 50% of heart failure patients, and its incidence is continuously increasing. The 1-year all-cause readmission rate and heart failure readmission rate for HFpEF patients were 22.2% and 13.6%, respectively, while the 1-year all-cause mortality rate and cardiovascular mortality rate were 8.5% and 3.1%, respectively. However, the treatment recommendations for HFpEF include etiological treatment and comorbidity management, and there is still a lack of safe and effective drugs to improve heart failure outcomes. The only recommended drug in the Class IA category of domestic guidelines is sodium-glucose cotransporter 2 inhibitor (SGLT2i).

[0003] The pathogenesis of heart failure with type 2 diabetes mellitus (HFpEF) is complex, usually secondary to comorbidities, and is associated with increased risk factors such as obesity, hypertension, and diabetes. Obesity is an independent predictor of HFpEF incidence and poor prognosis. Systemic overweight / obesity and increased epicardial fat induce systemic inflammatory responses, leading to ventricular remodeling and diastolic dysfunction. Simultaneously, metabolic abnormalities such as hypertension, insulin resistance, and dyslipidemia also significantly increase cardiovascular risk. STEP-HFpEF is an international, multicenter, double-blind, randomized controlled phase III clinical trial designed to evaluate the efficacy and safety of semaglutide in patients with obesity-related HFpEF. This program consists of two trials: STEP-HFpEF and STEP-HFpEF DM, enrolling patients with simple obesity and obese patients with type 2 diabetes, respectively. The primary endpoints were KCCQ-CSS score and weight loss. The STEP-HFpEF study results indicated that semaglutide resulted in a 10.7% weight loss and a 7.8-point improvement in the KCCQ-CSS score compared to placebo; the STEP-HFpEF-DM study results indicated that semaglutide resulted in a 6.4% weight loss and a 7.3-point improvement in the KCCQ-CSS score compared to placebo. The SUMMIT Phase III clinical trial of tirzepatide in adult patients with HFpEF was successful, showing a 38% reduction in the risk of heart failure events (including emergency visits to the hospital for heart failure, hospitalization for heart failure, intensive oral diuretic therapy, and cardiovascular death) and an improvement in the KCCQ-CSS score compared to placebo. Summary of the Invention

[0004] This disclosure includes a surprising finding that GLP-1 RA can effectively improve clinical outcomes in patients with heart failure or at risk of heart failure, including patients with heart failure with preserved ejection fraction (HFpEF) and / or heart failure with mildly reduced ejection fraction (HFmrEF) (including the aforementioned patients who are also obese).

[0005] This disclosure provides methods and pharmaceutical uses for the use of compounds of formula (I) or their pharmaceutically acceptable salts in the prevention or treatment of heart failure, or in delaying heart failure:

[0006] On the one hand, this disclosure provides the use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of heart failure, or for delaying heart failure.

[0007] On the one hand, this disclosure provides a method for preventing or treating heart failure, or delaying heart failure, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the heart failure is selected from HFmrEF and HFpEF; in some embodiments, the heart failure is HFpEF; in some embodiments, the heart failure is HFmrEF.

[0009] In some embodiments, the heart failure subject has a left ventricular ejection fraction (LVEF) of 45% ≤ 50%, LVEF ≥ 50%, or LVEF ≥ 45%; in some embodiments, the heart failure subject has an LVEF ≥ 45%; in some embodiments, the subject has a left ventricular ejection fraction (LVEF) ≥ 45% and the subject has no history of a left ventricular ejection fraction ≤ 40%.

[0010] In some embodiments, the heart failure is selected from HFmrEF / HFpEF; in some embodiments, the heart failure subject has a left ventricular ejection fraction of 40% < LVEF < 50%, LVEF ≥ 50%, or LVEF > 40%; in some embodiments, the heart failure subject has LVEF > 40%; in some embodiments, the subject's left ventricular ejection fraction (LVEF) is > 40% and < 50%; in other embodiments, the subject's left ventricular ejection fraction (LVEF) is ≥ 50%.

[0011] In some embodiments, the heart failure is chronic heart failure with a duration of at least 1 month; in some embodiments, the heart failure is chronic heart failure with a duration of at least 2 months; in some embodiments, the heart failure is chronic heart failure with a duration of at least 3 months; in some embodiments, the heart failure is chronic heart failure with a duration of at least 4 months; in some embodiments, the heart failure is chronic heart failure with a duration of at least 6 months; in some embodiments, the heart failure is chronic heart failure with a duration of at least 9 months; and in some embodiments, the heart failure is chronic heart failure with a duration of at least 12 months.

[0012] In some implementations, the heart failure subject is obese or overweight; in some implementations, the subject is obese; and in other implementations, the subject is overweight.

[0013] In some implementations, the body mass index (BMI) of the heart failure subject is ≥24 kg / m². 2 BMI ≥ 25 kg / m 2 BMI ≥ 26 kg / m 2 BMI ≥ 27 kg / m 2 BMI ≥ 28 kg / m 2 BMI ≥ 30 kg / m 2 BMI ≥ 35 kg / m 2 BMI ≥ 40 kg / m2 In some implementation schemes, the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥28 kg / m². 2 And <40kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥24.0 kg / m². 2 And <28.0kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤40.0kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is >32.5 kg / m². 2 And ≤40.0kg / m 2 In other implementation schemes, the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 .

[0014] In some implementations, the subjects had at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease).

[0015] In some embodiments, the heart failure subject is not obese or overweight. In some embodiments, the heart failure subject has type 2 diabetes; in some embodiments, the subject does not have type 2 diabetes.

[0016] In some embodiments, the subject is a human; in some embodiments, the subject is an adult; in some embodiments, the subject is male; and in some embodiments, the subject is female.

[0017] In some implementations, the weight change of the heart failure subjects in the 3 months prior to screening and randomization is no more than 5 kg; in some implementations, the weight change of the heart failure subjects in the 90 days prior to screening and randomization is no more than 4 kg; in some implementations, the weight change of the heart failure subjects in the 90 days prior to screening and randomization is no more than 3 kg; and in some implementations, the weight change of the heart failure subjects in the 90 days prior to screening and randomization is no more than 2 kg.

[0018] In some implementations, the heart failure subjects had controlled their weight through diet and exercise for 3 months or more before screening, and their weight change did not exceed 5 kg in the 3 months prior to screening and randomization; in some implementations, the subjects had controlled their weight through diet and exercise intervention for 3 months before starting treatment with compound (I) or its medicinal salt; in other implementations, the subjects' weight fluctuation did not exceed 5 kg in the 3 months prior to starting treatment with compound (I) or its medicinal salt.

[0019] In some implementations, the heart failure subject has a left ventricular ejection fraction ≥45% and a BMI ≥24 kg / m². 2 BMI ≥ 28 kg / m 2 Or BMI ≥ 30 kg / m 2 .

[0020] In some implementations, the heart failure subject has a left ventricular ejection fraction >40% and a BMI ≥24 kg / m². 2 BMI ≥ 28 kg / m 2 Or BMI ≥ 30 kg / m 2 .

[0021] In some implementations, the heart failure subject has a left ventricular ejection fraction ≥45% and has never previously had an LVEF ≤40%.

[0022] In some embodiments, the subject's serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level is ≥125 pg / mL (e.g., sinus rhythm subject). In some embodiments, the subject's serum NT-proBNP level is ≥300 pg / mL (e.g., atrial fibrillation subject).

[0023] In some implementations, the subject has one or more cardiac structural or functional abnormalities. In some implementations, the cardiac structural or functional abnormality is selected from the following: (1) echocardiography showing left ventricular diastolic dysfunction / elevated left ventricular filling pressure; (2) positive stress echocardiography or abnormal results of invasive hemodynamic examination. In some implementations, the subject with echocardiography showing left ventricular diastolic dysfunction / elevated left ventricular filling pressure has at least one of the following characteristics: (i) female left ventricular mass index ≥95 g / m². 2 Or, for men, a left ventricular mass index ≥115 g / m² 2 (ii) Relative ventricular wall thickness > 0.42; (iii) Early diastolic mitral valve flow velocity to early diastolic mitral valve annular velocity ratio (E / e') ≥ 15; (iv) Interventricular septal mitral valve annular velocity < 7 cm / s, or lateral wall mitral valve annular velocity < 10 cm / s, or mean mitral valve annular velocity < 8 cm / s; (v) Tricuspid regurgitation velocity > 2.8 cm / s, or estimated pulmonary artery systolic pressure > 35 mmHg; (vi) Left atrial enlargement, and meeting any of the following conditions: left atrial anteroposterior diameter ≥ 3.8 cm, left atrial superior-inferior diameter ≥ 5.0 cm, left atrial area ≥ 20 cm². 2 Left atrial volume ≥ 55 mL, or left atrial volume index (LAVI) ≥ 34 mL / m³ 2 (vii) Left ventricular hypertrophy, such as interventricular septal thickness or left ventricular posterior wall thickness ≥1.1 cm. In some implementations, subjects with positive stress echocardiography or abnormal invasive hemodynamic findings are considered to have at least one of the following: (i) an E / e' ratio ≥15 as measured by stress echocardiography; (ii) a pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or a left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg as measured by cardiac catheterization at rest; (iii) a peak pulmonary capillary wedge pressure ≥25 mmHg as measured by cardiac catheterization during stress.

[0024] In some implementations, the subject meets the following criteria: (1) a left ventricular ejection fraction (LVEF) ≥45% and no prior history of LVEF ≤40%; (2) a serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level ≥125 pg / mL (e.g., sinus rhythm subjects) or ≥300 pg / mL (e.g., atrial fibrillation subjects); and (3) the presence of one or more cardiac structural or functional abnormalities (e.g., the types of abnormalities described above). In some implementations, such subjects have heart failure with preserved ejection fraction (HFpEF).

[0025] In some implementations, the subject meets the following criteria: (1) left ventricular ejection fraction (LVEF) > 40%; (2) serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level ≥ 125 pg / mL (e.g., sinus rhythm subject) or ≥ 300 pg / mL (e.g., atrial fibrillation subject); (3) presence of one or more cardiac structural or functional abnormalities (e.g., the abnormality types described above).

[0026] In some implementations, the heart failure subject has a NYHA functional class of at least II, for example, class II to IV; and / or the heart failure subject has a KCCQ-CSS score ≤ 80.

[0027] In some implementations, the subject's New York Heart Association (NYHA) functional class II to IV; in some implementations, the subject's NYHA functional class II; in some implementations, the subject's NYHA functional class III; in some implementations, the subject's NYHA functional class IV; the criteria for determining NYHA functional class can be found, for example, in the National Heart Failure Guidelines 2023, Chinese Journal of Heart Failure and Cardiomyopathy 2023 Vol.07 Issue 04 Pages 215-31.

[0028] In some implementations, the subject's Kansas City Cardiomyopathy Questionnaire Clinical Total Score (KCCQ-CSS) is ≤80 points; the criteria for determining the Kansas City Cardiomyopathy Questionnaire Clinical Total Score (KCCQ-CSS) can be found, for example, in the National Heart Failure Guidelines 2023, Chinese Journal of Heart Failure and Cardiomyopathy 2023 Vol.07 Issue 04 Pages 215-31.

[0029] In some embodiments, administration of the compound of formula (I) or its pharmaceutical salt using the methods and uses described herein may achieve one or more therapeutic effects, such as efficacy after a specific duration and / or efficacy compared to a control population; in some embodiments, one or more of the above-mentioned therapeutic effects may be achieved at 8, 24, 36, or 40 weeks after administration; in some embodiments, the control population is a comparable population of subjects who have not received treatment with the compound of formula (I) or its pharmaceutical salt, such as a population of subjects receiving placebo; in some embodiments, the control population is a comparable population of subjects receiving standard treatment; in some embodiments, the determination of a therapeutic endpoint is referenced to the subject's baseline level; in some embodiments, a therapeutic endpoint is subject to placebo correction (e.g., subtracting the determination of the placebo-treated subject or population from the determination of the treated subject or population).

