Use of GLP-1 agonist in treatment for overweight or obesity

Abstract

Provided is the use of a GLP-1 agonist in the treatment of overweight or obesity, and the use of the GLP-1 agonist or a pharmaceutically acceptable salt thereof in preparation of a drug for treating overweight or obesity. The GLP-1 agonist is represented by formula (I).

Description

Use of GLP-1 agonists in the treatment of overweight or obesity Technical Field

[0001] This disclosure relates to the use of GLP-1 agonists in the treatment of overweight or obesity. Background Technology

[0002] Obesity is a chronic metabolic disease caused by a combination of genetic and environmental factors, resulting from excessive total body fat and / or increased localized fat content and abnormal distribution. Currently, China uses a standard 24.0 kg / m² fat density. 2 ≤Body Mass Index (BMI) <28.0 kg / m² 2 and ≥28.0kg / m 2 Adults were diagnosed as overweight and obese, respectively. Obesity has become a global "epidemic" and is a major risk factor for many chronic diseases such as diabetes, cardiovascular and cerebrovascular diseases, and dyslipidemia.

[0003] With changes in lifestyle and dietary structure, the rates of overweight, obesity, and related chronic diseases are showing a significant upward trend across all age groups in China. The "Report on Nutrition and Chronic Diseases of Chinese Residents (2020)" shows that the overweight / obesity rate among adults aged 18 and above has exceeded 50%, while the rates for children under 6 years old and children aged 6-17 years old have reached 10.4% and 19.0%, respectively. The latest epidemiological studies on obesity predict that by 2030, the prevalence of overweight / obesity among Chinese adults may reach 65.3%, further increasing the burden on the healthcare system.

[0004] In my country, the prevention and treatment of obesity is based on the three-tiered prevention and treatment principles. The main treatment methods include lifestyle interventions, weight-loss drugs, and metabolic surgery. Lifestyle interventions, including nutritional, exercise, and behavioral interventions, are the first-line treatment for obesity. When lifestyle interventions are ineffective, combined drug therapy or metabolic surgery can be considered. Although metabolic surgery has the most significant weight-loss effect, the invasive procedure may cause complications such as malnutrition, anemia, and gastrointestinal stricture, requiring strict adherence to indications and long-term follow-up. Therefore, there is a huge clinical demand for drug-based weight-loss methods in the field of obesity, urgently requiring more effective, safer, and more convenient pharmacological weight-loss approaches.

[0005] Glucagon-like peptide-1 (GLP-1) is mainly secreted by L cells in the ileum and colon. Its active forms are primarily GLP-1(7-36) and GLP-1(7-37), derived from proglucagon via translational cleavage, and share 50% homology with glucagon. GLP-1 receptors are widely distributed in the pancreas, intestines, and central nervous system, and are also expressed in the lungs, heart, kidneys, and immune cells. In the pancreas, GLP-1 stimulates β-cells to release insulin and inhibits α-cells to secrete glucagon in a glucose-dependent manner, thus lowering blood glucose levels. Expression in other sites provides benefits such as appetite suppression, delayed gastric emptying, improved memory, and cardiovascular protection. Summary of the Invention

[0006] This disclosure provides the use of a GLP-1 agonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating overweight or obesity, wherein the GLP-1 agonist is as shown in formula (I):

[0007] This disclosure also provides a method for treating overweight or obesity, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0008] This disclosure also provides a method for treating overweight or obesity with a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009] The present invention provides a method for weight loss, the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] The present invention provides a method for reducing overweight, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0011] The present invention provides a method for reducing body mass index (BMI), the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] The present invention provides a method for reducing waist circumference, the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the overweight or obese patient may or may not have diabetes; in some embodiments, the overweight or obese patient does not have diabetes; in some embodiments, the overweight or obese patient has diabetes.

[0014] In some embodiments, the overweight or obesity is accompanied by at least one weight-related comorbidity; in some embodiments, the overweight is accompanied by at least one weight-related comorbidity; in some embodiments, the weight-related comorbidity is selected from prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, and non-alcoholic fatty liver disease.

[0015] In some embodiments, the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is for use in the preparation of a medicament for treating obesity.

[0016] In some embodiments, the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is for use in the preparation of a medicament for the treatment of overweight.

[0017] In some implementation schemes, the subjects are overweight.

[0018] In some implementation schemes, the subjects are obese.

[0019] In some implementation plans, the treated patient's 24kg / m 2 ≤BMI<28kg / m 2 or BMI ≥ 28 kg / m 2 In some implementation schemes, the BMI is 28-40 kg / m². 2 In some implementation schemes, the subject's BMI is ≥28.0 kg / m². 2 And ≤40.0kg / m 2 In some implementation schemes, the subject's BMI is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 In some implementation schemes, the subject's BMI is ≥32.5 kg / m². 2 And ≤40.0kg / m 2 In some implementation schemes, the subject's BMI is ≥27 kg / m². 2 In some implementation schemes, the subject's BMI is ≥30 kg / m². 2 In some implementation schemes, the subject's BMI is ≥27 kg / m². 2 And <30kg / m 2 In some implementation schemes, the subject's BMI is ≥30 kg / m². 2 And <35kg / m 2 In some implementation schemes, the subject's BMI is ≥35 kg / m². 2 And <40kg / m 2 .

[0020] In some implementation plans, obese patients with a BMI ≥ 28 kg / m² are considered obese. 2In some implementation schemes, the value is 28-40 kg / m³. 2 In some implementation schemes, BMI ≥ 30 kg / m² 2 In some implementation schemes, BMI ≥ 32 kg / m² 2 In some implementation schemes, BMI ≥ 32.5 kg / m² 2 In some implementation schemes, BMI ≥ 35 kg / m² 2 In some implementation schemes, BMI ≥ 40 kg / m² 2 .

[0021] In some implementation plans, 24 kg / m² for overweight patients 2 ≤BMI<28kg / m 2 .

[0022] In some implementation schemes, the subject's body mass index (BMI) is ≥24.0 kg / m². 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some implementations, the subject's body mass index (BMI) is ≥24.0 kg / m². 2 And ≤28.0kg / m 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease).

[0023] In some implementation schemes, the subject's body mass index (BMI) is ≥27 kg / m². 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some implementations, the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some implementation schemes, the subject's body mass index (BMI) is ≥30 kg / m². 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some implementation schemes, the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some implementation schemes, the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 And have at least one weight-related comorbidity (e.g., prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease). In some embodiments, the weight-related comorbidity is diabetes. In some embodiments, the weight-related comorbidity is type 2 diabetes.

[0024] In some implementations, the subjects are humans. In some implementations, the subjects are adults. In some implementations, the subjects are males. In some implementations, the subjects are females.

[0025] In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 10-600 mg; in some embodiments, it is 5-720 mg; in some embodiments, it is 5-30 mg; in some embodiments, it is 20-600 mg; in some embodiments, it is 30-540 mg; in some embodiments, it is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg; in some embodiments, it is 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, 720 mg; in some embodiments, it is 18 mg. 0 mg; in some embodiments 360 mg; in some embodiments 540 mg; in some embodiments 720 mg; in some embodiments 15 mg, 30 mg, 40 mg, 45 mg, 50 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 and 180 mg; in some embodiments 15 mg, 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg and 180 mg; the dosages mentioned should be understood as calculated based on the weight of the corresponding free base or free acid.

[0026] In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 10-300 mg; in some embodiments, it is 20-200 mg; in some embodiments, it is 30-180 mg; in some embodiments, it is 30 mg, 60 mg, 120 mg and 180 mg; in some embodiments, it is 180 mg; in some embodiments, it is 15 mg, 30 mg, 40 mg, 45 mg, 50 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 and 180 mg; in some embodiments, it is 15 mg, 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg and 180 mg; the dosage shall be understood to be calculated based on the weight of the corresponding free base or free acid.

[0027] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered by titration; in some embodiments, it is administered by dose-escalating titration.

[0028] The method of administration by titration is referred to as titration method or titration scheme.

[0029] In some embodiments, the titration of the compound of formula (I) or its pharmaceutically acceptable salt is a dose-escalating or dose-decrease titration; in some embodiments, the titration is performed every 1-8 weeks with dose escalation or decrease; in some embodiments, the titration is performed every 2, 3, 4, 5, or 6 weeks with dose escalation or decrease; in some embodiments, the titration is performed every 2 weeks with dose escalation or decrease; in some embodiments, the titration is performed every 4 weeks with dose escalation or decrease.

[0030] 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 of first giving a subject one or more escalating doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof, followed by a maintenance dose.

[0031] In some embodiments, titration is performed in dose increments or decreases of 1 mg to 200 mg; in some embodiments, titration is performed in dose increments or decreases of 3 mg to 180 mg; in some embodiments, titration is performed in increments of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 1 ... The dosage may be increased or decreased in increments of 0.00 mg, 120 mg, 140 mg, 160 mg, or 180 mg; in some embodiments, the titration may be performed in increments of 15 mg, 30 mg, 60 mg, 120 mg, or 180 mg; in some embodiments, the titration may be performed in increments of 15 mg, 30 mg, 60 mg, 120 mg, or 180 mg; specifically, such increments or decreases refer to the current dose being increased or decreased by a specific amount based on the previous dose.

[0032] In some embodiments, titration is performed in increments or decreases of 1 mg to 100 mg; in some embodiments, titration is performed in increments or decreases of 5 mg to 100 mg; in some embodiments, titration is performed in increments or decreases of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg; in some embodiments, titration is performed in increments or decreases of 15 mg, 30 mg, or 60 mg; in some embodiments, titration is performed in increments of 15 mg, 30 mg, or 60 mg; specifically, such increments or decreases refer to the current dose being increased or decreased by a specific amount based on the previous dose.

[0033] In some embodiments, the titration is performed by increasing or decreasing the dose by multiples relative to the previous dose; in some embodiments, the titration is performed by increasing or decreasing the dose by 0.1 to 5 times relative to the previous dose; in some embodiments, the titration is performed by increasing or decreasing the dose by 0.1, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.75, 0.8, 0.9, 1.0, 1.25, 1.5, or 2 times relative to the previous dose; in some embodiments, the titration is performed by increasing or decreasing the dose by 0.5, 0.75, or 1.0 times relative to the previous dose. In some implementations, the titration method involves increasing or decreasing the dose by 1.125, 1.14, 1.17, 1.2, or 1.3 times compared to the previous dose; wherein, increasing or decreasing by multiples means that the current dose is increased or decreased by a specific multiple of the previous dose.

[0034] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is titrated by increasing or decreasing the dose by 15 mg or 30 mg each time compared to the previous dose, or by increasing or decreasing the dose by 0.5 or 1 times compared to the previous dose.

[0035] In some embodiments, the starting dose for titration is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg; in some embodiments, the starting dose is 15 mg; in some embodiments, the starting dose is 30 mg; and in some embodiments, the starting dose is 60 mg.

[0036] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt reaches the target dose within a titration period of 2 to 6 months; in some embodiments, the titration period is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5 or 6 months; in some embodiments, the titration period is 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 or 5 months.

[0037] In some embodiments, the compound of formula (I) is administered in escalating doses for a period of time; optionally, subsequent administrations are made in escalating doses (e.g., further escalating doses) for a period of time until a maintenance dose is reached. In some embodiments, a dose titration protocol includes administering one or more escalating doses for a period of time. In some embodiments, the dose titration protocol further includes administering a maintenance dose (e.g., long-term administration). In some embodiments, the duration of each dose escalation is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or longer.

[0038] As used in this disclosure, "escalation dose" refers to a dose below the subject's maintenance dose. In some embodiments, the escalation dose is a dose below the subject's highest effective dose. In some embodiments, the escalation dose is a dose below the highest effective dose that the subject can tolerate (e.g., a dose that does not cause adverse events or causes only minor adverse events). In some embodiments, if an escalation dose is observed to be suitable as a subject's maintenance dose, then that escalation dose may be used as a maintenance dose.

[0039] As used in this disclosure, "maintenance dose" refers to the highest target dose suitable for the subject. In some embodiments, the maintenance dose is the highest effective dose for the subject. In some embodiments, the maintenance dose is the highest effective dose that the subject can tolerate. In some embodiments, if a maintenance dose is observed not to be the highest target dose suitable for the subject, the maintenance dose may be used as an escalation dose. Maintenance doses are typically administered over a long period.

[0040] In some embodiments, the increments are 15 mg, 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, or 540 mg. In some embodiments, the increment for each dose is 15 mg, 30 mg, 60 mg, or 120 mg.

[0041] In some implementations, the maintenance dose is 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg, 480 mg, 540 mg, or 720 mg.

[0042] In some embodiments, the target dose of 180 mg of the compound of formula (I) or its pharmaceutically acceptable salt is titrated as 30 mg-60 mg-90 mg-120 mg-150 mg-180 mg or 30 mg-60 mg-120 mg-180 mg; in some embodiments, the titration is 30 mg-60 mg-90 mg-120 mg-150 mg-180 mg; in some embodiments, the titration is 30 mg-60 mg-120 mg-180 mg; in some embodiments, the titration is 15 mg-30 mg-45 mg-60 mg-90 mg-120 mg-150 mg-180 mg.

[0043] In some embodiments, the titration of a target dose of 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 60 mg-120 mg-240 mg-360 mg-540 mg-720 mg; in some embodiments, the titration is 30 mg-60 mg-120 mg-240 mg-360 mg-540 mg-720 mg; and in some embodiments, the titration is 30 mg-60 mg-120 mg-180 mg-240 mg-300 mg. mg-360mg-420mg-480mg-540mg-720mg; in some embodiments, the titration method is 15mg-30mg-60mg-120mg-240mg-360mg-540mg-720mg; in some embodiments, the titration method is 15mg-30mg-60mg-120mg-180mg-240mg-300mg-360mg-420mg-480mg-540mg-720mg.

[0044] In some embodiments, the target dose of 540 mg of the compound of formula (I) or its pharmaceutically acceptable salt is titrated in the manner of 30 mg-60 mg-120 mg-240 mg-360 mg-540 mg or 30 mg-60 mg-120 mg-180 mg-240 mg-300 mg-360 mg-420 mg-480 mg-540 mg;

[0045] In some embodiments, the target dose of 360 mg of the compound of formula (I) or its pharmaceutically acceptable salt is titrated as 30 mg-60 mg-120 mg-240 mg-360 mg; in some embodiments, the titration is titrated as 15 mg-30 mg-60 mg-90 mg-120 mg-180 mg-240 mg-300 mg-360 mg.

[0046] In some embodiments, a maintenance dose of 240 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered by titration in a gradient of 15 mg-30 mg-60 mg-90 mg-120 mg-180 mg-240 mg.

[0047] In some embodiments, a maintenance dose of 240 mg of the compound of formula (I) or its pharmaceutically acceptable salt is administered by titration in a gradient of 30 mg-60 mg-90 mg-120 mg-180 mg-240 mg.

[0048] In some embodiments, the target dose of the compound of formula (I) or its pharmaceutically acceptable salt is 120 mg in an escalation manner of 30 mg-60 mg-90 mg-120 mg.

[0049] In some embodiments, the target dose of the compound of formula (I) or its pharmaceutically acceptable salt is increased in the manner of 30 mg-45 mg-60 mg; in other embodiments, it is increased in the manner of 15 mg-30 mg-45 mg-60 mg.

[0050] In some embodiments, the target dose of the compound of formula (I) or its pharmaceutically acceptable salt is escalated in increments of 15 mg to 30 mg.

[0051] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is titrated for a period of 2, 3, or 4 weeks per dose until the target dose is reached; in some embodiments, the titration is performed for 4 weeks per dose until the target dose is reached; in some embodiments, the titration is performed for 2 weeks per dose until the target dose is reached.

[0052] In some embodiments, a subject is administered 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (4 weeks in some embodiments), followed by administration of 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (4 weeks in some embodiments); in some embodiments, administration of 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (2 or 4 weeks or longer in some embodiments) is further included; in some embodiments, administration of 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (2 or 4 weeks or longer in some embodiments) is further included; in some embodiments, administration of 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time (2 or 4 weeks or longer in some embodiments) is further included; in some embodiments, administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a period of time is further included. The subject is given 300 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (in some embodiments, 2 or 4 weeks or longer); in some embodiments, the subject is also given 360 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (in some embodiments, 2 or 4 weeks or longer); in some embodiments, the subject is also given 420 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (in some embodiments, 2 or 4 weeks or longer); in some embodiments, the subject is also given 480 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (in some embodiments, 2 or 4 weeks or longer); in some embodiments, the subject is also given 540 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (in some embodiments, 2 or 4 weeks or longer).