[0030] In some implementations, the compound of formula (I) or its pharmaceutically acceptable salt improves symptoms of heart failure, motor function, and / or reduces weight in subjects.

[0031] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof improves any of the following indicators in the subject:

[0032] 1) Reduce mortality rate;

[0033] 2) Improve KCCQ-CSS scores and / or KCCQ-OSS scores, for example, improve KCCQ-CSS scores by ≥5, ≥10, or ≥15 points;

[0034] 3) Reduce hsCRP levels;

[0035] 4) Reduce NT-proBNP levels;

[0036] 5) Improves cardiac function indicators;

[0037] 6) Improves NYHA functional classification;

[0038] 7) Improve body mass index (BMI), for example, a weight reduction of ≥5%, ≥10%, or ≥15% relative to baseline;

[0039] 8) Reduces the risk of hospitalization due to heart failure;

[0040] 9) Reduces the risk of death from heart failure;

[0041] 10) Reduce the risk of complex heart failure endpoints;

[0042] 11) Reduces the risk of clinical events that worsen heart failure;

[0043] 12) Reduce waist circumference.

[0044] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof improves or reduces any of the following indicators in the subject: fasting blood glucose, glycated hemoglobin (HbA1c).

[0045] In some implementations, after administration of compound (I) or its pharmaceutically acceptable salt, subjects showed an improvement in their Kansas City Cardiomyopathy Questionnaire Clinical Overall Score (KCCQ-CSS) from baseline over specific durations (e.g., 8, 24, 36, or 40 weeks of administration). In some implementations, the improvement in subjects' KCCQ-CSS scores was ≥5, ≥10, or ≥15 points over specific durations (e.g., 8, 24, 36, or 40 weeks of administration). In some implementations, subjects receiving compound (I) or its pharmaceutically acceptable salt showed a more significant improvement in their KCCQ-CSS scores compared to subjects receiving placebo.

[0046] In some embodiments, after administration of compound (I) or its pharmaceutically acceptable salt, subjects experience a decrease in body weight from baseline over a specific duration (e.g., 8, 24, 36, or 40 weeks). In some embodiments, after a specific duration (e.g., 8, 24, 36, or 40 weeks), the subjects experience a weight loss of at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%. In some embodiments, subjects treated with compound (I) or its pharmaceutically acceptable salt experience a more significant weight loss compared to subjects receiving placebo.

[0047] In some implementations, after specific durations (e.g., 8, 24, 36, or 40 weeks of administration), a higher proportion of subjects receiving compound (I) or its medicinal salts showed improvement in KCCQ-CSS scores from baseline compared to the placebo group. In some implementations, the proportion of subjects receiving compound (I) or its medicinal salts who achieved KCCQ-CSS score improvements of ≥5%, ≥10%, and / or ≥15% was higher than the corresponding proportion in the placebo group.

[0048] In some implementations, after administration of compound (I) or its pharmaceutically acceptable salt, subjects showed an improvement in their Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OSS) from baseline over specific durations (e.g., 8, 24, 36, or 40 weeks of administration). In some implementations, the improvement in subjects' KCCQ-OSS scores was ≥5, ≥10, or ≥15 points over specific durations (e.g., 8, 24, 36, or 40 weeks of administration). In some implementations, subjects receiving compound (I) or its pharmaceutically acceptable salt showed a more significant improvement in their KCCQ-OSS scores compared to subjects receiving placebo.

[0049] In some implementations, after administration of compound (I) or its pharmaceutically acceptable salt, subjects showed improvement in their 6-minute walk test (6MWT) results from baseline over specific durations (e.g., 8, 24, 36, or 40 weeks of administration). In some implementations, subjects receiving compound (I) or its pharmaceutically acceptable salt showed more significant improvement in their 6-minute walk test (6MWT) results from baseline compared to subjects receiving placebo.

[0050] In some embodiments, administration of compound (I) or its pharmaceutically acceptable salt over specific durations (e.g., 8, 24, 36, or 40 weeks) can result in a decrease in the subject's body weight from baseline. In some embodiments, administration of compound (I) or its pharmaceutically acceptable salt over specific durations (e.g., 8, 24, 36, or 40 weeks) can result in a decrease in the subject's body weight from baseline of ≥5%, ≥10%, and / or ≥15%.

[0051] In some implementations, after specific durations (e.g., 8, 24, 36, or 40 weeks of administration), a higher proportion of subjects receiving compound (I) or its pharmaceutically acceptable salts experienced a decrease in weight from baseline compared to the placebo group. In some implementations, the proportion of subjects receiving compound (I) or its pharmaceutically acceptable salts who experienced a weight loss of ≥5%, ≥10%, and / or ≥15% was higher than the corresponding proportion in the placebo group.

[0052] In some embodiments, after administration of compound (I) or its pharmaceutically acceptable salt, subjects showed a reduction in high-sensitivity C-reactive protein (hsCRP) levels from baseline over a specific duration (e.g., 8, 24, 36, or 40 weeks). In some embodiments, subjects treated with compound (I) or its pharmaceutically acceptable salt showed a more significant reduction in hsCRP levels from baseline compared to subjects receiving placebo.

[0053] In some embodiments, after administration of compound (I) or its pharmaceutically acceptable salt, the N-terminal pro-brain natriuretic peptide (NT-proBNP) level in subjects decreased from baseline after a specific duration (e.g., 8, 24, 36, or 40 weeks of administration). In some embodiments, subjects treated with compound (I) or its pharmaceutically acceptable salt exhibited a more significant reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels from baseline compared to subjects receiving placebo.

[0054] In some embodiments, after administration of the compound of formula (I) or its pharmaceutically acceptable salt, over specific durations (e.g., 8, 24, 36, or 40 weeks of administration), subjects showed improvements in mitral diastolic flow velocity (e.g., peak E and / or peak A), mitral annular lateral wall and ventricular septal motion velocity (e'), and / or the mean E / e' ratio. In some embodiments, subjects treated with the compound of formula (I) or its pharmaceutically acceptable salt showed more significant improvements in mitral diastolic flow velocity (e.g., peak E and / or peak A), mitral annular lateral wall and ventricular septal motion velocity (e'), and / or the mean E / e' ratio compared to subjects receiving placebo.

[0055] In some implementations, after administration of the compound of formula (I) or its pharmaceutical salt for a specific duration (e.g., 8, 24, 36, or 40 weeks of administration), the mortality rate of subjects was reduced (e.g., compared to subjects receiving placebo).

[0056] In some implementations, after administration of compound (I) or its pharmaceutically acceptable salt for a specific duration (e.g., 8, 24, 36, or 40 weeks), the New York Heart Association (NYHA) functional classification of the subjects improved. In some implementations, subjects treated with compound (I) or its pharmaceutically acceptable salt showed more significant improvements in their NYHA functional classification compared to subjects receiving placebo.

[0057] In some embodiments, after administration of the compound of formula (I) or its pharmaceutically acceptable salt, a decrease in the subject's body mass index (BMI) occurs over a specific duration (e.g., 8, 24, 36, or 40 weeks). In some embodiments, the decrease in the subject's BMI is at least 0.5 kg / m². 2 1.0kg / m 2 1.5kg / m 2 2.0kg / m 2 2.5kg / m 2 3.0kg / m 2 3.5kg / m 2 4.0kg / m 2 4.5kg / m 2 Or 5.0 kg / m 2 In some implementations, subjects receiving compound (I) or its pharmaceutical salts experienced a more significant reduction in BMI compared to subjects receiving placebo.

[0058] In some implementations, after administration of the compound of formula (I) or its pharmaceutically acceptable salt for a specific duration (e.g., 8, 24, 36, or 40 weeks), the subject's waist circumference decreased. In some implementations, the reduction in waist circumference was at least 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, or 15 cm. In some implementations, the reduction in waist circumference was more significant in subjects receiving the compound of formula (I) or its pharmaceutically acceptable salt compared to subjects receiving a placebo.

[0059] In some implementations, administration of compound (I) or its pharmaceutical salt can reduce the risk or incidence of hospitalization for heart failure in subjects. In some implementations, subjects treated with compound (I) or its pharmaceutical salt experienced a more significant reduction in the risk or incidence of hospitalization for heart failure compared to subjects receiving placebo.

[0060] In some implementations, administration of compound (I) or its pharmaceutical salt can reduce the risk or incidence of death from heart failure in subjects. In some implementations, subjects treated with compound (I) or its pharmaceutical salt experienced a more significant reduction in the risk or incidence of death from heart failure compared to subjects receiving placebo.

[0061] In some implementations, administration of the compound of formula (I) or its pharmaceutically acceptable salt can reduce the risk or incidence of the composite endpoint event of heart failure in subjects. In some implementations, subjects treated with the compound of formula (I) or its pharmaceutically acceptable salt experienced a more significant reduction in the risk or incidence of the composite endpoint event of heart failure compared to subjects receiving placebo.

[0062] In some implementations, administration of compound (I) or its pharmaceutically acceptable salt can reduce the risk or incidence of exacerbations of clinical events of heart failure in subjects. In some implementations, subjects treated with compound (I) or its pharmaceutically acceptable salt experienced a more significant reduction in the risk or incidence of exacerbations of clinical events of heart failure compared to subjects receiving placebo.

[0063] In some embodiments, after administration of the compound of formula (I) or its pharmaceutically acceptable salt, the subject's glycated hemoglobin (HbA1c) level decreased from baseline after a specific duration (e.g., 8, 24, 36, or 40 weeks of administration). In some embodiments, the decrease in the subject's glycated hemoglobin (HbA1c) was at least 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.0%, 2.1%, or 2.2%. In some embodiments, subjects treated with the compound of formula (I) or its pharmaceutically acceptable salt showed a more significant decrease in their glycated hemoglobin (HbA1c) level from baseline compared to subjects receiving placebo.

[0064] In some embodiments, after administration of compound (I) or its pharmaceutically acceptable salt, subjects experienced a reduction in fasting blood glucose levels from baseline over a specific duration (e.g., 8, 24, 36, or 40 weeks). In some embodiments, the reduction in fasting blood glucose levels was at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L. In some embodiments, subjects treated with compound (I) or its pharmaceutically acceptable salt experienced a more significant reduction in fasting blood glucose levels from baseline compared to subjects receiving placebo.

[0065] On the other hand, this disclosure provides a method for preventing or treating HFmrEF / HFpEF in a subject, or for delaying the development of HFmrEF / HFpEF, comprising administering to a subject in need a preventive or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0066] On the other hand, this disclosure provides methods for improving symptoms of heart failure, motor function and / or reducing weight in subjects in need, including administering to subjects in need a preventive or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered orally; in other embodiments, it is administered with water.

[0068] In some embodiments, the compound of formula (I) or a pharmaceutical salt thereof is administered in an oral dosage form; in some embodiments, the compound of formula (I) or a pharmaceutical salt thereof is administered in a tablet form; and in some embodiments, the compound of formula (I) or a pharmaceutical salt thereof is administered in a capsule form.

[0069] In some embodiments, the compound of formula (I) or its pharmaceutical salt is taken after a meal; in some embodiments, the compound or its pharmaceutical salt is taken after breakfast; in some embodiments, the compound of formula (I) or its pharmaceutical salt is taken before a meal, for example, after an 8-hour fast.

[0070] In some implementations, the compound of formula (I) is administered as a free base.

[0071] In some implementations, the compound of formula (I) is administered in the form of a free acid.

[0072] In some embodiments, the compound of formula (I) is administered in the form of a salt; in some embodiments, the pharmaceutical salt of the compound of formula (I) is selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, mesylate and hydrobromide.

[0073] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject by dose titration; in some embodiments, the dose is increased every 2 weeks, every 3 weeks, every 4 weeks, or every 5 weeks; in some embodiments, the dose is increased every 4 weeks.