[0053] In some embodiments, a 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, a 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, a 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, a 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, a 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, a 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, a 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, a subject is given 180 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 240 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 300 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 360 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 420 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 480 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 540 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is given 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration).

[0054] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered orally.

[0055] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an oral dosage form; in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a tablet form; in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a capsule form.

[0056] 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, once every three days, once every four days, once every five days, and once weekly; in some embodiments, once daily; in some embodiments, selected from three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, once weekly, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, and once every twelve weeks.

[0057] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is taken after a meal; in some embodiments, it is taken after breakfast; in some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is taken before a meal, for example, after an 8-hour fast.

[0058] In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is ≥16 weeks; in some embodiments ≥20 weeks; in some embodiments ≥24 weeks; in some embodiments ≥26 weeks; in some embodiments ≥36 weeks; in some embodiments ≥40 weeks; in some embodiments ≥44 weeks; in some embodiments ≥48 weeks; in some embodiments ≥50 weeks; in some embodiments, the administration period is 3 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, 24 weeks, 26 weeks, 28 weeks, or 30 weeks. The dosing cycles are 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 56 weeks, 60 weeks, 64 weeks, 68 weeks, 72 weeks, 76 weeks, 80 weeks, 84 weeks, 88 weeks, and 92 weeks; in some embodiments, 36 weeks or 50 weeks; in some embodiments, 50 weeks; in some embodiments, 36 weeks; in some embodiments, 26 weeks; in some embodiments, 24 weeks; in some embodiments, the dosing cycle includes a 26-week core treatment period and a 10-week extended treatment period.

[0059] In some embodiments, administering the compound of formula (I) using the methods and uses described in this disclosure can achieve one or more therapeutic effects, for example, after a specific time period and / or compared to a control population. In some embodiments, the one or more therapeutic effects are achieved 24 weeks, 26 weeks, 36 weeks, or 50 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), for example, a population of subjects receiving placebo. In some embodiments, the control population is a comparable population of subjects receiving standard treatment.

[0060] In some embodiments, the percentage reduction in body weight relative to baseline in subjects treated with the compound of formula (I) or its pharmaceutically acceptable salt is ≥1.00%; in some embodiments, ≥2.00%; in some embodiments, ≥3.00%; in some embodiments, ≥4.00%; in some embodiments, ≥5.00%; in some embodiments, ≥6.00%; in some embodiments, ≥7.00%; in some embodiments, ≥8.00%; in some embodiments, ≥9.00%; in some embodiments, ≥10.0%; in some embodiments, ≥11.0%; in some embodiments, ≥ 12.0%; ≥13.0% in some embodiments; ≥14.0% in some embodiments; ≥15.0% in some embodiments; ≥17.0% in some embodiments; ≥19.0% in some embodiments; ≥20.0% in some embodiments; in some embodiments, the percentage of weight loss relative to baseline is 2.99%, 6.17%, 7.17%, 9.36%, and 9.47%; in some embodiments, the percentage of weight loss is determined after treatment with the compound of formula (I) for a specific duration, such as 24, 26, 36, or 50 weeks of treatment.

[0061] In some embodiments, the percentage decrease in body weight relative to baseline in subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts, minus the percentage decrease in body weight relative to baseline in the placebo group, is ≥5.00%; in some embodiments, ≥6.00%; in some embodiments, ≥7.00%; in some embodiments, ≥8.00%; in some embodiments, ≥9.00%; in some embodiments, ≥10.0%; in some embodiments, ≥11.0%; in some embodiments, ≥12.0%; in some embodiments, ≥13.0%; in some embodiments, ≥14.0%; in some embodiments, ≥15.0%; in some embodiments, ≥17.0%. %; ≥19.0% in some embodiments; ≥20.0% in some embodiments; ≥22.0% in some embodiments; ≥25.0% in some embodiments; ≥27.0% in some embodiments; ≥29.0% in some embodiments; ≥30.0% in some embodiments; in some embodiments, the percentage decrease in weight relative to baseline of the subject, excluding the percentage decrease in weight relative to baseline of the placebo group, is 0.49%, 3.67%, 4.63%, and 6.87%; in some embodiments, the percentage decrease in weight is determined after treatment with the compound of formula (I) for a specific duration, such as 24, 26, 36, or 50 weeks of treatment.

[0062] The percentage decrease in weight relative to baseline of subjects treated with the compound of formula (I) or its medicinal salts, minus the percentage decrease in weight relative to baseline of the placebo group, is: percentage decrease in weight relative to baseline of subjects treated with the compound of formula (I) or its medicinal salts - percentage decrease in weight relative to baseline of the placebo group.

[0063] In some embodiments, the proportion of subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts that experienced a weight reduction of at least 10.0% from baseline was ≥10.0%; in some embodiments, ≥15.0%; in some embodiments, ≥20.0%; in some embodiments, ≥25.0%; in some embodiments, ≥30.0%; in some embodiments, ≥35.0%; in some embodiments, ≥40.0%; in some embodiments, ≥45.0%; in some embodiments, ≥50.0%; in some embodiments, ≥55.0%; in some embodiments, ≥60.0%; in some embodiments, ≥65.0%; in some embodiments, the proportion of subjects whose weight reduction of at least 10.0% from baseline was 35.4%; in some embodiments, the proportion of subjects whose weight reduction from baseline was at least 10.0% was determined after a specific duration of treatment with the compound of formula (I), such as 24 weeks, 26 weeks, 36 weeks, or 50 weeks of treatment.

[0064] In some embodiments, the proportion of subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts who experienced a weight reduction of ≥10.0% from baseline was twice that of the placebo group; in some embodiments, it was 1; in some embodiments, it was 2.5; in some embodiments, it was 3; in some embodiments, it was 3.5; in some embodiments, it was 4; and in some embodiments, it was 0.5, 0.8, 1.0, 1.2, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6, 6.5, and 7 times. And the difference between the two was statistically significant. In some embodiments, the proportion of subjects who experienced a weight reduction of at least 10.0% from baseline was determined after treatment with the compound of formula (I) for a specific duration, such as 24, 26, 36, or 50 weeks.

[0065] In some implementations, the percentage increase in the proportion of subjects receiving treatment with the compound of formula (I) or its pharmaceutically acceptable salts and experiencing a weight loss of ≥10.0% from baseline, compared to the placebo group, is ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥9%, ≥10%, ≥15%, ≥20%, ≥25%, ≥30%, ≥35%, ≥40%, ≥45%, ≥50%, ≥55%, or higher. In some implementations, the percentage of subjects experiencing a weight loss of at least 10.0% from baseline is determined after a specific duration of treatment with the compound of formula (I), such as 24, 26, 36, or 50 weeks of treatment.

[0066] In some embodiments, the proportion of subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts that experienced a weight reduction of at least 5.0% from baseline was ≥35.0%; in some embodiments ≥40.0%; in some embodiments ≥45.0%; in some embodiments ≥50.0%; in some embodiments ≥55.0%; in some embodiments ≥60.0%; in some embodiments ≥65.0%; in some embodiments ≥70.0%; and in some embodiments ≥75.0%. In some embodiments, the proportion of subjects who experienced a weight reduction of at least 5.0% from baseline was determined after a specific duration of treatment with the compound of formula (I), such as 24, 26, 36, or 50 weeks of treatment.

[0067] In some embodiments, the proportion of subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts who experienced a weight loss of ≥5.00% relative to baseline was twice that of the placebo group; in some embodiments, it was 2.5 times; in some embodiments, it was 3 times; in some embodiments, it was 3.5 times; in some embodiments, it was 4 times; and in some embodiments, it was 0.5 times, 0.8 times, 1.0 times, 1.2 times, 1.5 times, 2.0 times, 2.5 times, 3.0 times, 3.5 times, 4.0 times, 4.5 times, or 5.0 times. And the difference between the two was statistically significant. In some embodiments, the proportion of subjects who experienced a weight loss of at least 5.0% from baseline was determined after a specific duration of treatment with the compound of formula (I), such as 24 weeks, 26 weeks, 36 weeks, or 50 weeks of treatment.

[0068] In some implementations, the percentage increase in the proportion of subjects receiving treatment with the compound of formula (I) or its pharmaceutically acceptable salts and experiencing a weight loss of ≥5.0% from baseline compared to the placebo group is ≥1%, ≥2%, ≥3%, ≥4%, ≥5%, ≥6%, ≥7%, ≥8%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, ≥60%, or higher. In some implementations, the percentage of subjects experiencing a weight loss of at least 5.0% from baseline is determined after a specific duration of treatment with the compound of formula (I), such as 24, 26, 36, or 50 weeks of treatment.

[0069] In some embodiments, the percentage of subjects who received treatment with the compound of formula (I) or its pharmaceutically acceptable salts and achieved a weight loss of at least 15.0% from baseline was ≥10%, ≥12%, ≥15%, ≥20%, ≥22%, ≥25%, ≥30%, ≥32%, or higher. In some embodiments, the percentage of subjects who achieved a weight loss of at least 15.0% from baseline was determined after a specific duration of treatment with the compound of formula (I), such as 24, 26, 36, or 50 weeks of treatment.

[0070] In some embodiments, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) of the percentage change in body weight from baseline was -2.99% (-4.84%, -1.14%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -7.09% (-8.95%, -5.24%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -6.17% (-8.03%, -4.31%); and in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -9.36% (-11.21%). -7.52%); in some embodiments, the least squares mean of the percentage change in weight from baseline is -2.9% to -9.4% or -2.9% to -12.6%; in some embodiments, the least squares mean of the percentage change in weight from baseline is -2.9%, -2.99%, -3.0%, -4.0%, -5.0%, -6.0%, -6.17%, -6.5%, -7.0%, -7.09%, -7.1%, -7.5%, -8.0%, -9.0%, -9.3%, -9.36%, -9.4%, -10.0%, -11.0%, -12.0%, -12.5%, -12.6%, or any value between any two.

[0071] In some embodiments, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -0.49% (-3.11%, -2.12%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -4.60% (-7.21%, -1.98%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -3.67% (-6.29%, -1.05%); and in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -6.87% (-9.48%, -4%). 26%); in some embodiments, the least squares mean of the percentage change in weight relative to placebo is -0.4% to -7.0% or -0.4% to -10.2%; in some embodiments, the least squares mean of the percentage change in weight relative to placebo is -0.4%, -0.49%, -0.5%, -1.0%, -2.0%, -3.0%, -6.5%, -3.67%, -3.7%, -4.0%, -4.5%, -4.60%, -5.0%, -5.5%, -6.0%, -6.5%, -6.8%, -6.87%, -6.9%, -7.0%, -8.0%, -9.0%, -10.0%, -10.2%, or any value between any two.

[0072] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) of the percentage change in body weight from baseline was -2.44% (-4.62%, -0.27%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -5.36% (-7.51%, -3.22%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -5.36% (-7.51%, -3.21%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -5.36% (-7.51%, -3.21%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight from baseline was -2.44% (-4.62%, -0.27%). The 5% CI was -9.46% (-11.61%, -7.32%); in some embodiments, the least squares mean of the percentage change in weight from baseline was -2.4% to -10.0%; in some embodiments, the least squares mean of the percentage change in weight from baseline was -2.4%, -2.44%, -2.5%, -3.0%, -4.0%, -5.0%, -5.3%, -5.36%, -5.4%, -5.5%, -6.0%, -7.0%, -8.0%, -9.0%, -9.4%, -9.46%, -9.5%, -10.0%, or any value between any two.

[0073] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -1.06% (-4.10%, -1.99%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -3.98% (-7.00%, -0.96%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was -3.97% (-7.00%, -0.95%); in some embodiments, the least squares mean (95% CI) of the percentage change in body weight compared to placebo was... The mean (95% CI) was -8.08% (-11.10%, -5.05%); in some embodiments, the least squares mean of the percentage change in weight compared to placebo was -1.0% to -8.5%; in some embodiments, the least squares mean of the percentage change in weight compared to placebo was -1.0%, -1.06%, -1.1%, -2.0%, -3.0%, -3.5%, -3.9%, -3.97%, -3.98%, -4.0%, -5.0%, -6.0%, -7.0%, -8.0%, -8.08%, -8.1%, -8.5%, or any value between any two.

[0074] In some embodiments, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in weight from baseline was -2.59 kg (-4.22 kg, -0.95 kg); in some embodiments, the least squares mean (95% CI) change in weight from baseline was -6.33 kg (-7.97 kg, -4.70 kg); in some embodiments, the least squares mean (95% CI) change in weight from baseline was -5.40 kg (-7.03 kg, -3.76 kg); and in some embodiments, the least squares mean (95% CI) change in weight from baseline was -8.4 kg. 0 kg (-10.02 kg, -6.77 kg); in some embodiments, the least squares mean of the change in weight from baseline is -2.5 kg to -8.5 kg; in some embodiments, the least squares mean of the change in weight from baseline is -2.5 kg, -2.59 kg, -2.6 kg, -3.0 kg, -4.0 kg, -5.0 kg, -5.40 kg, -5.5 kg, -6.0 kg, -6.3 kg, -6.33 kg, -6.5 kg, -7.0 kg, -7.5 kg, -8.0 kg, -8.2 kg, -8.40 kg, -8.5 kg, or any value between any two.

[0075] In some embodiments, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in body weight compared to placebo was -0.39 kg (-2.69 kg, -1.92 kg); in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -4.13 kg (-6.44 kg, -1.83 kg); in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -3.20 kg (-5.50 kg, -0.89 kg); and in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -6.20 kg. g(-8.50kg, -3.90kg); in some implementations, the least squares mean of the change in weight from placebo is -0.3kg to -6.5kg; in some implementations, the least squares mean of the change in weight from placebo is -0.3kg, -0.39kg, -0.4kg, -0.5kg, -1.0kg, -2.0kg, -3.0kg, -3.20kg, -3.5kg, -4.0kg, -4.1kg, -4.13kg, -4.5kg, -5.0kg, -5.5kg, -6.0kg, -6.1kg, -6.20kg, -6.5kg, or any value between any two.

[0076] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in weight from baseline was -2.12 kg (-4.07 kg, -0.18 kg); in some embodiments, the least squares mean (95% CI) change in weight from baseline was -4.76 kg (-6.67 kg, -2.85 kg); in some embodiments, the least squares mean (95% CI) change in weight from baseline was -4.58 kg (-6.50 kg, -2.66 kg); and in some embodiments, the least squares mean (95% CI) change in weight from baseline was -8.52 kg. (-10.43kg, -6.60kg); in some embodiments, the least squares mean of the change in weight from baseline is -2.0kg to -9.0kg; in some embodiments, the least squares mean of the change in weight from baseline is -2.0kg, -2.12kg, -2.2kg, -3.0kg, -4.0kg, -4.5kg, -4.58kg, -4.6kg, -4.7kg, -4.76kg, -4.8kg, -5.0kg, -6.0kg, -7.0kg, -8.0kg, -8.5kg, -8.52kg, -8.6kg, -9.0kg, or any value between any two.

[0077] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in body weight compared to placebo was -1.02 kg (-3.73 kg, 1.70 kg); in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -3.65 kg (-6.34 kg, -0.96 kg); in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -3.48 kg (-6.18 kg, -0.78 kg); and in some embodiments, the least squares mean (95% CI) change in body weight compared to placebo was -7. 41 kg (-10.11 kg, -4.71 kg); in some implementations, the least squares mean of the change in weight from placebo is -1.0 kg to -8.0 kg; in some implementations, the least squares mean of the change in weight from placebo is -1.0 kg, -1.02 kg, -1.1 kg, -2.0 kg, -3.0 kg, -3.4 kg, -3.48 kg, -3.5 kg, -3.65 kg, -3.7 kg, -4.0 kg, -5.0 kg, -6.0 kg, -7.0 kg, -7.4 kg, -7.41 kg, -7.5 kg, -8.0 kg, or any value between any two.

[0078] In some implementations, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least-squares mean change in BMI relative to baseline was -0.9 to -5 kg / m². 2 In some implementation schemes, the values ​​are -0.9, -0.92, -1.0, -1.5, -1.9, -1.99, -2.0, -2.1, -2.2, -2.28, -2.3, -2.5, -3.0, -3.04, -3.1, -3.5, -4.0, and -5.0 kg / m³. 2 Or any value between any two numbers.

[0079] In some implementations, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least-squares mean change in BMI relative to placebo was -0.1 to -3 kg / m². 2 In some implementation schemes, the values ​​are -0.1, -0.14, -0.2, -0.4, -0.6, -0.8, -1.0, -1.1, -1.2, -1.3, -1.4, -1.49, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.25, -2.3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9, and -3.0 kg / m³. 2 Or any value between any two numbers.

[0080] In some implementations, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least-squares mean change in BMI relative to baseline was -0.7 to -5 kg / m². 2 In some implementation schemes, the values ​​are -0.7, -0.78, -0.8, -0.9, -1.0, -1.2, -1.4, -1.6, -1.7, -1.72, -1.73, -1.8, -2.0, -2.2, -2.4, -2.6, -2.8, -3.0, -3.08, -3.1, -3.2, -3.3, -3.4, -3.5, -4.0, and -5.0 kg / m³. 2 Or any value between any two numbers.

[0081] In some implementations, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least-squares mean change in BMI relative to placebo ranged from -0.3 to -2.7 kg / m². 2 In some implementation schemes, the values ​​are -0.3, -0.37, -0.4, -0.6, -0.8, -1.0, -1.2, -1.3, -1.31, -1.32, -1.4, -1.6, -1.8, -2.0, -2.2, -2.4, -2.6, -2.67, -2.7, and -2.8 kg / m³. 2 Or any value between any two numbers.

[0082] In some embodiments, after 26 weeks of treatment with a compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in waist circumference relative to baseline is -3.25 cm to -15.0 cm; in some embodiments, it is -3.25, -3.26, -3.3, -3.5, -3.7, -3.9, -4.0, -4.5, -5.0, -5.5, -5.6, -5.7, -5.79, -5.8, -6.0, -6.1, -6.12, -6.2, -6.4, -6.6, -6.8, -7.0, -7.5, -8.0, -9.0, -10.0, -11.0, -12.0, -13.0, -14.0, -15.0 cm or any value between any two.

[0083] In some embodiments, after 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in waist circumference relative to placebo was -0.05 cm to -5.0 cm; in some embodiments, it was -0.05, -0.07, -0.09, -0.1, -0.15, -0.2, -0.4, -0.6, -0.8, -1.0, -1.5, -2.0, -2.5, -2.57, -2.6, -2.9, -2.91, -3.0, -3.5, -4.0, -4.5, -5.0 cm.

[0084] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in waist circumference relative to baseline was -2.9 cm to -8.1 cm or -3.2 cm to -15.0 cm; in other embodiments, it was -2.9, -3.0, -3.2, -3.4, -3.6, -3.8, -4.0, -4.5, -5.0, -5.2, -5.25, -5.3, -5.4, -5.48, -5.5, -6.0, -6.5, -7.0, -7.5, -8.0, -8.03, -8.1, -8.5, -9.0, -10.0, -11.0, -12.0, -13.0, -14.0, -15.0 cm.

[0085] In some embodiments, after 36 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in waist circumference relative to placebo was -0.5 cm to -6.0 cm; in some embodiments, it was -0.5, -1.0, -1.5, -2.0, -2.1, -2.14, -2.2, -2.3, -2.37, -2.4, -2.6, -2.8, -3.0, -3.5, -4.0, -4.5, -4.9, -4.92, -5.0, -5.5, -6.0 cm.

[0086] In some implementation schemes, a BMI ≤ 32.5 kg / m² is given. 2 After 26 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in BMI relative to baseline was -3.5% to -10.0%; in some embodiments, it was -3.5%, -3.6%, -3.7%, -3.8%, -3.85%, -3.9%, -4.0%, -4.5%, -5.0%, -5.5%, -6.0%, -6.5%, -6.59%, -6.6%, -6.8%, -7.0%, -7.5%, -8.0%, -8.5%, -8.7%, -8.75%, -8.8%, -9.0%, -9.2%, -9.30%, -9.4%, -9.5%, -10.0%, or any value between any two.

[0087] In some implementation schemes, a BMI > 32.5 kg / m² is given. 2After 26 weeks of treatment with compound (I) or its pharmaceutically acceptable salts, the least squares mean change in BMI relative to baseline ranged from -1.3% to -10.0%; in some embodiments, the values ​​were -1.3, -1.5, -1.7, -1.78, -1.8, -2.0, -2.5, -3.0, -3.5, -3.6, -3.7, -3.8, -3.9, -4.0. -4.5, -5.0, -5.04, -5.1, -5.5, -5.6, -5.63, -5.7, -6.0, -6.5, -6.6, -6.8, -7.0, -7.5, -8.0, -8.5, -8.7, -8.8, -9.0, -9.2, -9.3, -9.31, -9.4, -9.5, -10.0% or any value between any two of these values.

[0088] In some implementation schemes, a BMI ≤ 32.5 kg / m² is given. 2 After 26 weeks of treatment with compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in BMI relative to placebo was -0.3 to -6.5%; in some embodiments, it was -0.3, -0.35, -0.4, -0.41, -0.5, -1.0, -1.5, -2.0, -2.5, -3.0, -3.1, -3.15, -3.2, -3.5, -4.0, -4.5, -5.0, -5.1, -5.3, -5.31, -5.4, -5.5, -5.6, -5.7, -5.8, -5.86, -5.9, -6.0, -6.5%, or any value between any two.

[0089] In some implementation schemes, a BMI > 32.5 kg / m² is given. 2 After 26 weeks of treatment with compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean change in BMI relative to placebo was -0.3 to -9.5%; in some embodiments, it was -0.3, -0.4, -0.5, -0.52, -0.6, -0.8, -1.0, -1.5, -2.0, -2.5, -3.0, -3.1, -3.2, -3.5, -3.78, -4.0, -4.3, -4.38, -4.4, -4.5, -5.0, -5.1, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, -5.9, -6.0, -6.5, -8.0, -8.05, -8.1, -8.5, -9.0, -9.5%, or any value between any two.

[0090] The percentage change of the above parameters is the least squares (LS) average percentage change.

[0091] In some embodiments, weight loss of 5-20% occurs after administration of the compound of formula (I) or its pharmaceutically acceptable salt for 26 weeks; in some embodiments, the weight loss is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20%, or any value between any two of these.

[0092] In some embodiments, administration of the compound of formula (I) or its pharmaceutically acceptable salt for 24 weeks resulted in a weight loss of 5-20%; in other embodiments, administration of the compound of formula (I) or its pharmaceutically acceptable salt for 24 weeks resulted in a weight loss of 10-15%.

[0093] In some embodiments, waist circumference is reduced by 5-15 cm after 24 weeks of administration of the compound of formula (I) or its pharmaceutically acceptable salt; in other embodiments, waist circumference is reduced by 7-12 cm after 24 weeks of administration of the compound of formula (I) or its pharmaceutically acceptable salt.

[0094] In some embodiments, administration of the compound of formula (I) or its pharmaceutically acceptable salt for 24 weeks resulted in a BMI reduction of 3-5 kg / m². 2 .

[0095] In some embodiments, administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof achieves (i) a Cmax of 400-4250 ng / mL; and / or (ii) an AUC. 0-t The concentration is 5700-45500 ng*h / mL; in some embodiments, administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof achieves (i) a Cmax of 2500-4250 ng / mL; and / or (ii) an AUC. 0-t It is 37000-45500 ng*h / mL.

[0096] In some embodiments, after 24 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the change in body weight from baseline is -5 kg ​​to -15 kg; in some embodiments, the change in body weight from baseline is -5.0, -6.0, -7.0, -8.0, -9.0, -9.4, -9.48, -9.5, -10.0, -10.4, -10.47, -10.5, -11.0, -11.05, -11.1, -13.0, -13.04, -13.1, -13.4, -13.43, 13.5, -14.0, 14.5, -15.0 kg or any value between any two.

[0097] In some embodiments, after 24 weeks of treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the percentage change in body weight from baseline is -5% to -20%; in some embodiments, the percentage change in body weight from baseline is -5.0, -6.0, -7.0, -8.0, -9.0, -10.0, -10.3, -10.38, -10.4, -10.8, -10.83, -10.9, -11.0, -11.6, -11.67, -11.7, -12.0, -12.5, -13.0, -13.5, -13.6, -13.64, -13.7, -14.0, -14.5, -14.53, -14.6, -15.0, -16.0, -17.0, -18.0, -19.0, -20.0%, or any value between any two of these values.

[0098] In some embodiments, administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof achieves C max The concentration is 400-4250 ng / mL; in some implementations, Cmax is 400, 450, 458, 460, 500, 650, 600, 650, 700, 750, 800, 850, 860, 861, 870, 900, 950, 1000, 1500, 1900, 2000, 2500, 2600, 2690, 2700, 3000, 3500, 3900, 3990, 4000, 4100, 4120, 4200, 4250 ng / mL or any value between any two.

[0099] In some embodiments, the AUC is achieved upon administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. 0-t The concentration is 5700-52000 ng*h / mL; in some implementation schemes, the AUC is... 0-t For 5700, 5730, 5800, 6000, 7000, 8000, 9000, 10000, 11000, 11800, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, 21000, 22000, 23000, 24000, 25000, 26000, 27000, 28000, 28300, 290 00, 30000, 31000, 32000, 33000, 34000, 35000, 36000, 37000, 37100, 38000, 39000, 40000, 41000, 42 000, 43000, 44000, 45000, 45200, 46000, 47000, 48000, 49000, 50000, 51000, 51700, 52000ng*h / mL.

[0100] In some embodiments, the compound represented by formula (I) or its pharmaceutically acceptable salt is present in a unit dose formulation.

[0101] In some embodiments, the unit dose formulation contains at least 15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; in other embodiments, the unit dose formulation contains at least 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound of formula (I) is administered in the form of a free base.

[0103] In some embodiments, the compound of formula (I) is administered in the form of a free acid.

[0104] 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, methanesulfonate, and hydrobromide.

[0105] In some implementations, patients also receive additional therapies for overweight or obesity; in others, these additional therapies are diet therapy or exercise therapy.

[0106] In some implementations, the patient had previously failed to lose weight through diet or exercise intervention alone.

[0107] In some implementations, patients given the compound of formula (I) or its pharmaceutically acceptable salts experience a reduction in visceral fat and / or HbA1c levels.

[0108] In some embodiments, a core finding of this disclosure is that: administration of the compound of formula (I) at a dose of 5–30 mg (e.g., 5, 10, 15, 20, 25, or 30 mg) produces one or more effects compared to administration of the compound at a dose greater than 30 mg; in some embodiments, the compound of formula (I) is administered once daily at a dose of 5–30 mg (e.g., 5, 10, 15, 20, 25, or 30 mg); in some embodiments, the compound of formula (I) is administered twice daily at a dose of 5–30 mg (e.g., 5, 10, 15, 20, 25, or 30 mg), corresponding to a total daily dose of 10–60 mg; in some embodiments, the compound of formula (I) is administered at a dose of 5–30 mg in combination with dietary regulation and / or exercise intervention; in some embodiments, administration of the compound of formula (I) at a dose of 5–30 mg can achieve a weight loss of less than 5% from baseline; in some embodiments… In the administration regimen, compared to the placebo group, administration of compound (I) at a dose of 5–30 mg can achieve a weight loss of less than 5% from baseline; in some embodiments, administration of compound (I) at a dose of 5–30 mg has a lower weight loss effect than administration of the compound at a dose greater than 30 mg; in some embodiments, administration at a low dose (e.g., 5–30 mg) can reduce the incidence, severity, and / or frequency of one or more adverse events compared to administration of compound (I) at a dose greater than 30 mg; in some embodiments, administration at a low dose (e.g., 5–30 mg) can improve tolerability, treatment adherence, and / or optimize the benefit-risk ratio compared to administration of compound (I) at a dose greater than 30 mg; these improvements help improve patient adherence, enhance medication convenience, and expand the applicable population, benefiting more subjects who need weight management.

[0109] According to the relevant research data disclosed herein, the compound of formula (I) or its pharmaceutically acceptable salt has outstanding efficacy in treating overweight or obese patients, significantly increasing the proportion of subjects who respond to treatment, and is safe and controllable. Further development and application of this drug is expected to greatly change the current treatment status of overweight or obese patients.

[0110] The following numbered embodiments are not restrictive, but exemplify several technical aspects of this disclosure:

[0111] 1. A method for treating overweight or obesity, said method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0112] 2. A method for reducing the weight of a subject, the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0113] 3. A method for reducing overweight in a subject, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject in need.

[0114] 4. A method for reducing a subject's body mass index (BMI), the method comprising administering to a subject in need a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0115] 5. A method for reducing waist circumference, said method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0116] 6. The method according to 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.

[0117] 7. The method according to 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.

[0118] 8. The method according to 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.

[0119] 9. The method according to 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.

[0120] 10. The method according to 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.

[0121] 11. The method according to 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.

[0122] 12. The method according to 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.

[0123] 13. The method according to 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.

[0124] 14. The method according to 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.

[0125] 15. The method according to 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.

[0126] 16. The method according to 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.

[0127] 17. The method according to 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.

[0128] 18. The method according to 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.

[0129] 19. The method according to 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.

[0130] 20. The method according to 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.

[0131] 21. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0132] 22. The method according to 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.

[0133] 23. The method according to 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.

[0134] 24. The method according to 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.

[0135] 25. The method according to 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.

[0136] 26. The method according to 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.

[0137] 27. The method according to 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.

[0138] 28. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 255 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0139] 29. The method according to 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.

[0140] 30. The method according to 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.

[0141] 31. The method according to 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.

[0142] 32. The method according to 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.

[0143] 33. The method according to 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.

[0144] 34. The method according to 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.

[0145] 35. The method according to 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.

[0146] 36. The method according to 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.

[0147] 37. The method according to 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.

[0148] 38. The method according to 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.

[0149] 39. The method according to 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.

[0150] 40. The method according to 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.

[0151] 41. The method according to 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.

[0152] 42. The method according to 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.

[0153] 43. The method according to 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.

[0154] 44. The method according to 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.

[0155] 45. The method according to 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.

[0156] 46. ​​The method according to 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.

[0157] 47. The method according to 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.

[0158] 48. The method according to 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.

[0159] 49. The method according to 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.

[0160] 50. The method according to 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.

[0161] 51. The method according to 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.

[0162] 52. The method according to 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.

[0163] 53. The method according to 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.

[0164] 54. The method according to 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.

[0165] 55. The method according to 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.

[0166] 56. The method according to 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.

[0167] 57. The method according to 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.

[0168] 58. The method according to 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.

[0169] 59. The method according to 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.

[0170] 60. The method according to any one of embodiments 1 to 59, wherein the method comprises applying a compound of formula (I).

[0171] 61. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

[0172] 62. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily.

[0173] 63. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once weekly.

[0174] 64. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice weekly.

[0175] 65. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered three times a week.

[0176] 66. The method according to any one of embodiments 1 to 65, wherein the compound of formula (I) or its pharmaceutically acceptable salt is continuously administered for a period of time.

[0177] 67. The method according to implementation scheme 66, wherein the duration is at least one week.

[0178] 68. The method according to embodiment 66, wherein the duration is at least two weeks.

[0179] 69. The method according to embodiment 66, wherein the duration is at least three weeks.

[0180] 70. The method according to embodiment 66, wherein the duration is at least four weeks.

[0181] 71. The method according to any one of embodiments 1 to 70, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an escalating dose.

[0182] 72. The method according to any one of embodiments 1 to 71, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a maintenance dose.

[0183] 73. The method according to any one of embodiments 1 to 72, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered according to a titration administration regimen.

[0184] 74. The method according to embodiment 73, wherein the titration administration regimen includes administering one or more escalating doses, each dose being administered continuously for a period of time.

[0185] 75. The method according to embodiment 74, wherein the duration is 1 to 4 weeks.

[0186] 76. The method according to implementation scheme 74, wherein the duration is less than one week.

[0187] 77. The method according to implementation scheme 74, wherein the duration is more than four weeks.

[0188] 78. The method according to implementation scheme 74, wherein the duration is one week.