[0074] In some implementations, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject at an initial dose, followed by dose escalation to maintain treatment once a target dose is reached.

[0075] In some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, once every two days, and once every three days; in some embodiments, the frequency of administration is once daily.

[0076] In some embodiments, the dosage of compound (I) or its pharmaceutical salt is 5–720 mg; in some embodiments, the dosage is 5–30 mg; in some embodiments, the dosage is 30–540 mg; in some embodiments, the dosage is 15 mg to 400 mg; in some embodiments, the dosage is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg; in some embodiments, the dosage is about 15 mg, 20 mg, 30 mg, or 40 mg. mg, 50mg, 55mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 220mg, 240mg, 260mg, 280mg, 300mg, 320mg, 340mg, 360mg, 380mg, 400mg, 420mg, 480mg, 540mg, 720mg. In some embodiments, the dosage is approximately 180mg or 360mg. It should be noted that all dosage values ​​provided herein are calculated based on the weight of the corresponding free base or free acid.

[0077] In some embodiments, this disclosure provides a method of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising administering the compound according to a dosing regimen in which a subject first receives one or more escalating doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof, followed by a maintenance dose; in some embodiments, this disclosure provides a method of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising administering the compound according to a dosing regimen in which a subject first receives an initial dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, followed by one or more escalating doses, and finally a maintenance dose.

[0078] In some embodiments, the dosing regimen of the compound of formula (I) or its pharmaceutically acceptable salt includes any one of the following:

[0079] A)

[0080] Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for at least one week, followed by

[0081] Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least one week, followed by

[0082] Administer a maintenance dose of the compound of formula (I) or its pharmaceutically acceptable salt once daily for at least 2 weeks;

[0083] B)

[0084] Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for at least 2 weeks, followed by

[0085] Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 2 weeks, followed by

[0086] Administer a maintenance dose of the compound of formula (I) or its pharmaceutically acceptable salt once daily for at least 4 weeks;

[0087] C)

[0088] Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0089] Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for approximately 4 weeks per escalating dose, followed by...

[0090] Administer a maintenance dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 16 weeks (e.g., 28 weeks).

[0091] D) As described in any of the groups A and C, at least one escalation dose may be selected from one escalation dose, two escalation doses, three escalation doses, four escalation doses, or five escalation doses.

[0092] E) As described in any group of AD, each increment dose is either identical or different from the others.

[0093] In this disclosure, "at least 1 week" includes 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, and 30 weeks. "At least 2 weeks" includes 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, and 30 weeks. "At least 4 weeks" includes 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, and 40 weeks. "At least 16 weeks" includes 16 weeks, 17 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 40 weeks, etc.

[0094] In some embodiments, the initial dose is 5 mg to 60 mg; in some embodiments, the initial dose is 10 mg to 50 mg, for example, about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, or 60 mg; in some embodiments, the initial dose is about 30 mg; in some embodiments, the initial dose is 15 mg; and in some embodiments, the initial dose is 30 mg.

[0095] In some embodiments, the escalating dose is from 30 mg to 540 mg; in other embodiments, the escalating dose is from 55 mg to 400 mg, for example, about 30 mg, 45 mg, 55 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, etc. 0 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 420 mg, 480 mg, 540 mg; in some embodiments, the incremental dose is about 60 mg, 120 mg, 180 mg, 240 mg, 300 mg; in some embodiments, the incremental dose is about 30 mg, 60 mg, 120 mg, 180 mg.

[0096] In some implementations, the escalation dose includes one or more stepwise dose increases; in some implementations, the increase in dose for each stepwise increase is 15 mg, 30 mg, 60 mg, or 120 mg.

[0097] In some implementations, the incremental dose includes: 1) one incremental dose; 2) two incremental doses; 3) three incremental doses; 4) four incremental doses; 5) five incremental doses, or more than five incremental doses.

[0098] In some implementations, 1) the incremental dose includes an incremental dose:

[0099] The first incremental dose is selected from 55 mg to 120 mg;

[0100] 2) The incremental dosage includes two incremental dosages:

[0101] The first incremental dose is selected from 60 mg to 90 mg;

[0102] The second incremental dose is selected from 95 mg to 120 mg;

[0103] 3) The incremental dosage includes three incremental dosages:

[0104] The first incremental dose is selected from 55 mg to 70 mg;

[0105] The second incremental dose is selected from 75 mg to 100 mg;

[0106] The third escalation dose is selected from 105 mg to 120 mg;

[0107] 4) The incremental dosage includes four incremental dosages:

[0108] The first incremental dose is selected from 50 mg to 70 mg;

[0109] The second incremental dose is selected from 100 mg to 130 mg;

[0110] The third escalation dose is selected from 150 mg to 200 mg;

[0111] The fourth escalating dose is selected from 220 mg to 260 mg;

[0112] 5) The incremental dosage includes five incremental dosages:

[0113] The first incremental dose is selected from 50 mg to 70 mg;

[0114] The second incremental dose is selected from 100 mg to 130 mg;

[0115] The third escalation dose is selected from 150 mg to 200 mg;

[0116] The fourth escalating dose is selected from 220 mg to 260 mg;

[0117] The fifth increment dose is selected from 280 mg to 320 mg.

[0118] In some implementations, 1) the incremental dose includes an incremental dose:

[0119] The first incremental dose is approximately 60 mg, 90 mg, or 120 mg;

[0120] 2) The incremental dosage includes two incremental dosages:

[0121] The first incremental dose is approximately 60 mg or 90 mg;

[0122] The second incremental dose is approximately 120 mg;

[0123] 3) The incremental dosage includes three incremental dosages:

[0124] The first incremental dose is approximately 60 mg;

[0125] The second incremental dose is approximately 90 mg;

[0126] The third escalation dose is approximately 120 mg.

[0127] 4) The incremental dosage includes four incremental dosages:

[0128] The first incremental dose is approximately 60 mg;

[0129] The second incremental dose is approximately 120 mg;

[0130] The third incremental dose is approximately 180 mg;

[0131] The fourth incremental dose is approximately 240 mg;

[0132] 5) The incremental dosage includes five incremental dosages:

[0133] The first incremental dose is approximately 60 mg;

[0134] The second incremental dose is approximately 120 mg;

[0135] The third incremental dose is approximately 180 mg;

[0136] The fourth incremental dose is approximately 240 mg;

[0137] The fourth incremental dose is approximately 300 mg.

[0138] In some implementations, 1) the incremental dose includes an incremental dose:

[0139] The first incremental dose is approximately 60 mg, 90 mg, or 120 mg;

[0140] 2) The incremental dosage includes two incremental dosages:

[0141] The first incremental dose is approximately 60 mg;

[0142] The second incremental dose is approximately 120 mg;

[0143] 3) The incremental dosage includes three incremental dosages:

[0144] The first incremental dose is approximately 60 mg;

[0145] The second incremental dose is approximately 90 mg;

[0146] The third escalation dose is approximately 120 mg;

[0147] 4) The incremental dosage includes four incremental dosages:

[0148] The first incremental dose is approximately 60 mg;

[0149] The second incremental dose is approximately 120 mg;

[0150] The third incremental dose is approximately 180 mg;

[0151] The fourth incremental dose is approximately 240 mg;

[0152] 5) The incremental dosage includes five incremental dosages:

[0153] The first incremental dose is approximately 60 mg;

[0154] The second incremental dose is approximately 120 mg;

[0155] The third incremental dose is approximately 180 mg;

[0156] The fourth incremental dose is approximately 240 mg;

[0157] The fifth increment dose is approximately 300 mg.

[0158] 6) The incremental dosage includes five or more steps of stepwise dose increase:

[0159] The first stepwise dose increase is approximately 60 mg.

[0160] The second-level stepwise dose increase is approximately 120 mg;

[0161] The third stepwise dose increase is approximately 180 mg.

[0162] The fourth stepwise dose increase is approximately 240 mg;

[0163] The fifth step-up dose is approximately 300 mg.

[0164] The sixth step up dose is approximately 360 mg;

[0165] Optionally, the seventh step up dose is approximately 420 mg;

[0166] Optionally, the eighth step up dose is approximately 480 mg;

[0167] Optionally, the ninth step up dose is approximately 540 mg.

[0168] In some implementations: 1) the incremental dose includes a first-level stepwise dose increase:

[0169] The first stepwise dose increase is approximately 30mg, 60mg, 90mg, or 120mg;

[0170] 2) The incremental dosage includes a two-stage stepwise increase in dosage:

[0171] The first stepwise dose increase is approximately 30 mg.

[0172] The second-level stepwise dose increase is approximately 60 mg.

[0173] 3) The incremental dosage includes a three-step up-regulation dosage:

[0174] The first stepwise dose increase is approximately 30 mg.

[0175] The second-level stepwise dose increase is approximately 60 mg.

[0176] The third stepwise dose increase is approximately 90 mg.

[0177] 4) The incremental dosage includes a four-step stepwise increase in dosage:

[0178] The first stepwise dose increase is approximately 30 mg.

[0179] The second-level stepwise dose increase is approximately 60 mg.

[0180] The third stepwise dose increase is approximately 90 mg.

[0181] The fourth stepwise dose increase is approximately 120 mg;

[0182] 5) The incremental dosage includes a five-step up-regulation dosage:

[0183] The first stepwise dose increase is approximately 30 mg.

[0184] The second-level stepwise dose increase is approximately 60 mg.

[0185] The third stepwise dose increase is approximately 120 mg.

[0186] The fourth stepwise dose increase is approximately 180 mg;

[0187] The fifth step-up dose is approximately 240 mg.

[0188] 6) The incremental dosage includes five or more steps of stepwise dose increase:

[0189] The first stepwise dose increase is approximately 30 mg.

[0190] The second-level stepwise dose increase is approximately 60 mg.

[0191] The third stepwise dose increase is approximately 120 mg.

[0192] The fourth stepwise dose increase is approximately 180 mg;

[0193] The fifth step-up dose is approximately 240 mg.

[0194] The sixth stepwise dose increase is approximately 300 mg;

[0195] Optionally, the seventh step up dose is approximately 360 mg;

[0196] Optionally, the eighth step up dose is approximately 420 mg;

[0197] Optionally, the ninth step up dose is approximately 480 mg;

[0198] Optionally, the dose is increased in a tenth step up to approximately 540 mg.

[0199] In some embodiments, the maintenance dose is 60 mg to 720 mg; in some embodiments, the maintenance dose is 155 mg to 400 mg. In some embodiments, the maintenance dose is about 60 mg, 90 mg, 120 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 720 mg. In some embodiments, the maintenance dose is about 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg. In some embodiments, the maintenance dose is about 180 mg or 360 mg.

[0200] In some embodiments, the dosing regimen of the compound of formula (I) or its pharmaceutically acceptable salt includes any one of the following:

[0201] 1)

[0202] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0203] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0204] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0205] Administer approximately 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 16 weeks (e.g., 24 or 28 weeks);

[0206] 2)

[0207] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0208] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0209] Administer approximately 90 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0210] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0211] Administer approximately 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 16 weeks (e.g., 28 weeks);

[0212] 3)

[0213] Administer approximately 15 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0214] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0215] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0216] Administer approximately 90 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0217] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0218] Administer approximately 180 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 16 weeks (e.g., 28 weeks);

[0219] 3)

[0220] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0221] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0222] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0223] Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0224] Administer approximately 240 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0225] Administer approximately 300 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0226] Administer approximately 360 mg of compound (I) or its pharmaceutically acceptable salt once daily for at least 4 weeks (e.g., 12 weeks).

[0227] In some embodiments, the dosing regimen of the compound of formula (I) or its pharmaceutically acceptable salt includes any one of the following:

[0228] 1)

[0229] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0230] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0231] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0232] Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 24 weeks;

[0233] 2)

[0234] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0235] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0236] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0237] Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 28 weeks;

[0238] 3)

[0239] Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0240] Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0241] Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0242] Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0243] Administer approximately 240 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0244] Administer approximately 300 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by...