[0189] 79. The method according to implementation scheme 74, wherein the duration is two weeks.

[0190] 80. The method according to implementation scheme 74, wherein the duration is three weeks.

[0191] 81. The method according to implementation scheme 74, wherein the duration is four weeks.

[0192] 82. The method according to any one of embodiments 73 to 81, wherein the titration administration regimen further includes administering a maintenance dose.

[0193] 83. The method according to any one of embodiments 71 to 82, wherein the one or more incremental doses are 15 to 720 mg.

[0194] 84. The method according to any one of embodiments 71 to 82, wherein the one or more incremental doses are 5 to 60 mg.

[0195] 85. The method according to any one of embodiments 71 to 84, wherein the incremental dose is 5 mg.

[0196] 86. The method according to any one of embodiments 71 to 85, wherein the incremental dose is 10 mg.

[0197] 87. The method according to any one of embodiments 71 to 86, wherein the incremental dose is 15 mg.

[0198] 88. The method according to any one of embodiments 71 to 87, wherein the incremental dose is 20 mg.

[0199] 89. The method according to any one of embodiments 71 to 88, wherein the incremental dose is 25 mg.

[0200] 90. The method according to any one of embodiments 71 to 89, wherein the incremental dose is 30 mg.

[0201] 91. The method according to any one of embodiments 71 to 90, wherein the incremental dose is 45 mg.

[0202] 92. The method according to any one of embodiments 71 to 91, wherein the incremental dose is 60 mg.

[0203] 93. The method according to any one of embodiments 71 to 92, wherein the incremental dose is 90 mg.

[0204] 94. The method according to any one of embodiments 71 to 93, wherein the incremental dose is 120 mg.

[0205] 95. The method according to any one of embodiments 71 to 94, wherein the incremental dose is 150 mg.

[0206] 96. The method according to any one of embodiments 71 to 95, wherein the incremental dose is 180 mg.

[0207] 97. The method according to any one of embodiments 71 to 96, wherein the incremental dose is 210 mg.

[0208] 98. The method according to any one of embodiments 71 to 97, wherein the incremental dose is 240 mg.

[0209] 99. The method according to any one of embodiments 71 to 98, wherein the incremental dose is 270 mg.

[0210] 100. The method according to any one of embodiments 71 to 99, wherein the incremental dose is 300 mg.

[0211] 101. The method according to any one of embodiments 71 to 100, wherein the incremental dose is 330 mg.

[0212] 102. The method according to any one of embodiments 71 to 101, wherein the incremental dose is 360 mg.

[0213] 103. The method according to any one of embodiments 71 to 102, wherein the incremental dose is 390 mg.

[0214] 104. The method according to any one of embodiments 71 to 103, wherein the incremental dose is 420 mg.

[0215] 105. The method according to any one of embodiments 71 to 104, wherein the incremental dose is 450 mg.

[0216] 106. The method according to any one of embodiments 71 to 105, wherein the incremental dose is 480 mg.

[0217] 107. The method according to any one of embodiments 71 to 106, wherein the incremental dose is 510 mg.

[0218] 108. The method according to any one of embodiments 71 to 107, wherein the incremental dose is 540 mg.

[0219] 109. The method according to any one of embodiments 71 to 108, wherein the incremental dose is 570 mg.

[0220] 110. The method according to any one of embodiments 71 to 109, wherein the incremental dose is 600 mg.

[0221] 111. The method according to any one of embodiments 71 to 110, wherein the incremental dose is 630 mg.

[0222] 112. The method according to any one of embodiments 71 to 111, wherein the incremental dose is 660 mg.

[0223] 113. The method according to any one of embodiments 71 to 112, wherein the incremental dose is 690 mg.

[0224] 114. The method according to any one of embodiments 71 to 113, wherein the incremental dose is 720 mg.

[0225] 115. The method according to any one of embodiments 72 to 114, wherein the maintenance dose is 5 to 720 mg.

[0226] 116. The method according to any one of embodiments 72 to 115, wherein the maintenance dose is 5 to 30 mg.

[0227] 117. The method according to embodiment 115, wherein the maintenance dose is 5 mg.

[0228] 118. The method according to embodiment 115, wherein the maintenance dose is 10 mg.

[0229] 119. The method according to embodiment 115, wherein the maintenance dose is 15 mg.

[0230] 120. The method according to embodiment 115, wherein the maintenance dose is 20 mg.

[0231] 121. The method according to embodiment 115, wherein the maintenance dose is 25 mg.

[0232] 122. The method according to embodiment 115, wherein the maintenance dose is 30 mg.

[0233] 123. The method according to embodiment 115, wherein the maintenance dose is 45 mg.

[0234] 124. The method according to embodiment 115, wherein the maintenance dose is 60 mg.

[0235] 125. The method according to embodiment 115, wherein the maintenance dose is 90 mg.

[0236] 126. The method according to embodiment 115, wherein the maintenance dose is 120 mg.

[0237] 127. The method according to embodiment 115, wherein the maintenance dose is 150 mg.

[0238] 128. The method according to embodiment 115, wherein the maintenance dose is 180 mg.

[0239] 129. The method according to embodiment 115, wherein the maintenance dose is 210 mg.

[0240] 130. The method according to embodiment 115, wherein the maintenance dose is 240 mg.

[0241] 131. The method according to embodiment 115, wherein the maintenance dose is 270 mg.

[0242] 132. The method according to embodiment 115, wherein the maintenance dose is 300 mg.

[0243] 133. The method according to embodiment 115, wherein the maintenance dose is 330 mg.

[0244] 134. The method according to embodiment 115, wherein the maintenance dose is 360 mg.

[0245] 135. The method according to embodiment 115, wherein the maintenance dose is 390 mg.

[0246] 136. The method according to embodiment 115, wherein the maintenance dose is 420 mg.

[0247] 137. The method according to embodiment 115, wherein the maintenance dose is 450 mg.

[0248] 138. The method according to embodiment 115, wherein the maintenance dose is 480 mg.

[0249] 139. The method according to embodiment 115, wherein the maintenance dose is 510 mg.

[0250] 140. The method according to embodiment 115, wherein the maintenance dose is 540 mg.

[0251] 141. The method according to embodiment 115, wherein the maintenance dose is 570 mg.

[0252] 142. The method according to embodiment 115, wherein the maintenance dose is 600 mg.

[0253] 143. The method according to embodiment 115, wherein the maintenance dose is 630 mg.

[0254] 144. The method according to embodiment 115, wherein the maintenance dose is 660 mg.

[0255] 145. The method according to embodiment 115, wherein the maintenance dose is 690 mg.

[0256] 146. The method according to embodiment 115, wherein the maintenance dose is 720 mg.

[0257] 147. The method according to any one of embodiments 1 to 146, wherein the method comprises oral administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0258] 148. The method according to embodiment 147, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an oral dosage form.

[0259] 149. The method according to embodiment 148, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a solid oral dosage form.

[0260] 150. The method according to embodiment 149, wherein the solid oral dosage form is a tablet.

[0261] 151. The method according to embodiment 149, wherein the solid oral dosage form is a capsule.

[0262] 152. The method according to any one of embodiments 1 to 151, wherein the subject is an obese person.

[0263] 153. The method according to any one of embodiments 1 to 152, wherein the subject is an overweight person.

[0264] 154. The method according to any one of embodiments 1 to 153, wherein the subject suffers from at least one weight-related comorbidity.

[0265] 155. The method according to embodiment 154, wherein the weight-related comorbidities are selected from prediabetes, dyslipidemia, obstructive sleep apnea, and non-alcoholic fatty liver disease.

[0266] 156. The method according to any one of embodiments 1 to 155, wherein the subject is an adult.

[0267] 157. The method according to any one of embodiments 1 to 155, wherein the subject is a child.

[0268] 158. The method according to any one of embodiments 1 to 157, wherein the subject is a human.

[0269] 159. The method according to any one of embodiments 1 to 158, wherein the subject is male.

[0270] 160. The method according to any one of embodiments 1 to 158, wherein the subject is female.

[0271] 161. The method according to any one of embodiments 1 to 160, wherein the subject suffers from diabetes.

[0272] 162. The method according to embodiment 161, wherein the diabetes is type 2 diabetes.

[0273] 163. The method according to any one of embodiments 1 to 160, wherein the subject does not have diabetes.

[0274] 164. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥24.0 kg / m². 2 And <28.0kg / m 2 .

[0275] 165. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥28.0 kg / m². 2 .

[0276] 166. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 .

[0277] 167. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is > 32.5 kg / m². 2 And ≤40.0kg / m 2 .

[0278] 168. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 .

[0279] 169. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 .

[0280] 170. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 .

[0281] 171. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2 .

[0282] 172. The method according to any one of embodiments 1 to 163, wherein the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 .

[0283] 173. The method according to any one of embodiments 1 to 172, wherein the method further includes dietary therapy (e.g., a low-calorie diet).

[0284] 174. The method according to any one of embodiments 1 to 173, wherein the method further includes exercise therapy (e.g., increasing physical activity).

[0285] 175. The method according to any one of embodiments 1 to 174, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects in accordance with a predetermined dosing regimen to achieve a weight loss of at least 5% from baseline after 24, 26, 36 or 50 weeks of administration.

[0286] 176. The method according to any one of embodiments 1 to 175, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, in accordance with a predetermined dosing regimen, to achieve a weight loss of at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 17%, 19%, or 20% from baseline after 24, 26, 36, or 50 weeks of administration.

[0287] 177. The method according to any one of embodiments 1 to 176, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects in accordance with a predetermined dosing regimen to achieve a weight loss of at least 5% from baseline compared to the placebo group after 24, 26, 36 or 50 weeks of dosing.

[0288] 178. The method according to any one of embodiments 1 to 177, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, in accordance with a predetermined dosing regimen, to achieve a weight loss of at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 17%, 19%, 20%, 22%, 25%, 27%, 29%, or 30% from baseline compared to the placebo group after 24, 26, 36, or 50 weeks of dosing.

[0289] 179. The method according to any one of embodiments 1 to 178, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a weight loss of at least 5% from baseline in at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of subjects after 24, 26, 36, or 50 weeks of administration.

[0290] 180. The method according to any one of embodiments 1 to 179, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, in accordance with a predetermined dosing regimen, to achieve a weight loss from baseline of at least 0.5, 0.8, 1, 1.2, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5.0 times that of the placebo group after 24, 26, 36, or 50 weeks of administration.

[0291] 181. The method according to any one of embodiments 1 to 180, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 24, 26, 36, or 50 weeks of administration, a proportion of subjects achieving at least a 5% weight loss from baseline, compared to the placebo group, by at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 10%, 20%, 30%, 40%, 50%, or 60%.

[0292] 182. The method according to any one of embodiments 1 to 181, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a weight loss of at least 10% to 65% of subjects after 24, 26, 36, or 50 weeks of administration, respectively, from baseline.

[0293] 183. The method according to any one of embodiments 1 to 182, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, in accordance with a predetermined dosing regimen, to achieve a weight loss from baseline of at least 0.5, 0.8, 1, 1.2, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5.0, 5.5, 6, 6.5, or 7 times that of the placebo group after 24, 26, 36, or 50 weeks of administration.

[0294] 184. The method according to any one of embodiments 1 to 183, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 24, 26, 36, or 50 weeks of administration, a proportion of subjects achieving at least a 10% weight loss from baseline, at least 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% higher than the placebo group.

[0295] 185. The method according to any one of embodiments 1 to 184, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a weight loss of at least 15% from baseline in at least 10%, 12%, 15%, 20%, 22%, 25%, 30%, or 32% of subjects after 24, 26, 36, or 50 weeks of administration.

[0296] 186. The method according to any one of embodiments 1 to 185, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of dosing, a least-squares mean (95% confidence interval) percentage change in body weight from baseline of -2.9%, -2.99%, -3.0%, -4.0%, -5.0%, -6.0%, -6.17%, -6.5%, -7.0%, -7.09%, -7.1%, -7.5%, -8.0%, -9.0%, -9.3%, -9.36%, -9.4%, -10.0%, -11.0%, -12.0%, -12.5%, or -12.6%.

[0297] 187. The method according to any one of embodiments 1 to 186, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of dosing, a least-squares mean (95% confidence interval) percentage change in body weight from baseline compared to the placebo group of -0.4%, -0.49%, -0.5%, -1.0%, -2.0%, -3.0%, -6.5%, -3.67%, -3.7%, -4.0%, -4.5%, -4.60%, -5.0%, -5.5%, -6.0%, -6.5%, -6.8%, -6.87%, -6.9%, -7.0%, -8.0%, -9.0%, -10.0%, or -10.2%.

[0298] 188. The method according to any one of embodiments 1 to 187, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a least-squares mean (95% confidence interval) percentage change in body weight from baseline of -2.4%, -2.44%, -2.5%, -3.0%, -4.0%, -5.0%, -5.3%, -5.36%, -5.4%, -5.5%, -6.0%, -7.0%, -8.0%, -9.0%, -9.4%, -9.46%, -9.5%, or -10.0% after 36 weeks of administration.

[0299] 189. The method according to any one of embodiments 1 to 188, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of dosing, a least-squares mean (95% confidence interval) percentage change in body weight from baseline compared to the placebo group of -1.0%, -1.06%, -1.1%, -2.0%, -3.0%, -3.5%, -3.9%, -3.97%, -3.98%, -4.0%, -5.0%, -6.0%, -7.0%, -8.0%, -8.08%, -8.1%, or -8.5%.

[0300] 190. The method according to any one of embodiments 1 to 189, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of administration, a least-squares mean (95% confidence interval) weight change from baseline of -2.5 kg, -2.59 kg, -2.6 kg, -3.0 kg, -4.0 kg, -5.0 kg, -5.40 kg, -5.5 kg, -6.0 kg, -6.3 kg, -6.33 kg, -6.5 kg, -7.0 kg, -7.5 kg, -8.0 kg, -8.2 kg, -8.40 kg, or -8.5 kg.

[0301] 191. The method according to any one of embodiments 1 to 190, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of administration, a least-squares mean (95% confidence interval) weight change from baseline compared to the placebo group of -0.3 kg, -0.39 kg, -0.4 kg, -0.5 kg, -1.0 kg, -2.0 kg, -3.0 kg, -3.20 kg, -3.5 kg, -4.0 kg, -4.1 kg, -4.13 kg, -4.5 kg, -5.0 kg, -5.5 kg, -6.0 kg, -6.1 kg, -6.20 kg, or -6.5 kg.

[0302] 192. The method according to any one of embodiments 1 to 191, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of administration, a least-squares mean (95% confidence interval) weight change from baseline of -2.0 kg, -2.12 kg, -2.2 kg, -3.0 kg, -4.0 kg, -4.5 kg, -4.58 kg, -4.6 kg, -4.7 kg, -4.76 kg, -4.8 kg, -5.0 kg, -6.0 kg, -7.0 kg, -8.0 kg, -8.5 kg, -8.52 kg, -8.6 kg, or -9.0 kg.

[0303] 193. The method according to any one of embodiments 1 to 192, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of administration, a least-squares mean (95% confidence interval) weight change from baseline compared to the placebo group of -1.0 kg, -1.02 kg, -1.1 kg, -2.0 kg, -3.0 kg, -3.4 kg, -3.48 kg, -3.5 kg, -3.65 kg, -3.7 kg, -4.0 kg, -5.0 kg, -6.0 kg, -7.0 kg, -7.4 kg, -7.41 kg, -7.5 kg, or -8.0 kg.

[0304] 194. The method according to any one of embodiments 1 to 193, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of administration, a least-squares mean change in body mass index (BMI) from baseline of -0.9, -0.92, -1.0, -1.5, -1.9, -1.99, -2.0, -2.1, -2.2, -2.28, -2.3, -2.5, -3.0, -3.04, -3.1, -3.5, -4.0 or -5.0 kg / m². 2 .

[0305] 195. The method according to any one of embodiments 1 to 194, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of administration, a least-squares mean change in body mass index (BMI) from baseline compared to the placebo group of at least -0.1, -0.14, -0.2, -0.4, -0.6, -0.8, -1.0, -1.1, -1.2, -1.3, -1.4, -1.49, -1.5, -1.6, -1.7, -1.8, -1.9, -2.0, -2.1, -2.2, -2.25, -2.3, -2.4, -2.5, -2.6, -2.7, -2.8, -2.9 or -3.0 kg / m². 2 .

[0306] 196. The method according to any one of embodiments 1 to 195, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of administration, a least-squares mean change in body mass index (BMI) from baseline of -0.7, -0.78, -0.8, -0.9, -1.0, -1.2, -1.4, -1.6, -1.7, -1.72, -1.73, -1.8, -2.0, -2.2, -2.4, -2.6, -2.8, -3.0, -3.08, -3.1, -3.2, -3.3, -3.4, -3.5, -4.0 or -5.0 kg / m². 2 .

[0307] 197. The method according to any one of embodiments 1 to 196, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of dosing, a least-squares mean change in body mass index (BMI) from baseline compared to the placebo group of -0.3, -0.37, -0.4, -0.6, -0.8, -1.0, -1.2, -1.3, -1.31, -1.32, -1.4, -1.6, -1.8, -2.0, -2.2, -2.4, -2.6, -2.67, -2.7, or -2.8 kg / m². 2 .

[0308] 198. The method according to any one of embodiments 1 to 197, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a least-squares mean change in waist circumference from baseline of -3.25, -3.26, -3.3, -3.5, -3.7, -3.9, -4.0, -4.5, -5.0, -5.5, -5.6, -5.7, -5.79, -5.8, -6.0, -6.1, -6.12, -6.2, -6.4, -6.6, -6.8, -7.0, -7.5, -8.0, -9.0, -10.0, -11.0, -12.0, -13.0 or -14.0 cm.

[0309] 199. The method according to any one of embodiments 1 to 198, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 26 weeks of administration, a least-squares mean change in waist circumference from baseline compared to the placebo group of -0.05, -0.07, -0.09, -0.1, -0.15, -0.2, -0.4, -0.6, -0.8, -1.0, -1.5, -2.0, -2.5, -2.57, -2.6, -2.9, -2.91, -3.0, -3.5, -4.0, -4.5, or -5.0 cm.

[0310] 200. The method according to any one of embodiments 1 to 199, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of administration, a least-squares mean change in waist circumference from baseline of at least -2.9, -3.0, -3.2, -3.4, -3.6, -3.8, -4.0, -4.5, -5.0, -5.2, -5.25, -5.3, -5.4, -5.48, -5.5, -6.0, -6.5, -7.0, -7.5, -8.0, -8.03, -8.1, -8.5, -9.0, -10.0, -11.0, -12.0, -13.0, -14.0, or -15.0 cm.

[0311] 201. The method according to any one of embodiments 1 to 200, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve, after 36 weeks of administration, a least-squares mean change in waist circumference from baseline compared to the placebo group of -0.5, -1.0, -1.5, -2.0, -2.1, -2.14, -2.2, -2.3, -2.37, -2.4, -2.6, -2.8, -3.0, -3.5, -4.0, -4.5, -4.9, -4.92 or -5.0 cm.

[0312] 202. The method according to any one of embodiments 1 to 201, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable subject population according to a predetermined dosing regimen to achieve a body mass index (BMI) ≤ 32.5 kg / m² after 26 weeks of dosing. 2For the subjects, the least squares mean percentage change in body mass index (BMI) from baseline was -3.5%, -3.6%, -3.7%, -3.8%, -3.85%, -3.9%, -4.0%, -4.5%, -5.0%, -5.5%, -6.0%, -6.5%, -6.59%, -7.0%, -7.5%, -8.0%, -8.5%, -8.7%, -8.75%, -8.8%, -9.0%, -9.2%, -9.30%, -9.4%, -9.5%, or -10.0%.

[0313] 203. The method according to any one of embodiments 1 to 202, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a body mass index (BMI) > 32.5 kg / m² after 26 weeks of administration. 2 The least-squares mean percentage change in body mass index (BMI) from baseline for the subjects was -1.3%, -1.5%, -1.7%, -1.78%, -1.8%, -2.0%, -2.5%, -3.5%, -3.6%, -3.7%, -3.8%, -3.9%, -4.0%, -4.5%, -5.0%, -5.04%, - 5.1%, -5.5%, -5.6%, -5.63%, -5.7%, -6.0%, -6.5%, -6.6%, -6.8%, -7.0%, -7.5%, -8.0%, -8.5%, -8.7%, -8.8%, -9.0%, -9.2%, -9.3%, -9.31%, -9.4%, -9.5%, or -10.0%.

[0314] 204. The method according to any one of embodiments 1 to 203, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a body mass index (BMI) ≤ 32.5 kg / m² after 26 weeks of administration. 2 For the subjects, the least squares mean percentage change in body mass index (BMI) from baseline, compared to the placebo group, was at least -0.3%, -0.35%, -0.4%, -0.41%, -0.5%, -1.0%, -1.5%, -2.0%, -2.5%, -3.0%, -3.1%, -3.15%, -3.5%, -4.0%, -4.5%, -5.0%, -5.1%, -5.3%, -5.31%, -5.4%, -5.5%, -5.6%, -5.7%, -5.8%, -5.86%, -5.9%, -6.0%, or -6.5%.

[0315] 205. The method according to any one of embodiments 1 to 204, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a body mass index (BMI) > 32.5 kg / m² after 26 weeks of administration. 2 Among the participants, the least squares mean percentage change in body mass index (BMI) from baseline, compared to the placebo group, was -0.3%, -0.4%, -0.5%, -0.52%, -0.6%, -0.8%, -1.0%, -1.5%, -2.0%, -2.5%, -3.0%, -3.1%, -3.2%, -3.5%, -3.78%, -4.0%, -4.3%, -4.5%, -5.0%, -5.1%, -5.3%, -5.4%, -5.5%, -5.6%, -5.7%, -5.8%, -5.9%, -6.0%, -6.5%, -8.0%, -8.05%, -8.1%, -8.5%, -9.0%, or -9.5%.

[0316] 206. The method according to any one of embodiments 1 to 205, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects in accordance with a predetermined dosing regimen to achieve a weight loss of 5% to 20% after 24 or 26 weeks of administration.

[0317] 207. The method according to any one of embodiments 1 to 206, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a reduction in waist circumference of 5 to 10 cm in the subjects.

[0318] 208. The method according to any one of embodiments 1 to 207, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a reduction in body mass index (BMI) of 3 to 5 kg / m² after 24 weeks of administration. 2 .

[0319] 209. The method according to any one of embodiments 1 to 208, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a weight change from baseline of -5.0, -6.0, -7.0, -8.0, -9.0, -9.4, -9.48, -9.5, -10.0, -10.4, -10.47, -10.5, -11.0, -11.05, -11.1, -13.0, -13.04, -13.1, -13.4, -13.43, -13.5, -14.0, -14.5, -13.5, -14.0, -14.5 kg after 24 weeks of administration.

[0320] 210. The method according to any one of embodiments 1 to 209, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, according to a predetermined dosing regimen, to achieve a percentage change in body weight from baseline of -5.0%, -6.0%, -7.0%, -8.0%, -9.0%, -10.0%, -10.3%, -10.38%, -10.4%, -10.8%, - 10.83%, -10.9%, -11.0%, -11.6%, -11.67%, -11.7%, -12.0%, -12.5%, -13.0%, -13.5%, -13.6%, -13.64%, -13.7%, -14.0%, -14.5%, -14.53%, -14.6%, -15.0%, -16.0%, -17.0%, -18.0%, -19.0%, or -20.0%.

[0321] 211. The method according to any one of embodiments 1 to 210, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve a percentage change in body weight from baseline of <5%.

[0322] 212. The method according to any one of embodiments 1 to 211, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects in accordance with a predetermined dosing regimen to improve weight management efficacy.

[0323] 213. The method according to any one of embodiments 1 to 212, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve peak plasma concentration (C0). maxThe concentrations reached 400, 450, 458, 460, 500, 650, 600, 650, 700, 750, 800, 850, 860, 861, 870, 900, 950, 1000, 1500, 1900, 2000, 2500, 2600, 2690, 2700, 3000, 3500, 3900, 3990, 4000, 4100, 4120, 4200, or 4250 ng / mL.

[0324] 214. The method according to any one of embodiments 1 to 213, wherein the method comprises: administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects according to a predetermined dosing regimen to achieve the area under the plasma concentration-time curve (AUC). 0-t Reaching 5700, 5730, 5800, 6000, 7000, 8000, 9000, 10000, 11000, 11800, 12000, 13000, 14000, 15000, 16000, 17000, 18000, 19000, 20000, 21000, 22000, 23000, 24000, 25000, 26000, 27000, 28000, 28300, 29 000, 30000, 31000, 32000, 33000, 34000, 35000, 36000, 37000, 37100, 38000, 39000, 40000, 41000, 42000, 43000, 44000, 45000, 45200, 46000, 47000, 48000, 49000, 50000, 51000, 51700 or 52000 ng*h / mL.

[0325] 215. The method according to any one of embodiments 1 to 214, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is the only active ingredient administered to the subject.

[0326] Terminology Definition

[0327] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0328] "Overweight" refers to a subject weighing 24.0 kg / m². 2 ≤BMI<28.0kg / m 2 .

[0329] "Obesity" refers to a subject's BMI ≥ 28.0 kg / m². 2 .

[0330] BMI (Body Mass Index) is calculated by dividing weight (in kilograms, kg) by the square of height (in meters, m) (kg / m²). 2 The formula is as follows:

[0331] BMI = weight / height² (kg / m²) 2 ).

[0332] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0333] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the total impurity content, where the error variation after measurement does not exceed ±10%, can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and in some embodiments, ±5%.

[0334] When the term "about" is applied to parameters such as pH, concentration, temperature, and range of variation, it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0335] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0336] In this document, the term "comparability" refers to two or more reagents, individuals, situations, condition groups, environments, subjects, or populations that are not necessarily identical, but possess sufficient similarity to support a comparison between them; those skilled in the art can draw reasonable conclusions based on observed differences or similarities. In some embodiments, comparable reagents, individuals, situations, condition groups, environments, subjects, or populations are characterized by the presence of multiple substantially consistent characteristics and only one or a few different characteristics. Those skilled in the art can determine, depending on the specific context, the degree of consistency required between two or more of the aforementioned reagents, individuals, situations, condition groups, environments, subjects, or populations in any given situation to be considered comparable. For example, those skilled in the art can understand that when two or more groups of situations, reagents, individuals, situations, subjects, or populations possess a sufficient number and type of substantially consistent characteristics, they can be considered comparable; in this case, it is reasonable to conclude that the differences in results or phenomena observed in / under different reagents, individuals, situations, condition groups, environments, subjects, or populations are caused by one or more of these different characteristics, or are representations of these different characteristics.

[0337] The term "pharmaceutical-acceptable excipient" or "pharmaceutical-acceptable excipient" includes any material that, when combined with an active ingredient, allows that ingredient to retain its biological activity and does not react with the subject's immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0338] The terms “give,” “apply,” and “treat,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. “Give,” “apply,” and “treat” also mean treatment, such as of 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, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0339] The term "treatment" means administering a therapeutic agent, such as a compound comprising any of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, to a subject who has, is suspected of having, or is predisposed to being overweight or obese, and for whom the therapeutic agent is known to have a therapeutic effect. Typically, administering a therapeutic agent in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases is done by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test method 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 the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, 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. The patients to be treated are mammals, and in some embodiments, are humans.

[0340] The term “prevention” refers to reducing the risk or incidence of one or more conditions, symptoms, complications or ailments, or eliminating or slowing the progression of one or more conditions, symptoms, complications or ailments.

[0341] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0342] BMI stands for Body Mass Index.

[0343] HbA1c refers to glycated hemoglobin.

[0344] FPG refers to fasting blood glucose.

[0345] SBP refers to systolic blood pressure.

[0346] DBP refers to diastolic blood pressure.

[0347] eGFR refers to the estimated glomerular filtration rate.

[0348] TEAE refers to adverse events that occur during treatment.

[0349] AESI refers to adverse events of particular concern.

[0350] ULN refers to the upper limit of the normal value. Attached Figure Description

[0351] Figure 1. Titration methods for each dosage group in Example 1;

[0352] Figure 2 shows the titration methods for each dosage group in Example 2.

[0353] Figure 3 shows the percentage of patients who lost ≥5%, ≥10%, and ≥15% of their body weight by week 26 in Example 1.

[0354] Figure 4. Percentage change in body weight relative to baseline over 36 weeks in Example 1 (ITT, excluding subjects with two consecutive PK values ​​of BLQ).

[0355] Figure 5. Percentage change in body weight relative to baseline over 36 weeks in Example 1 (ITT, excluding subjects with PK value BLQ).

[0356] Figure 6 shows the absolute change in body weight relative to baseline over 36 weeks in Example 1.

[0357] Figure 7 shows the percentage of patients who lost ≥5%, ≥10%, and ≥15% of their body weight by week 36 in Example 1.

[0358] Figure 8. Percentage change in body weight relative to baseline at week 36 in patients in the once-daily oral (I) compound and placebo groups in Example 1 (post-hoc analysis). (A) Female; (B) Male.

[0359] Figure 9 shows the changes in BMI (A) and waist circumference (B) relative to baseline during 36 weeks of treatment in Example 1.

[0360] Figure 10. The proportion of participants who reported gastrointestinal adverse events (full causation) during the 36-week treatment period in Example 1.

[0361] Figure 11. Participant information in Example 1.

[0362] Figure 12 shows the percentage change in body weight relative to baseline over 36 weeks in Example 1.

[0363] Figure 13. Scheme design diagram of Example 3.

[0364] Figure 14. Case 3: Early termination of treatment in the subject.

[0365] Figure 15 shows the percentage change in body weight relative to baseline over 24 weeks in Example 3.

[0366] Figure 16 shows the proportion of subjects whose weight decreased by ≥5%, ≥10%, and ≥15% from baseline in Example 3.

[0367] Figure 17 shows the average change in body weight relative to baseline in Example 3.

[0368] Figure 18 shows the change in waist circumference relative to the baseline in Example 3.

[0369] Figure 19 shows the change in BMI relative to baseline in Example 3. Detailed Implementation

[0370] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0371] Example 1. Study on the efficacy of compound (I) in treating obese patients.

[0372] I. Research on drugs

[0373] Test drug: The compound shown in formula (I), 15 mg / tablet and 30 mg / tablet.

[0374] Control group: placebo, 15 mg / tablet and 30 mg / tablet. The placebo did not contain the test drug and was identical in appearance, color and shape to the compound tablet shown in formula (I).

[0375] II. Inclusion criteria, exclusion criteria, and randomization criteria

[0376] Patients must meet all of the following inclusion criteria to be enrolled in this study:

[0377] 1. Age limit for screening: 18 years old ≤ age ≤ 65 years old, gender not limited;

[0378] 2. The body mass index (BMI) at screening and randomization time was 28.0 kg / m². 2 ≤BMI≤40.0kg / m 2 ;

[0379] 3. Self-report that you have controlled your diet and exercise for 3 months or more before screening and randomization, and that your weight change (weight gain and / or loss) in the past 3 months does not exceed 5%;

[0380] Subjects with any of the following characteristics / conditions should not be enrolled in this study:

[0381] The following checks were found to be abnormal during the screening process:

[0382] 1. The following laboratory test results were available during screening:

[0383] - Fasting glucose ≥7.0 mmol / L, or glycated hemoglobin (HbA1c) ≥6.5%;

[0384] - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN);

[0385] - Total bilirubin > 1.5 × ULN;

[0386] -Amylase and / or lipase >2×ULN;

[0387] - Renal insufficiency (estimated glomerular filtration rate [eGFR] calculated using the formula in Annex II of the Chronic Kidney Disease Epidemiology Collaboration Group [CKD-EPI] <60 mL / min / 1.73 m 2 );

[0388] - Calcitonin ≥20ng / L.