[0245] Administer approximately 360 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 12 weeks.

[0246] In some embodiments, the subject is given 15 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, the subject is given 30 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, the subject is given 45 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, the subject is given 60 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, the subject is given 90 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, the subject is given 120 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 or 4 weeks). In some embodiments, the subject is given 150 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 or 4 weeks). In some embodiments, the subject is given 180 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 240 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 300 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 360 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 420 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 480 mg of compound (I) or a pharmaceutically acceptable salt thereof for a duration of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 540 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, the subject is given 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 weeks, 4 weeks, or long-term administration).

[0247] In some embodiments, the inventive concept of this disclosure includes the finding that administering a subject a dose of 5–30 mg of compound (I) (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg) may produce one or more therapeutic effects compared to administering a dose of compound (I) >30 mg. In some embodiments, the compound (I) is administered once daily at a dose of 5–30 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg). In some embodiments, the compound (I) is administered twice daily at a dose of 5–30 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg), for a total daily dose of 10–60 mg. In some embodiments, the compound (I) is administered at a dose of 5–30 mg in combination with dietary control and / or exercise intervention. In some implementations, administering a low dose of compound (I) (e.g., 5–30 mg) to subjects may reduce the incidence, severity, and / or frequency of one or more adverse events compared to administering a dose of compound (I) >30 mg. In some implementations, administering a low dose of compound (I) (e.g., 5–30 mg) to subjects may improve drug tolerability, treatment adherence, and / or provide a better benefit-risk ratio compared to administering a dose of compound (I) >30 mg. These improvements help improve patient treatment adherence, enhance medication accessibility, and / or expand the eligible patient population for the treatment of heart failure.

[0248] In any of the dosing regimens disclosed herein, the dosage and duration of administration may be adjusted based on the subject’s tolerance, the desired preventive or therapeutic outcome, or other circumstances determined by the physician or healthcare provider.

[0249] The following numbered embodiments are not restrictive, but exemplify several technical aspects of this disclosure:

[0250] 1. A method for treating or preventing heart failure, the method comprising administering a compound of formula (I):

[0251] Or its pharmaceutically acceptable salt, given to subjects who require it.

[0252] 2. A method for treating heart failure, the method comprising administering a compound of formula (I):

[0253] Or its pharmaceutically acceptable salt, given to subjects who require it.

[0254] 3. A method for preventing heart failure, the method comprising administering a compound of formula (I):

[0255] Or its pharmaceutically acceptable salt, given to subjects who require it.

[0256] 4. A method for improving symptoms of heart failure and / or exercise capacity, said method comprising administering a compound of formula (I):

[0257] Or its pharmaceutically acceptable salt, given to subjects who require it.

[0258] 5. A method for reducing the weight of a subject with heart failure, the method comprising administering a compound of formula (I):

[0259] Or its pharmaceutically acceptable salt, given to subjects who require it.

[0260] 6. The method of any one of embodiments 1 to 5, wherein the method comprises administering 5 to 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0261] 7. The method of any one of embodiments 1 to 6, wherein the method comprises administering 5 to 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0262] 8. The method of any one of embodiments 1 to 6, wherein the method comprises administering 5 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0263] 9. The method of any one of embodiments 1 to 6, wherein the method comprises administering 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0264] 10. The method of any one of embodiments 1 to 6, wherein the method comprises administering 15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0265] 11. The method of any one of embodiments 1 to 6, wherein the method comprises administering 20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0266] 12. The method of any one of embodiments 1 to 6, wherein the method comprises administering 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0267] 13. The method of any one of embodiments 1 to 6, wherein the method comprises administering 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0268] 14. The method of any one of embodiments 1 to 6, wherein the method comprises administering 45 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0269] 15. The method of any one of embodiments 1 to 6, wherein the method comprises administering 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0270] 16. The method of any one of embodiments 1 to 6, wherein the method comprises administering 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0271] 17. The method of any one of embodiments 1 to 6, wherein the method comprises administering 90 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0272] 18. The method of any one of embodiments 1 to 6, wherein the method comprises administering 105 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0273] 19. The method of any one of embodiments 1 to 6, wherein the method comprises administering 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0274] 20. The method of any one of embodiments 1 to 6, wherein the method comprises administering 135 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0275] 21. The method of any one of embodiments 1 to 6, wherein the method comprises administering 150 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0276] 22. The method of any one of embodiments 1 to 6, wherein the method comprises administering 165 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0277] 23. The method of any one of embodiments 1 to 6, wherein the method comprises administering 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0278] 24. The method of any one of embodiments 1 to 6, wherein the method comprises administering 195 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0279] 25. The method of any one of embodiments 1 to 6, wherein the method comprises administering 210 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0280] 26. The method of any one of embodiments 1 to 6, wherein the method comprises administering 225 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0281] 27. The method of any one of embodiments 1 to 6, wherein the method comprises administering 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0282] 28. The method of any one of embodiments 1 to 6, wherein the method comprises administering 255 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0283] 29. The method of any one of embodiments 1 to 6, wherein the method comprises administering 270 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0284] 30. The method of any one of embodiments 1 to 6, wherein the method comprises administering 285 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0285] 31. The method of any one of embodiments 1 to 6, wherein the method comprises administering 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0286] 32. The method of any one of embodiments 1 to 6, wherein the method comprises administering 315 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0287] 33. The method of any one of embodiments 1 to 6, wherein the method comprises administering 330 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0288] 34. The method of any one of embodiments 1 to 6, wherein the method comprises administering 345 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0289] 35. The method of any one of embodiments 1 to 6, wherein the method comprises administering 360 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0290] 36. The method of any one of embodiments 1 to 6, wherein the method comprises administering 375 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0291] 37. The method of any one of embodiments 1 to 6, wherein the method comprises administering 390 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0292] 38. The method of any one of embodiments 1 to 6, wherein the method comprises administering 405 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0293] 39. The method of any one of embodiments 1 to 6, wherein the method comprises administering 420 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0294] 40. The method of any one of embodiments 1 to 6, wherein the method comprises administering 435 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0295] 41. The method of any one of embodiments 1 to 6, wherein the method comprises administering 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0296] 42. The method of any one of embodiments 1 to 6, wherein the method comprises administering 465 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0297] 43. The method of any one of embodiments 1 to 6, wherein the method comprises administering 480 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0298] 44. The method of any one of embodiments 1 to 6, wherein the method comprises administering 495 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0299] 45. The method of any one of embodiments 1 to 6, wherein the method comprises administering 510 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0300] 46. ​​The method of any one of embodiments 1 to 6, wherein the method comprises administering 525 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0301] 47. The method of any one of embodiments 1 to 6, wherein the method comprises administering 540 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0302] 48. The method of any one of embodiments 1 to 6, wherein the method comprises administering 555 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0303] 49. The method of any one of embodiments 1 to 6, wherein the method comprises administering 570 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0304] 50. The method of any one of embodiments 1 to 6, wherein the method comprises administering 585 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0305] 51. The method of any one of embodiments 1 to 6, wherein the method comprises administering 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0306] 52. The method of any one of embodiments 1 to 6, wherein the method comprises administering 615 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0307] 53. The method of any one of embodiments 1 to 6, wherein the method comprises administering 630 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0308] 54. The method of any one of embodiments 1 to 6, wherein the method comprises administering 645 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0309] 55. The method of any one of embodiments 1 to 6, wherein the method comprises administering 660 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0310] 56. The method of any one of embodiments 1 to 6, wherein the method comprises administering 675 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0311] 57. The method of any one of embodiments 1 to 6, wherein the method comprises administering 690 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0312] 58. The method of any one of embodiments 1 to 6, wherein the method comprises administering 705 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0313] 59. The method of any one of embodiments 1 to 6, wherein the method comprises administering 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0314] 60. The method of any one of embodiments 1 to 59, wherein the method comprises giving a compound of formula (I) (e.g., in a non-salt form).

[0315] 61. The method of any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0316] 62. The method of any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

[0317] 63. The method of any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times daily.

[0318] 64. The method of any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once every two days.

[0319] 65. The method of any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once every three days.

[0320] 66. The method of any one of embodiments 1 to 65, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered continuously for a period of time.

[0321] 67. The method of embodiment 66, wherein the duration of continuous administration is at least one week.

[0322] 68. The method of embodiment 66, wherein the duration of continuous administration is at least two weeks.

[0323] 69. The method of embodiment 66, wherein the duration of continuous administration is at least three weeks.

[0324] 70. The method of embodiment 66, wherein the duration of continuous administration is at least four weeks.

[0325] 71. The method of any one of embodiments 1 to 70, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an initial dose.

[0326] 72. The method of any one of embodiments 1 to 71, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an incremental dose manner.

[0327] 73. The method of any one of embodiments 1 to 72, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a maintenance dose form.

[0328] 74. The method of any one of embodiments 1 to 73, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered according to a dose titration regimen.

[0329] 75. The method of embodiment 74, wherein the dose titration protocol includes administering an initial dose.

[0330] 76. The method of embodiment 75, wherein the dose titration protocol further comprises administering one or more incremental doses, each incremental dose being administered for a period of time.

[0331] 77. The method as described in embodiment 76, wherein the duration of continuous administration for each incremental dose is 1 to 4 weeks.

[0332] 78. The method as described in embodiment 76, wherein the duration of continuous administration for each increment of dose is less than one week.

[0333] 79. The method of embodiment 76, wherein the duration of continuous administration of each incremental dose is more than 4 weeks.

[0334] 80. The method as described in embodiment 76, wherein the duration of continuous administration for each increment of dose is one week.

[0335] 81. The method as described in embodiment 76, wherein the duration of continuous administration for each increment of dose is two weeks.

[0336] 82. The method as described in embodiment 76, wherein the duration of continuous administration for each increment of dose is three weeks.

[0337] 83. The method as described in embodiment 76, wherein the duration of continuous administration for each increment of dose is four weeks.

[0338] 84. The method as described in any one of embodiments 74 to 83, wherein the dose titration protocol further includes administering a maintenance dose.

[0339] 85. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 5 to 60 mg.

[0340] 86. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 5 mg.

[0341] 87. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 10 mg.

[0342] 88. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 15 mg.

[0343] 89. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 20 mg.

[0344] 90. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 25 mg.

[0345] 91. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 30 mg.

[0346] 92. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 40 mg.

[0347] 93. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 45 mg.

[0348] 94. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 50 mg.

[0349] 95. The method as described in any one of embodiments 71 to 84, wherein the initial dose is 60 mg.

[0350] 96. The method as described in any one of embodiments 72 to 95, wherein the one or more incremental doses are 5 to 720 mg.

[0351] 97. The method as described in any one of embodiments 72 to 96, wherein the one or more incremental doses are 5 to 60 mg.

[0352] 98. The method as described in any one of embodiments 72 to 96, wherein the incremental dose is 5 mg.

[0353] 99. The method as described in any one of embodiments 72 to 98, wherein the incremental dose is 10 mg.

[0354] 100. The method as described in any one of embodiments 72 to 99, wherein the incremental dose is 15 mg.

[0355] 101. The method as described in any one of embodiments 72 to 100, wherein the incremental dose is 20 mg.

[0356] 102. The method as described in any one of embodiments 72 to 101, wherein the incremental dose is 25 mg.

[0357] 103. The method as described in any one of embodiments 72 to 102, wherein the incremental dose is 30 mg.

[0358] 104. The method as described in any one of embodiments 72 to 103, wherein the incremental dose is 45 mg.

[0359] 105. The method as described in any one of embodiments 72 to 104, wherein the incremental dose is 60 mg.

[0360] 106. The method as described in any one of embodiments 72 to 105, wherein the incremental dose is 90 mg.

[0361] 107. The method as described in any one of embodiments 72 to 106, wherein the incremental dose is 120 mg.

[0362] 108. The method as described in any one of embodiments 72 to 107, wherein the incremental dose is 150 mg.

[0363] 109. The method as described in any one of embodiments 72 to 108, wherein the incremental dose is 180 mg.

[0364] 110. The method as described in any one of embodiments 72 to 109, wherein the incremental dose is 210 mg.

[0365] 111. The method as described in any one of embodiments 72 to 110, wherein the incremental dose is 240 mg.

[0366] 112. The method as described in any one of embodiments 72 to 111, wherein the incremental dose is 270 mg.

[0367] 113. The method as described in any one of embodiments 72 to 112, wherein the incremental dose is 300 mg.

[0368] 114. The method as described in any one of embodiments 72 to 113, wherein the incremental dose is 330 mg.

[0369] 115. The method as described in any one of embodiments 72 to 114, wherein the incremental dose is 360 mg.

[0370] 116. The method as described in any one of embodiments 72 to 115, wherein the incremental dose is 390 mg.

[0371] 117. The method as described in any one of embodiments 72 to 116, wherein the incremental dose is 420 mg.

[0372] 118. The method as described in any one of embodiments 72 to 117, wherein the incremental dose is 450 mg.

[0373] 119. The method as described in any one of embodiments 72 to 118, wherein the incremental dose is 480 mg.

[0374] 120. The method as described in any one of embodiments 72 to 119, wherein the incremental dose is 510 mg.

[0375] 121. The method as described in any one of embodiments 72 to 120, wherein the incremental dose is 540 mg.

[0376] 122. The method as described in any one of embodiments 72 to 121, wherein the incremental dose is 570 mg.

[0377] 123. The method as described in any one of embodiments 72 to 122, wherein the incremental dose is 600 mg.

[0378] 124. The method as described in any one of embodiments 72 to 123, wherein the incremental dose is 630 mg.

[0379] 125. The method as described in any one of embodiments 72 to 124, wherein the incremental dose is 660 mg.

[0380] 126. The method as described in any one of embodiments 72 to 125, wherein the incremental dose is 690 mg.

[0381] 127. The method as described in any one of embodiments 72 to 126, wherein the incremental dose is 720 mg.

[0382] 128. The method as described in any one of embodiments 73 to 127, wherein the maintenance dose is 5 to 720 mg.

[0383] 129. The method as described in any one of embodiments 73 to 128, wherein the maintenance dose is 5 to 30 mg.

[0384] 130. The method as described in embodiment 128, wherein the maintenance dose is 5 mg.

[0385] 131. The method as described in embodiment 128, wherein the maintenance dose is 10 mg.

[0386] 132. The method as described in embodiment 128, wherein the maintenance dose is 15 mg.

[0387] 133. The method as described in embodiment 128, wherein the maintenance dose is 20 mg.

[0388] 134. The method as described in embodiment 128, wherein the maintenance dose is 25 mg.

[0389] 135. The method as described in embodiment 128, wherein the maintenance dose is 30 mg.

[0390] 136. The method as described in embodiment 128, wherein the maintenance dose is 45 mg.

[0391] 137. The method as described in embodiment 128, wherein the maintenance dose is 60 mg.

[0392] 138. The method as described in embodiment 128, wherein the maintenance dose is 90 mg.

[0393] 139. The method as described in embodiment 128, wherein the maintenance dose is 120 mg.

[0394] 140. The method as described in embodiment 128, wherein the maintenance dose is 150 mg.

[0395] 141. The method as described in embodiment 128, wherein the maintenance dose is 180 mg.

[0396] 142. The method as described in embodiment 128, wherein the maintenance dose is 210 mg.

[0397] 143. The method as described in embodiment 128, wherein the maintenance dose is 240 mg.

[0398] 144. The method as described in embodiment 128, wherein the maintenance dose is 270 mg.

[0399] 145. The method as described in embodiment 128, wherein the maintenance dose is 300 mg.

[0400] 146. The method as described in embodiment 128, wherein the maintenance dose is 330 mg.

[0401] 147. The method as described in embodiment 128, wherein the maintenance dose is 360 mg.

[0402] 148. The method as described in embodiment 128, wherein the maintenance dose is 390 mg.

[0403] 149. The method as described in embodiment 128, wherein the maintenance dose is 420 mg.

[0404] 150. The method as described in embodiment 128, wherein the maintenance dose is 450 mg.

[0405] 151. The method as described in embodiment 128, wherein the maintenance dose is 480 mg.

[0406] 152. The method as described in embodiment 128, wherein the maintenance dose is 510 mg.

[0407] 153. The method as described in embodiment 128, wherein the maintenance dose is 540 mg.

[0408] 154. The method as described in embodiment 128, wherein the maintenance dose is 570 mg.

[0409] 155. The method as described in embodiment 128, wherein the maintenance dose is 600 mg.

[0410] 156. The method as described in embodiment 128, wherein the maintenance dose is 630 mg.

[0411] 157. The method as described in embodiment 128, wherein the maintenance dose is 660 mg.

[0412] 158. The method as described in embodiment 128, wherein the maintenance dose is 690 mg.

[0413] 159. The method as described in embodiment 128, wherein the maintenance dose is 720 mg.

[0414] 160. The method of any one of embodiments 1 to 159, wherein the method comprises orally administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0415] 161. The method of any one of embodiments 1 to 160, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an oral dosage form.

[0416] 162. The method of embodiment 161, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a solid oral dosage form.

[0417] 163. The method of embodiment 161, wherein the solid oral dosage form is a tablet.

[0418] 164. The method of embodiment 161, wherein the solid oral dosage form is a capsule.

[0419] 165. The method as described in any one of embodiments 1 to 164, wherein the subject is an obese person.

[0420] 166. The method as described in any one of embodiments 1 to 165, wherein the subject is an overweight individual.

[0421] 167. The method of any one of embodiments 1 to 166, wherein the subject suffers from at least one weight-related comorbidity.

[0422] 168. The method of embodiment 167, wherein the weight-related comorbidities are selected from prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, and non-alcoholic fatty liver disease.

[0423] 169. The method as described in any one of embodiments 1 to 168, wherein the subject is an adult.

[0424] 170. The method as described in any one of embodiments 1 to 169, wherein the subject is a human being.

[0425] 171. The method as described in any one of embodiments 1 to 170, wherein the subject is male.

[0426] 172. The method as described in any one of embodiments 1 to 170, wherein the subject is female.

[0427] 173. The method as described in any one of embodiments 1 to 172, wherein the subject has diabetes.

[0428] 174. The method as described in embodiment 173, wherein the diabetes is type 2 diabetes.

[0429] 175. The method as described in any one of embodiments 1 to 172, wherein the subject does not have diabetes (e.g., type 2 diabetes).

[0430] 176. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥24.0 kg / m². 2 .

[0431] 177. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥24.0 kg / m². 2 And <28.0kg / m 2 .

[0432] 178. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥28.0 kg / m². 2 .

[0433] 179. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 .

[0434] 180. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is > 32.5 kg / m². 2 And ≤40.0kg / m 2 .

[0435] 181. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 .

[0436] 182. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 .

[0437] 183. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 .

[0438] 184. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2 .

[0439] 185. The method as described in any one of embodiments 1 to 175, wherein the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 .

[0440] 186. The method as described in any one of embodiments 1 to 185, wherein the method further comprises dietary therapy (e.g., a low-calorie diet).

[0441] 187. The method as described in any one of embodiments 1 to 186, wherein the method further comprises exercise therapy (e.g., increasing physical activity).

[0442] 188. The method of any one of embodiments 1 to 187, wherein the heart failure is heart failure with intermediate ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF).

[0443] 189. The method as described in any one of embodiments 1 to 188, wherein the heart failure is heart failure with intermediate ejection fraction (HFmrEF).

[0444] 190. The method as described in any one of embodiments 1 to 188, wherein the heart failure is heart failure with preserved ejection fraction (HFpEF).

[0445] 191. The method as described in any one of embodiments 1 to 190, wherein the subject's left ventricular ejection fraction (LVEF) is ≥40% and ≤50%.

[0446] 192. The method as described in any one of embodiments 1 to 190, wherein the subject has a left ventricular ejection fraction (LVEF) ≥ 50%.

[0447] 193. The method as described in any one of embodiments 1 to 190, wherein the subject has a left ventricular ejection fraction (LVEF) ≥ 45%.

[0448] 194. The method as described in any one of embodiments 1 to 190, wherein the subject's left ventricular ejection fraction (LVEF) is >40%.

[0449] 195. The method as described in any one of embodiments 1 to 190, wherein the subject's left ventricular ejection fraction (LVEF) is >40% and <50%.

[0450] 196. The method as described in any one of embodiments 1 to 190, wherein the subject has no history of left ventricular ejection fraction (LVEF) ≤ 40%.

[0451] 197. The method as described in any one of embodiments 1 to 196, wherein the subject suffers from chronic heart failure.

[0452] 198. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 1 month.

[0453] 199. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 2 months.

[0454] 200. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 3 months.

[0455] 201. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 4 months.

[0456] 202. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 6 months.

[0457] 203. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 9 months.

[0458] 204. The method as described in embodiment 197, wherein the subject has suffered from chronic heart failure for at least 12 months.

[0459] 205. The method as described in any one of embodiments 1 to 204, wherein the subject has a serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) level ≥125 pg / mL (e.g., a sinus rhythm subject).

[0460] 206. The method as described in any one of embodiments 1 to 204, wherein the subject has a serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) level ≥300 pg / mL (e.g., atrial fibrillation subject).

[0461] 207. The method as described in any one of embodiments 1 to 206, wherein the subject has at least one cardiac structural or functional abnormality.

[0462] 208. The method of embodiment 207, wherein the cardiac structural abnormality is characterized by echocardiographic findings of left ventricular diastolic dysfunction / elevated left ventricular filling pressure.

[0463] 209. The method as described in embodiment 208, wherein the left ventricular mass index of the subject is at least: ≥95 g / m² for females. 2 Male ≥115g / m 2 .

[0464] 210. The method as described in embodiment 209, wherein the relative wall thickness of the subject is >0.42.

[0465] 211. The method of any one of embodiments 208 to 210, wherein the ratio of the early diastolic mitral valve blood flow velocity to the early diastolic mitral valve annular velocity (E / e') of the subject is ≥15.

[0466] 212. The method as described in any one of embodiments 208 to 211, wherein the subject's interventricular septum e' < 7 cm / s, or lateral wall e' < 10 cm / s, or mean e' < 8 cm / s.

[0467] 213. The method as described in any one of embodiments 208 to 212, wherein the subject has a tricuspid regurgitation velocity > 2.8 cm / s or an estimated pulmonary artery systolic pressure > 35 mmHg.

[0468] 214. The method as described in any one of embodiments 208 to 213, wherein the subject has left atrial enlargement and meets any of the following conditions: left atrial anteroposterior diameter ≥ 3.8 cm, or left atrial superior-inferior diameter ≥ 5.0 cm, or left atrial area ≥ 20 cm². 2 Or a left atrial volume ≥55mL, or a left atrial volume index (LAVI) ≥34mL / m³ 2 .

[0469] 215. The method of any one of embodiments 208 to 214, wherein the subject has left ventricular hypertrophy, such as interventricular septal thickening or left ventricular posterior wall thickness ≥1.1 cm.

[0470] 216. The method of embodiment 207, wherein the cardiac structural abnormality is confirmed by stress echocardiography or invasive hemodynamic testing.

[0471] 217. The method of embodiment 216, wherein the subject has an E / e' ≥ 15 as measured by stress echocardiography.

[0472] 218. The method as described in embodiment 216 or 217, wherein the subject has a resting pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or a left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg as measured by cardiac catheterization.

[0473] 219. The method of any one of embodiments 216 to 218, wherein the subject has a peak pulmonary capillary wedge pressure (PCWP) ≥25 mmHg as measured by a stress cardiac catheterization.

[0474] 220. The method as described in any one of embodiments 1 to 219, wherein the subject has a New York Heart Association (NYHA) functional class II to IV.