[0389] 2. Those whose electrocardiogram results showed clinically significant abnormalities during screening, such as supraventricular tachycardia, atrial fibrillation, atrial flutter, second- or third-degree atrioventricular block, etc., and who were deemed unsuitable for inclusion in this study by the researchers;

[0390] 3. Heart rate or pulse >100 beats / min during screening;

[0391] 4. During screening, the electrocardiogram (ECG) results indicated that the ECG QTcF was >450ms;

[0392] 5. PHQ-9 score ≥ 15 points;

[0393] 6. Severe hypertension that is not under control at the time of screening (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0394] Those with the following diseases or medical history prior to screening:

[0395] 7. The presence or history of endocrine disorders that may significantly affect weight (such as Cushing's syndrome, hypothyroidism or hyperthyroidism, etc., except for hypothyroidism if thyroid hormone therapy has maintained normal thyroid function and the replacement dose has been stable for at least 3 months);

[0396] 8. History of diabetes (excluding gestational diabetes);

[0397] 9. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2;

[0398] 10. History of acute or chronic pancreatitis;

[0399] 11. History of cholecystitis, or previous gallbladder disease with symptoms (except for subjects who have previously undergone cholecystectomy and are deemed eligible for enrollment by the researchers);

[0400] Ranking can only proceed after the subject has completed the induction treatment and is confirmed to meet the following randomization criteria again on the day of randomization.

[0401] 1. Medication adherence during the introductory period is ≥80% and ≤120%;

[0402] 2. Weight and BMI meet the inclusion criteria;

[0403] 3. Urine pregnancy test (if applicable) negative;

[0404] During this study, participants are required to:

[0405] 1. Dietary control: After enrollment, the total energy expenditure (TEE) should be 500 kcal more per day than the estimated total energy expenditure (TEE) calculated at the time of screening. If the subject's BMI is ≤22.5 kg / m2 during the trial, the dietary control can be appropriately relaxed.

[0406] 2. Exercise recommendations: Encourage 150 minutes of physical activity per week, such as walking or climbing stairs;

[0407] 3. Within 24 hours prior to each hospital visit, you must not consume alcohol (or alcoholic beverages), smoke (or consume any other tobacco products);

[0408] 4. Avoid strenuous exercise within 24 hours before each blood draw for laboratory testing.

[0409] 5. Female subjects who are of childbearing age, and male subjects whose female partners are of childbearing age, must be informed and instructed by the investigator or their designated personnel to use the highly effective contraceptive method specified in the protocol from the time they sign the informed consent form until two weeks after the last dose of the investigational drug.

[0410] III. Administration Method

[0411] This study consists of five parts: a screening period (no more than 2 weeks), a 2-week induction period, a 26-week core treatment period, a 10-week extended treatment period, and a 2-week follow-up period.

[0412] Screening period: Subjects must sign an informed consent form in writing before participating in the screening, based on the principle of voluntariness. The screening process will be conducted from day -14 to day -1 (D-14 to D-1). Only subjects who meet all inclusion criteria and do not meet any exclusion criteria can participate in the randomization.

[0413] Introduction phase: Qualified subjects enter the introduction phase in V2, are given introduction medication, and are given instructions on how to complete the subject diary card.

[0414] Core treatment period: Successfully randomized subjects were randomly assigned to one of five dose groups (treatment group / placebo group) at the V3 visit. The core treatment period consisted of eight visits, during which subjects completed medication as required by the protocol.

[0415] Extended treatment period: Subjects who have completed the core treatment period will officially enter the extended treatment period during the V11 visit, and the types and methods of medication will be the same as those required for the core treatment period.

[0416] Follow-up period: Subjects who have taken double-blind treatment medication after randomization (14 days after the last dose) need to complete the follow-up period check according to the study flowchart.

[0417] 235 adults (BMI 28-40 kg / m²) 2 They were randomly assigned (1:1:1:1:1) to receive oral (I) compound or placebo at target doses of 30, 60, 120 and 180 mg once daily (QD) for 36 weeks (26 weeks of core treatment and 10 weeks of extension treatment).

[0418] Subjects should take 7 tablets of compound (I) or 7 placebo tablets with water immediately after breakfast each day. The tablets must be swallowed whole and should not be left in place or chewed before swallowing. Subjects are advised to take the medication at the same or similar time each day and not to exceed the prescribed dose each time.

[0419] The titration methods for each dosage group are detailed in Figure 1.

[0420] The number of tablets administered in each dosage group is shown in Table 1 below:

[0421] Table 1. Number of tablets in each dosage group

[0422] Missed Dosage Instructions: If a subject misses a dose of the study medication on a given day, they must still take the missed dose the following day as prescribed. The missed dose from the first day cannot be taken retroactively. If a subject forgets to take their medication in the morning, they can take it before 12:00 PM that day (it is recommended to take the medication after eating).

[0423] Instructions for medication-induced vomiting: If a subject vomits after taking the medication, they should not take another dose, but should take the prescribed dose the following day.

[0424] Instructions for subjects who unintentionally overdose on medication: If a subject overdoses on medication, they must immediately inform the researcher, and the researcher and the sponsor will jointly decide whether to adjust the dosage the following day.

[0425] During the introductory phase of the study (single-blind), participants received placebo treatment. In order not to affect participants' medication adherence, researchers had to comply with the single-blind design requirements and not inform participants of the drug components they were taking.

[0426] IV. Clinical endpoint:

[0427] Between February 23 and March 18, 2024, 339 Chinese adults were screened, and 235 eligible participants were randomly assigned to receive once-daily (I) compound treatment at target doses of 30 mg (n=48), 60 mg (n=47), 120 mg (n=46), 180 mg (n=48), or placebo (n=46) (Figure 11). 31 participants (13.2%) discontinued their assigned treatment during the 26-week core period, the most common reason being participant withdrawal (22 / 235, 9.4%), followed by adverse events (5 / 235, 2.1%). In addition, 31 participants terminated the trial early, the most common reason being participant withdrawal (25 / 235, 10.6%), followed by investigator decisions (3 / 235, 1.3%).

[0428] The primary efficacy endpoint of this trial was the percentage change in body weight relative to baseline after 26 weeks of treatment.

[0429] At baseline, the subjects' average BMI was 32.5 kg / m². 2 The average weight was 91.6 kg; 48.5% of the participants (pts) were female.

[0430] Secondary efficacy endpoints were the proportion of subjects whose weight decreased by ≥5%, ≥10%, and ≥15% relative to baseline after 26 and 36 weeks of administration, respectively; the percentage change in weight relative to baseline after 36 weeks of administration; the changes in weight, waist circumference, and body mass index (BMI) relative to baseline after 26 and 36 weeks of administration; and the changes in systolic blood pressure, diastolic blood pressure, fasting plasma glucose, fasting serum insulin, glycated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) relative to baseline after 26 and 36 weeks of administration.

[0431] Safety assessment included monitoring for adverse events (AEs), vital signs, clinical laboratory tests, physical examination, 12-lead electrocardiogram, and participant-reported outcomes. Participants experiencing symptoms of hypoglycemia or blood glucose levels below 3.9 mmol / L (<70 mg / dL) should have the event recorded in a dedicated hypoglycemia log (defined in Table 21).

[0432] V. Experimental Results

[0433] The proportion of subjects in the 180mg dose group who experienced a weight reduction of ≥10% from baseline after 36 weeks of treatment is shown in Table 2 below.

[0434] Table 2. Percentage of patients with a weight reduction of ≥10% from baseline after 36 weeks of treatment. N represents the number of participants in each treatment group's analysis set. Percentages are calculated with N as the denominator and only when the numerator is not zero. * This represents the number of subjects in each group who had observations during this visit. n represents the number of subjects who experienced a weight loss of ≥10% after 36 weeks of drug administration.

[0435] After 26 weeks of treatment, the percentage change in body weight relative to baseline for each dose group is shown in Table 3 below; after 36 weeks of administration in the 180mg dose group, the percentage change in body weight relative to baseline for the subjects is shown in Table 4 below.

[0436] Table 3. Percentage change in body weight relative to baseline after 26 weeks of treatment. N represents the number of participants in each analysis group, and n represents the number of subjects who had observations during that visit.

[0437] A hypothetical strategy was adopted, in which data collected after the accompanying event were not included in the analysis and were assumed to be randomly missing.

[0438] Based on a repeated measures mixed-effects model (MMRM), baseline weight was used as a covariate, along with gender and baseline BMI (<32.5 kg / m²). 2 With ≥32.5kg / m 2 The treatment group, visits, and the interaction between treatment and visits were fixed effects, and each statistic was calculated using an unstructured covariance matrix (UN).

[0439] Table 4. Percentage change in body weight relative to baseline after 36 weeks of treatment. N represents the number of participants in each analysis group, and n represents the number of subjects who had observations during that visit.

[0440] A hypothetical strategy was adopted, in which data collected after the accompanying event were not included in the analysis and were assumed to be randomly missing.

[0441] Based on a repeated measures mixed-effects model (MMRM), baseline weight was used as a covariate, along with gender and baseline BMI (<32.5 kg / m²). 2With ≥32.5kg / m 2 The treatment group, visits, and the interaction between treatment and visits were fixed effects, and each statistic was calculated using an unstructured covariance matrix (UN).

[0442] Conclusion: In obese adults without diabetes, once-daily oral doses of compound (I) of formula (60 mg, 120 mg, or 180 mg) significantly reduced body weight at week 26 compared with placebo, and these benefits persisted into week 36.

[0443] At baseline, BMI was 32.5 kg / m². 2 The average weight was 91.6 kg; 48.5% of the patients were female (see Table 5).

[0444] Table 5. Demographic and Baseline Characteristics Note: Data are expressed as n (%), mean ± standard deviation, or otherwise. a The measurements in this table were obtained from tests conducted by a local laboratory. b eGFR was assessed using the methods of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).

[0445] At week 26, 41.7% of patients who received 180 mg of compound (I) experienced a weight loss of at least 10%, compared to only 6.5% of patients who received placebo (see Figure 3).

[0446] Post-hoc analyses excluding patients who did not receive baseline pharmacokinetic exposure showed that the mean percentage change in body weight by LS was 12.08% and 14.98% from baseline, respectively (see Figures 4 and 5).

[0447] At week 26, the least squares (LS) percentage changes in body weight relative to baseline were -2.99 (95% CI, -4.84 to -1.14), -7.09 (95% CI, -8.95 to -5.24), -6.17 (95% CI, -8.03 to -4.31), and -9.36 (95% CI, -11.21 to -7.52) in the 30 mg, 60 mg, 120 mg, and 180 mg groups of compound (I), respectively, compared to -2.50 (95% CI, -4.34 to -0.65) in the placebo group. All formula (I) compounds at doses ≥60 mg showed statistically significant superiority: the treatment differences between the 60 mg, 120 mg, and 180 mg groups were -4.60 (95% CI, -7.21 to -1.98; P = 0.0006), -3.67 (-6.29 to -1.05; P = 0.0062), and -6.87 (-9.48 to -4.26; P < 0.0001), respectively (Table 7).

[0448] At week 36, the percentage change in body weight from baseline was -2.44 (95% CI, -4.62 to -0.27) in the 30 mg group of compound (I), -5.36 (-7.51 to -3.22) in the 60 mg group, -5.36 (-7.51 to -3.21) in the 120 mg group, -9.46 (-11.61 to -7.32) in the 180 mg group, and -1.39 (-3.52 to 0.74) in the placebo group. Compound (I) again demonstrated superiority over placebo at doses ≥60 mg, with treatment differences of -3.98 (95% CI, -7.00 to -0.96; P = 0.0101) in the 60 mg group, -3.97 (-7.00 to -0.95; P = 0.0103) in the 120 mg group, and -8.08 (-11.10 to -5.05; P < 0.0001) in the 180 mg group. These results confirmed an overall dose-dependent reduction in body weight at weeks 26 and 36, with the most significant effect observed at the 180 mg dose (Table 7, Figure 12). In a post-hoc analysis excluding subjects with missing pharmacokinetic exposure data after baseline, the least squares mean percentage reduction reached as high as -12.08% and -14.98% of baseline (Figures 4 and 5).

[0449] Stratified by sex, the weight loss trend was more pronounced in female subjects at both weeks 26 and 36. In the pre-specified subgroup analysis at week 26, the least-squares mean weight change was -10.18% in female subjects receiving a 180 mg dose of compound (I), compared to -3.94% in males (Table 8). This difference persisted in the post-hoc analysis at week 36, with a least-squares mean change of -12.76% in female subjects and -6.41% in males (Figure 8, data are expressed as least-squares mean ± standard error (AB). Note: The primary estimation target was based on the assumption strategy that data collected after the occurrence of a complication (defined as early termination of study treatment or initiation of a discontinued weight-loss treatment before week 36) were excluded from the efficacy analysis. All missing data, whether due to complication or other irrelevant causes, were assumed to be randomized missing). These results suggest that female subjects may derive a greater relative benefit from compound (I), particularly at the 180 mg dose.

[0450] At week 26, the mean weight loss (kg) in the 180 mg dose group of compound (I) reached -8.40 (95% CI, -10.02 to -6.77), compared to -2.20 (-3.82 to -0.57) in the placebo group. All doses of compound (I) ≥60 mg produced a more significant weight loss effect than placebo, with the largest placebo-adjusted difference observed in the 180 mg dose group being -6.20 (95% CI, -8.50 to -3.90) (Table 7; Figure 6). Weight loss continued into week 36, with a placebo-adjusted change as high as -7.41 (95% CI, -10.11 to -4.71) in the 180 mg group, and there was no evidence of a plateau in the weight loss trajectory.

[0451] Compound (I) was also associated with sustained reductions in body mass index (BMI) and waist circumference, with effects lasting until weeks 26 and 36. In participants receiving ≥60 mg doses, the placebo-adjusted least-squares mean change in BMI was -1.20 to -2.25 kg / m² at week 26 and -1.31 to -2.67 kg / m² at week 36. The corresponding placebo-adjusted least-squares mean change in waist circumference was -2.57 to -4.43 cm at week 26 and -2.14 to -4.92 cm at week 36 (Table 7, Figure 9).

[0452] Table 7. Changes in weight-related continuous endpoints from baseline to week 26 and week 36 (ITT population) a The number of participants whose data were observed during the specified visits. b A repeated measures mixed-effects model fitted using restricted maximum likelihood was used to compare each compound dose group of formula (I) with placebo. The model included treatment, visitation, sex, and baseline BMI (<32.5 vs ≥32.5 kg / m²). 2 Fixed effects of the treatment-visit interaction were included, with baseline responses as covariates; participants were treated as random effects, and an unstructured covariance matrix was applied. All p-values ​​for secondary endpoints were nominal (without multiplicity correction). ITT: Intention to Treatment; LS Mean: Least Squares Mean; CI: Confidence Interval; BMI: Body Mass Index.

[0453] Table 8. Percentage change in body weight from baseline to week 26 in pre-specified subgroups based on sex and baseline BMI. a Number of participants with observations in week 26. bRepeated measures mixed-effects models (MMRM) fitted using restricted maximum likelihood (REML) were used to compare each compound dose group of formula (I) with placebo. The model included treatment, visit duration, sex, and baseline BMI classification (<32.5 vs ≥32.5 kg / m²). 2 The fixed effects of the treatment-visit interaction were included, with baseline weight as a covariate. Participants were treated as random effects, and an unstructured covariance matrix was used. All p-values ​​for subgroup analyses were nominal and not adjusted for multiplicity. BMI: Body Mass Index; LS: Least Squares; CI: Confidence Interval; MMRM: Repeated Measures Mixed Effects Model; REML: Restricted Maximum Likelihood Method.

[0454] At weeks 26 and 36, compared with the placebo group, a higher proportion of subjects in the group receiving ≥60 mg of compound (I) achieved weight loss of ≥5%, ≥10%, and ≥15%, respectively (Table 9; Figures 3 and 7). At week 26, 50.0%–54.2% of subjects receiving the ≥60 mg dose achieved a weight loss of ≥5% (baseline weight), compared to 23.9% in the placebo group. The proportions of subjects achieving weight loss of ≥10% and ≥15% were 25.5%–41.7% and 12.8%–22.9%, respectively, compared to 6.5% and 0% in the placebo group. These response patterns were maintained at week 36. Among participants receiving ≥60 mg of treatment, the response rates were 40.4–52.1% for ≥5% weight loss, 21.3–35.4% for ≥10% weight loss, and 13.0–20.8% for ≥15% weight loss, compared to 26.1%, 6.5%, and 0% in the placebo group, respectively.

[0455] Table 9. Percentage of participants who lost ≥5%, ≥10%, or ≥15% of their body weight a In each specified visit, the numerator is the number of participants who reached the target weight loss threshold according to the assumed strategy, and the denominator is the number of participants whose weight measurement was observed during that visit. b Two-sided exact binomial 95% confidence interval (Clopper-Pearson method). c Logistic regression was used to compare the dosage groups of each compound (I) with the placebo group, with baseline body weight as a covariate, and the treatment group, sex, and baseline BMI categories (<32.5 vs ≥32.5 kg / m²). 2 () is a fixed effect variable. All p-values ​​are nominal (without multiplicity correction). OR: odds ratio; CI: confidence interval.