[0475] 221. The method as described in embodiment 220, wherein the New York Heart Association (NYHA) functional classification is Class II.

[0476] 222. The method as described in embodiment 220, wherein the New York Heart Association (NYHA) functional classification is Class III.

[0477] 223. The method as described in embodiment 220, wherein the New York Heart Association (NYHA) functional classification is Class IV.

[0478] 224. The method as described in any one of embodiments 1 to 223, wherein the subject's Kansas City Cardiomyopathy Questionnaire Clinical Total Score (KCCQ-CSS) is ≤80 points.

[0479] 225. The method of any one of embodiments 1 to 224, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce mortality compared to placebo in similar subject populations (e.g., after 8, 24, 36, or 40 weeks of administration).

[0480] 226. The method of any one of embodiments 1 to 225, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to improve the Kansas City Cardiomyopathy Questionnaire Clinical Overall Score (KCCQ-CSS) by ≥5, ≥10, or ≥15 points from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0481] 227. The method of any one of embodiments 1 to 226, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen that has been shown to result in a higher proportion of subjects with ≥5%, ≥10%, and / or ≥15% improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Overall Score (KCCQ-CSS) compared to placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0482] 228. The method of any one of embodiments 1 to 227, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen that has been shown to improve the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OSS) by ≥5, ≥10, or ≥15 points from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, or 40 weeks).

[0483] 229. The method of any one of embodiments 1 to 228, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen that has been shown to reduce high-sensitivity C-reactive protein (hsCRP) levels from baseline after administration to a similar population of subjects for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0484] 230. The method of any one of embodiments 1 to 229, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being demonstrated to result in a greater reduction in high-sensitivity C-reactive protein (hsCRP) levels from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks) compared to subjects receiving placebo.

[0485] 231. The method of any one of embodiments 1 to 230, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) levels from baseline after administration to a similar subject population at a specific time period (e.g., 8, 24, 36, 40 weeks).

[0486] 232. The method of any one of embodiments 1 to 231, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being demonstrated to result in a greater reduction in N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) levels from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks) compared to subjects receiving placebo.

[0487] 233. The method of any one of embodiments 1 to 232, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen that has been shown to improve cardiac function parameters from baseline after administration to similar subject populations for specific time periods (e.g., 8, 24, 36, 40 weeks).

[0488] 234. The method of any one of embodiments 1 to 233, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to improve New York Heart Association (NYHA) functional classification after administration to a similar subject population over a specific time period (e.g., 8, 24, 36, or 40 weeks).

[0489] 235. The method of any one of embodiments 1 to 234, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in more significant improvement in New York Heart Association (NYHA) functional classification compared to subjects receiving placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0490] 236. The method of any one of embodiments 1 to 235, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce body weight by ≥5%, ≥10%, or ≥15% from baseline after administration to a similar population of subjects over a specific time period (e.g., 8, 24, 36, or 40 weeks).

[0491] 237. The method of any one of embodiments 1 to 236, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen that has been shown to result in a higher proportion of subjects with a weight loss of ≥5%, ≥10%, and / or ≥15% compared to placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0492] 238. The method of any one of embodiments 1 to 237, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce the risk or incidence of hospitalization for heart failure compared to placebo when administered to similar subject populations over specific time periods (e.g., 8, 24, 36, 40 weeks).

[0493] 239. The method of any one of embodiments 1 to 238, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce the risk or incidence of death from heart failure compared to placebo after administration to a similar group of subjects over a specific time period (e.g., 8, 24, 36, 40 weeks).

[0494] 240. The method of any one of embodiments 1 to 239, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce the risk or incidence of heart failure complex events after administration to a similar subject population over a specific time period (e.g., 8, 24, 36, 40 weeks).

[0495] 241. The method of any one of embodiments 1 to 240, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce the risk or incidence of worsening clinical events of heart failure compared to placebo, after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0496] 242. The method of any one of embodiments 1 to 241, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce waist circumference from baseline after administration to a similar group of subjects for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0497] 243. The method of any one of embodiments 1 to 242, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in greater reduction in waist circumference compared to subjects receiving a placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0498] 244. The method of any one of embodiments 1 to 243, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce fasting blood glucose and / or glycated hemoglobin (HbA1c) levels from baseline after administration to a similar subject population over a specific time period (e.g., 8, 24, 36, 40 weeks).

[0499] 245. The method of any one of embodiments 1 to 244, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce glycated hemoglobin (HbA1c) levels from baseline after administration to a similar population of subjects for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0500] 246. The method of any one of embodiments 1 to 245, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce fasting plasma glucose levels from baseline after administration to a similar population of subjects for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0501] 247. The method of any one of embodiments 1 to 246, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being demonstrated to result in a greater reduction in fasting plasma glucose levels from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks) compared to subjects receiving placebo.

[0502] 248. The method of any one of embodiments 1 to 247, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being demonstrated to result in a greater reduction in glycated hemoglobin (HbA1c) levels from baseline after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks) compared to subjects receiving placebo.

[0503] 249. The method of any one of embodiments 1 to 248, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce body weight by at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% from baseline after administration to a similar group of subjects over a specific time period (e.g., 8, 24, 36, or 40 weeks).

[0504] 250. The method of any one of embodiments 1 to 249, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to improve the 6-minute walk test (6MWT) results from baseline after administration to a similar subject population over a specific time period (e.g., 8, 24, 36, 40 weeks).

[0505] 251. The method of any one of embodiments 1 to 250, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in a more significant improvement from baseline in a 6-minute walk test (6MWT) compared to subjects receiving placebo, after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0506] 252. The method of any one of embodiments 1 to 251, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to increase diastolic mitral flow velocity (e.g., E peak and / or A peak) after administration to a similar subject population and at a specific time period (e.g., 8, 24, 36, 40 weeks).

[0507] 253. The method of any one of embodiments 1 to 252, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being demonstrated to result in a greater increase in diastolic mitral flow velocity (e.g., E peak and / or A peak) compared to subjects receiving placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0508] 254. The method of any one of embodiments 1 to 253, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to increase mitral annular lateral wall and septal velocity (e') after administration to a similar subject population and at a specific time period (e.g., 8, 24, 36, 40 weeks).

[0509] 255. The method of any one of embodiments 1 to 254, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in a greater increase in mitral annular lateral wall and septal velocity (e') after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks) compared to subjects receiving placebo.

[0510] 256. The method of any one of embodiments 1 to 255, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to increase the mean E / e' ratio after administration to a similar group of subjects over a specific time period (e.g., 8, 24, 36, 40 weeks).

[0511] 257. The method of any one of embodiments 1 to 256, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in a greater increase in the mean E / e' ratio compared to subjects receiving placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0512] 258. The method of any one of embodiments 1 to 257, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to result in a greater reduction in mortality compared to subjects receiving a placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0513] 259. The method of any one of embodiments 1 to 258, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce body mass index (BMI) after administration to a similar subject population for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0514] 260. The method of any one of embodiments 1 to 259, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, the regimen being shown to result in a greater reduction in body mass index (BMI) compared to subjects receiving a placebo after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0515] 261. The method as described in any one of embodiments 1 to 260, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, said regimen having been demonstrated to reduce body mass index (BMI) by at least 0.5 kg / m² after administration to a similar subject population over a specific time period (e.g., 8, 24, 36, 40 weeks). 2 1.0kg / m 2 1.5kg / m 2 2.0kg / m 2 2.5kg / m 2 3.0kg / m 2 3.5kg / m 2 4.0kg / m 2 4.5kg / m 2 Or 5.0 kg / m 2 .

[0516] 262. The method of any one of embodiments 1 to 261, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce waist circumference by at least 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm or 15 cm after administration to a similar group of subjects for a specific time period (e.g., 8, 24, 36, 40 weeks).

[0517] 263. The method of any one of embodiments 1 to 262, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to significantly reduce the risk or incidence of worsening clinical events of heart failure when administered to similar subject populations compared to subjects receiving a placebo.

[0518] 264. The method of any one of embodiments 1 to 263, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof according to a specific regimen, said regimen having been demonstrated to reduce glycated hemoglobin (HbA1c) levels from baseline by at least 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.0%, 2.1%, or 2.2% after administration to similar subject populations at specific time periods (e.g., 8, 24, 36, 40 weeks).

[0519] 265. The method of any one of embodiments 1 to 264, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt thereof in a specific regimen that has been shown to reduce fasting plasma glucose levels from baseline by at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L after administration to a similar population of subjects at a specific time period (e.g., 8, 24, 36, or 40 weeks).

[0520] the term

[0521] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0522] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having a inclusive meaning rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0523] The terms “about” and “approximately” mean that a numerical value is within the acceptable error range of a specific value as determined by a person skilled in the art, the numerical value depending in part on how it is measured or determined (i.e., the limits of the measurement system). For example, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, or between 0.5% and 1%. In this disclosure, each instance of a number or range of values ​​preceded by the term “about” also includes embodiments of a given number. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially includes” should be assumed to be within the acceptable error range of that specific value.

[0524] In this document, the term "comparability" refers to two or more reagents, individuals, situations, sets of conditions, environments, objects, or populations that are not necessarily identical but possess sufficient similarity to allow for comparative analysis, enabling those skilled in the art to draw reasonable conclusions based on observed differences or similarities. In some embodiments, comparable reagents, individuals, situations, sets of conditions, environments, objects, or populations are characterized by the presence of multiple substantially identical characteristics, while only one or a few different characteristics exist. Those skilled in the art can determine, based on the specific context, the degree of consistency required between two or more of the aforementioned reagents, individuals, situations, sets of conditions, environments, objects, or populations in any given situation to be considered comparable. For example, those skilled in the art will understand that when two or more sets of situations, reagents, individuals, sets of conditions, environments, objects, or populations possess a sufficient number and type of fundamentally consistent characteristics, they can be considered comparable; based on this, it is reasonable to infer that the differences in experimental results or phenomena observed under different situations, reagents, individuals, sets of conditions, environments, objects, or populations are caused by, or can be explained by, a few different characteristics.

[0525] The term “and / or”, such as “X and / or Y”, should be understood to mean “X and Y” or “X or Y” and should be used to provide clear support for both meanings or either meaning.

[0526] The term agonist is defined as a substance that activates the type of receptor under discussion. "Active," "activated," "activated," etc., refer to substances that are measured using detection methods known in the art.

[0527] All hydrogen atoms described in this disclosure can be replaced by their isotopes (protium, deuterium, tritium), and any hydrogen atom in the compounds disclosed herein can also be replaced by isotopic atoms.

[0528] "Pharmaceutical composition" means containing one or more of the compounds described herein or their physiologically / medically acceptable salts or

[0529] A mixture of a prodrug and other chemical components; wherein said other components include, for example, physiological / pharmaceutical-grade carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0530] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, "giving" and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Giving" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and cells, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cells. "Giving" and "treatment" also mean the treatment of, for example, cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, "treatment" refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0531] "Treatment" means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves one or more symptoms of the disease, inducing the regression of such symptoms or inhibiting their progression to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves any specific disease symptom (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the patient's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the patient. Whether the disease symptoms have been relieved can be evaluated using any clinical testing methods commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating symptoms of each target disease, they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0532] An "effective amount" includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease. An effective amount also means the amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0533] As used herein, "titration dose" or "escalation dose" refers to a dose smaller than the highest effective dose required by the patient. As used herein, the invention covers a "titration dose" or "escalation dose" that can be converted to the highest effective dose required, or a "maintenance dose" if it is observed that this dose is an effective dose required by the patient.

[0534] As used herein, "maintenance dose" refers to the dose that is the highest effective dose required by the patient, and when the maintenance dose is less than the required highest effective dose, this maintenance dose can become an escalation dose. That is, if for a particular patient the "about 120 mg" maintenance dose covered by this invention is not the required highest effective dose, then the 120 mg maintenance dose will, in turn, become an escalation dose, because the dose for that particular patient will be increased until the next highest maintenance dose covered by this disclosure is achieved, for example, 180 mg for at least about 2 weeks.

[0535] As used herein, "medicinal salt" is well known to those skilled in the art. In one embodiment, the GLP-1 receptor agonist is in a medicinal salt form. In another embodiment, the GLP-1 receptor agonist is in a non-salt form.

[0536] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0537] 6MWT refers to the 6-minute walk test.

[0538] HFrEF refers to heart failure with a reduced ejection fraction.

[0539] HfmrEF refers to heart failure with a mildly reduced ejection fraction.

[0540] HFpEF refers to heart failure with preserved ejection fraction.

[0541] KCCQ-CSS refers to the Kansas City Cardiomyopathy Questionnaire Clinical Total Score.

[0542] KCCQ-OSS refers to the Kansas City Cardiomyopathy Questionnaire Total Score.

[0543] hsCRP refers to high-sensitivity C-reactive protein.

[0544] NT-proBNP refers to N-terminal pro-B-type natriuretic peptide.

[0545] NYHA refers to the New York Heart Association. Detailed Implementation

[0546] Example 1. A multicenter, randomized, double-blind, placebo-controlled phase II clinical study evaluating the efficacy and safety of compound (I) in obese subjects with heart failure and preserved ejection fraction.

[0547] 1. Investigational drug

[0548] 1) Compound of formula (I), in tablet form.

[0549] 2. Experimental Objective

[0550] 2.1 Main Purpose:

[0551] 1) Evaluate the efficacy of compound (I) in improving heart failure symptoms and exercise function in obese subjects with heart failure with preserved ejection fraction (HFpEF);

[0552] 2) Evaluate the effectiveness of compound (I) in reducing weight in obese subjects with HFpEF.

[0553] 2.2 Secondary Objectives:

[0554] 1) Evaluate the other efficacy of compound (I) in improving heart failure symptoms and motor function in obese subjects with HFpEF;

[0555] 2) Evaluation of the safety and tolerability of compound (I) in obese subjects with HFpEF;

[0556] 3) Evaluation of the pharmacokinetics (PK) of compound (I) in obese subjects with HFpEF;

[0557] 2.3 Primary Endpoints

[0558] 1) Changes in the Kansas City Cardiomyopathy Questionnaire Clinical Total Score (KCCQ-CSS) relative to baseline at week 40 of treatment;

[0559] 2) Percentage change in weight from baseline at week 40 of treatment.

[0560] 2.4 Secondary Endpoints

[0561] 1) The proportion of subjects whose KCCQ-CSS scores improved by ≥5, ≥10, and ≥15 points relative to baseline at week 40 of treatment;

[0562] 2) Change in KCCQ-OSS from baseline at week 40 of treatment;

[0563] 3) Change in 6MWT from baseline after 40 weeks of treatment;

[0564] 4) The proportion of subjects whose body weight decreased by ≥5%, ≥10%, and ≥15% from baseline at week 40 of treatment;

[0565] 5) Percentage change in high-sensitivity C-reactive protein (hsCRP) from baseline at week 40 of treatment;

[0566] 6) Changes in N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) levels from baseline at week 40 of treatment;

[0567] 7) Changes in diastolic mitral valve flow velocity (E peak, A peak), mitral valve annular lateral wall and septal motion velocity (e′), and mean E / e′ value compared to baseline, measured by echocardiography at week 40 after the first dose;

[0568] 8) Safety endpoints: incidence and severity of adverse events (AEs), clinically significant results of hypoglycemic events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram, etc.

[0569] 9) Pharmacokinetic (PK) endpoint: plasma concentration of compound (I).

[0570] 3. Enrolled subjects

[0571] Participants must meet all of the following criteria to be eligible for this study:

[0572] 1. Voluntarily sign the informed consent form before the trial and fully understand the trial content, process, and possible adverse reactions;

[0573] 2. When signing the informed consent form, applicants must be between 18 and 80 years old (inclusive), and gender is not limited;

[0574] 3. A prior diagnosis of chronic heart failure for at least 3 months prior to screening, followed by a diagnosis of heart failure with preserved ejection fraction (HFpEF) during the screening period according to the "National Heart Failure Guidelines 2023," and meeting all three of the following diagnostic criteria:

[0575] 1) During the screening period, echocardiography showed a left ventricular ejection fraction (LVEF) ≥45%, and the patient had never previously had an LVEF ≤40% (tested under stable disease conditions);

[0576] 2) Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels before randomization during the screening period and on day 1: NT-proBNP ≥ 125 pg / ml in patients with sinus rhythm; NT-proBNP ≥ 300 pg / ml in patients with atrial fibrillation;

[0577] 3) Evidence of at least one of the following cardiac structural or functional abnormalities

[0578] ① Screening period echocardiography should show at least one of the following: left ventricular diastolic dysfunction / elevated left ventricular filling pressure:

[0579] i. Left ventricular mass index ≥95g / m 2 (Female) or ≥115g / m 2 (male);

[0580] ii. Relative wall thickness > 0.42;

[0581] iii. Early diastolic peak velocity / tissue Doppler mitral valve annulus (E / e') ≥ 15;

[0582] iv. Interval e' < 7 cm / s, or sidewall e' < 10 cm / s, or average e' < 8 cm / s;

[0583] v. Tricuspid regurgitation velocity > 2.8 m / s or estimated pulmonary artery systolic pressure (PASP) > 35 mmHg;

[0584] vi. Enlargement of the left atrium, meeting any one of the following criteria: anteroposterior diameter of the left atrium ≥ 3.8 cm, or superior-inferior diameter of the left atrium ≥ 5.0 cm, or area of ​​the left atrium ≥ 20 cm². 2 Or a left atrial volume ≥55mL, or a left atrial volume index (LAVI) ≥34mL / m 2

[0585] vii. Left ventricular hypertrophy: thickening of the interventricular septum or thickness of the left ventricular posterior wall ≥1.1cm;

[0586] ② (Examinations conducted during the screening period or 3 months prior to screening, subject to center review and confirmation) Stress echocardiography or other relevant tests.

[0587] Positive hemodynamic testing, meeting at least one of the following criteria:

[0588] i. Stress echocardiography showed an E / e' ≥ 15;

[0589] ii. Cardiac catheterization under resting conditions, pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg;

[0590] iii. Stress catheterization: peak PCWP ≥ 25 mmHg during exercise;

[0591] 4. During the screening period and on day 1, participants were randomly assigned to New York Heart Association (NYHA) functional class II-IV prior to the screening period.

[0592] 5. Body mass index (BMI) ≥ 28 kg / m² before randomization during the screening period and on day 1. 2 ;

[0593] 6. Self-report that you have controlled your diet and exercise for 3 months or more before screening, and that your weight change within 3 months before screening and randomization does not exceed 5 kg;

[0594] 7. The total clinical score of the Kansas City Cardiomyopathy Questionnaire (KCCQ-CSS) before randomization during the screening period and on day 1 is ≤80.

[0595] 8. Visits 1 and 2 shall each be conducted once with a 6MWT, both of which must be ≥100 meters and ≤425 meters, and the difference between the two values ​​must be <20% and <40 meters; if the difference exceeds the above range, Visit 2 may be conducted once more with a 6MWT, and the difference between the two 6MWT values ​​and the previous 6MWT value must be <20% and <40 meters.

[0596] 9. Prior to screening, the patient had maintained a stable dose of medications for underlying medical conditions (excluding oral diuretics) for ≥4 weeks.

[0597] 10. Have the ability and willingness to comply with the protocol, and have a full understanding of the trial content, process and possible adverse reactions; have the ability and willingness to comply with the protocol requirements to complete this study (e.g., subject log recording); and be able to fully understand and complete the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Patient Health Questionnaire-9 (PHQ-9) scores.

[0598] 4. Dosing regimen

[0599] Subjects should take the investigational drug with water daily, swallowing it whole. Do not chew or hold the medication in your mouth before swallowing. It can be taken before or after meals. Subjects are advised to take the medication at approximately the same time each day, and each dose should not exceed the dosage specified in the protocol. 180 mg / day should be the recommended dose for the subject; if this is not tolerated, the previous dose of 120 mg / day should be returned. The specific dosing schedule is as follows:

[0600] 5. Results Evaluation

[0601] 5.1 Effectiveness Evaluation

[0602] Effectiveness evaluation indicators include heart failure symptoms and exercise function assessment (KCCQ-CSS, KCCQ-OSS, 6MWT), NT-proBNP, hsCRP, weight, waist circumference, BMI, and cardiac function indicators.

[0603] 5.2 Safety Evaluation

[0604] Safety indicators include the incidence and severity of any adverse events (AEs) from the first dose to the end of the trial, as well as clinically significant findings in areas such as hypoglycemia, vital signs, physical examination, laboratory tests, and 12-lead electrocardiogram. All examinations are performed according to the study schedule, and investigators may increase the number and types of examinations as needed clinically (e.g., in the event of AEs or SAEs).

[0605] Example 2. A multicenter, randomized, double-blind, placebo-controlled phase II clinical study evaluating the efficacy and safety of compound (I) in obese subjects with heart failure accompanied by mildly reduced ejection fraction / preserved ejection fraction.

[0606] 1. Investigational drug

[0607] 1) Compound of formula (I), in tablet form.

[0608] 2. Experimental Objective

[0609] 2.1 Main Purpose:

[0610] 1) Evaluate the efficacy of compound (I) in improving heart failure symptoms and exercise function in obese subjects with heart failure with mildly reduced ejection fraction / preserved ejection fraction (HFmrEF / HFpEF);

[0611] 2) Evaluate the effectiveness of compound (I) in reducing body weight in obese subjects with HFmrEF / HFpEF.

[0612] 2.2 Secondary Objectives:

[0613] 1) Evaluate the other efficacy of compound (I) in improving heart failure symptoms and motor function in obese subjects with HFmrEF / HFpEF;

[0614] 2) Evaluation of the safety and tolerability of compound (I) in obese subjects with HFmrEF / HFpEF;

[0615] 3) Evaluate the pharmacokinetics (PK) of compound (I) in obese subjects with HFmrEF / HFpEF.

[0616] 2.3 Primary endpoint

[0617] 1) Changes in the Kansas City Cardiomyopathy Questionnaire Clinical Total Score (KCCQ-CSS) relative to baseline at week 36 of treatment;

[0618] 2) Percentage change in weight relative to baseline at week 36 of treatment.

[0619] 2.4 Secondary endpoints

[0620] 1) The proportion of subjects whose KCCQ-CSS scores improved by ≥5, ≥10, or ≥15 points relative to baseline at week 36 of treatment;

[0621] 2) Changes in the Kansas City Cardiomyopathy Questionnaire-OSS total score relative to baseline at week 36 of treatment;

[0622] 3) Changes in 6MWT relative to baseline at week 36 of treatment;

[0623] 4) The proportion of subjects whose weight decreased by ≥5%, ≥10%, or ≥15% relative to baseline at week 36 of treatment;

[0624] 5) Percentage change in high-sensitivity C-reactive protein (hsCRP) relative to baseline at week 36 of treatment;

[0625] 6) Changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) relative to baseline at week 36 of treatment;

[0626] 7) Echocardiographic measurements of mitral valve diastolic flow velocity (E peak, A peak), mitral valve annular lateral wall and septal motion velocity (e′), and mean E / e′ value relative to baseline at week 36 after the first dose;

[0627] 8) Safety endpoints: the incidence and severity of adverse events (AEs), clinically significant findings in areas such as hypoglycemia, vital signs, physical examination, laboratory tests, and 12-lead electrocardiogram;

[0628] 9) Pharmacokinetic endpoint: concentration of HRS-7535 in plasma.