[0456] Metabolic parameters improved synchronously. In the group taking ≥30 mg of compound (I), the placebo-corrected baseline least-squares mean change in HbA1c ranged from -0.19% to -0.23% at week 26 and from -0.09% to -0.18% at week 36. For the group taking ≥60 mg of compound (I), the corresponding least-squares mean change in fasting blood glucose ranged from -0.22 to -0.27 mmol / L at week 26 and from -0.22 to -0.37 mmol / L at week 36 (Table 10). All groups taking compound (I) showed a slight decrease in diastolic and systolic blood pressure from baseline, but this was neither clinically significant nor different from placebo (Table 11). Similarly, changes in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were consistent with those observed in the placebo group, indicating that compound (I) had no significant effect on lipid parameters (Table 12).

[0457] Table 10. Changes in fasting blood glucose, fasting serum insulin, and glycated hemoglobin A1c from baseline at weeks 26 and 36. a The number of participants with observation data in a specified access. b Repeated measures mixed-effects models (MMRM) fitted using restricted maximum likelihood (REML) were used to compare each compound dose group of formula (I) with placebo. The model included treatment, visitation, sex, and baseline BMI (<32.5 vs ≥32.5 kg / m²). 2 The fixed effects of the treatment-visit interaction were included, with baseline values ​​as covariates. Participants were treated as random effects, and an unstructured covariance matrix was used. P-values ​​for all secondary endpoints were nominal (i.e., without multiplicity correction). LS: Least squares; CI: Confidence interval; FPG: Fasting blood glucose; HbA1c: Glycated hemoglobin.

[0458] Table 11. Changes in systolic and diastolic blood pressure relative to baseline at weeks 26 and 36. a The number of participants with observation data in a specified access. b Repeated measures mixed-effects models (MMRM) fitted using restricted maximum likelihood (REML) were used to compare each compound dose group of formula (I) with placebo. The model included treatment, visitation, sex, and baseline BMI (<32.5 vs ≥32.5 kg / m²). 2The fixed effects of the treatment-visit interaction were included, with baseline values ​​as covariates. Participants were treated as random effects, and an unstructured covariance matrix was used. P-values ​​for all secondary endpoints were nominal (i.e., without multiplicity correction). LS: Least squares; CI: Confidence interval; SBP: Systolic blood pressure; DBP: Diastolic blood pressure.

[0459] Table 12. Changes in lipid parameters relative to baseline at weeks 26 and 36. a The number of participants with observation data in a specified access. b Repeated measures mixed-effects models (MMRM) fitted using restricted maximum likelihood (REML) were used to compare each compound dose group of formula (I) with placebo. The model included treatment, visitation, sex, and baseline BMI (<32.5 vs ≥32.5 kg / m²). 2 The fixed effects of the treatment-visit interaction were included, with baseline values ​​as covariates. Participants were treated as random effects, and an unstructured covariance matrix was used. P-values ​​for all secondary endpoints were nominal (i.e., without multiplicity correction). LS: Least squares; CI: Confidence interval; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; non-HDL-C: Non-HDL-C.

[0460] In terms of security,

[0461] During the 36-week core treatment period, 93.5%–97.9% of patients receiving compound (I) reported treatment-induced adverse events (TEAEs), compared to 91.3% of patients receiving placebo (see Table 6).

[0462] The most common TEAEs associated with compounds of formula (I) were gastrointestinal events, nausea (16.7%–58.3%), diarrhea (18.8%–26.1%), and vomiting (18.8%–43.8%), which were mostly mild to moderate in severity and occurred more frequently during dose titration.

[0463] No trend of elevated liver enzymes was observed.

[0464] Table 6. Adverse treatment events occurring during the 36-week treatment period Note: Data is expressed as n (%). a The accidental death was deemed unrelated to the research treatment. bPreset adverse events (AESIs) include abnormal liver function, amylase / lipase levels >3 times the upper limit of normal (ULN), acute and / or chronic pancreatitis, abnormal serum calcitonin, and severe hypoglycemic episodes. c After administration, serum calcitonin levels were ≥50 ng / L and increased by more than 50% from baseline.

[0465] Among participants receiving treatment with compound (I), 93.5%–97.9% (43 / 46–47 / 48) reported adverse events (AEs), compared to 91.3% (42 / 46) in the placebo group (Table 13). Gastrointestinal adverse events were the most common, affecting 37.5%–64.6% of participants receiving treatment with compound (I) (18 / 48–31 / 48), compared to 15.2% (7 / 46) in the placebo group (Table 14). Most gastrointestinal events were mild or moderate, occurred during dose escalation, and resolved without permanent discontinuation of treatment (Figure 10 shows the proportion of participants experiencing each specific gastrointestinal adverse event at any time during the 36-week treatment period; the ordinate is the proportion of subjects experiencing gastrointestinal adverse events that occurred during the current time period and those that occurred previously and are still ongoing). In the group containing compounds of formula (I), 16.7%–58.3% (8 / 48–28 / 48) of participants reported nausea, compared to 4.3% (2 / 46) in the placebo group; the incidence of vomiting was 18.8%–43.8% (9 / 48–21 / 48), compared to 2.2% (1 / 46) in the placebo group; and the incidence of diarrhea was 18.8%–26.1% (9 / 48–12 / 46), compared to 8.7% (4 / 46) in the placebo group. Nausea and vomiting exhibited a dose-dependent pattern, with higher incidences in the 120 mg and 180 mg groups, which may have been associated with more intensive titration protocols.

[0466] Table 13. Adverse events during the 36-week treatment period Note: The data is n (%). a Pre-specified AESIs include abnormal liver function, amylase / lipase >3ULN, acute pancreatitis, abnormal serum calcitonin, and severe hypoglycemic episodes. bElevated AST and / or ALT and TBIL levels should be reported as AESI if all of the following criteria are met, provided that these abnormalities have no other cause: 1) Normal AST and ALT at baseline; ALT or AST exceeds 3 × ULN during 36 weeks of treatment. If ALT and AST are abnormal at baseline, ALT or AST must exceed 2 × baseline, and that value should exceed 3 × ULN, or reach >8 × ULN during treatment (choose the lower value). 2) Normal TBIL at baseline; TBIL exceeds 2 × ULN during 36 weeks of treatment. If TBIL is abnormal at baseline, the increase relative to baseline should exceed 1 × ULN, or that value should exceed 3 × ULN during treatment (choose the lower value). 3) No evidence of cholestasis due to gallbladder or biliary tract disease, such as elevated serum alkaline phosphatase. c After medication, the serum calcitonin level is ≥50 ng / L, an increase of more than 50% compared to the baseline. d A serious hypoglycemic event is defined as an event occurring after medication administration that meets the Grade 3 hypoglycemic criteria outlined in the American Diabetes Association (ADA) 2020 guidelines. AE: Adverse Event; AESI: Adverse Event of Special Concern.

[0467] Table 14. Summary of therapeutic gastrointestinal adverse events occurring during the 36-week treatment period, categorized by severity.

[0468] Data is expressed as n (%).

[0469] AE: Adverse Event.

[0470] Five subjects (2.1%; 5 / 235) discontinued compound (I) due to adverse events, four of which were considered treatment-related: one subject in the 30 mg group experienced anxiety, and three subjects in the 180 mg group experienced tremor and palpitations (one experienced nausea, vomiting, and decreased appetite, and one experienced indigestion and decreased appetite) (Table 15). The incidence of serious adverse events was 2.1–6.3% (1 / 48–3 / 48) in the compound (I) treatment group and 2.2% (1 / 46) in the placebo group; none were considered related to the study drug. One death was due to hemorrhagic shock following limb conflict, which was determined to be unrelated to the study treatment (Table 16). Overall, the safety profile of compound (I) was consistent with that of marketed GLP-1 receptor agonists.

[0471] Table 15. Adverse events that led to treatment interruption during week 36 of treatment.

[0472] Data is expressed as n (%).

[0473] AE stands for Adverse Event.

[0474] Table 16. Summary of serious adverse events reported during 36 weeks of treatment

[0475] Data is expressed as n (%).

[0476] AE stands for Adverse Event.

[0477] During the 36-week treatment period, four pre-specified adverse events of particular concern (AESIs) were reported (4 / 235, 1.7%), all occurring in participants in the formula (I) compound treatment group; none of these events occurred in the placebo group (Table 13). One participant (2.2%) in the 120 mg group and two participants (4.2%) in the 180 mg group experienced transient increases in amylase or lipase >3 × upper limit of normal (ULN), but neither developed into acute pancreatitis. One participant (2.1%) in the 30 mg group experienced a transient increase in serum calcitonin ≥50 ng / L after administration, exceeding 50% from baseline, but this did not require dose adjustment. Hypoglycemic events recorded in all formula (I) compound groups were classified as Grade 1, Grade 2, or potentially symptomatic hypoglycemia; no serious (Grade 3) events occurred. Events were reported in 3 out of 48 patients (6.3%) in the 30 mg group, 2 out of 46 patients (4.3%) in the 60 mg group, 9 out of 46 patients (19.6%) in the 120 mg group, and 5 out of 48 patients (10.4%) in the 180 mg group, while no events occurred in the placebo group (Table 17). No subjects met the Hy's rule criteria (defined as simultaneous elevations in liver enzymes (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal), total bilirubin (>2 × upper limit of normal), and alkaline phosphatase (<2 × upper limit of normal)) (Table 18). After 36 weeks of treatment, the mean serum amylase and lipase levels in the formula (I) compound treatment group were slightly higher than baseline (Table 19). Other laboratory parameters, vital signs (blood pressure and pulse rate), physical examination results, and electrocardiogram results showed no clinically significant differences between the treatment groups (Table 20).

[0478] Table 17. Incidence of hypoglycemic events recorded during 36 weeks of treatment (safety analysis set)

[0479] The data is n (%). a For participants who experienced hypoglycemic symptoms but did not have their blood glucose measured, but whose symptoms were attributed to a blood glucose level below 3.9 mmol / L (70 mg / dL), these events were classified as "potentially symptomatic hypoglycemia".

[0480] Table 18. Potential Hay's Law Cases The summary is consistent with Hay's Law.

[0481] The baseline was defined as the last non-missing measurement prior to the first administration of the study treatment.

[0482] Table 19. Changes in other safety parameters relative to baseline in weeks 26 and 36

[0483] Results for continuous variables are based on observed cases and are expressed as mean ± standard deviation.

[0484] Table 20. Changes in systolic blood pressure, diastolic blood pressure, pulse rate, heart rate, and PR interval relative to baseline at weeks 26 and 36.

[0485] Results for continuous variables are based on observed cases and are expressed as mean ± standard deviation.

[0486] SBP, systolic blood pressure; DBP, diastolic blood pressure.

[0487] Table 21. Classification of Hypoglycemia * For participants who experienced hypoglycemic symptoms but did not have their blood glucose measured, these events were classified as "potentially symptomatic hypoglycemia" if their symptoms were determined to be caused by a blood glucose level below 3.9 mmol / L (70 mg / dL).

[0488] Example 2. Study on the efficacy of the compound of formula (I) in treating overweight or obese patients.

[0489] I. Research on drugs

[0490] Test drug: The compound shown in formula (I), 30 mg / tablet and 60 mg / tablet.

[0491] Control group: placebo, 30 mg / tablet and 60 mg / tablet. The placebo did not contain the test drug and was identical in appearance, color and shape to the compound tablet shown in formula (I).

[0492] II. Inclusion criteria, exclusion criteria, and randomization criteria

[0493] Participants must meet all of the following criteria to be eligible for this study:

[0494] 1. On the day the informed consent form is signed, the applicant must be 18 years of age or older and 75 years of age or younger.

[0495] 2. BMI must meet the following criteria during screening:

[0496] (1) BMI ≥ 28.0 kg / m 2 ,

[0497] (2) or BMI ≥ 24.0 kg / m 2 And it must be accompanied by at least one weight-related comorbidity: such as prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, or non-alcoholic fatty liver disease, with the specific criteria as follows:

[0498] - Prediabetes: Diagnosed with prediabetes within 6 months prior to screening (including impaired fasting glucose, impaired glucose tolerance, and a combination of both), or fasting blood glucose ≤ 6.1 mmol / L < 7.0 mmol / L at the time of screening, or HbA1c ≤ 5.7% < 6.5%.

[0499] - Hypertension: Those with a previous diagnosis of hypertension, and whose systolic blood pressure is ≤140mg / dose and systolic blood pressure is <160mmHg and / or whose diastolic blood pressure is ≤90mmHg and diastolic blood pressure is <100mmHg at the time of screening, or who are receiving antihypertensive medication;

[0500] - Dyslipidemia: Those receiving lipid-lowering drug treatment for dyslipidemia, or whose LDL-C ≥ 4.1 mmol / L, or TG ≥ 1.7 mmol / L, or HDL-C < 1.0 mmol / L (male) or < 1.3 mmol / L (female) at the time of screening;

[0501] - Obstructive sleep apnea: Obstructive sleep apnea is present;

[0502] - Non-alcoholic fatty liver disease: Radiographic or histological evidence of diffuse hepatocellular steatosis within 6 months prior to screening, and exclusion of other causes that can lead to hepatic steatosis, such as alcohol abuse;

[0503] 3. Self-report that you have controlled your diet and exercise for 3 months or more before screening and randomization, and that your weight change in the past 3 months (the difference between the maximum and minimum weight during the period / the maximum weight) does not exceed 5%;

[0504] Subjects with any of the following characteristics / conditions should not be enrolled in this study:

[0505] The following checks were found to be abnormal during the screening process:

[0506] 1. The following laboratory test results were available during screening:

[0507] - Fasting blood glucose ≥7.0 mmol / L, or HbA1c ≥6.5%;

[0508] - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN);

[0509] - Total bilirubin > 1.5 × ULN;

[0510] - Serum amylase and / or serum lipase >2×ULN;

[0511] - Thyroid-stimulating hormone (TSH) <0.4 or >6.0 mIU / L;

[0512] - Calcitonin ≥50ng / L.

[0513] 2. Those whose electrocardiogram results showed clinically significant abnormalities during screening, including but not limited to supraventricular tachycardia, atrial fibrillation, atrial flutter, second- or third-degree atrioventricular block, etc., and who were deemed unsuitable for inclusion in this study by the researchers;

[0514] 3. Heart rate or pulse >100 beats / min during screening;

[0515] 4. During screening, the electrocardiogram (ECG) results indicated a QTcF > 450ms;

[0516] 5. PHQ-9 score ≥ 15 points;

[0517] 6. Severe hypertension that is not under control at the time of screening (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg); or those with the following diseases or medical history prior to screening:

[0518] 7. The presence or history of endocrine disorders that may significantly affect weight (such as Cushing's syndrome, hypothyroidism or hyperthyroidism, etc., except for hypothyroidism if the thyroid hormone replacement dose has been stable for at least 3 months);

[0519] 8. History of diabetes (excluding gestational diabetes);

[0520] 9. History of acute or chronic pancreatitis;

[0521] 10. Those with a history of cholecystitis or symptomatic gallbladder disease (except for subjects who have previously undergone cholecystectomy and are deemed eligible for enrollment by the researchers);

[0522] III. Administration Method

[0523] Subjects meeting the inclusion criteria were randomly assigned in a 2:2:1 ratio to the Formula (I) compound tablet 180mg (5-Step) group, the Formula (I) compound tablet 180mg (3-Step) group, and the placebo group, with the proportion of female subjects controlled to not exceed 70% to ensure a sufficient number of male subjects.

[0524] This study consists of three parts: a screening period (no more than 2 weeks), a 50-week double-blind treatment period, and a 2-week follow-up period.

[0525] This study employed a titration-based administration method, with all subjects taking four tablets of the investigational drug (formula (I) compound tablets or placebo) daily, as shown in Figure 2. Administration continued for 50 weeks. Subjects were advised to take the medication at the same or similar times daily, and not to exceed the prescribed dose each time.

[0526] The number of tablets administered in each dosage group is shown in Table 5 below:

[0527] Table 5. Number of tablets administered in the placebo group and each dose treatment group

[0528] Compound (I) tablets / placebo are administered orally once daily with an appropriate amount of water. Subjects should swallow the investigational drug whole and should not leave it in place or chew it before swallowing.