[0629] 3. Enrolled subjects

[0630] Obese adults (BMI ≥ 28 kg / m²) with heart failure accompanied by mildly reduced / preserved ejection fraction (LVEF > 40%) 2 Subjects.

[0631] Candidates must have been diagnosed with chronic heart failure for at least one month prior to screening, and during the screening period, be diagnosed with mildly reduced ejection fraction / preserved ejection fraction heart failure (HFmrEF / HFpEF) according to the National Heart Failure Guidelines 2023, while also meeting the following three diagnostic criteria:

[0632] 1) During the screening period, echocardiography showed a left ventricular ejection fraction (LVEF) > 40%;

[0633] 2) Serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels before randomization during the screening period and on day 1: NT-proBNP ≥ 125 pg / ml in patients with sinus rhythm; NT-proBNP ≥ 300 pg / ml in patients with atrial fibrillation;

[0634] 3) Evidence of at least one of the following cardiac structural or functional abnormalities

[0635] ① Screening period echocardiography should show at least one of the following: left ventricular diastolic dysfunction / elevated left ventricular filling pressure:

[0636] a) Left ventricular mass index ≥95g / m 2 (Female) or ≥115g / m 2 (male);

[0637] b) Relative wall thickness > 0.42;

[0638] c) The peak diastolic velocity in the early diastolic phase of the mitral valve blood flow spectrum / the peak diastolic velocity in the early diastolic phase of the mitral valve annulus under tissue Doppler (E / e') ≥ 15;

[0639] d) Interval e' < 7 cm / s, or sidewall e' < 10 cm / s, or average e' < 8 cm / s;

[0640] e) Tricuspid regurgitation velocity > 2.8 m / s or estimated pulmonary artery systolic pressure (PASP) > 35 mmHg;

[0641] f) Enlargement of the left atrium, meeting any one of the following criteria: anteroposterior diameter of the left atrium ≥ 3.8 cm, or superior-inferior diameter of the left atrium ≥ 5.0 cm, or area of ​​the left atrium ≥ 20 cm². 2 Or a left atrial volume ≥55mL, or a left atrial volume index (LAVI) ≥34mL / m 2 ;

[0642] g) Left ventricular hypertrophy: thickening of the interventricular septum or thickness of the left ventricular posterior wall ≥1.1cm;

[0643] ② (Examinations conducted during the screening period or 3 months prior to screening, confirmed by the center) Positive stress echocardiography or invasive hemodynamic testing, meeting at least one of the following criteria:

[0644] a) Stress echocardiography showed an E / e' ≥ 15;

[0645] b) Cardiac catheterization at rest: pulmonary capillary wedge pressure (PCWP) ≥15 mmHg or left ventricular end-diastolic pressure (LVEDP) ≥16 mmHg;

[0646] c) During a stress catheterization, the peak PCWP is ≥25 mmHg.

[0647] 4. Dosing regimen

[0648] Subjects were randomly assigned in a 1:1:1 ratio to the 180 mg group, the 360 ​​mg group, and the placebo group. Subjects took the investigational drug with water daily, swallowing it whole without chewing or dissolving it in their mouth beforehand. The medication could be taken before or after meals. Subjects were advised to take the medication at approximately the same time each day, and not to exceed the prescribed dosage. Dosage titration was used.

[0649] 180mg group: For the first 4 weeks (D1–D28), 30mg of compound (I) / placebo was administered orally, QD; for weeks 5–8 (D29–D56), 60mg of compound (I) / placebo was administered orally, QD; for weeks 9–12 (D57–D84), 120mg of compound (I) / placebo was administered orally, QD; and after week 13 (D85–), 180mg of compound (I) / placebo was administered orally, QD.

[0650] 360mg group: For the first 4 weeks (D1–D28), 30mg of compound (I) / placebo was administered orally, QD; for weeks 5–8 (D29–D56), 60mg of compound (I) / placebo was administered orally, QD; for weeks 9–12 (D57–D84), 120mg of compound (I) / placebo was administered orally, QD; for weeks 13–16 (D85–D112), 180mg of compound (I) / placebo was administered orally, QD. After weeks 17–20 (D113–D140), compound (I) / placebo 240 mg was administered orally, QD; after weeks 21–24 (D141–D168), compound (I) / placebo 300 mg was administered orally, QD; after week 25 (D169–), compound (I) / placebo 360 mg was administered orally, QD.

[0651] Placebo group: Received an equal number of tablets of compound (I) analogue.

[0652] 5. Results Evaluation

[0653] 5.1 Effectiveness Evaluation

[0654] Effectiveness evaluation indicators include heart failure symptoms and exercise function assessment (KCCQ-CSS, KCCQ-OSS, 6MWT), NT-proBNP, hsCRP, weight, waist circumference, BMI, and cardiac function indicators.

[0655] 5.2 Safety Evaluation

[0656] Safety indicators include the incidence and severity of any adverse events (AEs) from the first dose to the end of the trial, as well as clinically significant findings in areas such as hypoglycemia, vital signs, physical examination, laboratory tests, and 12-lead electrocardiogram. All examinations are performed according to the study schedule, and investigators may increase the number and types of examinations as needed clinically (e.g., in the event of AEs or SAEs).

Claims

1. Use of a compound of formula (I) ###0001### or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of heart failure, 2. Use according to claim 1, wherein, The heart failure is selected from HFmrEF / HFpEF; and / or The heart failure subjects had a left ventricular ejection fraction of 40% < LVEF < 50%, LVEF ≥ 50%, or LVEF > 40%; preferably, LVEF > 40%.

3. Use according to claim 1 or 2, wherein, The body weight of the heart failure subject is obese or overweight, preferably the subject has a BMI > 28 kg / m2 2 .

4. Use according to any one of claims 1 to 3, wherein, The subjects with heart failure were not obese or overweight.

5. Use according to any one of claims 1 to 4, wherein, The heart failure subject is HFmrEF / HFpEF and has a body weight which is obese or overweight, preferably the heart failure subject has a left ventricular ejection fraction > 40% and a BMI > 28 kg / m2. 2 .

6. Use according to any one of claims 1 to 5, wherein, The heart failure subjects must have a NYHA functional class of at least II, preferably II to IV; And / or the KCCQ-CSS score of the heart failure subjects is ≤80.

7. Use according to any one of claims 1 to 6, wherein, The compound of formula (I) or its pharmaceutically acceptable salt improves heart failure symptoms, motor function and / or weight loss in subjects.

8. Use according to any one of claims 1 to 7, wherein, The compound of formula (I) or a pharmaceutically acceptable salt thereof improves any of the following indicators in the subject: 1) Reduce mortality rate; 2) Improve KCCQ-CSS score and / or KCCQ-OSS score, preferably, KCCQ-CSS score improvement ≥ 5 points; 3) Reduce hsCRP levels; 4) Reduce NT-proBNP levels; 5) Improves cardiac function indicators; 6) Improves NYHA functional classification; 7) Improve body mass index; 8) Reduces the risk of hospitalization due to heart failure; 9) Reduces the risk of death from heart failure; 10) Reduce the risk of complex heart failure endpoints; 11) Reduce the risk of clinical events that worsen heart failure.

9. The use according to any one of claims 1 to 8, wherein the dosage of the compound of formula (I) or its pharmaceutical salt is 5 to 720 mg, preferably 30 to 540 mg, and exemplary dosages include 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg or 720 mg.

10. The use according to any one of claims 1-9, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is administered to the subject by dose titration; Preferably, the dose is increased every 2 weeks, every 3 weeks, every 4 weeks, or every 5 weeks; and / or The dosing frequency can be selected from three times a day, twice a day, once a day, once every two days, or once every three days.

11. The use according to any one of claims 1-10, wherein, The dosing regimens of the compound of formula (I) or its pharmaceutically acceptable salts include any one of the following: A) Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for at least one week, followed by Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least one week, followed by Administer a maintenance dose of the compound of formula (I) or its pharmaceutically acceptable salt once daily for at least 2 weeks; B) Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for at least 2 weeks, followed by Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for at least 2 weeks, followed by Administer a maintenance dose of the compound of formula (I) or its pharmaceutically acceptable salt once daily for at least 4 weeks; C) Administer an initial dose of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer at least one escalating dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof once daily for approximately 4 weeks per escalating dose, followed by... Administer a maintenance dose of the compound of formula (I) or its pharmaceutically acceptable salt once daily for at least 16 weeks.

12. The use according to claim 11, wherein, The initial dose is selected from 5 mg to 60 mg, preferably about 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg; more preferably about 30 mg. The incremental dose is selected from 55 mg to 400 mg or 55 mg to 720 mg, preferably about 55 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 720 mg; more preferably about 60 mg, 120 mg, 180 mg, 240 mg, 300 mg; The maintenance dose is selected from 155 mg to 400 mg or 155 mg to 720 mg, preferably about 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 720 mg; more preferably about 180 mg or 360 mg.

13. The use according to claim 11 or 12, wherein, 1) The incremental dose includes one incremental dose: The first incremental dose is selected from 55 mg to 120 mg; preferably about 60 mg, 90 mg or 120 mg; 2) The incremental dosage includes two incremental dosages: The first incremental dose is selected from 60 mg to 90 mg; preferably about 60 mg or 90 mg, more preferably about 60 mg; The second incremental dose is selected from 95 mg to 120 mg; preferably about 120 mg; 3) The incremental dosage includes three incremental dosages: The first incremental dose is selected from 55 mg to 70 mg; preferably about 60 mg; The second incremental dose is selected from 75 mg to 100 mg; preferably about 90 mg; The third incremental dose is selected from 105 mg to 120 mg; preferably about 120 mg. 4) The incremental dosage includes four incremental dosages: The first incremental dose is selected from 50 mg to 70 mg; preferably about 60 mg; The second incremental dose is selected from 100 mg to 130 mg; preferably about 120 mg; The third incremental dose is selected from 150 mg to 200 mg; preferably about 180 mg; The fourth incremental dose is selected from 220 mg to 260 mg; preferably about 240 mg. 5) The incremental dosage includes five incremental dosages: The first incremental dose is selected from 50 mg to 70 mg; preferably about 60 mg; The second incremental dose is selected from 100 mg to 130 mg; preferably about 120 mg; The third incremental dose is selected from 150 mg to 200 mg; preferably about 180 mg; The fourth incremental dose is selected from 220 mg to 260 mg; preferably about 240 mg. The fifth incremental dose is selected from 280 mg to 320 mg; preferably about 300 mg.

14. The use according to any one of claims 1-13, wherein, The dosing regimens of the compound of formula (I) or its pharmaceutically acceptable salts include any one of the following: 1) Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for at least 16 weeks; 2) Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 90 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for at least 16 weeks; 3) Administer approximately 15 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 90 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for at least 16 weeks; 4) Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 240 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 300 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 360 mg of compound (I) or its pharmaceutically acceptable salt once daily for at least 4 weeks.

15. The use according to any one of claims 1-14, wherein, The dosing regimens of the compound of formula (I) or its pharmaceutically acceptable salts include any one of the following: 1) Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 24 or 28 weeks; 2) Administer approximately 30 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 60 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 120 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 180 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 240 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 300 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 4 weeks, followed by... Administer approximately 360 mg of compound (I) or its pharmaceutically acceptable salt once daily for approximately 12 weeks.

16. A method for preventing or treating heart failure, or for delaying the progression of heart failure, comprising administering to a subject in need a preventive or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; Preferably, the subject is an overweight or obese subject.

17. A method for preventing or treating HFmrEF / HFpEF in a subject, or for delaying the development of HFmrEF / HFpEF, comprising administering to a subject in need a preventive or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Preferably, the subject is an overweight or obese subject.

18. Methods for improving symptoms of heart failure, motor function and / or weight loss in subjects in need, including administering to subjects in need a preventive or therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; Preferably, the subject has HFmrEF / HFpEF, more preferably a subject with HFmrEF / HFpEF who is overweight or obese.

19. A method, which is the method of any one of embodiments 1 to 265 described herein.

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