[0529] Instructions for missed doses: If a subject misses a dose of the test drug on a certain day, the subject should still take the drug as prescribed on the second day. The missed dose from the first day should not be taken retroactively.

[0530] Instructions for medication-induced vomiting: If a subject vomits after taking the medication, they should not take another dose, but should take the prescribed dose the following day.

[0531] Instructions for taking more medication: If a subject takes more medication than prescribed, they must inform the researcher immediately. The researcher and the sponsor will then jointly decide whether to adjust the dosage the following day.

[0532] IV. Clinical endpoint:

[0533] The primary efficacy endpoint of this trial was the percentage change in body weight relative to baseline after 50 weeks of treatment, and the proportion of subjects who experienced a weight loss of ≥5%.

[0534] Secondary efficacy endpoints were changes in body weight (kg) and body mass index (BMI) relative to baseline after 50 weeks of treatment; and changes in systolic blood pressure, diastolic blood pressure, fasting plasma glucose, fasting serum insulin, glycated hemoglobin (HbA1c), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (Non-HDL-C), and triglycerides (TG) relative to baseline after 50 weeks of treatment.

[0535] Example 3: Safety, tolerability, and pharmacokinetic / pharmacodynamic study of compound (I) with repeated administration in obese subjects. I. Study Drug

[0536] Test drug: The compound shown in formula (I), 30 mg / tablet, 60 mg / tablet and 120 mg / tablet.

[0537] Placebo: 30 mg / tablet, 60 mg / tablet and 120 mg / tablet.

[0538] II. Inclusion criteria, exclusion criteria, and randomization criteria

[0539] Selection criteria

[0540] Participants must meet all of the following criteria to be eligible for this trial:

[0541] 1. With my consent and having signed an informed consent form, I am willing and able to complete this study in accordance with the requirements of the experimental protocol;

[0542] 2. The applicant must be between 18 and 65 years old (inclusive) on the day of signing the informed consent form, regardless of gender;

[0543] 3. Screening criteria: BMI ≥ 30 kg / m² 2 ;

[0544] 4. Those who have controlled their diet and exercise for 3 months or more before screening, and whose weight change (the difference between the maximum and minimum weight within 3 months) does not exceed 5% in the past 3 months;

[0545] 5. Male and female subjects of fertility must not have any plans to conceive within one month after signing the informed consent form and must use highly effective contraception (see Section 13.1.2 for details). Female subjects of fertility must not have any plans to donate eggs (male subjects should donate sperm); female subjects of fertility must have a negative serum pregnancy test within 7 days prior to the randomization date (including the randomization date).

[0546] Exclusion criteria:

[0547] Subjects who meet any of the following criteria shall not be eligible to participate in this trial:

[0548] 1. The following laboratory test abnormalities were observed during screening:

[0549] a) Fasting glucose ≥7.0 mmol / L, or glycated hemoglobin (HbA1c) 1c ≥6.5%;

[0550] b) Hemoglobin <100g / L;

[0551] c) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.2 × upper limit of normal (ULN);

[0552] The following diseases or medical history were present before screening:

[0553] 2. Subjects with endocrine disorders or a history of conditions that may significantly affect weight at the time of screening (such as Cushing's syndrome, hypothyroidism or hyperthyroidism, etc., except for subjects with hypothyroidism whose thyroid hormone replacement therapy regimen has been stable for at least 3 months and whose thyroid function has remained normal, and who do not plan to change the regimen during the trial).

[0554] 3. History of diabetes (excluding gestational diabetes);

[0555] 4. Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2;

[0556] 5. Those with a history of acute or chronic pancreatitis, cholecystitis or gallstones, chronic malabsorption syndrome or cholestasis;

[0557] 6. Any history of conditions that affect gastric emptying (such as gastric bypass surgery, pyloric stenosis, etc.), a history of significant gastrointestinal diseases (such as gastric outlet obstruction, inflammatory bowel disease, active ulcers, etc.), or having undergone gastrointestinal surgery (excluding gastrointestinal polyp removal and appendectomy), or long-term use of drugs that directly affect gastrointestinal motility.

[0558] 7. Having experienced a serious cardiovascular or cerebrovascular disease within the 6 months prior to screening, including but not limited to: heart failure (NYHA class II-IV), angina pectoris, stroke or transient ischemic attack, myocardial infarction, severe arrhythmia, or having undergone coronary artery bypass grafting or percutaneous coronary intervention; and / or planning to undergo coronary, carotid, or peripheral artery revascularization at the time of screening;

[0559] 8.5 years of history of any organ system malignancy, regardless of whether there is evidence of local recurrence or metastasis, except for cured local cancers such as: local basal cell carcinoma of the skin, cervical carcinoma in situ, and prostate carcinoma in situ;

[0560] 9. Individuals who have had a serious infection, severe trauma, or have undergone major or medium-sized surgery within the six months prior to screening, or who plan to undergo surgery during the trial period;

[0561] 10. Individuals with or suspected of having depression, bipolar disorder, suicidal tendencies, schizophrenia, or other severe mental illnesses; or those who are mentally incapacitated or have language impairments, are unable to fully understand the trial protocol, or are unwilling to cooperate with research center staff;

[0562] 11. History of acute or chronic hepatitis or other serious liver disease other than alcoholic fatty liver disease;

[0563] 12. There are any factors that could interfere with HbA1c. 1c Blood disorders being tested (such as hemolytic anemia, sickle cell disease, etc.);

[0564] 13. Autoimmune diseases (such as systemic lupus erythematosus, rheumatoid arthritis);

[0565] If any of the following conditions exist: 14. The longer of the two periods shall prevail: Participation in any clinical trial of a drug or medical device within 3 months prior to screening, or still within 5 half-lives of the investigational drug. Participation in a clinical trial is defined as: signing informed consent and using the investigational drug (including placebo) or investigational medical device; or participating in a clinical trial of a drug containing a GLP-1 receptor agonist (including placebo) within 6 months prior to screening.

[0566] 15. Known or suspected allergy to GLP-1 receptor agonists, the study drug, its components, or its excipients;

[0567] 16. Smoking and drinking (average weekly alcohol consumption ≥14 units in the 6 months prior to screening: 1 unit = 285ml beer, or 25ml spirits, or 100ml wine; average daily cigarette consumption ≥5 cigarettes in the 3 months prior to screening); those who are unable to control their smoking and drinking intake as required during the trial period;

[0568] 17. Individuals who have a history of blood donation within the past 3 months, or whose blood loss is ≥400ml, or who have received a blood transfusion within the past 2 months;

[0569] 18. Subjects who are mentally incapacitated or have language impairments and are unable to fully understand or participate in the trial process;

[0570] 19. Pregnant, breastfeeding, women planning to become pregnant during the trial, or subjects of childbearing age who do not wish to use highly effective contraception during the trial period (from the date of signing the informed consent form) and for one month after the last dose;

[0571] 20. Intolerance to intravenous puncture or fear of needles;

[0572] 21. Any condition that the investigators deem unsuitable for participation in this clinical trial.

[0573] III. Administration Method

[0574] The study plans to randomly enroll 72 obese adult subjects. Of the subjects participating in the double-blind treatment phase, approximately 20 will advance to the second phase of the study, where they will be randomly assigned and crossovered to explore the effects of food on the PK characteristics of compound (I) and the relative bioavailability of different sizes of compound (I) tablets.

[0575] The double-blind study was divided into two parts: Part I and Part II. Part I consisted of three cohorts, each planned to enroll 18 subjects who would be randomly assigned to either compound (I) or placebo in a 15:3 ratio. Each cohort included a sentinel (3 subjects receiving the active compound (I) and 1 subject receiving the placebo), totaling 12 subjects, who were enrolled two weeks in advance. The remaining subjects in Part I would only begin randomization two weeks after the last sentinel had been enrolled.

[0576] Part II will consist of one cohort, Cohort 4, which is planned to enroll 18 subjects who will be randomly assigned to either compound (I) or placebo in a 15:3 ratio. Randomization of subjects in Cohort 4 will only begin after the last subject in Part I has been randomly enrolled.

[0577] Queue 1

[0578] Titration begins with a starting dose of 30 mg, followed by doses of 30 mg, 60 mg, 120 mg, 240 mg, and 360 mg, with each dose administered for 4 consecutive weeks (360 mg for 8 consecutive weeks). If the subject tolerates the medication well, the dose is increased sequentially to the next dose.

[0579] Queue 2

[0580] Titration begins with a starting dose of 30 mg, followed by doses of 30 mg, 60 mg, 120 mg, 240 mg, 360 mg, and 540 mg. Each dose is administered for 4 consecutive weeks. If the subject tolerates the medication well, the dose is increased sequentially to the next dose.

[0581] Queue 3

[0582] Titration begins with a starting dose of 30 mg, with the following doses administered sequentially: 30 mg - 60 mg - 120 mg - 180 mg - 240 mg - 300 mg - 360 mg - 420 mg - 480 mg - 540 mg. The 30 mg and 60 mg doses are to be taken continuously for 4 weeks, while the other doses are to be taken continuously for 2 weeks. If the subject tolerates the medication well, the dose is increased sequentially to the next dose.

[0583] Queue 4

[0584] Titration begins with a starting dose of 60 mg, with subsequent doses of 60 mg, 120 mg, 240 mg, 360 mg, 540 mg, and 720 mg, each dose administered continuously for 4 weeks. If the patient tolerates the medication well, the dose may be increased to the next level. A maximum dose of 720 mg is an optional dose; if the 540 mg dose group tolerates the medication well, the dose may be increased to 720 mg. If a patient experiences intolerable gastrointestinal adverse events (GIAEs), the maximum tolerated dose of 540 mg may be maintained after evaluation by the investigator and sponsor.

[0585] The specific protocol design is shown in Figure 13, which includes three parts: a 3-week screening period, a 24-week core treatment period (including titration), and a 1-week follow-up period.

[0586] Subjects should take the investigational drug with water immediately after each meal, once daily, including compound (I) / placebo.

[0587] For the second phase of the study, the study of food effects and relative bioavailability, subjects in Sequence A first took three 60 mg tablets of compound (I) on an empty stomach, followed by three 60 mg tablets of compound (I) after a standard meal. After completing this phase, they first took one 120 mg tablet of compound (I) on an empty stomach, followed by two 60 mg tablets of compound (I) on an empty stomach. Subjects in Sequence B first took three 60 mg tablets of compound (I) after a standard meal, followed by three 60 mg tablets of compound (I) on an empty stomach. After completing this phase, they first took two 60 mg tablets of compound (I) on an empty stomach, followed by one 120 mg tablet of compound (I) on an empty stomach.

[0588] IV. Clinical endpoint:

[0589] Primary endpoint

[0590] Safety endpoints: adverse events, hypoglycemic events, physical examination, vital signs (pulse, respiration, blood pressure, body temperature), laboratory tests (complete blood count, urinalysis, blood biochemistry, coagulation tests, etc.), 12-lead electrocardiogram (ECG), PHQ-9 score, etc.

[0591] Secondary endpoint

[0592] • Pharmacokinetic endpoints: plasma concentration of compound (I), and C max,ss AUC 0-τ,ss (If applicable).

[0593] Pharmacokinetic endpoints: fasting body weight, waist circumference, and glycated hemoglobin (HbA1c). 1c Changes in fasting plasma glucose, fasting serum insulin, and fasting serum C-peptide at week 24.

[0594] Table 22. Baseline characteristics of equilibrium

[0595] For details on cases where subjects terminated treatment early, please see Figure 14.

[0596] At week 24, the mean weight loss from baseline was 14.53% in cohort 1 (360 mg); the pooled analysis of cohorts 2, 3, and 4 (540 mg) showed a weight loss of 11.67% from baseline; and the mean percentage weight loss from baseline was -10.38%, -13.64%, -10.83%, and -1.54% in cohorts 2, 3, 4, and the placebo group, respectively. See Table 23 and Figure 15.

[0597] Table 23. Mean (SD) Change in Body Weight Relative to Baseline

[0598] According to the PDS scoring criteria, cohort 1, cohort 2, cohort 3, cohort 4 and the placebo group (see Figure 16 for details):

[0599] The percentages of subjects whose weight decreased by ≥5% from baseline were 73.3%, 73.3%, 80%, 73.3%, and 16.7%, respectively.

[0600] The proportions of subjects whose weight decreased by ≥10% from baseline were 60%, 40%, 66.7%, 40%, and 8.3%, respectively;

[0601] The percentages of subjects whose weight decreased by ≥15% from baseline were 33.3%, 20%, 33.3%, 33.3%, and 0%, respectively.

[0602] Cohort 3 showed that a higher proportion of participants achieved their target weight loss percentage.

[0603] According to the PDS set, the mean changes in body weight relative to baseline in cohorts 1, 2, 3, 4, and the placebo group were -13.43 kg, -9.48 kg, -13.04 kg, -10.47 kg, and -1.33 kg, respectively. 360 mg was shown to maximally reduce body weight. (See Figure 17)

[0604] According to PDS scores, after 24 weeks of treatment, the changes in waist circumference relative to baseline in cohorts 1, 2, 3, 4, and the placebo group were -11.70 cm, -8.32 cm, -10.33 cm, -7.57 cm, and -1.52 cm, respectively. The 360 ​​mg dose was shown to maximally reduce waist circumference. (See Figure 18)

[0605] According to the PDS score, for cohort 1, cohort 2, cohort 3, cohort 4 and the placebo group: after 24 weeks of treatment, the change in BMI relative to baseline in cohort 1, cohort 2, cohort 3, cohort 4 and the placebo group was -4.85 kg / m². 2 -3.48kg / m 2 -4.63kg / m 2 -3.8kg / m2 and -0.54kg / m 2 The 360 ​​mg dose group showed the most significant reduction in BMI. (See Figure 19)

[0606] Table 24. Improvement of metabolic indicators

[0607] In the studies of compounds of formula (I), 15 cases (100.00%) of TEAE were reported in cohort 1 (360 mg), 15 cases (100.00%) in cohort 2 (540 mg), 15 cases (100.00%) in cohort 3 (540 mg), 17 cases (100.00%) in cohort 4 (540 mg), and 9 cases (75.00%) in the placebo group. All reported TEAEs were of mild or moderate severity.

[0608] Table 25. TEAE * Left kidney stones and hydronephrosis, hospitalization due to past medical history, relevance is unrelated.

[0609] At doses below 360 mg, pharmacokinetic exposure is approximately linear.

[0610] Table 26. Summary of PK Data

Claims

1. Use of a GLP-1 agonist or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of overweight or obesity, wherein the GLP-1 agonist is as shown in formula (I):

2. The use according to claim 1, wherein the overweight or obese patient has or does not have diabetes; preferably does not have diabetes.

3. The use according to claim 1 or 2, wherein the overweight or obesity is accompanied by at least one weight-related comorbidity; preferably, the weight-related comorbidity is selected from prediabetes, hypertension, dyslipidemia, obstructive sleep apnea, and non-alcoholic fatty liver disease.

4. The use according to any one of claims 1-3, wherein it is used in the preparation of a treatment for obesity.

5. The use according to any one of claims 1-3, wherein it is used in the preparation of a treatment for overweight.

6. The use according to any one of claims 1-5, wherein, The dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 5-720 mg, preferably 10-600 mg, more preferably 20-600 mg, more preferably 30-540 mg, and most preferably 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.

7. The use according to any one of claims 1-6, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is administered by titration; preferably by dose-escalating titration.

8. The use according to any one of claims 1-7, wherein, 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, once every three days, once every four days, once every five days, and once weekly; preferably once daily.

9. The use according to any one of claims 1-8, wherein, The compound of formula (I) or its pharmaceutically acceptable salt is taken after meals; preferably after breakfast.

10. The use according to any one of claims 1-9, wherein, The administration period of the compound of formula (I) or its pharmaceutically acceptable salt is ≥20 weeks; preferably ≥24 weeks; more preferably ≥26 weeks; and more preferably ≥36 weeks.

11. The use according to any one of claims 1-10, wherein, Subjects treated with the compound of formula (I) or its pharmaceutically acceptable salts showed a weight reduction of ≥5.00% relative to baseline.

12. A method selected from any one of embodiments 1-215 of this disclosure.

Images